Science.gov

Sample records for prevention targets examples

  1. Prevention among immigrants: the example of Germany

    PubMed Central

    2010-01-01

    Background A large and increasing part of the European population has a history of migration. Germany, for example, is home to about 15 million people with migrant background, which amounts to 19% of its population. Migrants may have differences in their lifestyle, health beliefs and risk factors compared to the autochthonous populations. Discussion As for example studies on children's participation in routine prevention activities have shown, these differences can have a relevant impact on the access of migrants to the health care system and are likely to lower their participation in prevention programs compared to the autochthonous population. To increase the uptake of prevention programs, barriers to access must be identified and approaches to reduce them must be developed. Summary Taking the example of Germany, a need exists for prevention programs that include (migrant sensitive) and specifically address (migrant specific) migrants. These should be of sufficient scale, evidence-based, sustainable and evaluated at regular intervals. PMID:20181232

  2. Bioinformatics by Example: From Sequence to Target

    NASA Astrophysics Data System (ADS)

    Kossida, Sophia; Tahri, Nadia; Daizadeh, Iraj

    2002-12-01

    With the completion of the human genome, and the imminent completion of other large-scale sequencing and structure-determination projects, computer-assisted bioscience is aimed to become the new paradigm for conducting basic and applied research. The presence of these additional bioinformatics tools stirs great anxiety for experimental researchers (as well as for pedagogues), since they are now faced with a wider and deeper knowledge of differing disciplines (biology, chemistry, physics, mathematics, and computer science). This review targets those individuals who are interested in using computational methods in their teaching or research. By analyzing a real-life, pharmaceutical, multicomponent, target-based example the reader will experience this fascinating new discipline.

  3. Strategies for universalistic and targeted HIV prevention.

    PubMed

    Des Jarlais, D C; Padian, N

    1997-10-01

    The controversy over "targeted" versus "universalistic" programs for HIV prevention has persisted throughout the history of the HIV/AIDS epidemic in the United States and in some European countries. Building on previous analyses, we outline methods for integrating universalistic and targeted HIV prevention programming. The outline considers possible synergy between targeted and universalistic programs, rather than a forced choice between the two. Components within this framework include a continuum of the intensity of targeted programs, specification of local risk behavior populations, categories of risk behavior, and HIV seroprevalence within local risk-behavior populations. Given the scarce resources currently available, preventing all new HIV infections is not a realistic public health goal, but with better use of current scientific knowledge, it should be possible to greatly reduce the rate of new HIV infections. PMID:9358108

  4. Some practical examples of cavitation erosion and their prevention

    NASA Technical Reports Server (NTRS)

    Conn, A. F.

    1974-01-01

    The problem of failures caused by cavitation erosion are discussed. The concepts of intensity of erosion, erosion strength, and the time dependence of erosion rate are analyzed. The relation of these parameters to system variables such as pressure and velocity, and to the properties of materials are investigated. Using several examples of actual cavitation erosion, methods of prevention and their limitations are examined.

  5. Research shows targeted HIV prevention succeeds.

    PubMed

    2002-03-01

    Systematic reviews of HIV prevention intervention literature for the target populations of African-Americans, Latinos, youths, and men who have sex with men in the United States shows that targeted interventions work in reducing HIV risk behaviors. Interventions that succeeded were culturally sensitive, of longer duration, and included skills training, according to a project supported by the Surgeon General's Leadership Campaign on AIDS and teh California HealthCare Foundation in Oakland. PMID:12206092

  6. Targeting AMPK for cancer prevention and treatment

    PubMed Central

    Young, Matthew R.; Chen, Guohong; Hua, Baojin

    2015-01-01

    AMP-activated protein kinase (AMPK) is an important mediator in maintaining cellular energy homeostasis. AMPK is activated in response to a shortage of energy. Once activated, AMPK can promote ATP production and regulate metabolic energy. AMPK is a known target for treating metabolic syndrome and type-2 diabetes; however, recently AMPK is emerging as a possible metabolic tumor suppressor and target for cancer prevention and treatment. Recent epidemiological studies indicate that treatment with metformin, an AMPK activator reduces the incidence of cancer. In this article we review the role of AMPK in regulating inflammation, metabolism, and other regulatory processes with an emphasis on cancer, as well as, discuss the potential for targeting AMPK to treat various types of cancer. Activation of AMPK has been found to oppose tumor progression in several cancer types and offers a promising cancer therapy. This review evaluates the evidence linking AMPK with tumor suppressor function and analyzes the molecular mechanisms involved. AMPK activity opposes tumor development and progression in part by regulating inflammation and metabolism. PMID:25812084

  7. Targeting tumor cell motility to prevent metastasis

    PubMed Central

    Palmer, Trenis D.; Ashby, William J.; Lewis, John D.; Zijlstra, Andries

    2011-01-01

    Mortality and morbidity in patients with solid tumors invariably results from the disruption of normal biological function caused by disseminating tumor cells. Tumor cell migration is under intense investigation as the underlying cause of cancer metastasis. The need for tumor cell motility in the progression of metastasis has been established experimentally and is supported empirically by basic and clinical research implicating a large collection of migration-related genes. However, there are few clinical interventions designed to specifically target the motility of tumor cells and adjuvant therapy to specifically prevent cancer cell dissemination is severely limited. In an attempt to define motility targets suitable for treating metastasis, we have parsed the molecular determinants of tumor cell motility into five underlying principles including cell autonomous ability, soluble communication, cell-cell adhesion, cell-matrix adhesion, and integrating these determinants of migration on molecular scaffolds. The current challenge is to implement meaningful and sustainable inhibition of metastasis by developing clinically viable disruption of molecular targets that control these fundamental capabilities. PMID:21664937

  8. Target levels--tools for prevention.

    PubMed

    Niemelä, R I; Rantanen, J; Kiilunen, M K

    1998-12-01

    Although occupational exposure limits are sought to establish health-based standards, they do not always give a sufficient basis for planning an indoor air climate that is good and comfortable for the occupants in industrial work rooms. This paper considers methodologies by which the desired level, i.e., target level, of air quality in industrial settings can be defined, taking into account feasibility issues. Risk assessment based on health criteria is compared with risk-assessment based on "Best Available Technology" (BAT). Because health-based risk estimates at low concentration regions are rather inaccurate, the technology-based approach is emphasized. The technological approach is based on information on the prevailing concentrations in industrial work environments and the benchmark air quality attained with the best achievable technology. The prevailing contaminant concentrations are obtained from a contaminant exposure databank, and the benchmark air quality by field measurements in industrial work rooms equipped with advanced ventilation and production technology. As an example, the target level assessment has been applied to formaldehyde, total inorganic dust and hexavalent chromium, which are common contaminants in work room air.

  9. Identifying Molecular Targets of Lifestyle Modifications in Colon Cancer Prevention

    PubMed Central

    Derry, Molly M.; Raina, Komal; Agarwal, Chapla; Agarwal, Rajesh

    2013-01-01

    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; approximately 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 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. PMID:23675573

  10. Curing a viral infection by targeting the host: The example of cyclophilin inhibitors

    PubMed Central

    Lin, Kai; Gallay, Philippe

    2015-01-01

    Every step of the viral life cycle is dependent on the host, which potentially can be explored for antiviral targets. Historically, however, drug discovery has focused mainly on viral targets, because of their perceived specificity. Efforts to pursue host targets have been largely hampered by concern over potential on-target toxicity, the lack of predictive cell culture and animal models, and the complexity of host–virus interactions. On the other hand, there are distinct advantages of targeting the host, such as creating a high barrier to resistance, providing broad coverage of different genotypes/serotypes and possibly even multiple viruses, and expanding the list of potential targets, when druggable viral targets are limited. Taking hepatitis C virus (HCV) as the example, there are more than 20 inhibitors of the viral protease, polymerase and NS5A protein currently in advanced clinical testing. However, resistance has become a main challenge with these direct-acting antivirals, because HCV, an RNA virus, is notoriously prone to mutation, and a single mutation in the viral target may prevent the binding of an inhibitor, and rendering it ineffective. Host cyclophilin inhibitors have shown promising effects both in vitro and in patients to prevent the emergence of resistance and to cure HCV infection, either alone or in combination with other agents. They are also capable of blocking the replication of a number of other viral pathogens. While the road to developing host-targeting antivirals has been less traveled, and significant challenges remain, delivering the most effective antiviral regimen, which may comprise inhibitors of both host and viral targets, should be well worth the effort. PMID:23578729

  11. Prevention 2.0: targeting cyberbullying @ school.

    PubMed

    Wölfer, Ralf; Schultze-Krumbholz, Anja; Zagorscak, Pavle; Jäkel, Anne; Göbel, Kristin; Scheithauer, Herbert

    2014-12-01

    Although cyberbullying is characterized by worrying prevalence rates and associated with a broad range of detrimental consequences, there is a lack of scientifically based and evaluated preventive strategies. Therefore, the present study introduces a theory-based cyberbullying prevention program (Media Heroes; German original: Medienhelden) and evaluates its effectiveness. In a pretest-posttest design (9-month interval), schools were asked to randomly assign their participating classes to either control or intervention group. Longitudinal data were available from 593 middle school students (M Age = 13.3 years, 53 % girls) out of 35 classes, who provided information on cyberbullying behavior as well as socio-demographic and psychosocial variables. While the present results revealed worrying prevalence rates of cyberbullying in middle school, multilevel analyses clearly demonstrate the program's effectiveness in reducing cyberbullying behavior within intervention classes in contrast to classes of the control group. Hence, this study presents a promising program which evidentially prevents cyberbullying in schools.

  12. Prevention 2.0: targeting cyberbullying @ school.

    PubMed

    Wölfer, Ralf; Schultze-Krumbholz, Anja; Zagorscak, Pavle; Jäkel, Anne; Göbel, Kristin; Scheithauer, Herbert

    2014-12-01

    Although cyberbullying is characterized by worrying prevalence rates and associated with a broad range of detrimental consequences, there is a lack of scientifically based and evaluated preventive strategies. Therefore, the present study introduces a theory-based cyberbullying prevention program (Media Heroes; German original: Medienhelden) and evaluates its effectiveness. In a pretest-posttest design (9-month interval), schools were asked to randomly assign their participating classes to either control or intervention group. Longitudinal data were available from 593 middle school students (M Age = 13.3 years, 53 % girls) out of 35 classes, who provided information on cyberbullying behavior as well as socio-demographic and psychosocial variables. While the present results revealed worrying prevalence rates of cyberbullying in middle school, multilevel analyses clearly demonstrate the program's effectiveness in reducing cyberbullying behavior within intervention classes in contrast to classes of the control group. Hence, this study presents a promising program which evidentially prevents cyberbullying in schools. PMID:24122481

  13. Targeting industrial processes for pollution prevention

    SciTech Connect

    Li, D.W.

    1997-05-01

    Before investing in pollution prevention projects, companies need to focus on the processes that have the potential to result in the greatest payback. All too often, companies hire outside consultants to conduct one-time, isolated opportunity assessments in response to state or Federal planning requirements but do not continue to seek opportunities as operations are modified. As a result, companies may end up investing in projects to meet their immediate needs while missing opportunities for savings that may result from broader, longer term solutions. Similarly, departments may implement projects independently and end up missing opportunities to take advantage of economies of scale or internal reuse/recycling possibilities. The companies that have profited the most from pollution prevention strategies are those that have fully integrated the concept into their major business decisions at all levels within the organization. In this respect, pollution prevention is one of several possible tools to minimize projected environmental impacts.

  14. Targets for the prevention of dementia.

    PubMed

    Middleton, Laura E; Yaffe, Kristine

    2010-01-01

    The prevalence of dementia is expected to increase dramatically over the upcoming decades due to the aging population. Since treatment is still short of a cure, preventative strategies are of the utmost importance. Stimulating activity (cognitive, physical, and social), vascular risk factors, and diet may be important in preventative strategies. Dementia risk may be modified by participation in stimulating activities. One study suggested that the cognitive, physical, and social components of activity were of equal importance to cognitive outcomes. However, while exercise interventions appear to benefit global cognition, the benefits from cognitive training appear to be domain specific. People with vascular risk factors (hypertension, diabetes, dyslipidemia, and obesity) appear to be at higher risk for dementia than those without in observational and clinical trials. Controlled trials suggest that vascular risk management via some pharmaceutical interventions may benefit cognition, though results are inconsistent. Finally, people who adhere to a Mediterranean diet or who have high intake of antioxidants and omega-3 fatty acids have reduced likelihood of dementia in observational studies. However, supplementation in controlled trials has not generally proved successful at improving cognitive outcomes. A single supplement may be insufficient to prevent dementia; it may be that the overall diet is more important. Future large randomized controlled studies should examine whether interventions can reduce the risk of dementia and whether combining cognitive, physical, and social activity, vascular risk reduction, and dietary interventions might have additive or multiplicative effects.

  15. Brazil's national programs targeting childhood obesity prevention.

    PubMed

    Silva, A C F; Bortolini, G A; Jaime, P C

    2013-06-01

    In Brazil, overweight and obesity are increasing in all age and income groups. Currently, 7.3% of children under 5 years of age, 30% of children aged 5-9 and 20% of preadolescents aged 10-19 are overweight. In the primary health-care (PHC) environment, activities are carried out to monitor eating habits and nutrition, as well as to prevent unhealthy habits and promote healthy eating behaviors consistent with the dietary guidelines for Brazilian children. Comprehensive care is being provided to overweight individuals. The Brazilian Breastfeeding and Complementary Feeding Strategy was launched in 2009 to support health teams to counsel families about healthy feeding, focused on child health and obesity prevention. Within the school environment, the School Health Program offers activities that are developed by PHC teams together with education professionals to focus on assessing health conditions, prevention and health promotion. To improve the nutritional profile of processed foods, terms of cooperation have been signed with the food industry to reduce fat and sodium content. Food industry advertising and marketing to infants and young children are now regulated by the Brazilian Regulation for the Marketing of Foods to Infants and Young Children. PMID:27152158

  16. Brazil's national programs targeting childhood obesity prevention

    PubMed Central

    Silva, A C F; Bortolini, G A; Jaime, P C

    2013-01-01

    In Brazil, overweight and obesity are increasing in all age and income groups. Currently, 7.3% of children under 5 years of age, 30% of children aged 5–9 and 20% of preadolescents aged 10–19 are overweight. In the primary health-care (PHC) environment, activities are carried out to monitor eating habits and nutrition, as well as to prevent unhealthy habits and promote healthy eating behaviors consistent with the dietary guidelines for Brazilian children. Comprehensive care is being provided to overweight individuals. The Brazilian Breastfeeding and Complementary Feeding Strategy was launched in 2009 to support health teams to counsel families about healthy feeding, focused on child health and obesity prevention. Within the school environment, the School Health Program offers activities that are developed by PHC teams together with education professionals to focus on assessing health conditions, prevention and health promotion. To improve the nutritional profile of processed foods, terms of cooperation have been signed with the food industry to reduce fat and sodium content. Food industry advertising and marketing to infants and young children are now regulated by the Brazilian Regulation for the Marketing of Foods to Infants and Young Children. PMID:27152158

  17. Molecular targets of aspirin and cancer prevention.

    PubMed

    Alfonso, L; Ai, G; Spitale, R C; Bhat, G J

    2014-07-01

    Salicylates from plant sources have been used for centuries by different cultures to treat a variety of ailments such as inflammation, fever and pain. A chemical derivative of salicylic acid, aspirin, was synthesised and mass produced by the end of the 19th century and is one of the most widely used drugs in the world. Its cardioprotective properties are well established; however, recent evidence shows that it can also act as a chemopreventive agent. Its antithrombotic and anti-inflammatory actions occur through the inhibition of cyclooxygenases. The precise mechanisms leading to its anticancer effects are not clearly established, although multiple mechanisms affecting enzyme activity, transcription factors, cellular signalling and mitochondrial functions have been proposed. This review presents a brief account of the major COX-dependent and independent pathways described in connection with aspirin's anticancer effects. Aspirin's unique ability to acetylate biomolecules besides COX has not been thoroughly investigated nor have all the targets of its primary metabolite, salicylic acid been identified. Recent reports on the ability of aspirin to acetylate multiple cellular proteins warrant a comprehensive study to investigate the role of this posttranslational modification in its anticancer effects. In this review, we also raise the intriguing possibility that aspirin may interact and acetylate cellular molecules such as RNA, and metabolites such as CoA, leading to a change in their function. Research in this area will provide a greater understanding of the mechanisms of action of this drug. PMID:24874482

  18. Evaluating HIV prevention strategies for populations in key affected groups: The example of Cabo Verde

    PubMed Central

    Monteiro, João Filipe G.; Galea, Sandro; Flanigan, Timothy; Monteiro, Maria de Lourdes; Friedman, Samuel R.; Marshall, Brandon DL

    2015-01-01

    Objectives We used an individual-based model to evaluate the effects of hypothetical prevention interventions on HIV incidence trajectories in a concentrated, mixed epidemic setting from 2011 to 2021, and using Cabo Verde as an example. Methods Simulations were conducted to evaluate the extent to which early HIV treatment and optimization of care, HIV testing, condom distribution, and substance abuse treatment could eliminate new infections (i.e., reduce incidence to less than 10 cases per 10,000 person-years) among non-drug users, female sex workers (FSW), and people who use drugs (PWUD). Results Scaling up all four interventions resulted in the largest decreases in HIV, with estimates ranging from 1.4 (95%CI:1.36–1.44) per 10,000 person-years among non-drug users to 8.2 (95%CI:7.8–8.6) per 10,000 person-years among PWUD in 2021. Intervention scenarios targeting FWS and PWUD also resulted in HIV incidence estimates at or below 10 per 10,000 person-years by 2021 for all population sub-groups. Conclusions Our results suggest that scaling up multiple interventions among entire population is necessary to achieve elimination. However, prioritizing key populations with this combination prevention strategy may also result in a substantial decrease in total incidence. PMID:25838121

  19. The Need to Consider Ethnocultural Context in Prevention Programming: A Case Example from Hawai'i

    ERIC Educational Resources Information Center

    Helm, Susana; Baker, Charlene K.

    2011-01-01

    Objective: This article highlights the importance of incorporating ethnocultural contexts in prevention research and programming. We provide a case example from our research in youth violence prevention in Hawai'i. Methods: Data were collected in multiethnic communities on O'ahu. Focus groups were conducted with high school-aged youths of Native…

  20. Targeting Structural Change for HIV Prevention: A Process and Tool for Community Application.

    PubMed

    Willard, Nancy; Chutuape, Kate; Stewart-Campbell, Rachel; Boyer, Cherrie B; Ellen, Jonathan

    2015-11-01

    To address the persistent HIV epidemic in the United States, prevention efforts are focusing on social determinants related to HIV risk by targeting systems and structures, such as organizational and institutional policies, practices and programs, and legislative and regulatory approaches to modify features of the environment that influence HIV risk. With limited evidenced-based examples, communities can benefit from strategic planning resources that help them consider developing structural-level changes that target root causes of HIV risk. In this article, we present the Connect to Protect® project that outlines a process and a tool to move from general ideas to specific structural changes. Examples from 14 coalitions are also provided. Using the process and tools presented here can provide a launching pad for other coalitions seeking to build an HIV prevention agenda and for practitioners seeking to incorporate structural changes for community health promotion. PMID:25776019

  1. Targeting Structural Change for HIV Prevention: A Process and Tool for Community Application

    PubMed Central

    Willard, Nancy; Chutuape, Kate; Stewart-Campbell, Rachel; Boyer, Cherrie B.; Ellen, Jonathan

    2015-01-01

    To address the persistent HIV epidemic in the United States, prevention efforts are focusing on social determinants related to HIV risk by targeting systems and structures, such as organizational and institutional policies, practices and programs, and legislative and regulatory approaches to modify features of the environment that influence HIV risk. With limited evidenced-based examples, communities can benefit from strategic planning resources that help them consider developing structural-level changes that target root causes of HIV risk. In this article, we present the Connect to Protect® project that outlines a process and a tool to move from general ideas to specific structural changes. Examples from 14 coalitions are also provided. Using the process and tools presented here can provide a launching pad for other coalitions seeking to build an HIV prevention agenda and for practitioners seeking to incorporate structural changes for community health promotion. PMID:25776019

  2. Targeting Structural Change for HIV Prevention: A Process and Tool for Community Application.

    PubMed

    Willard, Nancy; Chutuape, Kate; Stewart-Campbell, Rachel; Boyer, Cherrie B; Ellen, Jonathan

    2015-11-01

    To address the persistent HIV epidemic in the United States, prevention efforts are focusing on social determinants related to HIV risk by targeting systems and structures, such as organizational and institutional policies, practices and programs, and legislative and regulatory approaches to modify features of the environment that influence HIV risk. With limited evidenced-based examples, communities can benefit from strategic planning resources that help them consider developing structural-level changes that target root causes of HIV risk. In this article, we present the Connect to Protect® project that outlines a process and a tool to move from general ideas to specific structural changes. Examples from 14 coalitions are also provided. Using the process and tools presented here can provide a launching pad for other coalitions seeking to build an HIV prevention agenda and for practitioners seeking to incorporate structural changes for community health promotion.

  3. The Implementation of the Fast Track Program: An Example of a Large-Scale Prevention Science Efficacy Trial

    PubMed Central

    2009-01-01

    In 1990, the Fast Track Project was initiated to evaluate the feasibility and effectiveness of a comprehensive, multicomponent prevention program targeting children at risk for conduct disorders in four demographically diverse American communities (Conduct Problems Prevention Research Group [CPPRG], 1992). Representing a prevention science approach toward community-based preventive intervention, the Fast Track intervention design was based upon the available data base elucidating the epidemiology of risk for conduct disorder and suggesting key causal developmental influences (R. P. Weissberg & M. T. Greenberg, 1998). Critical questions about this approach to prevention center around the extent to which such a science-based program can be effective at (1) engaging community members and stakeholders, (2) maintaining intervention fidelity while responding appropriately to the local norms and needs of communities that vary widely in their demographic and cultural/ethnic composition, and (3) maintaining community engagement in the long-term to support effective and sustainable intervention dissemination. This paper discusses these issues, providing examples from the Fast Track project to illustrate the process of program implementation and the evidence available regarding the success of this science-based program at engaging communities in sustainable and effective ways as partners in prevention programming. PMID:11930968

  4. Molecular Targeted Approaches to Cancer Therapy and Prevention Using Chalcones

    PubMed Central

    Jandial, Danielle D.; Blair, Christopher A.; Zhang, Saiyang; Krill, Lauren S.; Zhang, Yan-Bing; Zi, Xiaolin

    2014-01-01

    There is an emerging paradigm shift in oncology that seeks to emphasize molecularly targeted approaches for cancer prevention and therapy. Chalcones (1,3-diphenyl-2-propen-1-ones), naturally-occurring compounds with widespread distribution in spices, tea, beer, fruits and vegetables, consist of open-chain flavonoids in which the two aromatic rings are joined by a three-carbon α, β-unsaturated carbonyl system. Due to their structural diversity, relative ease of chemical manipulation and reaction of α, β-unsaturated carbonyl moiety with cysteine residues in proteins, some lead chalcones from both natural products and synthesis have been identified in a variety of screening assays for modulating important pathways or molecular targets in cancers. These pathways and targets that are affected by chalcones include MDM2/p53, tubulin, proteasome, NF-kappa B, TRIAL/death receptors and mitochondria mediated apoptotic pathways, cell cycle, STAT3, AP-1, NRF2, AR, ER, PPAR-γ and β-catenin/Wnt. Compared to current cancer targeted therapeutic drugs, chalcones have the advantages of being inexpensive, easily available and less toxic; the ease of synthesis of chalcones from substituted benzaldehydes and acetophenones also makes them an attractive drug scaffold. Therefore, this review is focused on molecular targets of chalcones and their potential implications in cancer prevention and therapy. PMID:24467530

  5. Vaccine Prevention of Cancer: Can Endogenous Antigens be Targeted?

    PubMed Central

    Weiner, Louis M.; Surana, Rishi; Murray, Joseph

    2010-01-01

    This perspective on the report by Beatty et al. in this issue of the journal (beginning on page XX) discusses the prevention of cancer through vaccination strategies that target antigens associated with tumor promotion and progression. Such approaches were first developed for treating cancer. We address cancer vaccination in the context of a mouse model of inflammatory bowel disease expressing MUC1, an epithelial mucin aberrantly expressed during chronic inflammation and in colorectal carcinogenesis, and in a broader context that includes the potential of targeting the tumor microenvironment for immunoprevention in humans. Obstacles in developing effective cancer vaccines, including antigen selection, immunoediting, and tumor-mediated immunosuppression, also are discussed. PMID:20332297

  6. 40 CFR Appendix L to Part 51 - Example Regulations for Prevention of Air Pollution Emergency Episodes

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... Air Pollution Emergency Episodes L Appendix L to Part 51 Protection of Environment ENVIRONMENTAL... IMPLEMENTATION PLANS Pt. 51, App. L Appendix L to Part 51—Example Regulations for Prevention of Air Pollution... air pollution from reaching levels that would cause imminent and substantial endangerment to...

  7. 40 CFR Appendix L to Part 51 - Example Regulations for Prevention of Air Pollution Emergency Episodes

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... Air Pollution Emergency Episodes L Appendix L to Part 51 Protection of Environment ENVIRONMENTAL... IMPLEMENTATION PLANS Pt. 51, App. L Appendix L to Part 51—Example Regulations for Prevention of Air Pollution... air pollution from reaching levels that would cause imminent and substantial endangerment to...

  8. 40 CFR Appendix L to Part 51 - Example Regulations for Prevention of Air Pollution Emergency Episodes

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... Air Pollution Emergency Episodes L Appendix L to Part 51 Protection of Environment ENVIRONMENTAL... IMPLEMENTATION PLANS Pt. 51, App. L Appendix L to Part 51—Example Regulations for Prevention of Air Pollution... air pollution from reaching levels that would cause imminent and substantial endangerment to...

  9. 40 CFR Appendix L to Part 51 - Example Regulations for Prevention of Air Pollution Emergency Episodes

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... Air Pollution Emergency Episodes L Appendix L to Part 51 Protection of Environment ENVIRONMENTAL... IMPLEMENTATION PLANS Pt. 51, App. L Appendix L to Part 51—Example Regulations for Prevention of Air Pollution... air pollution from reaching levels that would cause imminent and substantial endangerment to...

  10. 40 CFR Appendix L to Part 51 - Example Regulations for Prevention of Air Pollution Emergency Episodes

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... Air Pollution Emergency Episodes L Appendix L to Part 51 Protection of Environment ENVIRONMENTAL... IMPLEMENTATION PLANS Pt. 51, App. L Appendix L to Part 51—Example Regulations for Prevention of Air Pollution... air pollution from reaching levels that would cause imminent and substantial endangerment to...

  11. Editorial: Prevention Strategies Targeting Different Preclinical Stages of Alzheimer's Disease.

    PubMed

    Zhou, Bin

    2015-01-01

    The incidence of dementia is rapidly increasing not only in developed countries but also in developing countries with rising aging populations. This trend is expected to worsen, with the number of cases possibly tripling in the coming decades. Over the last few decades, epidemiological studies have revealed that vascular-or lifestyle-related factors are associated with an increased risk of Alzheimer's disease (AD) and dementia. Researches into the pathophysiological processes of AD have revealed that the pathological brain lesions of AD begin decades before the onset of symptoms. Many prevention studies have indicated that physical activity and/or mental training can improve cognition and daily life in subjects with AD or mild cognitive impairment (MCI). However, issues with early detection and preclinical staging and effective preventive approaches that are based on these stages remain unresolved. Therefore, we propose different strategies for AD prevention based on its preclinical stages: one involves physical and mental training that targets the risk factors in subjects without pathophysiological changes, and the second approach combines nonpharmacological and pharmacological methods and aims to treat MCI in individuals with amyloid deposits and/or neurodegeneration with drugs that target the amyloid cascade. The results of several ongoing and promising trials are expected in the next few years.

  12. Targeting gut flora to prevent progression of hepatocellular carcinoma.

    PubMed

    Darnaud, Marion; Faivre, Jamila; Moniaux, Nicolas

    2013-02-01

    Increased translocation of intestinal bacteria is a hallmark of chronic liver disease and contributes to hepatic inflammation and fibrosis. Here we tested the hypothesis that the intestinal microbiota and Toll-like receptors (TLRs) promote hepatocellular carcinoma(HCC), a long-term consequence of chronic liver injury, inflammation,and fibrosis. Hepatocarcinogenesis in chronically injured livers depended on the intestinal microbiota and TLR4 activation in nonbone-marrow-derived resident liver cells. TLR4 and the intestinal microbiota were not required for HCC initiation but for HCC promotion, mediating increased proliferation, expression of the hepatomitogen epiregulin, and prevention of apoptosis. Gut sterilization restricted to late stages of hepatocarcinogenesis reduced HCC, suggesting that the intestinal microbiota and TLR4 represent therapeutic targets for HCC prevention in advanced liver disease.

  13. Bone-targeted agents: preventing skeletal complications in prostate cancer.

    PubMed

    Morgans, Alicia K; Smith, Matthew R

    2012-11-01

    In men, prostate cancer is the most common non-cutaneous malignancy and the second most common cause of cancer death. Skeletal complications occur at various points during the disease course, either due to bone metastases directly, or as an unintended consequence of androgen deprivation therapy (ADT). Bone metastases are associated with pathologic fractures, spinal cord compression, and bone pain and can require narcotics or palliative radiation for pain relief. ADT results in bone loss and fragility fractures. This review describes the biology of bone metastases, skeletal morbidity, and recent advances in bone-targeted therapies to prevent skeletal complications of prostate cancer.

  14. Human papillomavirus as a target for management, prevention and therapy.

    PubMed

    Crosbie, Emma J; Kitchener, Henry C

    2012-01-01

    The discovery that human papillomavirus (HPV) is the necessary causal factor in cervical carcinogenesis has made it a target for prophylactic and therapeutic vaccines, as well as a diagnostic tool in cervical screening. Whilst prophylactic vaccination has proven very effective in terms of preventing cervical cancer precursor lesions, therapeutic strategies have presented far greater challenges. HPV testing has shown itself to be extremely valuable in the triage of low grade cytological abnormalities, test of cure following treatment of cervical intraepithelial neoplasia (CIN), and will, over the next 10 years, gradually replace cytology as the mainstay of primary cervical screening. In this review, the latest evidence supporting HPV as both a biomarker of risk for cervical cancer and a target for prophylactic and therapeutic vaccination is presented. PMID:22690976

  15. Modelling the economic benefits of tuberculosis preventive therapy for people with HIV: the example of Zambia.

    PubMed

    Foster, S; Godfrey-Faussett, P; Porter, J

    1997-06-01

    The authors used available data from selected published literature to assess the economic costs and benefits of providing daily isoniazid preventive therapy for tuberculosis (TB) for 6 months in HIV-infected persons in Zambia. The base case scenario assumes recruitment at a voluntary testing and counseling site where HIV seroprevalence is 30%, HIV-infected individuals have a 25% probability of developing active TB during their lifetime, two additional cases of TB would be prevented per person completing a course of preventive therapy, compliance would be 63%, and an efficacy of isoniazid in preventing active TB of 60%. The costs under that scenario would exceed benefits by a factor of 1.16, or a benefit/cost ratio (BCR) of 0.86. However, if preventing one case of TB prevented an additional five cases, the benefits would exceed the costs by a BCR of 1.71. Other scenarios indicate likely significant net benefits from the targeted preventive therapy of HIV-infected persons whose occupation or living situation brings them into contact with a large number of other people.

  16. Proteins as binding targets of isothiocyanates in cancer prevention

    PubMed Central

    Mi, Lixin; Di Pasqua, Anthony J.

    2011-01-01

    Isothiocyanates are versatile cancer-preventive compounds. Evidence from animal studies indicates that the anticarcinogenic activities of ITCs involve all the major stages of tumor growth: initiation, promotion and progression. Epidemiological studies have also shown that dietary intake of ITCs is associated with reduced risk of certain human cancers. A number of mechanisms have been proposed for the chemopreventive activities of ITCs. To identify the molecular targets of ITCs is a first step to understand the molecular mechanisms of ITCs. Studies in recent years have shown that the covalent binding to certain protein targets by ITCs seems to play an important role in ITC-induced apoptosis and cell growth inhibition and other cellular effects. The knowledge gained from these studies may be used to guide future design and screen of better and more efficacious compounds. In this review, we intend to cover all potential protein targets of ITCs so far studied and summarize what are known about their binding sites and the potential biological consequences. In the end, we also offer discussions to shed light onto the relationship between protein binding and reactive oxygen species generation by ITCs. PMID:21665889

  17. The role of experimental science in ICF -- examples from X-ray diagnostics and targets

    NASA Astrophysics Data System (ADS)

    Kilkenny, J. D.

    2016-10-01

    The USA Inertial Confinement Fusion (ICF) Program evolved from the Nuclear Test Program which had restricted shot opportunities for experimentalists to develop sophisticated experimental techniques. In contrast the ICF program in the US was able to increase the shot availability on its large facilities, and develop sophisticated targets and diagnostics to measure and understand the properties of the high energy density plasmas (HEDP) formed. Illustrative aspects of this evolution at Lawrence Livermore National Laboratory (LLNL), with examples of the development of diagnostics and target fabrication are described.

  18. Identifying targets for preventing epilepsy using systems biology.

    PubMed

    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.

  19. Candidate Drug Targets for Prevention or Modification of Epilepsy

    PubMed Central

    Varvel, Nicholas H.; Jiang, Jianxiong; Dingledine, Raymond

    2015-01-01

    Epilepsy is a prevalent neurological disorder afflicting nearly 50 million people worldwide. The disorder is characterized clinically by recurrent spontaneous seizures attributed to abnormal synchrony of brain neurons. Despite advances in the treatment of epilepsy, nearly one-third of patients are resistant to current therapies, and the underlying mechanisms whereby a healthy brain becomes epileptic remain unresolved. Therefore, researchers have a major impetus to identify and exploit new drug targets. Here we distinguish between epileptic effectors, or proteins that set the seizure threshold, and epileptogenic mediators, which control the expression or functional state of the effector proteins. Under this framework, we then discuss attempts to regulate the mediators to control epilepsy. Further insights into the complex processes that render the brain susceptible to seizures and the identification of novel mediators of these processes will lead the way to the development of drugs to modify disease outcome and, potentially, to prevent epileptogenesis. PMID:25196047

  20. Matricellular proteins: new molecular targets to prevent heart failure.

    PubMed

    Okamoto, Hiroshi; Imanaka-Yoshida, Kyoko

    2012-08-01

    Matricellular proteins are highly expressed in reparative responses to pressure and volume overload, ischemia, oxidative stress after myocardial injury, and modulate the inflammatory and fibrotic process in ventricular remodeling, which leads to cardiac dysfunction and eventually overt heart failure. Generally, matricellular proteins loosen strong adhesion of cardiomyocytes to extracellular matrix, which would help cells to move for rearrangement and allow inflammatory cells and capillary vessels to spread during tissue remodeling. Among matricellular proteins, osteopontin (OPN) and tenascin-C (TN-C) are de-adhesion proteins and upregulate the expression and activity of matrix metalloproteinases. These matricellular proteins could be key molecules to diagnose cardiac remodeling and also might be targets for the prevention of adverse ventricular remodeling. This review provides an overview of the role of matricellular proteins such as OPN and TN-C in cardiac function and remodeling, as determined by both in basic and in clinical studies.

  1. BRCA1 as target for breast cancer prevention and therapy.

    PubMed

    Romagnolo, Alberto P G; Romagnolo, Donato F; Selmin, Ornella I

    2015-01-01

    The Breast Cancer 1 protein (BRCA1) is a tumor suppressor involved in basic cellular functions necessary for cell replication and DNA synthesis, but reduced expression of BRCA1, due to mutations or epigenetic inactivation, leads to impaired mammary gland differentiation and increased risk of breast cancer development. Although BRCA1 acts as a tumor suppressor and is present in all cells, where it is essential for the maintenance of the genome integrity, it is still not clear why mutations in the BRCA1 gene predispose to breast and ovarian, but not to other types of cancer. In the first part of this review, we briefly discuss the function and regulation of the BRCA1 protein, including its role associated with familial and sporadic breast cancer. The second part is an overview of the therapeutic compounds used for breast cancer treatment targeting BRCA1, and the natural food components that hold potential preventive effect against those types of breast cancer in which BRCA1 expression is either reduced or lacking. Further studies elucidating the interactions between dietary compounds and cellular pathways, involved in regulation of BRCA1expression, are necessary for the development of strategies that may successfully prevent or treat breast cancer.

  2. DNA Methyltransferases: A Novel Target for Prevention and Therapy

    PubMed Central

    Subramaniam, Dharmalingam; Thombre, Ravi; Dhar, Animesh; Anant, Shrikant

    2013-01-01

    Cancer is the second leading cause of death in US. Despite the emergence of new, targeted agents, and the use of various therapeutic combinations, none of the available treatment options are curative in patients with advanced cancer. Epigenetic alterations are increasingly recognized as valuable targets for the development of cancer therapies. DNA methylation at the 5-position of cytosine, catalyzed by DNA methyltransferases (DNMTs), is the predominant epigenetic modification in mammals. DNMT1, the major enzyme responsible for maintenance of the DNA methylation pattern is located at the replication fork and methylates newly biosynthesized DNA. DNMT2 or TRDMT1, the smallest mammalian DNMT is believed to participate in the recognition of DNA damage, DNA recombination, and mutation repair. It is composed solely of the C-terminal domain, and does not possess the regulatory N-terminal region. The levels of DNMTs, especially those of DNMT3B, DNMT3A, and DNMT3L, are often increased in various cancer tissues and cell lines, which may partially account for the hypermethylation of promoter CpG-rich regions of tumor suppressor genes in a variety of malignancies. Moreover, it has been shown to function in self-renewal and maintenance of colon cancer stem cells and need to be studied in several cancers. Inhibition of DNMTs has demonstrated reduction in tumor formation in part through the increased expression of tumor suppressor genes. Hence, DNMTs can potentially be used as anti-cancer targets. Dietary phytochemicals also inhibit DNMTs and cancer stem cells; this represents a promising approach for the prevention and treatment of many cancers. PMID:24822169

  3. Targeting as a Mode of Science Communication: Principles, Issues and a Practical Example

    NASA Astrophysics Data System (ADS)

    Holland, G. J.; Vigh, J. L.

    2011-12-01

    Today's media landscape contains a rich and diverse range of communications opportunities. New media, such as the internet, blogosphere and social networks, are complementing, supplementing and also replacing the traditional mass media communications through print, radio and television. This diversification certainly contains pitfalls and difficulties as has been demonstrated in the Climategate affair. But there are also real opportunities for utilizing the diversity to provide targeted science communications that are framed in the context of the specific group of interest. That such targeting of audience attitudes and beliefs is an important key to effective science communications has been demonstrated by, for example, Leiserowitz, Maibach et al (2009). This approach does require an understanding of the audience and a careful framing of the message in terms familiar to the targeted group. Here many factors come into play, including: including immediacy, economics, culture, community leaders, emotional framing, and ideological filters. In this talk we shall elaborate on the principles, issues and opportunities. A practical example of working with the religious community on communicating the science of climate change will also be presented. This will include the approach adopted, progress to date and the lessons learnt.

  4. On the importance of planned health education. Prevention of ski injury as an example.

    PubMed

    Kok, G; Bouter, L M

    1990-01-01

    The planning of health education aimed at preventing sports injuries is often incomplete and not stated explicitly. In most instances, the evaluation is incomplete or nonexistent. We present a theoretical framework for planning and evaluating health education, illustrating the main points by using as an example the health education for downhill skiers. Systematic planning consists of analyzing the magnitude of the problem and the behavioral risk factors, studying behavior determinants, designing an optimal intervention, and implementing the intervention. The evaluation phase deals with the effects on these five levels (implementation, intervention, determinants, behavior, and incidence of injury). Some common pitfalls are mentioned and special attention is given to the study of determinants of behavior and to the design of the intervention. The importance of pretesting health education material and the community approach in educating sports participants is underlined. Health education, together with regulations and facilities, constitutes the health promotion strategy in the prevention of sports injuries. For most sports, there seems to be a strong need for further research on the etiology and determinants of behavior before effective prevention can be realized.

  5. Targeting Serglycin Prevents Metastasis in Murine Mammary Carcinoma

    PubMed Central

    Roy, Ananya; Femel, Julia; Huijbers, Elisabeth J. M.; Spillmann, Dorothe; Larsson, Erik; Ringvall, Maria; Olsson, Anna-Karin; Åbrink, Magnus

    2016-01-01

    In hematopoietic cells, serglycin proteoglycans mainly contribute to proper storage and secretion of inflammatory mediators via their negatively charged glycosaminoglycans. Serglycin proteoglycans are also expressed in cancer cells where increased expression has been linked to poor prognosis. However, the serglycin-dependent mediators promoting cancer progression remain to be determined. In the present study we report that genetic ablation of serglycin proteoglycan completely blocks lung metastasis in the MMTV-PyMT-driven mouse breast cancer model, while serglycin-deficiency did not affect primary tumour growth or number of mammary tumours. Although E-cadherin expression was higher in the serglycin-deficient primary tumour tissue, indicating reduced invasiveness, serglycin-deficient tumour cells were still detected in the circulation. These data suggest that serglycin proteoglycans play a role in extravasation as well as colonization and growth of metastatic cells. A microarray expression analysis and functional annotation of differentially expressed genes identified several biological pathways where serglycin may be important. Our results suggest that serglycin and serglycin-dependent mediators are potential drug targets to prevent metastatic disease/dissemination of cancer. PMID:27223472

  6. Technology-Based Innovations in Child Maltreatment Prevention Programs: Examples from SafeCare®

    PubMed Central

    Cowart-Osborne, Melissa; Jackson, Matthew; Chege, Elizabeth; Baker, Evander; Whitaker, Daniel; Self-Brown, Shannon

    2014-01-01

    Each year, hundreds of thousands of children in the U.S. are victims of child maltreatment. Experts recommend behavioral, skill-based parent training programs as a strategy for the prevention of child abuse and neglect. These programs can be enhanced using innovative technology strategies. This paper presents a brief history of the use of technology in SafeCare®, a home visiting program shown to prevent child neglect and physical abuse, and highlights current work that takes a technology-based hybrid approach to SafeCare delivery. With this unique approach, the provider brings a tablet computer to each session, and the parent interacts with the software to receive psychoeducation and modeling of target skills. The provider and parent then work together to practice the targeted skills until mastery is achieved. Initial findings from ongoing research of both of these strategies indicate that they show potential for improving engagement and use of positive parenting skills for parents and ease of implementation for providers. Future directions for technology enhancements in SafeCare are also presented. PMID:25606347

  7. Broad targeting of angiogenesis for cancer prevention and therapy.

    PubMed

    Wang, Zongwei; Dabrosin, Charlotta; Yin, Xin; Fuster, Mark M; Arreola, Alexandra; Rathmell, W Kimryn; Generali, Daniele; Nagaraju, Ganji P; El-Rayes, Bassel; Ribatti, Domenico; Chen, Yi Charlie; Honoki, Kanya; Fujii, Hiromasa; Georgakilas, Alexandros G; Nowsheen, Somaira; Amedei, Amedeo; Niccolai, Elena; Amin, Amr; Ashraf, S Salman; Helferich, Bill; Yang, Xujuan; Guha, Gunjan; Bhakta, Dipita; Ciriolo, Maria Rosa; Aquilano, Katia; Chen, Sophie; Halicka, Dorota; Mohammed, Sulma I; Azmi, Asfar S; Bilsland, Alan; Keith, W Nicol; Jensen, Lasse D

    2015-12-01

    pathological tumor vasculature which would be well suited as targets for anti-angiogenic therapy: (1) endothelial cell migration/tip cell formation, (2) structural abnormalities of tumor vessels, (3) hypoxia, (4) lymphangiogenesis, (5) elevated interstitial fluid pressure, (6) poor perfusion, (7) disrupted circadian rhythms, (8) tumor promoting inflammation, (9) tumor promoting fibroblasts and (10) tumor cell metabolism/acidosis. Following this analysis, we scrutinized the available literature on broadly acting anti-angiogenic natural products, with a focus on finding qualitative information on phytochemicals which could inhibit these targets and came up with 10 prototypical phytochemical compounds: (1) oleanolic acid, (2) tripterine, (3) silibinin, (4) curcumin, (5) epigallocatechin-gallate, (6) kaempferol, (7) melatonin, (8) enterolactone, (9) withaferin A and (10) resveratrol. We suggest that these plant-derived compounds could be combined to constitute a broader acting and more effective inhibitory cocktail at doses that would not be likely to cause excessive toxicity. All the targets and phytochemical approaches were further cross-validated against their effects on other essential tumorigenic pathways (based on the "hallmarks" of cancer) in order to discover possible synergies or potentially harmful interactions, and were found to generally also have positive involvement in/effects on these other aspects of tumor biology. The aim is that this discussion could lead to the selection of combinations of such anti-angiogenic compounds which could be used in potent anti-tumor cocktails, for enhanced therapeutic efficacy, reduced toxicity and circumvention of single-agent anti-angiogenic resistance, as well as for possible use in primary or secondary cancer prevention strategies.

  8. Broad targeting of angiogenesis for cancer prevention and therapy

    PubMed Central

    Wang, Zongwei; Dabrosin, Charlotta; Yin, Xin; Fuster, Mark M.; Arreola, Alexandra; Rathmell, W. Kimryn; Generali, Daniele; Nagaraju, Ganji P.; El-Rayes, Bassel; Ribatti, Domenico; Chen, Yi Charlie; Honoki, Kanya; Fujii, Hiromasa; Georgakilas, Alexandros G.; Nowsheen, Somaira; Amedei, Amedeo; Niccolai, Elena; Amin, Amr; Ashraf, S. Salman; Helferich, Bill; Yang, Xujuan; Guha, Gunjan; Bhakta, Dipita; Ciriolo, Maria Rosa; Aquilano, Katia; Chen, Sophie; Halicka, Dorota; Mohammed, Sulma I.; Azmi, Asfar S.; Bilsland, Alan; Keith, W. Nicol; Jensen, Lasse D.

    2015-01-01

    angiogenesis and the pathological tumor vasculature which would be well suited as targets for anti-angiogenic therapy: (1) endothelial cell migration/tip cell formation, (2) structural abnormalities of tumor vessels, (3) hypoxia, (4) lymphangiogenesis, (5) elevated interstitial fluid pressure, (6) poor perfusion, (7) disrupted circadian rhythms, (8) tumor promoting inflammation, (9) tumor promoting fibroblasts and (10) tumor cell metabolism/acidosis. Following this analysis, we scrutinized the available literature on broadly acting anti-angiogenic natural products, with a focus on finding qualitative information on phytochemicals which could inhibit these targets and came up with 10 prototypical phytochemical compounds: (1) oleanolic acid, (2) tripterine, (3) silibinin, (4) curcumin, (5) epigallocatechin-gallate, (6) kaempferol, (7) melatonin, (8) enterolactone, (9) withaferin A and (10) resveratrol. We suggest that these plant-derived compounds could be combined to constitute a broader acting and more effective inhibitory cocktail at doses that would not be likely to cause excessive toxicity. All the targets and phytochemical approaches were further cross-validated against their effects on other essential tumorigenic pathways (based on the “hallmarks” of cancer) in order to discover possible synergies or potentially harmful interactions, and were found to generally also have positive involvement in/effects on these other aspects of tumor biology. The aim is that this discussion could lead to the selection of combinations of such anti-angiogenic compounds which could be used in potent anti-tumor cocktails, for enhanced therapeutic efficacy, reduced toxicity and circumvention of single-agent anti-angiogenic resistance, as well as for possible use in primary or secondary cancer prevention strategies. PMID:25600295

  9. Vascular wall proteoglycan synthesis and structure as a target for the prevention of atherosclerosis

    PubMed Central

    Little, Peter J; Ballinger, Mandy L; Osman, Narin

    2007-01-01

    Atherosclerosis is the underlying pathology of most cardiovascular disease and it represents the major cause of premature death in modern societies. Current therapies target risk factors being hypertension, hypercholesterolemia, hypertriglyceridemia and hyperglycemia when diabetes is present however the maximum efficacy of these strategies is often 30% or less. Areas of vascular biology that may lead to the development of a complementary vascular wall directed therapy are: inflammation, oxidation, endothelial dysfunction, diabetes-specific factors—hyperglycemia and advanced glycation endproducts and lipid retention by vascular matrix specifically proteoglycans. The major structural features of proteoglycans that determine low-density lipoprotein (LDL) binding are the length and sulfation pattern on the glycosaminoglycan (GAG) chains. Emerging data discussed in this review indicates that these structural properties are subject to considerable regulation by vasoactive substances possibly using novel signaling pathways. For example, GAG elongation stimulated by platelet-derived growth factor is not blocked by the receptor tyrosine kinase antagonist, genistein suggesting that there may be a previously unknown signaling pathway involved in this response. Thus, modifying proteoglycan synthesis and structure may represent a prime target to prevent LDL binding and entrapment in the vessel wall and thus prevent the development and progression of atherosclerosis. PMID:17583182

  10. Potential and Dunkelfeld offenders: two neglected target groups for prevention of child sexual abuse.

    PubMed

    Schaefer, Gerard A; Mundt, Ingrid A; Feelgood, Steven; Hupp, Elena; Neutze, Janina; Ahlers, Christoph J; Goecker, David; Beier, Klaus M

    2010-01-01

    Little is known about men who have not yet committed child sexual abuse but may be at risk of doing so (potential offenders) and the factors that distinguish these men from undetected child sexual abuse offenders with a sexual interest in children (Dunkelfeld offenders). The present study describes and compares potential and Dunkelfeld offenders, which can be viewed as ideal target groups for (primary) prevention efforts with respect to child sexual abuse. Also, this study seeks to demonstrate the feasibility of using a telephone screening procedure to conduct research with these groups. Using a computer assisted telephone interview (CATI), data on demographics, mental health, sexuality, criminal history, and victim characteristics were collected from respondents in a nation-wide media campaign, which informed potential (re-)offenders of child sexual abuse of a research and treatment project. Many participants reported recurrent sexual fantasies involving minors, as well as related distress, suggesting a high prevalence of pedophilia and hebephilia. More than half feared they would sexually abuse a minor, and Dunkelfeld offenders reported 3.2 victims on average. Group comparisons revealed that Dunkelfeld offenders were, for example, more likely to perceive themselves being at risk of offending, compared to potential offenders. The results suggest that targeting potential and Dunkelfeld offenders could prove a worthwhile approach in the prevention of child sexual abuse. PMID:20466423

  11. Tumor Angiogenesis as a Target for Dietary Cancer Prevention

    PubMed Central

    Li, William W.; Li, Vincent W.; Hutnik, Michelle; Chiou, Albert S.

    2012-01-01

    Between 2000 and 2050, the number of new cancer patients diagnosed annually is expected to double, with an accompanying increase in treatment costs of more than $80 billion over just the next decade. Efficacious strategies for cancer prevention will therefore be vital for improving patients' quality of life and reducing healthcare costs. Judah Folkman first proposed antiangiogenesis as a strategy for preventing dormant microtumors from progressing to invasive cancer. Although antiangiogenic drugs are now available for many advanced malignancies (colorectal, lung, breast, kidney, liver, brain, thyroid, neuroendocrine, multiple myeloma, myelodysplastic syndrome), cost and toxicity considerations preclude their broad use for cancer prevention. Potent antiangiogenic molecules have now been identified in dietary sources, suggesting that a rationally designed antiangiogenic diet could provide a safe, widely available, and novel strategy for preventing cancer. This paper presents the scientific, epidemiologic, and clinical evidence supporting the role of an antiangiogenic diet for cancer prevention. PMID:21977033

  12. A Critical Analysis of Approaches To Targeted PTSD Prevention: Current Status and Theoretically Derived Future Directions

    ERIC Educational Resources Information Center

    Feldner, Matthew T.; Monson, Candice M.; Friedman, Matthew J.

    2007-01-01

    Although efforts to prevent posttraumatic stress disorder (PTSD) have met with relatively limited success, theoretically driven preventive approaches with promising efficacy are emerging. The current article critically reviews investigations of PTSD prevention programs that target persons at risk for being exposed to a traumatic event or who have…

  13. Burn prevention in Zambia: a targeted epidemiological approach.

    PubMed

    Heard, Jason P; Latenser, Barbara A; Liao, Junlin

    2013-01-01

    The aim of this study is to assess primary burn prevention knowledge in a rural Zambian population that is disproportionately burdened by burn injuries. A 10-question survey was completed by youths, and a 15-question survey was completed by adults. The survey was available in both English and Nyanja. The surveys were designed to test their knowledge in common causes, first aid, and emergency measures regarding burn injuries. Logistic regression analysis was used to explore relationships between burn knowledge, age, school, and socioeconomic variables. A burn prevention coloring book, based on previous local epidemiological data, was also distributed to 800 school age youths. Five hundred fifty youths and 39 adults completed the survey. The most significant results show knowledge deficits in common causes of burns, first aid treatment of a burn injury, and what to do in the event of clothing catching fire. Younger children were more likely to do worse than older children. The adults performed better than the youths, but still lack fundamental burn prevention and treatment knowledge. Primary burn prevention data from the youths and adults surveyed demonstrate a clear need for burn prevention and treatment education in this population. In a country where effective and sustainable burn care is lacking, burn prevention may be a better investment to reduce burn injury than large investments in healthcare resources.

  14. HIV Prevention Messages Targeting Young Latino Immigrant MSM.

    PubMed

    Solorio, Rosa; Norton-Shelpuk, Pamela; Forehand, Mark; Martinez, Marcos; Aguirre, Joel

    2014-01-01

    Young Latino immigrant men who have sex with men (MSM) are at risk for HIV and for delayed diagnosis. A need exists to raise awareness about HIV prevention in this population, including the benefits of timely HIV testing. This project was developed through collaboration between University of WA researchers and Entre Hermanos, a community-based organization serving Latinos. Building from a community-based participatory research approach, the researchers developed a campaign that was executed by Activate Brands, based in Denver, Colorado. The authors (a) describe the development of HIV prevention messages through the integration of previously collected formative data; (b) describe the process of translating these messages into PSAs, including the application of a marketing strategy; (c) describe testing the PSAs within the Latino MSM community; and (c) determine a set of important factors to consider when developing HIV prevention messages for young Latino MSM who do not identify as gay.

  15. HIV Prevention Messages Targeting Young Latino Immigrant MSM

    PubMed Central

    Solorio, Rosa; Forehand, Mark; Aguirre, Joel

    2014-01-01

    Young Latino immigrant men who have sex with men (MSM) are at risk for HIV and for delayed diagnosis. A need exists to raise awareness about HIV prevention in this population, including the benefits of timely HIV testing. This project was developed through collaboration between University of WA researchers and Entre Hermanos, a community-based organization serving Latinos. Building from a community-based participatory research approach, the researchers developed a campaign that was executed by Activate Brands, based in Denver, Colorado. The authors (a) describe the development of HIV prevention messages through the integration of previously collected formative data; (b) describe the process of translating these messages into PSAs, including the application of a marketing strategy; (c) describe testing the PSAs within the Latino MSM community; and (c) determine a set of important factors to consider when developing HIV prevention messages for young Latino MSM who do not identify as gay. PMID:24864201

  16. HIV Prevention Messages Targeting Young Latino Immigrant MSM.

    PubMed

    Solorio, Rosa; Norton-Shelpuk, Pamela; Forehand, Mark; Martinez, Marcos; Aguirre, Joel

    2014-01-01

    Young Latino immigrant men who have sex with men (MSM) are at risk for HIV and for delayed diagnosis. A need exists to raise awareness about HIV prevention in this population, including the benefits of timely HIV testing. This project was developed through collaboration between University of WA researchers and Entre Hermanos, a community-based organization serving Latinos. Building from a community-based participatory research approach, the researchers developed a campaign that was executed by Activate Brands, based in Denver, Colorado. The authors (a) describe the development of HIV prevention messages through the integration of previously collected formative data; (b) describe the process of translating these messages into PSAs, including the application of a marketing strategy; (c) describe testing the PSAs within the Latino MSM community; and (c) determine a set of important factors to consider when developing HIV prevention messages for young Latino MSM who do not identify as gay. PMID:24864201

  17. Preventing the aortic complications of Marfan syndrome: a case-example of translational genomic medicine

    PubMed Central

    Li-Wan-Po, Alain; Loeys, Bart; Farndon, Peter; Latham, David; Bradley, Caroline

    2011-01-01

    The translational path from pharmacological insight to effective therapy can be a long one. We aim to describe the management of Marfan syndrome as a case-example of how pharmacological and genomic insights can contribute to improved therapy. We undertook a literature search for studies of Marfan syndrome, to identify milestones in description, understanding and therapy of the syndrome. From the studies retrieved we then weaved an evidence-based description of progress. Marfan syndrome shows considerable heterogeneity in clinical presentation. It relies on defined clinical criteria with confirmation based on FBN1 mutation testing. Surgical advances have prolonged life in Marfan syndrome. First-line prophylaxis of complications with β-adrenoceptor blockers became established on the basis that reduction of aortic pressure and heart rate would help. Over-activity of proteinases, first suggested in 1980, has since been confirmed by evidence of over-expression of matrix metalloproteinases (MMP), notably MMP-2 and MMP-9. The search for MMP inhibitors led to the evaluation of doxycycline, and both animal studies and small trials, provided early evidence that this widely used antimicrobial agent was useful. Identification of the importance of TGF-β led to evaluation of angiotensin II type I receptor (AT1R) blockers with highly promising results. Combination prophylactic therapy would appear rational. Pharmacological and genomic research has provided good evidence that therapy with losartan and doxycycline would prevent the aortic complications of Marfan syndrome. If on-going well designed trials confirm their efficacy, the outlook for Marfan syndrome patients would be improved considerably. PMID:21276043

  18. Targeting polyamine metabolism for cancer therapy and prevention.

    PubMed

    Murray-Stewart, Tracy R; Woster, Patrick M; Casero, Robert A

    2016-10-01

    The chemically simple, biologically complex eukaryotic polyamines, spermidine and spermine, are positively charged alkylamines involved in many crucial cellular processes. Along with their diamine precursor putrescine, their normally high intracellular concentrations require fine attenuation by multiple regulatory mechanisms to keep these essential molecules within strict physiologic ranges. Since the metabolism of and requirement for polyamines are frequently dysregulated in neoplastic disease, the metabolic pathway and functions of polyamines provide rational drug targets; however, these targets have been difficult to exploit for chemotherapy. It is the goal of this article to review the latest findings in the field that demonstrate the potential utility of targeting the metabolism and function of polyamines as strategies for both chemotherapy and, possibly more importantly, chemoprevention. PMID:27679855

  19. [Possibilities and limits of application of fluoride-containing varnish in caries prevention, for example, "Fluor-Protector" (2)].

    PubMed

    Della Volpe, M

    1990-09-01

    Using selected literature, the author provides an overview of the possibilities and limits of fluoride varnish application in caries prophylaxis based on the example of Fluor-Protector. He concludes, as did de Bruyn and Arends (1987), that Fluor-Protector is a safe and effective agent that can prevent caries very effectively and is also promising for use as a desensitising substance.

  20. Community based prevention programs targeting all injuries for children

    PubMed Central

    Spinks, A; Turner, C; McClure, R; Nixon, J

    2004-01-01

    Objective: Community based models for injury prevention have become an accepted part of the overall injury control strategy. This systematic review of the scientific literature examines the evidence for their effectiveness in reducing all-cause injury in children 0–14 years of age. Methods: A comprehensive search of the literature was performed using the following study selection criteria: community based intervention study; children under 14 years; outcome measure was injury rates; and either a community control or an historical control was used in the design. Quality assessment and data abstraction were guided by a standardized procedure and performed independently by two authors. Data synthesis was in tabular and text form with meta-analysis not being possible due to the discrepancy in methods and measures between the studies. Results: Thorough electronic and library search techniques yielded only nine formally evaluated community based all-cause child injury prevention programs that have reported actual injury outcomes. Of these nine studies, seven provided high level evidence where contemporary control communities were used for comparison; the remaining two used a pre and post-design or time trend analysis where historical data from the community were used as the comparison. Only three of the seven studies with contemporary control communities found significant effect of the intervention; the two studies without controls noted significant reductions in injury rates after the intervention period. Conclusion: There is a paucity of research from which evidence regarding the effectiveness of community based childhood injury prevention programs can be obtained and hence a clear need to increase the effort on developing this evidence base. PMID:15178676

  1. [Nutrition and physical activity: two targets for cancer prevention].

    PubMed

    Thibault, Ronan; Dupertuis, Yves M; Belabed, Linda; Pichard, Claude

    2010-05-26

    The links between nutrition and cancer onset are now well established by epidemiological studies. The scientific evidence is presented in a report of the World Cancer Research Foundation (WCRF). Protective factors towards overall cancer risk are fruit and vegetable consumption and physical activity. Overweight and obesity, intakes of alcoholic beverage, fat, salt, high temperature cooked and processed red meat, increase cancer risk. In addition, beta-carotene systematic supplementation could increase lung cancer risk in smokers. As optimal controlling of these risk factors can decrease cancer mortality by 25%, nutritional counselling must be integrated in the global strategy of primary and secondary prevention of cancers.

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

    PubMed Central

    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. Entamoeba Encystation: New Targets to Prevent the Transmission of Amebiasis

    PubMed Central

    Mi-ichi, Fumika; Yoshida, Hiroki; Hamano, Shinjiro

    2016-01-01

    Amebiasis is caused by Entamoeba histolytica infection and can produce a broad range of clinical signs, from asymptomatic cases to patients with obvious symptoms. The current epidemiological and clinical statuses of amebiasis make it a serious public health problem worldwide. The Entamoeba life cycle consists of the trophozoite, the causative agent for amebiasis, and the cyst, the form responsible for transmission. These two stages are connected by “encystation” and “excystation.” Hence, developing novel strategies to control encystation and excystation will potentially lead to new measures to block the transmission of amebiasis by interrupting the life cycle of the causative agent. Here, we highlight studies investigating encystation using inhibitory chemicals and categorize them based on the molecules inhibited. We also present a perspective on new strategies to prevent the transmission of amebiasis. PMID:27764256

  4. Prevention of vascular inflammation by nanoparticle targeting of adherent neutrophils

    NASA Astrophysics Data System (ADS)

    Wang, Zhenjia; Li, Jing; Cho, Jaehyung; Malik, Asrar B.

    2014-03-01

    Inflammatory diseases such as acute lung injury and ischaemic tissue injury are caused by the adhesion of a type of white blood cell--polymorphonuclear neutrophils--to the lining of the circulatory system or vascular endothelium and unchecked neutrophil transmigration. Nanoparticle-mediated targeting of activated neutrophils on vascular endothelial cells at the site of injury may be a useful means of directly inactivating neutrophil transmigration and hence mitigating vascular inflammation. Here, we report a method employing drug-loaded albumin nanoparticles, which efficiently deliver drugs into neutrophils adherent to the surface of the inflamed endothelium. Using intravital microscopy of tumour necrosis factor-α-challenged mouse cremaster post-capillary venules, we demonstrate that fluorescently tagged albumin nanoparticles are largely internalized by neutrophils adherent to the activated endothelium via cell surface Fcɣ receptors. Administration of albumin nanoparticles loaded with the spleen tyrosine kinase inhibitor, piceatannol, which blocks `outside-in' β2 integrin signalling in leukocytes, detached the adherent neutrophils and elicited their release into the circulation. Thus, internalization of drug-loaded albumin nanoparticles into neutrophils inactivates the pro-inflammatory function of activated neutrophils, thereby offering a promising approach for treating inflammatory diseases resulting from inappropriate neutrophil sequestration and activation.

  5. Prevention of vascular inflammation by nanoparticle targeting of adherent neutrophils.

    PubMed

    Wang, Zhenjia; Li, Jing; Cho, Jaehyung; Malik, Asrar B

    2014-03-01

    Inflammatory diseases such as acute lung injury and ischaemic tissue injury are caused by the adhesion of a type of white blood cell--polymorphonuclear neutrophils--to the lining of the circulatory system or vascular endothelium and unchecked neutrophil transmigration. Nanoparticle-mediated targeting of activated neutrophils on vascular endothelial cells at the site of injury may be a useful means of directly inactivating neutrophil transmigration and hence mitigating vascular inflammation. Here, we report a method employing drug-loaded albumin nanoparticles, which efficiently deliver drugs into neutrophils adherent to the surface of the inflamed endothelium. Using intravital microscopy of tumour necrosis factor-α-challenged mouse cremaster post-capillary venules, we demonstrate that fluorescently tagged albumin nanoparticles are largely internalized by neutrophils adherent to the activated endothelium via cell surface Fcɣ receptors. Administration of albumin nanoparticles loaded with the spleen tyrosine kinase inhibitor, piceatannol, which blocks 'outside-in' β2 integrin signalling in leukocytes, detached the adherent neutrophils and elicited their release into the circulation. Thus, internalization of drug-loaded albumin nanoparticles into neutrophils inactivates the pro-inflammatory function of activated neutrophils, thereby offering a promising approach for treating inflammatory diseases resulting from inappropriate neutrophil sequestration and activation.

  6. Drug target identification using network analysis: Taking active components in Sini decoction as an example

    PubMed Central

    Chen, Si; Jiang, Hailong; Cao, Yan; Wang, Yun; Hu, Ziheng; Zhu, Zhenyu; Chai, Yifeng

    2016-01-01

    Identifying the molecular targets for the beneficial effects of active small-molecule compounds simultaneously is an important and currently unmet challenge. In this study, we firstly proposed network analysis by integrating data from network pharmacology and metabolomics to identify targets of active components in sini decoction (SND) simultaneously against heart failure. To begin with, 48 potential active components in SND against heart failure were predicted by serum pharmacochemistry, text mining and similarity match. Then, we employed network pharmacology including text mining and molecular docking to identify the potential targets of these components. The key enriched processes, pathways and related diseases of these target proteins were analyzed by STRING database. At last, network analysis was conducted to identify most possible targets of components in SND. Among the 25 targets predicted by network analysis, tumor necrosis factor α (TNF-α) was firstly experimentally validated in molecular and cellular level. Results indicated that hypaconitine, mesaconitine, higenamine and quercetin in SND can directly bind to TNF-α, reduce the TNF-α-mediated cytotoxicity on L929 cells and exert anti-myocardial cell apoptosis effects. We envisage that network analysis will also be useful in target identification of a bioactive compound. PMID:27095146

  7. Documenting the need for translational research: an example from workplace violence prevention.

    PubMed

    Peek-Asa, Corinne; Casteel, Carri H

    2010-02-01

    The leading cause of occupational death in small retail establishments--workplace violence--provides an example of how data can be used to document the need for type 2 translational research. First, strategies effective in reducing workplace violence in small retail businesses were identified. Next, the effectiveness of the researched strategies was compared with the types of strategies voluntarily implemented by small businesses. The strongest evidence-based strategies were the least likely to be implemented by businesses, and the relationship between effectiveness and implementation was nearly inverse. For example, cash control policies were found to be effective in 92% of studies, but fewer than 10% of businesses had implemented adequate cash control policies. Surveillance cameras were found to be effective in only 50% of studies, but more than 70% of businesses had implemented them. In the absence of effective translation of knowledge and practice, business owners installed the least effective strategies, often at a higher cost.

  8. A Review of Culturally Targeted/Tailored Tobacco Prevention and Cessation Interventions for Minority Adolescents

    PubMed Central

    Singh, Nisha; Krishnan-Sarin, Suchitra

    2012-01-01

    Aim: Emerging racial/ethnic disparities in tobacco use behaviors and resulting long-term health outcomes highlight the importance of developing culturally tailored/targeted tobacco prevention and cessation interventions. This manuscript describes the efficacy and the components of prevention and cessation interventions developed for minority adolescents. Methods: Thirteen studies focused on culturally tailoring and targeting tobacco prevention/cessation interventions were selected and information on intervention design (type, number of sessions), setting (school or community), theoretical constructs, culture-specific components (surface/deep structures), and treatment outcomes were extracted. Results: Of the 13 studies, 5 focused on prevention, 4 on cessation, and 4 combined prevention and cessation, and most of the studies were primarily school-based, while a few used community locations. Although diverse minority groups were targeted, a majority of the studies (n = 6) worked with Hispanic adolescents. The most common theoretical construct examined was the Social Influence Model (n = 5). The overall findings indicated that culturally tailoring cessation interventions did not appear to improve tobacco quit rates among minority adolescents, but culturally tailored prevention interventions appeared to produce lower tobacco initiation rates among minority adolescents than control conditions. Conclusions: The results of review suggest that there is a critical need to develop better interventions to reduce tobacco use among minority adolescents and that developing a better understanding of cultural issues related to both cessation and initiation of tobacco use among minority populations is a key component of this endeavor. PMID:22614548

  9. Occupational asthma prevention and management in industry--an example of a global programme.

    PubMed

    Gannon, Paul F G; Berg, A S; Gayosso, R; Henderson, B; Sax, S E; Willems, H M J

    2005-12-01

    Isocyanates are widely used in the manufacture of polyurethane foams, plastics, coatings and adhesives, and are known to cause occupational asthma in a proportion of exposed workers. Substitution as a prevention strategy is not currently a feasible option. For this reason, health and safety professionals working together in an automotive coatings business created a proactive global programme to address the known potential effects of isocyanates on its workers. The goals of the programme are prevention, early detection and mitigation of effect of key endpoints, especially asthma and to a lesser degree dermatitis, in people who are occupationally exposed, or potentially exposed, to isocyanates and products containing isocyanates. The surveillance programme for isocyanates has several important components, which include assessment of exposure, pre-placement questionnaire and spirometry, training and education of employees, regularly administered periodic questionnaires, medical assessment for abnormal questionnaire responses, process for early reporting and investigation of symptomatic employees and incidents, group data review and management reporting. Although regional differences exist regarding availability of specialized services, we have successfully implemented this programme in parts of North America, Europe and Latin America, and are currently implementing elsewhere. These simple control measures are relatively inexpensive and can be applied in even small business settings. It is recommended that all employers who manufacture, handle or use isocyanate-containing products consider such a strategy.

  10. Non-Target Activity Detection by Post-Radioembolization Yttrium-90 PET/CT: Image Assessment Technique and Case Examples.

    PubMed

    Kao, Yung Hsiang; Tan, Andrew E H; Lo, Richard H G; Tay, Kiang Hiong; Tan, Bien Soo; Chow, Pierce K H; Ng, David C E; Goh, Anthony S W

    2014-01-01

    High resolution yttrium-90 ((90)Y) imaging of post-radioembolization microsphere biodistribution may be achieved by conventional positron emission tomography with integrated computed tomography (PET/CT) scanners that have time-of-flight capability. However, reconstructed (90)Y PET/CT images have high background noise, making non-target activity detection technically challenging. This educational article describes our image assessment technique for non-target activity detection by (90)Y PET/CT, which qualitatively overcomes the problem of background noise. We present selected case examples of non-target activity in untargeted liver, stomach, gallbladder, chest wall, and kidney, supported by angiography and (90)Y bremsstrahlung single-photon emission computed tomography with integrated computed tomography (SPECT/CT) or technetium-99m macroaggregated albumin SPECT/CT.

  11. Teens on Target Violence Prevention Curriculum for Grades 6-12.

    ERIC Educational Resources Information Center

    Becker, Marla G.; Calhoun, Deane

    This curriculum is designed to help schools implement programs to prevent violence among students in grades 6-12. It is a six-session, school based curriculum intended for adolescents who are living in communities experiencing high rates of violence. It is facilitated by trained Teens on Target (TNT) members/peer educators, young people who are…

  12. [Mitochondrial quality control: the target for exercise to promote health and prevent disease].

    PubMed

    Zhao, Yun-Gang; Li, Can; Ding, Shu-Zhe; Zhang, Yong

    2014-10-01

    Regular exercise has been known to have many benefits, for example, improving physical performance, promoting health and preventing chronic diseases such as metabolic diseases. As a very important organelles in eukaryotic cells, mitochondria exhibit superb plasticity in response to exercise. Exercise may promote mitochondrial biogenesis and eliminate the dysfunctional mitochondria via mitophagy in order to maintain the normal function of the mitochondrial network. These dynamic changes keep mitochondria in health state and ensure the energy supply for cells. This review summarized the studies on the regulation of mitochondrial quality control by exercise, and provided a reasonable explanation for exercise to promote health and prevent diseases. PMID:25764790

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

    PubMed Central

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

    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 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. PMID:27812288

  14. Targeting the HER/EGFR/ErbB family to prevent breast cancer.

    PubMed

    Howe, Louise R; Brown, Powel H

    2011-08-01

    Preventing breast cancer is possible with selective estrogen receptor (ER) modulators and aromatase inhibitors, which reduce the risk of invasive disease by up to 65% (up to 73% for ER-positive and no effect for ER-negative cancer) and the risk of preinvasive disease [ductal carcinoma in situ (DCIS)] by up to 50%. Clearly, approaches for preventing ER-negative, and increased prevention of ER-positive breast cancers would benefit public health. A growing body of work (including recent preclinical and clinical data) support targeting the HER family [epidermal growth factor receptor (EGFR), or human epidermal growth factor receptor (HER) 1 or ErbB1) and HER2, HER3, and HER4] for preventing ER-negative and possibly ER-positive breast cancer. Preclinical studies of HER family-targeting drugs in mammary neoplasia show suppression of (i) ER-negative tumors in HER2-overexpressing mouse strains, (ii) ER-negative tumors in mutant Brca1/p53(+/-) mice, and (iii) ER-positive tumors in the methylnitrosourea (MNU) rat model; tumors arising in both the MNU and mutant Brca1/p53(+/-) models lack HER2 overexpression. Clinical trials include a recent placebo-controlled phase IIb presurgical trial of the dual EGFR HER2 inhibitor lapatinib that suppressed growth of breast premalignancy [including atypical ductal hyperplasia (ADH) and DCIS] and invasive cancer in patients with early-stage, HER2-overexpressing or -amplified breast cancer. These results suggest that lapatinib can clinically suppress the progression of ADH and DCIS to invasive breast cancer, an effect previously observed in a mouse model of HER2-overexpressing, ER-negative mammary cancer. The preclinical and clinical signals provide a compelling rationale for testing HER-targeting drugs for breast cancer prevention in women at moderate-to-high risk, leading perhaps to combinations that prevent ER-negative and ER-positive breast cancer.

  15. The value of prevention: managing the risks associated with targeted violence and active shooters.

    PubMed

    Doherty, Matthew

    2016-01-01

    Every time we turn on the news, or open our Internet browsers, a story about an active shooter--at a school, house of worship, public place and even in our workplace--spills onto the page, the author reports. In this article he focuses on how we can prevent these incidents from occurring. What exactly is "targeted violence"--and why is what experts call "behavioral threat assessment" one of the single most effective ways to prevent the next active shooter incident in any organization?

  16. The value of prevention: managing the risks associated with targeted violence and active shooters.

    PubMed

    Doherty, Matthew

    2016-01-01

    Every time we turn on the news, or open our Internet browsers, a story about an active shooter--at a school, house of worship, public place and even in our workplace--spills onto the page, the author reports. In this article he focuses on how we can prevent these incidents from occurring. What exactly is "targeted violence"--and why is what experts call "behavioral threat assessment" one of the single most effective ways to prevent the next active shooter incident in any organization? PMID:26978957

  17. From Target Selection to Post-Stimulation Analysis: Example of an Unconventional Faulted Reservoir

    NASA Astrophysics Data System (ADS)

    LeCalvez, J. H.; Williams, M.; Xu, W.; Stokes, J.; Moros, H.; Maxwell, S. C.; Conners, S.

    2011-12-01

    As the global balance of supply and demand forces the hydrocarbon industry toward unconventional resources, technology- and economics-driven shale oil and gas production is gaining momentum throughout many basins worldwide. Production from such unconventional plays is facilitated by massive hydraulic fracturing treatments aimed at increasing permeability and reactivating natural fractures. Large-scale faulting and fracturing partly control stress distribution, hence stimulation-derived hydraulically-induced fracture systems development. Therefore, careful integrated approaches to target selection, treatment staging, and stimulation methods need to be used to economically maximize ultimate hydrocarbon recovery. We present a case study of a multistage, multilateral stimulation project in the Fort Worth Basin, Texas. Wells had to be drilled within city limits in a commercially developing building area. Well locations and trajectories were determined in and around large-scale faults using 3D surface seismic with throws varying from seven to thirty meters. As a result, three horizontal wells were drilled in the Lower Barnett Shale section, 150 m apart with the central well landed about 25 m shallower than the outside laterals. Surface seismic indicates that the surface locations are on top of a major fault complex with the lateral sections drilling away from the major fault system and through a smaller fault. Modeling of the borehole-based microseismic monitoring options led to the selection of an optimum set of configurations given the operational restrictions faced: monitoring would mainly take place using a horizontal array to be tractored downhole and moved according to the well and stage to be monitored. Wells were completed using a perf-and-plug approach allowing for each stimulation stage to obtain a precise orientation of the various three-component accelerometers of the monitoring array as well as the calibration of the velocity model used to process the

  18. Multilevel perspectives on community intervention: an example from an Indo-US HIV prevention project in Mumbai, India.

    PubMed

    Schensul, Stephen L; Saggurti, Niranjan; Singh, Rajendra; Verma, Ravi K; Nastasi, Bonnie K; Mazumder, Papiya Guha

    2009-06-01

    This paper explores the meaning and applicability of multilevel interventions and the role of ethnography in identifying intervention opportunities and accounting for research design limitations. It utilizes as a case example the data and experiences from a 6-year, NIMH-funded, intervention to prevent HIV/STI among married men in urban poor communities in Mumbai, India. The experiences generated by this project illustrate the need for multilevel interventions to include: (1) ethnographically driven formative research to delineate appropriate levels, stakeholders and collaborators; (2) identification of ways to link interventions to the local culture and community context; (3) the development of a model of intervention that is sufficiently flexible to be consistently applied to different intervention levels using comparable culturally congruent concepts and approaches; (4) mechanisms to involve community residents, community based organizations and community-based institutions; and (5) approaches to data collection that can evaluate the impact of the project on multiple intersecting levels. PMID:19357946

  19. Tetanus toxin entry. Nidogens are therapeutic targets for the prevention of tetanus.

    PubMed

    Bercsenyi, Kinga; Schmieg, Nathalie; Bryson, J Barney; Wallace, Martin; Caccin, Paola; Golding, Matthew; Zanotti, Giuseppe; Greensmith, Linda; Nischt, Roswitha; Schiavo, Giampietro

    2014-11-28

    Tetanus neurotoxin (TeNT) is among the most poisonous substances on Earth and a major cause of neonatal death in nonvaccinated areas. TeNT targets the neuromuscular junction (NMJ) with high affinity, yet the nature of the TeNT receptor complex remains unknown. Here, we show that the presence of nidogens (also known as entactins) at the NMJ is the main determinant for TeNT binding. Inhibition of the TeNT-nidogen interaction by using small nidogen-derived peptides or genetic ablation of nidogens prevented the binding of TeNT to neurons and protected mice from TeNT-induced spastic paralysis. Our findings demonstrate the direct involvement of an extracellular matrix protein as a receptor for TeNT at the NMJ, paving the way for the development of therapeutics for the prevention of tetanus by targeting this protein-protein interaction. PMID:25430769

  20. Tetanus toxin entry. Nidogens are therapeutic targets for the prevention of tetanus.

    PubMed

    Bercsenyi, Kinga; Schmieg, Nathalie; Bryson, J Barney; Wallace, Martin; Caccin, Paola; Golding, Matthew; Zanotti, Giuseppe; Greensmith, Linda; Nischt, Roswitha; Schiavo, Giampietro

    2014-11-28

    Tetanus neurotoxin (TeNT) is among the most poisonous substances on Earth and a major cause of neonatal death in nonvaccinated areas. TeNT targets the neuromuscular junction (NMJ) with high affinity, yet the nature of the TeNT receptor complex remains unknown. Here, we show that the presence of nidogens (also known as entactins) at the NMJ is the main determinant for TeNT binding. Inhibition of the TeNT-nidogen interaction by using small nidogen-derived peptides or genetic ablation of nidogens prevented the binding of TeNT to neurons and protected mice from TeNT-induced spastic paralysis. Our findings demonstrate the direct involvement of an extracellular matrix protein as a receptor for TeNT at the NMJ, paving the way for the development of therapeutics for the prevention of tetanus by targeting this protein-protein interaction.

  1. Periparturient stress and immune suppression as a potential cause of retained placenta in highly productive dairy cows: examples of prevention.

    PubMed

    Mordak, Ryszard; Stewart, Peter Anthony; Anthony, Stewart Peter

    2015-12-02

    The immune system during the periparturient period is impaired. At this time the most important factor causing immune-suppression in highly productive cows is metabolic stress resulting from hormonal and metabolic fluctuations, a negative energy balance, shortage of proteins, minerals and vitamins which are required to meet the demands of the fetus as well as the onset of lactation. This stress can activate the hypothalamic-pituitary-adrenocortical axis (HPA), which results in increase plasma corticosteroids. As a result, the cortisol concentration during the periparturient period increases by several folds particularly on the day of calving. Cortisol is a powerful immune-suppressive agent. During stress, this hormone causes depression of the leukocyte proliferation and their functions. Decreased phagocytosis of neutrophils, decreased cytotoxic ability of lymphocytes, as well as depressed activity of their cytokines, make it impossible for the normal, efficient maternal immune recognition and rejection of fetal membranes (as a foreign, allogeneic tissue expressed fetal antigens-MHC class I proteins by trophoblast cells) and finally results in their retention in cows. The metabolic periparturient stress also activates production of catecholamines, especially adrenalin. Adrenalin activates adrenoreceptors of the myometrium and then causes hypotony or atony of the uterus. Thus, cortisol and adrenalin inhibit rejection and expulsion of fetal membranes and cause their retention. These mechanisms of retained placenta (RP) often have a metabolic etiology and occur in herds, where important infectious diseases causing placentitis are absent or prevented. The aim of this article is to show the fundamental mechanisms occurring during periparturient stress and the accompanied immune-suppression in cows, as well as their consequences in relation to RP. The paper also gives examples of the symptomatic prevention of RP in cows caused by metabolic and immune suppressive factors

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

    PubMed

    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. PMID:27088658

  3. Targeting MicroRNAs in Prevention and Treatment of Neurodegenerative Disorders.

    PubMed

    Gupta, Smriti; Verma, Savita; Mantri, Shrikant; Berman, Nancy E; Sandhir, Rajat

    2015-11-01

    Preclinical Research microRNAs (miRNAs) are small noncoding RNAs (ncRNAs) that are key regulators of gene expression. They act on wide range of targets by binding to mRNA via imperfect complementarity at 3' UTR. Evidence suggests that miRNAs regulate many biological processes including neuronal development, differentiation, and disease. Altered expression of several miRNAs has been reported in many neurodegenerative disorders (NDDs). Many miRNAs are altered in these diseases, but miRNA 15, miRNA 21, and miRNA 146a have been shown to play critical role in many neurodegenerative conditions. As these miRNAs regulate many genes, miRNA targeted approaches would allow concurrently targeting of multiple effectors of pathways that regulate disease progression. In this review, we describe the role of miRNAs in various NDDs and their potential as therapeutic tools in prevention and treatment of neurological conditions.

  4. Targeted Nitric Oxide Delivery by Supramolecular Nanofibers for the Prevention of Restenosis After Arterial Injury

    PubMed Central

    Bahnson, Edward S.M.; Kassam, Hussein A.; Moyer, Tyson J.; Jiang, Wulin; Morgan, Courtney E.; Vercammen, Janet M.; Jiang, Qun; Flynn, Megan E.; Stupp, Samuel I.

    2016-01-01

    Abstract Aims: Cardiovascular interventions continue to fail as a result of arterial restenosis secondary to neointimal hyperplasia. We sought to develop and evaluate a systemically delivered nanostructure targeted to the site of arterial injury to prevent neointimal hyperplasia. Nanostructures were based on self-assembling biodegradable molecules known as peptide amphiphiles. The targeting motif was a collagen-binding peptide, and the therapeutic moiety was added by S-nitrosylation of cysteine residues. Results: Structure of the nanofibers was characterized by transmission electron microscopy and small-angle X-ray scattering. S-nitrosylation was confirmed by mass spectrometry, and nitric oxide (NO) release was assessed electrochemically and by chemiluminescent detection. The balloon carotid artery injury model was performed on 10-week-old male Sprague-Dawley rats. Immediately after injury, nanofibers were administered systemically via tail vein injection. S-nitrosylated (S-nitrosyl [SNO])-targeted nanofibers significantly reduced neointimal hyperplasia 2 weeks and 7 months following balloon angioplasty, with no change in inflammation. Innovation: This is the first time that an S-nitrosothiol (RSNO)-based therapeutic was shown to have targeted local effects after systemic administration. This approach, combining supramolecular nanostructures with a therapeutic NO-based payload and a targeting moiety, overcomes the limitations of delivering NO to a site of interest, avoiding undesirable systemic side effects. Conclusion: We successfully synthesized and characterized an RSNO-based therapy that when administered systemically, targets directly to the site of vascular injury. By integrating therapeutic and targeting chemistries, these targeted SNO nanofibers provided durable inhibition of neointimal hyperplasia in vivo and show great potential as a platform to treat cardiovascular diseases. Antioxid. Redox Signal. 27, 401–418. PMID:26593400

  5. Host-Targeting Agents to Prevent and Cure Hepatitis C Virus Infection

    PubMed Central

    Zeisel, Mirjam B.; Crouchet, Emilie; Baumert, Thomas F.; Schuster, Catherine

    2015-01-01

    Chronic hepatitis C virus (HCV) infection is a major cause of liver cirrhosis and hepatocellular carcinoma (HCC) which are leading indications of liver transplantation (LT). To date, there is no vaccine to prevent HCV infection and LT is invariably followed by infection of the liver graft. Within the past years, direct-acting antivirals (DAAs) have had a major impact on the management of chronic hepatitis C, which has become a curable disease in the majority of DAA-treated patients. In contrast to DAAs that target viral proteins, host-targeting agents (HTAs) interfere with cellular factors involved in the viral life cycle. By acting through a complementary mechanism of action and by exhibiting a generally higher barrier to resistance, HTAs offer a prospective option to prevent and treat viral resistance. Indeed, given their complementary mechanism of action, HTAs and DAAs can act in a synergistic manner to reduce viral loads. This review summarizes the different classes of HTAs against HCV infection that are in preclinical or clinical development and highlights their potential to prevent HCV infection, e.g., following LT, and to tailor combination treatments to cure chronic HCV infection. PMID:26540069

  6. Co-targeting AR and HSP90 suppresses prostate cancer cell growth and prevents resistance mechanisms.

    PubMed

    Centenera, Margaret M; Carter, Sarah L; Gillis, Joanna L; Marrocco-Tallarigo, Deborah L; Grose, Randall H; Tilley, Wayne D; Butler, Lisa M

    2015-10-01

    Persistent androgen receptor (AR) signaling in castration resistant prostate cancer (CRPC) underpins the urgent need for therapeutic strategies that better target this pathway. Combining classes of agents that target different components of AR signaling has the potential to delay resistance and improve patient outcomes. Many oncoproteins, including the AR, rely on the molecular chaperone heat shock protein 90 (Hsp90) for functional maturation and stability. In this study, enhanced anti-proliferative activity of the Hsp90 inhibitors 17-allylamino-demethoxygeldanamycin (17-AAG) and AUY922 in androgen-sensitive and CRPC cells was achieved when the agents were used in combination with AR antagonists bicalutamide or enzalutamide. Moreover, significant caspase-dependent cell death was achieved using sub-optimal agent doses that individually have no effect. Expression profiling demonstrated regulation of a broadened set of AR target genes with combined 17-AAG and bicalutamide compared with the respective single agent treatments. This enhanced inhibition of AR signaling was accompanied by impaired chromatin binding and nuclear localization of the AR. Importantly, expression of the AR variant AR-V7 that is implicated in resistance to AR antagonists was not induced by combination treatment. Likewise, the heat shock response that is typically elicited with therapeutic doses of Hsp90 inhibitors, and is a potential mediator of resistance to these agents, was significantly reduced by combination treatment. In summary, the co-targeting strategy in this study more effectively inhibits AR signaling than targeting AR or HSP90 alone and prevents induction of key resistance mechanisms in prostate cancer cells. These findings merit further evaluation of this therapeutic strategy to prevent CRPC growth.

  7. [Integrative neuroimaging for schizophrenia targeting early intervention and prevention (IN-STEP)].

    PubMed

    Kasai, Kiyoto

    2010-11-01

    The editorial of the new-year issue of Nature 2010 features "A decade for psychiatric disorders". The DALY estimation clearly shows that psychiatric disorders are the top source for burden of diseases to the individual life and society. Schizophrenia is a most devastating psychiatric disorder in which the onset is usually at youth and the cognitive dysfunction persists for life-long in some patients. Schizophrenia is associated with neurodevelopmental abnormalities. It has been unknown whether post-onset progressive pathology is also present in schizophrenia until the recent sophistication of in vivo neuroimaging techniques. Longitudinal neuroimaging studies on first-episode schizophrenia have shown a progressive deterioration of structure and function of neocortical regions in the early stage of the disorder. Insult to dendritic spines through glutamatergic dysfunction may underlie this process, which may in turn be a promising molecular target for intervention to improve the functional outcome of schizophrenia. More recently, the question of whether early intervention can be targeted at prodromal stage of schizophrenia has called special attention in psychiatry. In University of Tokyo, the integrative neuroimaging studies for schizophrenia targeting early intervention and prevention (IN-STEP) is ongoing. Through these efforts, we would like to contribute to the establishment of "youth mental health", where every youth in the community can know, prevent, and have easy access to needs- and value-based services, and pursue mental well-being and recovery. PMID:21921453

  8. siRNAs targeted to Smad4 prevent renal fibrosis in vivo.

    PubMed

    Morishita, Yoshiyuki; Yoshizawa, Hiromichi; Watanabe, Minami; Ishibashi, Kenichi; Muto, Shigeaki; Kusano, Eiji; Nagata, Daisuke

    2014-09-19

    Renal fibrosis is the final common pathway leading to decreased renal function. No therapy has been established to prevent it. In order to establish a therapeutic approach and target molecule for renal fibrosis, we investigated the effects of Smad4 knockdown by siRNAs on renal fibrosis in vivo. Renal fibrosis mice were produced by single intraperitoneal injection of folic acid. siRNAs targeted to Smad4 (Smad4-siRNAs) (5 nmol) were injected into each mouse by systemic tail vein injection three times per week. Non-targeted siRNAs (control-siRNAs) were injected in the same way for a control group. The siRNAs were delivered to the interstitial fibrous area and tubules. Smad4-siRNAs significantly knocked down Smad4 expression and inhibited renal fibrosis. They also inhibited α-SMA-positive myofibroblasts. Control-siRNAs did not show these effects. The results of this study suggest that Smad4 knockdown is one of the crucial therapeutic options for the prevention of renal fibrosis in vivo.

  9. [Molecular targets and novel pharmacological options to prevent myocardial hypertrophic remodeling].

    PubMed

    Coppini, Raffaele; Ferrantini, Cecilia; Poggesi, Corrado; Mugelli, Alessandro; Olivotto, Iacopo

    2016-03-01

    Myocardial hypertrophic remodeling is a pathophysiological feature of several cardiac conditions and is the hallmark of hypertrophic cardiomyopathy (HCM), the most common monogenic inherited disease of the heart. In recent years, preclinical and clinical studies investigated the underlying molecular mechanisms and intracellular signaling pathways involved in pathologic cardiomyocyte hypertrophy and highlighted a number of possible molecular targets of therapy aimed at preventing its development. Early prevention of myocardial hypertrophic remodeling is particularly sought after in HCM, as current therapeutic strategies are unable to remove the primary cause of disease, i.e. the disease-causing gene mutation. Studies on transgenic animal models or human myocardial samples from patients with HCM identified intracellular calcium overload as a central mechanism driving pathological hypertrophy. In this review, we analyze recent preclinical and clinical studies on animal models and patients with HCM aimed at preventing or modifying hypertrophic myocardial remodeling. Mounting evidence shows that prevention of pathological hypertrophy is a feasible strategy in HCM and will enter the clinical practice in the near future. Considering the close mechanistic similarities between HCM and secondary hypertrophy, these studies are also relevant for the common forms of cardiac hypertrophy, such as hypertensive or valvular heart disease. PMID:27029877

  10. [Molecular targets and novel pharmacological options to prevent myocardial hypertrophic remodeling].

    PubMed

    Coppini, Raffaele; Ferrantini, Cecilia; Poggesi, Corrado; Mugelli, Alessandro; Olivotto, Iacopo

    2016-03-01

    Myocardial hypertrophic remodeling is a pathophysiological feature of several cardiac conditions and is the hallmark of hypertrophic cardiomyopathy (HCM), the most common monogenic inherited disease of the heart. In recent years, preclinical and clinical studies investigated the underlying molecular mechanisms and intracellular signaling pathways involved in pathologic cardiomyocyte hypertrophy and highlighted a number of possible molecular targets of therapy aimed at preventing its development. Early prevention of myocardial hypertrophic remodeling is particularly sought after in HCM, as current therapeutic strategies are unable to remove the primary cause of disease, i.e. the disease-causing gene mutation. Studies on transgenic animal models or human myocardial samples from patients with HCM identified intracellular calcium overload as a central mechanism driving pathological hypertrophy. In this review, we analyze recent preclinical and clinical studies on animal models and patients with HCM aimed at preventing or modifying hypertrophic myocardial remodeling. Mounting evidence shows that prevention of pathological hypertrophy is a feasible strategy in HCM and will enter the clinical practice in the near future. Considering the close mechanistic similarities between HCM and secondary hypertrophy, these studies are also relevant for the common forms of cardiac hypertrophy, such as hypertensive or valvular heart disease.

  11. Liver targeting of catalase by cationization for prevention of acute liver failure in mice.

    PubMed

    Ma, Shen-Feng; Nishikawa, Makiya; Katsumi, Hidemasa; Yamashita, Fumiyoshi; Hashida, Mitsuru

    2006-01-10

    To achieve hepatic delivery of CAT for the prevention of CCl4-induced acute liver failure in mice, two types of cationized CAT derivatives, HMD- and ED-conjugated CAT, were developed. Slight structural changes occurred during cationization and the number of increased free amino groups was 3.1 in HMD-CAT and 13.6 in ED-CAT. 111In-cationized CAT derivatives showed an increased binding to HepG2 cells, and were rapidly taken up by the liver. H2O2-induced cytotoxicity in HepG2 cells was significantly prevented by preincubation of the cells with cationized CAT derivatives. A bolus intravenous injection of the cationized CAT derivatives reduced the hepatotoxicity induced by CCl4 in mice. The ED-CAT, which showed more rapid and greater binding to the liver than the HMD-CAT, exhibited more beneficial effects as far as all the parameters examined (serum GOT, GPT, LDH and hepatic GSH) were concerned, suggesting that a high degree of cationization is effective in delivering CAT to the liver to prevent CCl4-induced hepatotoxicity. These results suggest that cationized CAT derivatives are effective in preventing acute liver failure, and ED-based cationization is a suitable method for developing liver-targetable cationized CAT derivatives, because it provides CAT with a high degree of cationization and a high remaining enzymatic activity. PMID:16316705

  12. Asparagine requirement in Plasmodium berghei as a target to prevent malaria transmission and liver infections.

    PubMed

    Nagaraj, Viswanathan A; Mukhi, Dhanunjay; Sathishkumar, Vinayagam; Subramani, Pradeep A; Ghosh, Susanta K; Pandey, Rajeev R; Shetty, Manjunatha C; Padmanaban, Govindarajan

    2015-01-01

    The proteins of Plasmodium, the malaria parasite, are strikingly rich in asparagine. Plasmodium depends primarily on host haemoglobin degradation for amino acids and has a rudimentary pathway for amino acid biosynthesis, but retains a gene encoding asparagine synthetase (AS). Here we show that deletion of AS in Plasmodium berghei (Pb) delays the asexual- and liver-stage development with substantial reduction in the formation of ookinetes, oocysts and sporozoites in mosquitoes. In the absence of asparagine synthesis, extracellular asparagine supports suboptimal survival of PbAS knockout (KO) parasites. Depletion of blood asparagine levels by treating PbASKO-infected mice with asparaginase completely prevents the development of liver stages, exflagellation of male gametocytes and the subsequent formation of sexual stages. In vivo supplementation of asparagine in mice restores the exflagellation of PbASKO parasites. Thus, the parasite life cycle has an absolute requirement for asparagine, which we propose could be targeted to prevent malaria transmission and liver infections. PMID:26531182

  13. Cancer Prevention with Promising Natural Products: Mechanisms of Action and Molecular Targets

    PubMed Central

    Pratheeshkumar, Poyil; Sreekala, Chakkenchath; Zhang, Zhuo; Budhraja, Amit; Ding, Songze; Son, Young-Ok; Wang, Xin; Hitron, Andrew; Hyun-Jung, Kim; Wang, Lei; Lee, Jeong-Chae; Shi, Xianglin

    2016-01-01

    Cancer is the second leading cause of death worldwide. There is greater need for more effective and less toxic therapeutic and preventive strategies. Natural products are becoming an important research area for novel and bioactive molecules for drug discovery. Phytochemicals and dietary compounds have been used for the treatment of cancer throughout history due to their safety, low toxicity, and general availability. Many active phytochemicals are in human clinical trials. Studies have indicated that daily consumption of dietary phytochemicals have cancer protective effects against carcinogens. They can inhibit, delay, or reverse carcinogenesis by inducing detoxifying and antioxidant enzymes systems, regulating inflammatory and proliferative signaling pathways, and inducing cell cycle arrest and apoptosis. Epidemiological studies have also revealed that high dietary intakes of fruits and vegetables reduce the risk of cancer. This review discusses potential natural cancer preventive compounds, their molecular targets, and their mechanisms of actions. PMID:22583402

  14. Asparagine requirement in Plasmodium berghei as a target to prevent malaria transmission and liver infections.

    PubMed

    Nagaraj, Viswanathan A; Mukhi, Dhanunjay; Sathishkumar, Vinayagam; Subramani, Pradeep A; Ghosh, Susanta K; Pandey, Rajeev R; Shetty, Manjunatha C; Padmanaban, Govindarajan

    2015-01-01

    The proteins of Plasmodium, the malaria parasite, are strikingly rich in asparagine. Plasmodium depends primarily on host haemoglobin degradation for amino acids and has a rudimentary pathway for amino acid biosynthesis, but retains a gene encoding asparagine synthetase (AS). Here we show that deletion of AS in Plasmodium berghei (Pb) delays the asexual- and liver-stage development with substantial reduction in the formation of ookinetes, oocysts and sporozoites in mosquitoes. In the absence of asparagine synthesis, extracellular asparagine supports suboptimal survival of PbAS knockout (KO) parasites. Depletion of blood asparagine levels by treating PbASKO-infected mice with asparaginase completely prevents the development of liver stages, exflagellation of male gametocytes and the subsequent formation of sexual stages. In vivo supplementation of asparagine in mice restores the exflagellation of PbASKO parasites. Thus, the parasite life cycle has an absolute requirement for asparagine, which we propose could be targeted to prevent malaria transmission and liver infections.

  15. Asparagine requirement in Plasmodium berghei as a target to prevent malaria transmission and liver infections

    PubMed Central

    Nagaraj, Viswanathan A.; Mukhi, Dhanunjay; Sathishkumar, Vinayagam; Subramani, Pradeep A.; Ghosh, Susanta K.; Pandey, Rajeev R.; Shetty, Manjunatha C.; Padmanaban, Govindarajan

    2015-01-01

    The proteins of Plasmodium, the malaria parasite, are strikingly rich in asparagine. Plasmodium depends primarily on host haemoglobin degradation for amino acids and has a rudimentary pathway for amino acid biosynthesis, but retains a gene encoding asparagine synthetase (AS). Here we show that deletion of AS in Plasmodium berghei (Pb) delays the asexual- and liver-stage development with substantial reduction in the formation of ookinetes, oocysts and sporozoites in mosquitoes. In the absence of asparagine synthesis, extracellular asparagine supports suboptimal survival of PbAS knockout (KO) parasites. Depletion of blood asparagine levels by treating PbASKO-infected mice with asparaginase completely prevents the development of liver stages, exflagellation of male gametocytes and the subsequent formation of sexual stages. In vivo supplementation of asparagine in mice restores the exflagellation of PbASKO parasites. Thus, the parasite life cycle has an absolute requirement for asparagine, which we propose could be targeted to prevent malaria transmission and liver infections. PMID:26531182

  16. Identifying Well-Connected Opinion Leaders for Informal Health Promotion: The Example of the ASSIST Smoking Prevention Program

    PubMed Central

    Holliday, Jo; Audrey, Suzanne; Campbell, Rona; Moore, Laurence

    2016-01-01

    ABSTRACT Methods used to select opinion leaders for informal behavior change interventions vary, affecting the role they adopt and the outcomes of interventions. The development of successful identification methods requires evidence that these methods achieve their aims. This study explored whether the “whole community” nomination process used in the ASSIST smoking prevention program successfully identified “peer supporters” who were well placed within their school social networks to diffuse an antismoking message to their peers. Data were collected in the United Kingdom during A Stop Smoking in Schools Trial. Behavioral data were provided at baseline and post intervention by all students. Social network data were provided post intervention by students in four control and six intervention schools. Centrality measures calculated using UCINET demonstrate that the ASSIST nomination process successfully identified peer supporters who were more socially connected than others in their year and who had social connections across the entire year group including the program’s target group. The results indicate that three simple questions can identify individuals who are held in high esteem by their year group and who also have the interpersonal networks required of opinion leaders to successfully disseminate smoke-free messages through their social networks. This approach could be used in other informal health promotion initiatives. PMID:26699125

  17. Mitochondria-Targeted Antioxidant Prevents Cardiac Dysfunction Induced by Tafazzin Gene Knockdown in Cardiac Myocytes

    PubMed Central

    He, Quan; Harris, Nicole; Ren, Jun; Han, Xianlin

    2014-01-01

    Tafazzin, a mitochondrial acyltransferase, plays an important role in cardiolipin side chain remodeling. Previous studies have shown that dysfunction of tafazzin reduces cardiolipin content, impairs mitochondrial function, and causes dilated cardiomyopathy in Barth syndrome. Reactive oxygen species (ROS) have been implicated in the development of cardiomyopathy and are also the obligated byproducts of mitochondria. We hypothesized that tafazzin knockdown increases ROS production from mitochondria, and a mitochondria-targeted antioxidant prevents tafazzin knockdown induced mitochondrial and cardiac dysfunction. We employed cardiac myocytes transduced with an adenovirus containing tafazzin shRNA as a model to investigate the effects of the mitochondrial antioxidant, mito-Tempo. Knocking down tafazzin decreased steady state levels of cardiolipin and increased mitochondrial ROS. Treatment of cardiac myocytes with mito-Tempo normalized tafazzin knockdown enhanced mitochondrial ROS production and cellular ATP decline. Mito-Tempo also significantly abrogated tafazzin knockdown induced cardiac hypertrophy, contractile dysfunction, and cell death. We conclude that mitochondria-targeted antioxidant prevents cardiac dysfunction induced by tafazzin gene knockdown in cardiac myocytes and suggest mito-Tempo as a potential therapeutic for Barth syndrome and other dilated cardiomyopathies resulting from mitochondrial oxidative stress. PMID:25247053

  18. Probiotic metabolites as epigenetic targets in the prevention of colon cancer.

    PubMed

    Kumar, Manoj; Nagpal, Ravinder; Verma, Vinod; Kumar, Ashok; Kaur, Navrinder; Hemalatha, Rajkumar; Gautam, Sanjeev K; Singh, Birbal

    2013-01-01

    Dietary interventions for preventing colon cancer have recently attracted increased attention from researchers and clinicians. The probiotics have emerged as potential therapeutic agents but are also regarded as healthy dietary supplements for nutrition and health applications. The probiotic metabolome may interfere with various cellular and molecular processes, including the onset and progression of colon cancer. Probiotic metabolites may lead to the modulation of diverse cellular signal transduction and metabolic pathways. The gut microbial metabolites (organic acids, bacteriocins, peptides, etc.) have been noted to interact with multiple key targets in various metabolic pathways that regulate cellular proliferation, differentiation, apoptosis, inflammation, angiogenesis, and metastasis. Progress in this field suggests that epigenetic alterations will be widely used in the near future to manage colon cancer. The present review provides insights into the molecular basis of the therapeutic applications and the chemopreventive activities of certain probiotic metabolites, with emphasis on the interaction between these metabolites and the molecular signaling cascades that are considered to be epigenetic targets in preventing colon cancer. PMID:23282249

  19. A systematic review of universal campaigns targeting child physical abuse prevention.

    PubMed

    Poole, Mary Kathryn; Seal, David W; Taylor, Catherine A

    2014-06-01

    The purpose of this review was to better understand the impact of universal campaign interventions with a media component aimed at preventing child physical abuse (CPA). The review included 17 studies featuring 15 campaigns conducted from 1989 to 2011 in five countries. Seven studies used experimental designs, but most were quasi-experimental. CPA incidence was assessed in only three studies and decreased significantly in two. Studies also found significant reductions in relevant outcomes such as dysfunctional parenting, child problem behaviors and parental anger as well as increases in parental self-efficacy and knowledge of concepts and actions relevant to preventing child abuse. The following risk factors were most frequently targeted in campaigns: lack of knowledge regarding positive parenting techniques, parental impulsivity, the stigma of asking for help, inadequate social support and inappropriate expectations for a child's developmental stage. The evidence base for universal campaigns designed to prevent CPA remains inconclusive due to the limited availability of rigorous evaluations; however, Triple-P is a notable exception. Given the potential for such interventions to shift population norms relevant to CPA and reduce rates of CPA, there is a need to further develop and rigorously evaluate such campaigns. PMID:24711483

  20. A systematic review of universal campaigns targeting child physical abuse prevention

    PubMed Central

    Poole, Mary Kathryn; Seal, David W.; Taylor, Catherine A.

    2014-01-01

    The purpose of this review was to better understand the impact of universal campaign interventions with a media component aimed at preventing child physical abuse (CPA). The review included 17 studies featuring 15 campaigns conducted from 1989 to 2011 in five countries. Seven studies used experimental designs, but most were quasi-experimental. CPA incidence was assessed in only three studies and decreased significantly in two. Studies also found significant reductions in relevant outcomes such as dysfunctional parenting, child problem behaviors and parental anger as well as increases in parental self-efficacy and knowledge of concepts and actions relevant to preventing child abuse. The following risk factors were most frequently targeted in campaigns: lack of knowledge regarding positive parenting techniques, parental impulsivity, the stigma of asking for help, inadequate social support and inappropriate expectations for a child’s developmental stage. The evidence base for universal campaigns designed to prevent CPA remains inconclusive due to the limited availability of rigorous evaluations; however, Triple-P is a notable exception. Given the potential for such interventions to shift population norms relevant to CPA and reduce rates of CPA, there is a need to further develop and rigorously evaluate such campaigns. PMID:24711483

  1. Preventive effect of dietary quercetin on disuse muscle atrophy by targeting mitochondria in denervated mice.

    PubMed

    Mukai, Rie; Matsui, Naoko; Fujikura, Yutaka; Matsumoto, Norifumi; Hou, De-Xing; Kanzaki, Noriyuki; Shibata, Hiroshi; Horikawa, Manabu; Iwasa, Keiko; Hirasaka, Katsuya; Nikawa, Takeshi; Terao, Junji

    2016-05-01

    Quercetin is a major dietary flavonoid in fruits and vegetables. We aimed to clarify the preventive effect of dietary quercetin on disuse muscle atrophy and the underlying mechanisms. We established a mouse denervation model by cutting the sciatic nerve in the right leg (SNX surgery) to lack of mobilization in hind-limb. Preintake of a quercetin-mixed diet for 14days before SNX surgery prevented loss of muscle mass and atrophy of muscle fibers in the gastrocnemius muscle (GM). Phosphorylation of Akt, a key phosphorylation pathway of suppression of protein degradation, was activated in the quercetin-mixed diet group with and without SNX surgery. Intake of a quercetin-mixed diet suppressed the generation of hydrogen peroxide originating from mitochondria and elevated mitochondrial peroxisome proliferator-activated receptor-γ coactivator 1α mRNA expression as well as NADH dehydrogenase 4 expression in the GM with SNX surgery. Quercetin and its conjugated metabolites reduced hydrogen peroxide production in the mitochondrial fraction obtained from atrophied muscle. In C2C12 myotubes, quercetin reached the mitochondrial fraction. These findings suggest that dietary quercetin can prevent disuse muscle atrophy by targeting mitochondria in skeletal muscle tissue through protecting mitochondria from decreased biogenesis and reducing mitochondrial hydrogen peroxide release, which can be related to decreased hydrogen peroxide production and/or improvements on antioxidant capacity of mitochondria. PMID:27133425

  2. A profile of six community-based HIV prevention programs targeting Asian and Pacific Islander Americans.

    PubMed

    Wong, F Y; Chng, C L; Lo, W

    1998-06-01

    Based on a framework (i.e., research and evaluation, prevention and services, and advocacy and policy), the goal of this article is to profile six community-based HIV prevention programs targeting Asian and Pacific Islander (API) Americans, especially among men who have sex with men. These six programs were chosen based on one or more of the following three criteria: (a) epidemiological profiles of AIDS cases among Asian and Pacific Islander Americans, (b) ethnic diversity, and (b) community development among Asian and Pacific Islander Americans in the fight against HIV. The six programs are (a) the Kokua Kalih Valley Health Center, Honolulu; (b) the Asian and Pacific Islander Wellness Center, San Francisco; (c) the Asian Pacific AIDS Intervention Team, Los Angeles; (d) the Asian and Pacific Islander Coalition on HIV and AIDS, New York City; (e) the AIDS Services in Asian Communities, Philadelphia; and (f) the Massachusetts Asian AIDS Prevention Project, Boston. The present analysis reveals that five programs have their roots in the gay or bisexual communities. Two programs have existed for about 3 years (the epidemic is going into its 17th year). Major financial support for the six programs are federal, state, or county sources; private support is generally minimal. All six programs offer a wide range of culturally competent and linguistically appropriate prevention activities and services (including two national projects) targeting a diverse API population. However, gaps in services exist in the younger programs. In addition to a paucity of epidemiological, surveillance, and empirical data, most reported that barriers fall into one or two interrelated categories: (a) structural (e.g., lack of governmental or private funding) or (b) cultural (e.g., denial of risk, homophobia, fear of confidentiality). These findings suggest that HIV prevention activities and services for Asian and Pacific Islander Americans should be based on empirical and cultural data, and that

  3. Efficacy Trial of a Selective Prevention Program Targeting Both Eating Disorder Symptoms and Unhealthy Weight Gain among Female College Students

    ERIC Educational Resources Information Center

    Stice, Eric; Rohde, Paul; Shaw, Heather; Marti, C. Nathan

    2012-01-01

    Objective: Evaluate a selective prevention program targeting both eating disorder symptoms and unhealthy weight gain in young women. Method: Female college students at high-risk for these outcomes by virtue of body image concerns (N = 398; M age = 18.4 years, SD = 0.6) were randomized to the Healthy Weight group-based 4-hr prevention program,…

  4. Transcriptome analysis of GVHD reveals aurora kinase A as a targetable pathway for disease prevention.

    PubMed

    Furlan, Scott N; Watkins, Benjamin; Tkachev, Victor; Flynn, Ryan; Cooley, Sarah; Ramakrishnan, Swetha; Singh, Karnail; Giver, Cindy; Hamby, Kelly; Stempora, Linda; Garrett, Aneesah; Chen, Jingyang; Betz, Kayla M; Ziegler, Carly G K; Tharp, Gregory K; Bosinger, Steven E; Promislow, Daniel E L; Miller, Jeffrey S; Waller, Edmund K; Blazar, Bruce R; Kean, Leslie S

    2015-11-25

    Graft-versus-host disease (GVHD) is the most common complication of hematopoietic stem cell transplant (HCT). However, our understanding of the molecular pathways that cause this disease remains incomplete, leading to inadequate treatment strategies. To address this, we measured the gene expression profile of nonhuman primate (NHP) T cells during acute GVHD. Utilizing microarray technology, we measured the expression profiles of CD3(+) T cells from five cohorts: allogeneic transplant recipients receiving (i) no immunoprophylaxis (No Rx), (ii) sirolimus monotherapy (Siro), (iii) tacrolimus-methotrexate (Tac-Mtx), as well as (iv) autologous transplant recipients (Auto) and (v) healthy controls (HC). This comparison allowed us to identify transcriptomic signatures specific for alloreactive T cells and determine the impact of both mTOR (mechanistic target of rapamycin) and calcineurin inhibition on GVHD. We found that the transcriptional profile of unprophylaxed GVHD was characterized by significant perturbation of pathways regulating T cell proliferation, effector function, and cytokine synthesis. Within these pathways, we discovered potentially druggable targets not previously implicated in GVHD, prominently including aurora kinase A (AURKA). Utilizing a murine GVHD model, we demonstrated that pharmacologic inhibition of AURKA could improve survival. Moreover, we found enrichment of AURKA transcripts both in allo-proliferating T cells and in sorted T cells from patients with clinical GVHD. These data provide a comprehensive elucidation of the T cell transcriptome in primate acute GVHD and suggest that AURKA should be considered a target for preventing GVHD, which, given the many available AURKA inhibitors in clinical development, could be quickly deployed for the prevention of GVHD. PMID:26606970

  5. Targeting 5α-reductase for prostate cancer prevention and treatment

    PubMed Central

    Nacusi, Lucas P.; Tindall, Donald J.

    2014-01-01

    Testosterone is the most abundant circulating androgen, and can be converted to dihydrotestosterone (DHT), a more potent androgen, by the 5α-reductase enzymes in target tissues. Current treatments for prostate cancer consist of reducing androgen levels by chemical or surgical castration or pure antiandrogen therapy that directly targets the androgen receptor (AR). Although these therapies reduce tumor burden and AR activity, the cancer inevitably recurs within 18–30 months. An approach targeting the androgen–AR axis at different levels could, therefore, improve the efficacy of prostate cancer therapy. Inhibition of 5α-reductase is one such approach; however, the two largest trials to investigate the use of the 5α-reductase inhibitors (5ARIs) finasteride and dutasteride in patients with prostate cancer have shown that, although the incidence of cancer was reduced by 5ARI treatment, those cancers that were detected were more aggressive than in patients treated with placebo. Thus, the best practice for using these drugs to prevent and treat prostate cancer remains unclear. PMID:21629218

  6. Targeting 5α-reductase for prostate cancer prevention and treatment.

    PubMed

    Nacusi, Lucas P; Tindall, Donald J

    2011-07-01

    Testosterone is the most abundant circulating androgen, and can be converted to dihydrotestosterone (DHT), a more potent androgen, by the 5α-reductase enzymes in target tissues. Current treatments for prostate cancer consist of reducing androgen levels by chemical or surgical castration or pure antiandrogen therapy that directly targets the androgen receptor (AR). Although these therapies reduce tumor burden and AR activity, the cancer inevitably recurs within 18-30 months. An approach targeting the androgen-AR axis at different levels could, therefore, improve the efficacy of prostate cancer therapy. Inhibition of 5α-reductase is one such approach; however, the two largest trials to investigate the use of the 5α-reductase inhibitors (5ARIs) finasteride and dutasteride in patients with prostate cancer have shown that, although the incidence of cancer was reduced by 5ARI treatment, those cancers that were detected were more aggressive than in patients treated with placebo. Thus, the best practice for using these drugs to prevent and treat prostate cancer remains unclear. PMID:21629218

  7. Transcription Factor STAT3 as a Novel Molecular Target for Cancer Prevention

    PubMed Central

    Xiong, Ailian; Yang, Zhengduo; Shen, Yicheng; Zhou, Jia; Shen, Qiang

    2014-01-01

    Signal Transducers and Activators of Transcription (STATs) are a family of transcription factors that regulate cell proliferation, differentiation, apoptosis, immune and inflammatory responses, and angiogenesis. Cumulative evidence has established that STAT3 has a critical role in the development of multiple cancer types. Because it is constitutively activated during disease progression and metastasis in a variety of cancers, STAT3 has promise as a drug target for cancer therapeutics. Recently, STAT3 was found to have an important role in maintaining cancer stem cells in vitro and in mouse tumor models, suggesting STAT3 is integrally involved in tumor initiation, progression and maintenance. STAT3 has been traditionally considered as nontargetable or undruggable, and the lag in developing effective STAT3 inhibitors contributes to the current lack of FDA-approved STAT3 inhibitors. Recent advances in cancer biology and drug discovery efforts have shed light on targeting STAT3 globally and/or specifically for cancer therapy. In this review, we summarize current literature and discuss the potential importance of STAT3 as a novel target for cancer prevention and of STAT3 inhibitors as effective chemopreventive agents. PMID:24743778

  8. REDD1 Is a Major Target of Testosterone Action in Preventing Dexamethasone-Induced Muscle Loss

    PubMed Central

    Wu, Yong; Zhao, Weidong; Zhao, Jingbo; Zhang, Yuanfei; Qin, Weiping; Pan, Jiangping; Bauman, William A.; Blitzer, Robert D.; Cardozo, Christopher

    2010-01-01

    Glucocorticoids are a well-recognized and common cause of muscle atrophy that can be prevented by testosterone. However, the molecular mechanisms underlying such protection have not been described. Thus, the global effects of testosterone on dexamethasone-induced changes in gene expression were evaluated in rat gastrocnemius muscle using DNA microarrays. Gene expression was analyzed after 7-d administration of dexamethasone, dexamethasone plus testosterone, or vehicle. Dexamethasone changed expression of 876 probe sets by at least 2-fold. Among these, 474 probe sets were changed by at least 2-fold in the opposite direction in the dexamethasone plus testosterone group (genes in opposition). Major biological themes represented by genes in opposition included IGF-I signaling, myogenesis and muscle development, and cell cycle progression. Testosterone completely prevented the 22-fold increase in expression of the mammalian target of rapamycin (mTOR) inhibitor regulated in development and DNA damage responses 1 (REDD1), and attenuated dexamethasone induced increased expression of eIF4E binding protein 1, Forkhead box O1, and the p85 regulatory subunit of the IGF-I receptor but prevented decreased expression of IRS-1. Testosterone attenuated increases in REDD1 protein in skeletal muscle and L6 myoblasts and prevented dephosphorylation of p70S6 kinase at the mTOR-dependent site Thr389 in L6 myoblast cells. Effects of testosterone on REDD1 mRNA levels occurred within 1 h, required the androgen receptor, were blocked by bicalutamide, and were due to inhibition of transcriptional activation of REDD1 by dexamethasone. These data suggest that testosterone blocks dexamethasone-induced changes in expression of REDD1 and other genes that collectively would otherwise down-regulate mTOR activity and hence also down-regulate protein synthesis. PMID:20032058

  9. Using Process Data to Understand Outcomes in Sexual Health Promotion: An Example from a Review of School-Based Programmes to Prevent Sexually Transmitted Infections

    ERIC Educational Resources Information Center

    Shepherd, J.; Harden, A.; Barnett-Page, E.; Kavanagh, J.; Picot, J.; Frampton, G. K.; Cooper, K.; Hartwell, D.; Clegg, A.

    2014-01-01

    This article discusses how process indicators can complement outcomes as part of a comprehensive explanatory evaluation framework, using the example of skills-based behavioural interventions to prevent sexually transmitted infections and promote sexual health among young people in schools. A systematic review was conducted, yielding 12 eligible…

  10. The opportunities for and obstacles against prevention: the example of Germany in the areas of tobacco and alcohol

    PubMed Central

    2010-01-01

    Background Recent years have seen a growing research and policy interest in prevention in many developed countries. However, the actual efforts and resources devoted to prevention appear to have lagged well behind the lip service paid to the topic. Discussion We review the evidence on the considerable existing scope for health gains from prevention as well as for greater prevention policy efforts in Germany. We also discuss the barriers to "more and better" prevention and provide modest suggestions about how some of the obstacles could be overcome. Summary In Germany, there are substantial health gains to be reaped from the implementation of evidence-based, cost-effective preventive interventions and policies. Barriers to more prevention include social, historical, political, legal and economic factors. While there is sufficient evidence to scale up prevention efforts in some public health domains in Germany, in general there is a comparative shortage of research on non-clinical preventive interventions. Some of the existing barriers in Germany are at least in principle amenable to change, provided sufficient political will exists. More research on prevention by itself is no panacea, but could help facilitate more policy action. In particular, there is an economic efficiency-based case for public funding and promotion of research on non-clinical preventive interventions, in Germany and beyond, to confront the peculiar challenges that set this research apart from its clinical counterpart. PMID:20718995

  11. Chesapeake Bay regions of concern: Geographical targeting protocol for remediation, reduction, prevention and assessment actions

    SciTech Connect

    Batiuk, R.A.

    1994-12-31

    As a result of a two year reevaluation of a Basinwide Toxics Reduction Strategy, the Chesapeake Bay Program identified the need to more effectively direct reduction and prevention actions toward regional areas with known toxic problems as well as areas where significant potential exists for toxic impacts on living resources and habitats. Building upon the geographical targeting efforts in the Great Lakes and Puget Sound, a protocol was established for identifying and categorizing areas ranging from known toxic problems to areas with low probability for adverse effects to insufficient data. The identification protocol is based on a series of criteria which include evaluation of sediment contamination concentrations and ambient sediment toxicity. The process for development and application of the Regions of Concern protocol along with a focus on the sediment assessment criteria and how they influenced the over-all categorization of regions will be presented.

  12. Secondary Effects of an Alcohol Prevention Program Targeting Students and/or Parents.

    PubMed

    Koning, Ina M; Vollebergh, Wilma A M

    2016-08-01

    The secondary effects of an alcohol prevention program (PAS) on onset of weekly smoking and monthly cannabis use are examined among >3000 Dutch early adolescents (M age=12.64) randomized over four conditions: 1) parent intervention (PI), 2) student intervention (SI), 3) combined intervention (CI) and 4) control condition (CC). Rules about alcohol, alcohol use, and adolescents' self-control were investigated as possible mediators. PI had a marginal aversive effect, slightly increasing the risk of beginning to smoke at T1, and increased the likelihood of beginning to use cannabis use at T1 and T2. SI delayed the onset of monthly cannabis use at T3. CI increased the risk to use cannabis at T3. No mediational processes were found. In conclusion, though this study show mixed results, negative side effects of the PI were found, particularly at earlier ages. Moreover, these results indicate the need for multi-target interventions. PMID:27296663

  13. RANK ligand as a potential target for breast cancer prevention in BRCA1-mutation carriers.

    PubMed

    Nolan, Emma; Vaillant, François; Branstetter, Daniel; Pal, Bhupinder; Giner, Göknur; Whitehead, Lachlan; Lok, Sheau W; Mann, Gregory B; Rohrbach, Kathy; Huang, Li-Ya; Soriano, Rosalia; Smyth, Gordon K; Dougall, William C; Visvader, Jane E; Lindeman, Geoffrey J

    2016-08-01

    Individuals who have mutations in the breast-cancer-susceptibility gene BRCA1 (hereafter referred to as BRCA1-mutation carriers) frequently undergo prophylactic mastectomy to minimize their risk of breast cancer. The identification of an effective prevention therapy therefore remains a 'holy grail' for the field. Precancerous BRCA1(mut/+) tissue harbors an aberrant population of luminal progenitor cells, and deregulated progesterone signaling has been implicated in BRCA1-associated oncogenesis. Coupled with the findings that tumor necrosis factor superfamily member 11 (TNFSF11; also known as RANKL) is a key paracrine effector of progesterone signaling and that RANKL and its receptor TNFRSF11A (also known as RANK) contribute to mammary tumorigenesis, we investigated a role for this pathway in the pre-neoplastic phase of BRCA1-mutation carriers. We identified two subsets of luminal progenitors (RANK(+) and RANK(-)) in histologically normal tissue of BRCA1-mutation carriers and showed that RANK(+) cells are highly proliferative, have grossly aberrant DNA repair and bear a molecular signature similar to that of basal-like breast cancer. These data suggest that RANK(+) and not RANK(-) progenitors are a key target population in these women. Inhibition of RANKL signaling by treatment with denosumab in three-dimensional breast organoids derived from pre-neoplastic BRCA1(mut/+) tissue attenuated progesterone-induced proliferation. Notably, proliferation was markedly reduced in breast biopsies from BRCA1-mutation carriers who were treated with denosumab. Furthermore, inhibition of RANKL in a Brca1-deficient mouse model substantially curtailed mammary tumorigenesis. Taken together, these findings identify a targetable pathway in a putative cell-of-origin population in BRCA1-mutation carriers and implicate RANKL blockade as a promising strategy in the prevention of breast cancer. PMID:27322743

  14. Bone targeted therapies for the prevention of skeletal morbidity in men with prostate cancer

    PubMed Central

    Saylor, Philip J

    2014-01-01

    Men with prostate cancer suffer substantially from bone-related complications. Androgen deprivation therapy itself is a cause of loss of bone mineral density and is associated with an increased incidence of osteoporotic fractures. In advanced disease, bone is by far the most common site of metastasis. Complications of bone metastases prominently include pain and the potential for skeletal events such as spinal cord compression and pathologic fractures. Elevated osteoclast activity is an important aspect of the pathophysiology of both treatment-related osteoporosis and skeletal complications due to metastases. The osteoclast is therefore a therapeutic target. Denosumab is a fully human monoclonal antibody to receptor activator of nuclear factor-κ-B ligand that was designed to potently inhibit osteoclast activity and is the central focus of this review. Bisphosphonates, radiopharmaceuticals and systemically-active hormonal agents such as abiraterone acetate and enzalutamide have each been shown to improve skeletal morbidity in specific clinical situations. Denosumab is the only agent that has been shown to prevent osteoporotic fractures in men receiving androgen deprivation therapy and at elevated risk for fracture. It has also demonstrated superiority to the potent bisphosphonate zoledronic acid for the prevention of skeletal-related events in men with castration-resistant prostate cancer metastatic to bone. Efficacy and toxicity data will be discussed. PMID:24435057

  15. The intra-S phase checkpoint targets Dna2 to prevent stalled replication forks from reversing.

    PubMed

    Hu, Jiazhi; Sun, Lei; Shen, Fenfen; Chen, Yufei; Hua, Yu; Liu, Yang; Zhang, Mian; Hu, Yiren; Wang, Qingsong; Xu, Wei; Sun, Fei; Ji, Jianguo; Murray, Johanne M; Carr, Antony M; Kong, Daochun

    2012-06-01

    When replication forks stall at damaged bases or upon nucleotide depletion, the intra-S phase checkpoint ensures they are stabilized and can restart. In intra-S checkpoint-deficient budding yeast, stalling forks collapse, and ∼10% form pathogenic chicken foot structures, contributing to incomplete replication and cell death (Lopes et al., 2001; Sogo et al., 2002; Tercero and Diffley, 2001). Using fission yeast, we report that the Cds1(Chk2) effector kinase targets Dna2 on S220 to regulate, both in vivo and in vitro, Dna2 association with stalled replication forks in chromatin. We demonstrate that Dna2-S220 phosphorylation and the nuclease activity of Dna2 are required to prevent fork reversal. Consistent with this, Dna2 can efficiently cleave obligate precursors of fork regression-regressed leading or lagging strands-on model replication forks. We propose that Dna2 cleavage of regressed nascent strands prevents fork reversal and thus stabilizes stalled forks to maintain genome stability during replication stress.

  16. Sphingosine kinase: a novel putative target for the prevention of infection-triggered preterm birth.

    PubMed

    Vyas, Vibhuti; Ashby, Charles R; Reznik, Sandra E

    2013-01-01

    Preterm birth is defined as any delivery before 37 complete weeks of gestation. It is a universal challenge in the field of obstetrics owing to its high rate of mortality, long-term morbidity, associated human suffering and economic burden. In the United States, about 12.18% deliveries in 2009 were preterm, producing an exorbitant cost of $5.8 billion. Infection-associated premature rupture of membranes (PROM) accounts for 40% of extremely preterm births (<28 weeks of gestation). Major research efforts are directed towards improving the understanding of the pathophysiology of preterm birth and ways to prevent or at least postpone delivery. Endothelin-1 (ET-1) is a potent vasoconstrictor that plays a significant role in infection-triggered preterm birth. Its involvement in a number of pathological mechanisms and its elevation in preterm delivered amniotic fluid samples implicate it in preterm birth. Sphingosine kinase (SphK) is a ubiquitous enzyme responsible for the production of sphingosine-1-phosphate (S1P). S1P acts as second messenger in a number of cell proliferation and survival pathways. SphK is found to play a key role in ET-1 mediated myometrial contraction. This review highlights SphK as a prospective target with great potential to prevent preterm birth. PMID:23818902

  17. Targeting substrate-site in Jak2 kinase prevents emergence of genetic resistance

    PubMed Central

    Kesarwani, Meenu; Huber, Erika; Kincaid, Zachary; Evelyn, Chris R.; Biesiada, Jacek; Rance, Mark; Thapa, Mahendra B.; Shah, Neil P.; Meller, Jarek; Zheng, Yi; Azam, Mohammad

    2015-01-01

    Emergence of genetic resistance against kinase inhibitors poses a great challenge for durable therapeutic response. Here, we report a novel mechanism of JAK2 kinase inhibition by fedratinib (TG101348) that prevents emergence of genetic resistance. Using in vitro drug screening, we identified 211 amino-acid substitutions conferring resistance to ruxolitinib (INCB018424) and cross-resistance to the JAK2 inhibitors AZD1480, CYT-387 and lestaurtinib. In contrast, these resistant variants were fully sensitive to fedratinib. Structural modeling, coupled with mutagenesis and biochemical studies, revealed dual binding sites for fedratinib. In vitro binding assays using purified proteins showed strong affinity for the substrate-binding site (Kd = 20 nM) while affinity for the ATP site was poor (Kd = ~8 μM). Our studies demonstrate that mutations affecting the substrate-binding pocket encode a catalytically incompetent kinase, thereby preventing emergence of resistant variants. Most importantly, our data suggest that in order to develop resistance-free kinase inhibitors, the next-generation drug design should target the substrate-binding site. PMID:26419724

  18. Nuclear Receptors and Epigenetic Regulation: Opportunities for Nutritional Targeting and Disease Prevention12

    PubMed Central

    Romagnolo, Donato F.; Zempleni, Janos; Selmin, Ornella I.

    2014-01-01

    Posttranslational modifications of histones, alterations in the recruitment and functions of non-histone proteins, DNA methylation, and changes in expression of noncoding RNAs contribute to current models of epigenetic regulation. Nuclear receptors (NRs) are a group of transcription factors that, through ligand-binding, act as sensors to changes in nutritional, environmental, developmental, pathophysiologic, and endocrine conditions and drive adaptive responses via gene regulation. One mechanism through which NRs direct gene expression is the assembly of transcription complexes with cofactors and coregulators that possess chromatin-modifying properties. Chromatin modifications can be transient or become part of the cellular “memory” and contribute to genomic imprinting. Because many food components bind to NRs, they can ultimately influence transcription of genes associated with biologic processes, such as inflammation, proliferation, apoptosis, and hormonal response, and alter the susceptibility to chronic diseases (e.g., cancer, diabetes, obesity). The objective of this review is to highlight how NRs influence epigenetic regulation and the relevance of dietary compound–NR interactions in human nutrition and for disease prevention and treatment. Identifying gene targets of unliganded and bound NRs may assist in the development of epigenetic maps for food components and dietary patterns. Progress in these areas may lead to the formulation of disease-prevention models based on epigenetic control by individual or associations of food ligands of NRs. PMID:25022987

  19. Prevention of skin tumorigenesis and impairment of epidermal cell proliferation by targeted aquaporin-3 gene disruption.

    PubMed

    Hara-Chikuma, Mariko; Verkman, A S

    2008-01-01

    Aquaporin-3 (AQP3) is a water/glycerol-transporting protein expressed strongly at the plasma membranes of basal epidermal cells in skin. We found that human skin squamous cell carcinoma strongly overexpresses AQP3. A novel role for AQP3 in skin tumorigenesis was discovered using mice with targeted AQP3 gene disruption. We found that AQP3-null mice were remarkably resistant to the development of skin tumors following exposure to a tumor initiator and phorbol ester promoter. Though tumor initiator challenge produced comparable apoptotic responses in wild-type and AQP3-null mice, promoter-induced cell proliferation was greatly impaired in the AQP3-null epidermis. Reductions of epidermal cell glycerol, its metabolite glycerol-3-phosphate, and ATP were found in AQP3 deficiency without impairment of mitochondrial function. Glycerol supplementation corrected the reduced proliferation and ATP content in AQP3 deficiency, with cellular glycerol, ATP, and proliferative ability being closely correlated. Our data suggest involvement of AQP3-facilitated glycerol transport in epidermal cell proliferation and tumorigenesis by a novel mechanism implicating cellular glycerol as a key determinant of cellular ATP energy. AQP3 may thus be an important determinant in skin tumorigenesis and hence a novel target for tumor prevention and therapy. PMID:17967887

  20. Targeting estrogen receptor β as preventive therapeutic strategy for Leber's hereditary optic neuropathy.

    PubMed

    Pisano, Annalinda; Preziuso, Carmela; Iommarini, Luisa; Perli, Elena; Grazioli, Paola; Campese, Antonio F; Maresca, Alessandra; Montopoli, Monica; Masuelli, Laura; Sadun, Alfredo A; d'Amati, Giulia; Carelli, Valerio; Ghelli, Anna; Giordano, Carla

    2015-12-15

    Leber's hereditary optic neuropathy (LHON) is a maternally inherited blinding disease characterized by degeneration of retinal ganglion cells (RGCs) and consequent optic nerve atrophy. Peculiar features of LHON are incomplete penetrance and gender bias, with a marked male prevalence. Based on the different hormonal metabolism between genders, we proposed that estrogens play a protective role in females and showed that these hormones ameliorate mitochondrial dysfunction in LHON through the estrogen receptors (ERs). We also showed that ERβ localize to the mitochondria of RGCs. Thus, targeting ERβ may become a therapeutic strategy for LHON specifically aimed at avoiding or delaying the onset of disease in mutation carriers. Here, we tested the effects of ERβ targeting on LHON mitochondrial defective metabolism by treating LHON cybrid cells carrying the m.11778G>A mutation with a combination of natural estrogen-like compounds that bind ERβ with high selectivity. We demonstrated that these molecules improve cell viability by reducing apoptosis, inducing mitochondrial biogenesis and strongly reducing the levels of reactive oxygen species in LHON cells. These effects were abolished in cells with ERβ knockdown by silencing receptor expression or by using specific receptor antagonists. Our observations support the hypothesis that estrogen-like molecules may be useful in LHON prophylactic therapy. This is particularly important for lifelong disease prevention in unaffected LHON mutation carriers. Current strategies attempting to combat degeneration of RGCs during the acute phase of LHON have not been very effective. Implementing a different and preemptive approach with a low risk profile may be very helpful.

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

    PubMed Central

    2013-01-01

    Background 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. Methods 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. Results 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. Conclusions 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

  2. Prevention

    MedlinePlus

    ... our e-newsletter! Aging & Health A to Z Prevention Basic Facts & Information Some factors that affect your ... control of the things that you can change. Preventive Recommendations for Adults Aged 65 and Older The ...

  3. PREVENTION OF COLITIS-ASSOCIATED CANCER: NATURAL COMPOUNDS THAT TARGET THE IL-6 SOLUBLE RECEPTOR

    PubMed Central

    Moriasi, Cate; Subramaniam, Dharmalingam; Awasthi, Shanjana; Anant, Shrikant; Ramalingam, Satish

    2014-01-01

    The risk of developing colorectal cancer increases in patients with inflammatory bowel disease (IBD) and a growing body of evidence shows the critical role of interleukin (IL-6) in this process. IL-6 is both a pro- and anti-inflammatory cytokine whose effects are mediated through activation of STAT3. Recent studies have also demonstrated that IL-6 trans-signaling through its soluble receptor occurs in IBD and cancer. IL-6 trans-signaling therefore is emerging as an attractive approach to diminish the inflammatory signals in conditions of chronic inflammation. The purpose of cancer chemoprevention is to either delay the onset or progression from precancerous lesions. Natural compounds because of their low toxicity render themselves excellent candidates that can be administered over the lifetime of an individual. With the focus of managing IBD over a long time and preventing onset of colitis-associated cancer, we believe that there should be increased research focus on identifying chemopreventive compounds that can render themselves to long term use possibly for the lifetime of predisposed individuals. Here, we review the role of IL-6 signaling in IBD and colitis-associated cancer and underscore the importance of searching for natural compounds that would target the IL-6 trans-signaling pathway as a way to diminish chronic inflammatory conditions in the gastrointestinal tract and possibly hamper the progression to colon cancer. We propose that effective screening and identification of natural chemopreventive compounds that target IL-6 trans-signaling has important implications for the development of optimal strategies against cancer development triggered by inflammation. PMID:22583410

  4. Integrated Strategies for Combination HIV Prevention: Principles and examples for men who have sex with men in the Americas and heterosexual African populations

    PubMed Central

    Celum, Connie; Baeten, Jared M.; Hughes, James P.; Barnabas, Ruanne; Liu, Albert; Van Rooyen, Heidi; Buchbinder, Susan

    2013-01-01

    Combination HIV prevention is a high priority for increasing the impact of partially efficacious HIV prevention interventions for specific populations and settings. Developing the package requires critical review of local epidemiology of HIV infection regarding populations most impacted and most at risk, drivers of HIV infection, and available interventions to address these risk factors. Interventions should be considered in terms of the evidence basis for efficacy, potential synergies, feasibility of delivery at scale, which is important in order to achieve high coverage and impact, coupled with high acceptability to populations, which will impact uptake, adherence, and retention. Evaluation requires process measures of uptake, adherence, retention, and outcome measures of reduction in HIV infectiousness and acquisition. Three examples of combination prevention concepts are summarized for men who have sex with men (MSM) in the Americas, young women in sub-Saharan Africa, and HIV-1 serodiscordant couples. PMID:23764638

  5. Integrated strategies for combination HIV prevention: principles and examples for men who have sex with men in the Americas and heterosexual African populations.

    PubMed

    Celum, Connie; Baeten, Jared M; Hughes, James P; Barnabas, Ruanne; Liu, Albert; Van Rooyen, Heidi; Buchbinder, Susan

    2013-07-01

    Combination HIV prevention is of high priority for increasing the impact of partially efficacious HIV prevention interventions for specific populations and settings. Developing the package requires critical review of local epidemiology of HIV infection regarding most-impacted populations and those at high risk of HIV transmission and acquisition, drivers of HIV infection, and available interventions to address these risk factors. Interventions should be considered in terms of the evidence basis for efficacy, potential synergies, and feasibility of delivery at scale, which is important to achieve high coverage and impact, coupled with high acceptability to populations, which will impact uptake, adherence, and retention. Evaluation requires process measures of uptake, adherence, retention, and outcome measures of reduction in HIV infectiousness and acquisition. Three examples of combination prevention concepts are summarized for men who have sex with men in the Americas, young women in sub-Saharan Africa, and HIV serodiscordant couples.

  6. Chronic mechanistic target of rapamycin inhibition: preventing cancer to delay aging, or vice versa?.

    PubMed

    Sharp, Zelton Dave; Curiel, Tyler Jay; Livi, Carolina Becker

    2013-01-01

    Cancer and aging appear to be inexorably linked, yet approaches to ameliorate them in concert are lacking. Although not (easily) feasible in humans, years of preclinical research show that diet and growth factor restriction each successfully address cancer and aging together. Chronic treatment of genetically heterogeneous mice with an enteric formulation of rapamycin (eRapa) extended maximum lifespan of both genders when started in mid or late life. In part, cancer amelioration in treated mice suggested that long-term eRapa, like diet restriction, could be a pharmacological approach feasible for use in the clinic. We review the current understanding of the role of the mechanistic target of rapamycin (mTOR) in cancer and aging. We also discuss the tumor immune surveillance system, and the need for a better understanding of its responses to mTOR inhibitors. We also address the issue of the misperception that rapamycin is a potent immunosuppressant. Finally, we review the current state of mTOR inhibitors in the cancer clinic. Because of the burgeoning elderly population most at risk for cancer, there is a great need for our eRapa findings to be a proof of concept for the development of new and more comprehensive approaches to cancer prevention that are safe and also mitigate other deleterious effects of aging.

  7. Factor XII: a novel target for safe prevention of thrombosis and inflammation.

    PubMed

    Kenne, E; Nickel, K F; Long, A T; Fuchs, T A; Stavrou, E X; Stahl, F R; Renné, T

    2015-12-01

    Plasma protein factor XII (FXII) activates the procoagulant and proinflammatory contact system that drives both the kallikrein-kinin system and the intrinsic pathway of coagulation. When zymogen FXII comes into contact with negatively charged surfaces, it auto-activates to the serine proteaseactivated FXII (FXIIa). Recently, various in vivo activators of FXII have been identified including heparin, misfolded protein aggregates, polyphosphate and nucleic acids. Murine models have established a central role of FXII in arterial and venous thrombosis. Despite its central function in thrombosis, deficiency in FXII does not impair haemostasis in animals and humans. In a preclinical cardiopulmonary bypass system in large animals, the FXIIa-blocking antibody 3F7 prevented thrombosis; however, in contrast to traditional anticoagulants, bleeding was not increased. In addition to its function in thrombosis, FXIIa initiates formation of the inflammatory mediator bradykinin. This mediator increases vascular leak, causes vasodilation, and induces chemotaxis with implications for septic, anaphylactic and allergic disease states. Therefore, targeting FXIIa appears to be a promising strategy for thromboprotection without associated bleeding risks but with anti-inflammatory properties.

  8. Staphylococcus aureus Clumping Factor A Remains a Viable Vaccine Target for Prevention of S. aureus Infection

    PubMed Central

    Scully, Ingrid L.; Buurman, Ed T.; Eiden, Joseph; Jansen, Kathrin U.

    2016-01-01

    ABSTRACT In a recent article, X. Li et al. [mBio 7(1):e02232-15, 2016, http://dx.doi.org/10.1128/mBio.02232-15] investigate the utility of a vaccine composed of the Staphylococcus aureus protein clumping factor A (ClfA) in protecting mice from S. aureus infection. ClfA, one of the first proteins to be identified as a potential vaccine antigen for S. aureus prophylaxis, is currently a component of several investigational vaccines. The authors conclude that ClfA may not be effective for S. aureus prophylaxis. In contrast, previously published papers reporting positive data suggested that ClfA was potentially an important vaccine target to prevent invasive S. aureus disease. This commentary addresses the observed differences between the findings of Li et al. and those from other publications, highlighting the importance for preclinical vaccine antigen assessments to reflect the biological role of said antigen in virulence and, consequently, the importance of choosing appropriate preclinical disease models to test such antigens. PMID:26956591

  9. Qualitative investigation of targets for and barriers to interventions to prevent psychosis relapse

    PubMed Central

    2014-01-01

    Background Early signs based relapse prevention interventions for psychosis show promise. In order to examine how they might be improved we sought to better understand the early relapse process, service users’ abilities to identify early signs, and any potential facilitators and barriers to early signs interventions. Methods Data from in-depth interviews with a convenience sample of service users with psychosis varying in gender, age, duration of mental health problems, and time since last relapse were analysed using a thematic approach. Interview transcripts were coded inductively and relationships between emerging themes were examined by the research team to provide a thorough synthesis of the data. Results Three central themes emerged from the analysis: 1) recognising risk factors (how risk factors were identified and linked to relapse, and reactions to such risk factors); 2) identifying early signs (issues related to both recognising and recalling signs of relapse); 3) reacting to deterioration (participants’ thoughts and feelings in response to early signs, including help seeking and its challenges). Conclusions There was considerable variation in the attention participants had paid to pre-relapse signs, the ease with which they were able to recall them, and their reactions to them. For many, there were substantial barriers to help seeking from services. A family or friend confidant was an important means of assistance, although the supportive presence of significant others was not always available. Based on these results, a number of recommendations about facilitating service users’ recognition of early signs and targeting potential accelerants of relapse are made. PMID:25030092

  10. MicroRNAs: New players in cancer prevention targeting Nrf2, oxidative stress and inflammatory pathways

    PubMed Central

    Zhang, Chengyue; Shu, Limin; Kong, Ah-Ng Tony

    2015-01-01

    miRNAs are endogenous small non-coding RNAs of 20-22 nucleotides that repress gene expression at the post-transcriptional level. There is growing interest in the role of miRNAs in cancer chemoprevention, and several naturally occurring chemopreventive agents have been found to be modulators of miRNA expression both in vitro and in vivo. Moreover, these chemopreventive phytochemicals commonly possess anti-oxidative and/or anti-inflammatory properties, and Nrf2 has been extensively studied as a molecular target in cancer prevention. The crosstalk between miRNAs and the traditional cellular signaling pathways of chemoprevention remain to be fully elucidated. This review summarizes the data regarding the potential interactions between miRNAs and anti-oxidative and anti-inflammatory pathways. Cellular redox homeostasis can affect the biogenesis and processing of miRNAs, which in turn regulate the Nrf2 pathway of detoxifying/anti-oxidative genes. We also discuss the miRNA regulatory mechanisms in relation to inflammation-related cancer signaling pathways. PMID:26618104

  11. Mitochondria-Targeted Antioxidant SS31 Prevents Amyloid Beta-Induced Mitochondrial Abnormalities and Synaptic Degeneration in Alzheimer's Disease.

    PubMed

    Calkins, Marcus J; Manczak, Maria; Reddy, P Hemachandra

    2012-01-01

    In neuronal systems, the health and activity of mitochondria and synapses are tightly coupled. For this reason, it has been postulated that mitochondrial abnormalities may, at least in part, drive neurodegeneration in conditions such as Alzheimer's disease (AD). Mounting evidence from multiple Alzheimer's disease cell and mouse models and postmortem brains suggest that loss of mitochondrial integrity may be a key factor that mediates synaptic loss. Therefore, the prevention or rescue of mitochondrial dysfunction may help delay or altogether prevent AD-associated neurodegeneration. Since mitochondrial health is heavily dependent on antioxidant defenses, researchers have begun to explore the use of mitochondria-targeted antioxidants as therapeutic tools to prevent neurodegenerative diseases. This review will highlight advances made using a model mitochondria-targeted antioxidant peptide, SS31, as a potential treatment for AD. PMID:23226091

  12. Impulsive delayed reward discounting as a genetically-influenced target for drug abuse prevention: a critical evaluation

    PubMed Central

    Gray, Joshua C.; MacKillop, James

    2015-01-01

    This review evaluates the viability of delayed reward discounting (DRD), an index of how much an individual devalues a future reward based on its delay in time, for genetically-informed drug abuse prevention. A review of the literature suggests that impulsive DRD is robustly associated with drug addiction and meets most of the criteria for being an endophenotype, albeit with mixed findings for specific molecular genetic influences. Several modes of experimental manipulation have been demonstrated to reduce DRD acutely. These include behavioral strategies, such as mindfulness, reward bundling, and episodic future thinking; pharmacological interventions, including noradrenergic agonists, adrenergic agonists, and multiple monoamine agonists; and neuromodulatory interventions, such as transcranial magnetic stimulation and transcranial direct current stimulation. However, the generalization of these interventions to positive clinical outcomes remains unclear and no studies to date have examined interventions on DRD in the context of prevention. Collectively, these findings suggest it would be premature to target DRD for genetically-informed prevention. Indeed, given the evidence of environmental contributions to impulsive DRD, whether genetically-informed secondary prevention would ever be warranted is debatable. Progress in identifying polymorphisms associated with DRD profiles could further clarify the underlying biological systems for pharmacological and neuromodulatory interventions, and, as a qualitatively different risk factor from existing prevention programs, impulsive DRD is worthy of investigation at a more general level as a novel and promising drug abuse prevention target. PMID:26388788

  13. Targeting galectin-1 overcomes breast cancer-associated immunosuppression and prevents metastatic disease.

    PubMed

    Dalotto-Moreno, Tomás; Croci, Diego O; Cerliani, Juan P; Martinez-Allo, Verónica C; Dergan-Dylon, Sebastián; Méndez-Huergo, Santiago P; Stupirski, Juan C; Mazal, Daniel; Osinaga, Eduardo; Toscano, Marta A; Sundblad, Victoria; Rabinovich, Gabriel A; Salatino, Mariana

    2013-02-01

    Galectin-1 (Gal1), an evolutionarily conserved glycan-binding protein, contributes to the creation of an immunosuppressed microenvironment at sites of tumor growth. In spite of considerable progress in elucidating its role in tumor-immune escape, the mechanisms underlying the inhibitory functions of Gal1 remain obscure. Here, we investigated the contribution of tumor Gal1 to tumor growth, metastasis, and immunosuppression in breast cancer. We found that the frequency of Gal1(+) cells in human breast cancer biopsies correlated positively with tumor grade, while specimens from patients with benign hyperplasia showed negative or limited Gal1 staining. To examine the pathophysiologic relevance of Gal1 in breast cancer, we used the metastatic mouse mammary tumor 4T1, which expresses and secretes substantial amounts of Gal1. Silencing Gal1 expression in this model induced a marked reduction in both tumor growth and the number of lung metastases. This effect was abrogated when mice were inoculated with wild-type 4T1 tumor cells in their contralateral flank, suggesting involvement of a systemic modulation of the immune response. Gal1 attenuation in 4T1 cells also reduced the frequency of CD4(+)CD25(+) Foxp3(+) regulatory T (T(reg)) cells within the tumor, draining lymph nodes, spleen, and lung metastases. Further, it abrogated the immunosuppressive function of T(reg) cells and selectively lowered the expression of the T-cell regulatory molecule LAT (linker for activation of T cells) on these cells, disarming their suppressive activity. Taken together, our results offer a preclinical proof of concept that therapeutic targeting of Gal1 can overcome breast cancer-associated immunosuppression and can prevent metastatic disease. PMID:23204230

  14. miR-145 Is a Promising Therapeutic Target to Prevent Cornea Scarring.

    PubMed

    Ratuszny, Dominica; Gras, Christiane; Bajor, Anna; Börger, Ann-Kathrin; Pielen, Amelie; Börgel, Martin; Framme, Carsten; Blasczyk, Rainer; Figueiredo, Constança

    2015-10-01

    Corneal scarring is an expected outcome of corneal injury or infection and is one of the major causes for visual loss. The formation of light-scattering myofibroblasts is thought to be the underlying cause of corneal haze formation. Recently, microRNA (miRNA) gene therapies have been proposed as novel approach for complex processes such as fibrosis and scarring. In this study, we focused on the role of miR-145 in corneal myofibroblast differentiation and function. Analysis of human corneal scar tissue and transforming growth factor (TGF)-β1-induced corneal myofibroblasts showed a 13- and 4-fold increase of miR-145, respectively, compared with healthy cornea and nonstimulated fibroblasts (p<0.01). Furthermore, myofibroblasts showed an increase in α-smooth muscle actin (α-SMA) expression and a decreased expression of Kruppel-like factor 4 (KLF4). These results indicated that TGF-β1 increases miR-145 expression, which indirectly induces α-SMA expression via downregulation of KLF4, a known negative regulator of α-SMA. Consistently, miR-145 silencing in corneal myofibroblasts using a specific antimiR resulted in increased KLF4 and strongly decreased α-SMA expression. In addition, miR-145 inhibition also significantly decreased myofibroblast contractility, migratory capacity, and TGF-β1 secretion, which are all thought to contribute to corneal scarring. Hence, miR-145 plays an important role in TGF-β1-stimulated corneal myofibroblast differentiation and activation, which can be reversed by miR-145 silencing. Therefore, we suggest miR-145 as a promising therapeutic target for miRNA-based gene therapy to prevent or treat visual loss caused by corneal fibrosis.

  15. Genetics of coronary heart disease: towards causal mechanisms, novel drug targets and more personalized prevention.

    PubMed

    Orho-Melander, M

    2015-11-01

    Coronary heart disease (CHD) is an archetypical multifactorial disorder that is influenced by genetic susceptibility as well as both modifiable and nonmodifiable risk factors, and their interactions. Advances during recent years in the field of multifactorial genetics, in particular genomewide association studies (GWASs) and their meta-analyses, have provided the statistical power to identify and replicate genetic variants in more than 50 risk loci for CHD and in several hundreds of loci for cardiometabolic risk factors for CHD such as blood lipids and lipoproteins. Although for a great majority of these loci both the causal variants and mechanisms remain unknown, progress in identifying the causal variants and underlying mechanisms has already been made for several genetic loci. Furthermore, identification of rare loss-of-function variants in genes such as PCSK9, NPC1L1, APOC3 and APOA5, which cause a markedly decreased risk of CHD and no adverse side effects, illustrates the power of translating genetic findings into novel mechanistic information and provides some optimism for the future of developing novel drugs, given the many genes associated with CHD in GWASs. Finally, Mendelian randomization can be used to reveal or exclude causal relationships between heritable biomarkers and CHD, and such approaches have already provided evidence of causal relationships between CHD and LDL cholesterol, triglycerides/remnant particles and lipoprotein(a), and indicated a lack of causality for HDL cholesterol, C-reactive protein and lipoprotein-associated phospholipase A2. Together, these genetic findings are beginning to lead to promising new drug targets and novel interventional strategies and thus have great potential to improve prevention, prediction and therapy of CHD. PMID:26477595

  16. Predictors of Success in Implementing HIV Prevention in Rural America: A State-Level Structural Factor Analysis of HIV Prevention Targeting Men who have Sex with Men

    PubMed Central

    Horvath, Keith J.

    2013-01-01

    Relatively few studies have examined the impact of modifying structural factors on HIV prevention efforts in the United States despite their high potential for lowering HIV prevalence rates. The aim of this study was to identify state-level characteristics of successful HIV prevention implementation. Structured interviews with 73 key informants in 13 rural states identified ‘more successful’ and ‘less successful’ states in HIV prevention. States were compared on demographic, religious, gay community, and funding variables. The 7 more successful states had both a wider variety and more MSM-targeted interventions. Overall funding, degree of epidemic, and “ruralness” were not significantly associated with success. Rather, successful states had less religious and Evangelical Protestant adherents and more ‘gay community’ infrastructure. They also spent a greater proportion of funds contracting community-based organizations and on MSMtargeted programming. Success in HIV prevention varies across rural states. Key demographic, social and economic indicators distinguish success in HIV prevention. PMID:17440806

  17. Targeted ethnography as a critical step to inform cultural adaptations of HIV prevention interventions for adults with severe mental illness.

    PubMed

    Wainberg, Milton L; Alfredo González, M; McKinnon, Karen; Elkington, Katherine S; Pinto, Diana; Gruber Mann, Claudio; Mattos, Paulo E

    2007-07-01

    As in other countries worldwide, adults with severe mental illness (SMI) in Brazil are disproportionately infected with HIV relative to the general population. Brazilian psychiatric facilities lack tested HIV prevention interventions. To adapt existing interventions, developed only in the US, we conducted targeted ethnography with adults with SMI and staff from two psychiatric institutions in Brazil. We sought to characterize individual, institutional, and interpersonal factors that may affect HIV risk behavior in this population. We conducted 350 hours of ethnographic field observations in two mental health service settings in Rio de Janeiro, and 9 focus groups (n=72) and 16 key-informant interviews with patients and staff in these settings. Data comprised field notes and audiotapes of all exchanges, which were transcribed, coded, and systematically analyzed. The ethnography identified and/or characterized the institutional culture: (1) patients' risk behaviors; (2) the institutional setting; (3) intervention content; and (4) intervention format and delivery strategies. Targeted ethnography also illuminated broader contextual issues for development and implementation of HIV prevention interventions for adults with SMI in Brazil, including an institutional culture that did not systematically address patients' sexual behavior, sexual health, or HIV sexual risk, yet strongly impacted the structure of patients' sexual networks. Further, ethnography identified the Brazilian concept of "social responsibility" as important to prevention work with psychiatric patients. Targeted ethnography with adults with SMI and institutional staff provided information critical to the adaptation of tested US HIV prevention interventions for Brazilians with SMI.

  18. Clinical Efficacy of a Specifically Targeted Antimicrobial Peptide Mouth Rinse: Targeted Elimination of Streptococcus mutans and Prevention of Demineralization

    PubMed Central

    Sullivan, R.; Santarpia, P.; Lavender, S.; Gittins, E.; Liu, Z.; Anderson, M.H.; He, J.; Shi, W.; Eckert, R.

    2011-01-01

    Background/Aims Streptococcus mutans, the major etiological agent of dental caries, has a measurable impact on domestic and global health care costs. Though persistent in the oral cavity despite conventional oral hygiene, S. mutans can be excluded from intact oral biofilms through competitive exclusion by other microorganisms. This suggests that therapies capable of selectively eliminating S. mutans while limiting the damage to the normal oral flora might be effective long-term interventions to fight cariogenesis. To meet this challenge, we designed C16G2, a novel synthetic specifically targeted antimicrobial peptide with specificity for S. mutans. C16G2 consists of a S. mutans-selective ‘targeting region’ comprised of a fragment from S. mutans competence stimulation peptide (CSP) conjoined to a ‘killing region’ consisting of a broad-spectrum antimicrobial peptide (G2). In vitro studies have indicated that C16G2 has robust efficacy and selectivity for S. mutans, and not other oral bacteria, and affects targeted bacteria within seconds of contact. Methods In the present study, we evaluated C16G2 for clinical utility in vitro, followed by a pilot efficacy study to examine the impact of a 0.04% (w/v) C16G2 rinse in an intra-oral remineralization/demineralization model. Results and Conclusions C16G2 rinse usage was associated with reductions in plaque and salivary S. mutans, lactic acid production, and enamel demineralization. The impact on total plaque bacteria was minimal. These results suggest that C16G2 is effective against S. mutans in vivo and should be evaluated further in the clinic. PMID:21860239

  19. A feasibility study of non-targeted adulterant screening based on NIRM spectral library of soybean meal to guarantee quality: The example of non-protein nitrogen.

    PubMed

    Shen, Guanghui; Fan, Xia; Yang, Zengling; Han, Lujia

    2016-11-01

    The quality and safety of soybean meal is a key matter for the livestock breeding and food industries, since it is one of the most important and widely used protein feed raw materials. As driven by commercial interests, new illegal adulterants which are unknown to consumers and regulators emerge constantly. In order to make up for the inadequacy of traditional detection methods, a novel non-targeted adulterant screening method based on a near-infrared microscopy spectral library of soybean meal is proposed. This study focused on the feasibility of non-targeted screening methods for the detection of adulteration in soybean meal. Six types of non-protein nitrogen were taken as examples and partial least squares discriminant analysis was employed to verify the feasibility of this novel method. The results showed that the non-targeted screening method could screen out adulterations in soybean meal with satisfactory results. PMID:27211617

  20. A feasibility study of non-targeted adulterant screening based on NIRM spectral library of soybean meal to guarantee quality: The example of non-protein nitrogen.

    PubMed

    Shen, Guanghui; Fan, Xia; Yang, Zengling; Han, Lujia

    2016-11-01

    The quality and safety of soybean meal is a key matter for the livestock breeding and food industries, since it is one of the most important and widely used protein feed raw materials. As driven by commercial interests, new illegal adulterants which are unknown to consumers and regulators emerge constantly. In order to make up for the inadequacy of traditional detection methods, a novel non-targeted adulterant screening method based on a near-infrared microscopy spectral library of soybean meal is proposed. This study focused on the feasibility of non-targeted screening methods for the detection of adulteration in soybean meal. Six types of non-protein nitrogen were taken as examples and partial least squares discriminant analysis was employed to verify the feasibility of this novel method. The results showed that the non-targeted screening method could screen out adulterations in soybean meal with satisfactory results.

  1. Small molecule targeting malaria merozoite surface protein-1 (MSP-1) prevents host invasion of divergent plasmodial species.

    PubMed

    Chandramohanadas, Rajesh; Basappa; Russell, Bruce; Liew, Kingsley; Yau, Yin Hoe; Chong, Alvin; Liu, Min; Gunalan, Karthigayan; Raman, Rahul; Renia, Laurent; Nosten, Francois; Shochat, Susana Geifman; Dao, Ming; Sasisekharan, Ram; Suresh, Subra; Preiser, Peter

    2014-11-15

    Malaria causes nearly 1 million deaths annually. Recent emergence of multidrug resistance highlights the need to develop novel therapeutic interventions against human malaria. Given the involvement of sugar binding plasmodial proteins in host invasion, we set out to identify such proteins as targets of small glycans. Combining multidisciplinary approaches, we report the discovery of a small molecule inhibitor, NIC, capable of inhibiting host invasion through interacting with a major invasion-related protein, merozoite surface protein-1 (MSP-1). This interaction was validated through computational, biochemical, and biophysical tools. Importantly, treatment with NIC prevented host invasion by Plasmodium falciparum and Plasmodium vivax--major causative organisms of human malaria. MSP-1, an indispensable antigen critical for invasion and suitably localized in abundance on the merozoite surface represents an ideal target for antimalarial development. The ability to target merozoite invasion proteins with specific small inhibitors opens up a new avenue to target this important pathogen.

  2. Prevention

    MedlinePlus

    ... Prevention Treatment 2003 U.S. Outbreak African Rodent Importation Ban For Clinicians Clinical Recognition Specimen Collection Treatment Smallpox ... Examining Animals with Suspected Monkeypox African Rodent Importation Ban Resources Related Links Poxvirus Molluscum Contagiosum Orf Virus ( ...

  3. An exploratory review of HIV prevention mass media campaigns targeting men who have sex with men

    PubMed Central

    2014-01-01

    Background Men who have sex with men (MSM) are at increased risk of HIV infection in both high- and low-income settings. Mass media campaigns have been used as a means of communicating HIV health promotion messages to large audiences of MSM. There is no consensus on which designs are most appropriate to evaluate the process and outcomes of such interventions. Methods An exploratory review was conducted to assess research examining awareness, acceptability, effects on HIV testing, disclosure and sexual risk, and cost-effectiveness of HIV mass media campaigns targeting MSM. We searched for quantitative and qualitative studies published between 1990 and May 2011 via the Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, Psych Info, ISI Web of Science, OpenGrey and COPAC, and contacting experts. No exclusions were made on the basis of study design or methods because our primary aim was to map evidence. We appraised study quality and present a narrative synthesis of findings. Results Sixteen reports from 12 studies were included. All were from high-income countries and most examined multi-media interventions. Half of the studies were single cross-sectional surveys. Three repeat cross-sectional studies collected data pre and post the campaign launch. The remaining three studies monitored routine data. Three studies included a nested qualitative component. Campaign coverage was the most commonly reported outcome (9 studies). Imagery, tone of language, content and relevance were identified in the qualitative research as factors influencing campaign acceptability. HIV testing rates (or intention to test) were reported by five studies. Two studies reported that testing rates were higher among men who had seen the campaigns compared to men who had not, but this may reflect confounding. Findings were less consistent regarding reductions in sexual risk behaviours (4 studies). None of the studies examined cost-effectiveness. Conclusions Campaigns aim to provide MSM

  4. Guidance for a personal target value of F(E)NO in allergic asthma: case report and theoretical example.

    PubMed

    Högman, Marieann; Meriläinen, Pekka

    2013-03-01

    In clinically stable asthma the exhaled NO values (F(E)NO) are generally higher than in control subjects. Therefore, reference values are of limited importance in clinical practice. This is demonstrated in this case report, but it is also shown that NO parameters from non-linear modelling do have a clinical value. A subject with asthma was treated with inhaled corticosteroids for 1 week. The non-linear NO model was used to measure the response to treatment. The NO parameters from subjects with atopic rhinitis and asthma were fed into a computer program to generate theoretical F(E)NO₀.₀₅ values, i.e. target values. There was a dramatic decrease in F(E)NO₀.₀₅ due to treatment, from 82 to 34 ppb, but it remained higher than in healthy controls. This is due to the elevated diffusion rate of NO, unchanged by treatment. When the NO parameters are known, a personal best value of F(E)NO₀.₀₅ (fractional concentration of exhaled NO in the gas phase, 0.05 L/s) can be calculated, which can be the target value when only F(E)NO₀.₀₅ can be monitored. In conclusion, reference values for NO parameters are shown to be clinically useful. It is essential that every patient receives his/her target value of F(E)NO₀.₀₅, when only a single NO measurement is available. In our opinion, this is the reason why there are few successful studies of trying to target the NO value with inhaled corticosteroids.

  5. Targeting Type 2: Linguistic Agency Assignment in Diabetes Prevention Policy Messaging.

    PubMed

    Glowacki, Elizabeth M; McGlone, Matthew S; Bell, Robert A

    2016-01-01

    We explored the effects of linguistic agency assignment on the persuasive impact of a fictitious medical journal editorial about Type 2 diabetes. Participants (N = 422) read 1 of 4 versions of an editorial that differed in the language used to describe the health threat posed by the disease (threat agency) and to outline a program for preventing it (prevention agency). Threat agency was assigned either to the disease (e.g., diabetes puts individuals' lives at risk) or to humans (e.g., individuals who acquire diabetes put their lives at risk). Prevention agency was assigned either to the recommended prevention behaviors (e.g., a healthy diet and regular exercise protect children from Type 2) or to humans (e.g., children who eat a healthy diet and exercise regularly protect themselves from Type 2). Respondents' perceptions of disease severity were higher when threat agency was assigned to diabetes rather than humans. However, attitudes toward the proposed prevention program were higher when prevention agency was assigned to humans rather than to the recommended behaviors. The latter finding contrasts with agency effects observed in previous research on a viral threat, suggesting that the optimal pattern of agency assignment in prevention messaging may be different for acute and chronic lifestyle diseases. PMID:26959860

  6. Targeting Type 2: Linguistic Agency Assignment in Diabetes Prevention Policy Messaging.

    PubMed

    Glowacki, Elizabeth M; McGlone, Matthew S; Bell, Robert A

    2016-01-01

    We explored the effects of linguistic agency assignment on the persuasive impact of a fictitious medical journal editorial about Type 2 diabetes. Participants (N = 422) read 1 of 4 versions of an editorial that differed in the language used to describe the health threat posed by the disease (threat agency) and to outline a program for preventing it (prevention agency). Threat agency was assigned either to the disease (e.g., diabetes puts individuals' lives at risk) or to humans (e.g., individuals who acquire diabetes put their lives at risk). Prevention agency was assigned either to the recommended prevention behaviors (e.g., a healthy diet and regular exercise protect children from Type 2) or to humans (e.g., children who eat a healthy diet and exercise regularly protect themselves from Type 2). Respondents' perceptions of disease severity were higher when threat agency was assigned to diabetes rather than humans. However, attitudes toward the proposed prevention program were higher when prevention agency was assigned to humans rather than to the recommended behaviors. The latter finding contrasts with agency effects observed in previous research on a viral threat, suggesting that the optimal pattern of agency assignment in prevention messaging may be different for acute and chronic lifestyle diseases.

  7. Confounding by indication in non-experimental evaluation of vaccine effectiveness: the example of prevention of influenza complications

    PubMed Central

    Hak, E; Verheij, T.; Grobbee, D; Nichol, K; Hoes, A

    2002-01-01

    Randomised allocation of vaccine or placebo is the preferred method to assess the effects of the vaccine on clinical outcomes relevant to the individual patient. In the absence of phase 3 trials using clinical end points, notably post-influenza complications, alternative non-experimental designs to evaluate vaccine effects or safety are often used. The application of these designs may, however, lead to invalid estimates of vaccine effectiveness or safety. As patients with poor prognosis are more likely to be immunised, selection for vaccination is confounded by patient factors that are also related to clinical end points. This paper describes several design and analytical methods aimed at limiting or preventing this confounding by indication in non-experimental studies. In short, comparison of study groups with similar prognosis, restriction of the study population, and statistical adjustment for dissimilarities in prognosis are important tools and should be considered. Only if the investigator is able to show that confounding by indication is sufficiently controlled for, results of a non-experimental study may be of use to direct an evidence based vaccine policy. PMID:12461118

  8. Acceptability of Sexually Explicit Images in HIV Prevention Messages Targeting Men Who Have Sex with Men

    PubMed Central

    Iantaffi, Alex; Wilkerson, J. Michael; Grey, Jeremy A.; Rosser, B. R. Simon

    2014-01-01

    Sexually explicit media (SEM) have been used in HIV-prevention advertisements to engage men who have sex with men (MSM), and to communicate content. These advertisements exist within larger discourses, including a dominant heternormative culture, and a growing homonormative culture. Cognizant of these hegemonic cultures, this analysis examined the acceptable level of sexual explicitness in prevention advertisements. 79 MSM participated in 13 online focus groups, which were part of a larger study of SEM. Three macro-themes—audience, location and community representation—emerged from the analysis, as did the influence of homonormativity on the acceptability of SEM in HIV-prevention messages. PMID:26075485

  9. Acceptability of Sexually Explicit Images in HIV Prevention Messages Targeting Men Who Have Sex With Men.

    PubMed

    Iantaffi, Alex; Wilkerson, J Michael; Grey, Jeremy A; Rosser, B R Simon

    2015-01-01

    Sexually explicit media (SEM) have been used in HIV-prevention advertisements to engage men who have sex with men (MSM) and to communicate content. These advertisements exist within larger discourses, including a dominant heteronormative culture and a growing homonormative culture. Cognizant of these hegemonic cultures, this analysis examined the acceptable level of sexual explicitness in prevention advertisements. Seventy-nine MSM participated in 13 online focus groups, which were part of a larger study of SEM. Three macro themes-audience, location, and community representation-emerged from the analysis, as did the influence of homonormativity on the acceptability of SEM in HIV-prevention messages. PMID:26075485

  10. Acceptability of Sexually Explicit Images in HIV Prevention Messages Targeting Men Who Have Sex With Men.

    PubMed

    Iantaffi, Alex; Wilkerson, J Michael; Grey, Jeremy A; Rosser, B R Simon

    2015-01-01

    Sexually explicit media (SEM) have been used in HIV-prevention advertisements to engage men who have sex with men (MSM) and to communicate content. These advertisements exist within larger discourses, including a dominant heteronormative culture and a growing homonormative culture. Cognizant of these hegemonic cultures, this analysis examined the acceptable level of sexual explicitness in prevention advertisements. Seventy-nine MSM participated in 13 online focus groups, which were part of a larger study of SEM. Three macro themes-audience, location, and community representation-emerged from the analysis, as did the influence of homonormativity on the acceptability of SEM in HIV-prevention messages.

  11. The National Cancer Institute's PREVENT Cancer Preclinical Drug Development Program: overview, current projects, animal models, agent development strategies, and molecular targets.

    PubMed

    Shoemaker, Robert H; Suen, Chen S; Holmes, Cathy A; Fay, Judith R; Steele, Vernon E

    2016-02-01

    The PREVENT Cancer Preclinical Drug Development Program (PREVENT) is a National Cancer Institute, Division of Cancer Prevention (NCI, DCP)-supported program whose primary goal is to bring new cancer preventive interventions (small molecules and vaccines) and biomarkers through preclinical development towards clinical trials by creating partnerships between the public sector (eg, academia, industry) and DCP. PREVENT has a formalized structure for moving interventions forward in the prevention pipeline using a stage-gate process with go/no go decision points along the critical path for development. This review describes the structure of the program, its focus areas, and provides examples of projects currently in the pipeline.

  12. Assessing the efficiency gains of improved spatial targeting of policy interventions; the example of an agri-environmental scheme.

    PubMed

    van der Horst, Dan

    2007-12-01

    GIS-based spatial targeting is increasingly recognised as a potentially useful tool to design more efficient policy interventions. The use of this tool has also been advocated in the context of incentive-based agri-environmental schemes, but there has been little work to date to estimate the level of efficiency gains which it may help to achieve. This paper investigates the requirements to arrive at such estimates, using a Scottish farm woodland scheme as a case study. This agri-environmental scheme aims to provide visual amenity and biodiversity. Maps of these two benefits are used to develop improved spatial targeting scenarios that deliver significant efficiency gains in comparison to the existing scheme design. The paper discusses the nature of the spatial distribution of the relevant benefits at the landscape scale and the data requirements for the realistic estimation of efficiency gains. It concludes that although much work needs to be done, the methods available today could and should play a much greater role in improving the landscape-scale design of existing land use schemes focused on the delivery of non-market benefits. PMID:17350157

  13. Early life respiratory infections and asthma development: role in disease pathogenesis and potential targets for disease prevention

    PubMed Central

    Beigelman, Avraham; Bacharier, Leonard B.

    2016-01-01

    Purpose of review To present recent findings and perspectives on the relationship between early life respiratory infections and asthma inception and to discuss emerging concepts on strategies that target these infectious agents for asthma prevention. Recent findings Cumulative evidence supports the role of early life viral infections, especially respiratory syncytial virus and human rhinovirus, as major antecedents of childhood asthma. These viruses may have different mechanistic roles in the pathogenesis of asthma. The airway microbiome and virus-bacteria interactions in early life have emerged as additional determinants of childhood asthma. Innovative strategies for the prevention of these early life infections, or for attenuation of acute infection severity, are being investigated and may identify effective strategies for the primary and secondary prevention of childhood asthma. Summary Early life infections are major determinants of asthma development. The pathway from early life infections to asthma is the result of complex interactions between the specific type of the virus, genetic and environmental factors. Novel intervention strategies that target these infectious agents have been investigated in proof-of-concepts trials, and further study is necessary to determine their capacity for asthma prevention. PMID:26854761

  14. [School shootings in Germany: current trends in the prevention of severe, targeted violence in German schools].

    PubMed

    Bondü, Rebecca; Scheithauer, Herbert

    2009-01-01

    In March and September 2009 the school shootings in Winnenden and Ansbach once again demonstrated the need for preventive approaches in order to prevent further offences in Germany. Due to the low frequency of such offences and the low specificity of relevant risk factors known so far, prediction and prevention seems difficult though. None the less, several preventive approaches are currently discussed. The present article highlights these approaches and their specific advantages and disadvantages. As school shootings are multicausally determined, approaches focussing only on single aspects (i.e. prohibiting violent computer games or further strengthening gun laws) do not meet requirements. Other measures such as installing technical safety devices or optimizing actions of police and school attendants are supposed to reduce harm in case of emergency. Instead, scientifically founded and promising preventive approaches focus on secondary prevention and for this purpose employ the threat assessment approach, which is widespread within the USA. In this framework, responsible occupational groups such as teachers, school psychologists and police officers are to be trained in identifying students' warning signs, judging danger of these students for self and others in a systematic process and initiating suitable interventions. PMID:20066854

  15. Targeted prevention of childhood anxiety: engaging parents in an underserved community.

    PubMed

    Mian, Nicholas D; Eisenhower, Abbey S; Carter, Alice S

    2015-03-01

    Selective prevention programs hold the promise of alleviating child anxiety symptoms, decreasing the risk for emotional problems across the lifespan. Such programs have particular public health import for young children of poor, underserved communities. Identifying factors related to parent engagement, and methods to improve engagement, are paramount in the effort to develop anxiety-focused, community prevention programs. This feasibility study investigated the effect of an enhanced recruitment strategy to maximize parent engagement, as well as factors related to attendance in a single session focused on anxiety prevention. Participants were poor, ethnic minority parents of children aged 11-71 months (n = 256) who completed a survey that assessed anxiety risk according to trauma exposure, child anxiety, or parent anxiety, as well as preferences for preventive services (phase 1). Those meeting risk criteria (n = 101) were invited to a preventive group session (phase 2). Half of parents received enhanced recruitment (ER), which included personalized outreach, matching parent preferences, and community endorsement. Other parents were invited by mail. Chi square analyses indicated that ER was associated with planning to attend (49 vs. 6% of control). Parents receiving ER were 3.5 times more likely to attend. Higher sociodemographic risk was correlated with higher child anxiety symptoms but not attendance. Results highlight the need for improved strategies for engaging parents in preventive, community-based interventions.

  16. [School shootings in Germany: current trends in the prevention of severe, targeted violence in German schools].

    PubMed

    Bondü, Rebecca; Scheithauer, Herbert

    2009-01-01

    In March and September 2009 the school shootings in Winnenden and Ansbach once again demonstrated the need for preventive approaches in order to prevent further offences in Germany. Due to the low frequency of such offences and the low specificity of relevant risk factors known so far, prediction and prevention seems difficult though. None the less, several preventive approaches are currently discussed. The present article highlights these approaches and their specific advantages and disadvantages. As school shootings are multicausally determined, approaches focussing only on single aspects (i.e. prohibiting violent computer games or further strengthening gun laws) do not meet requirements. Other measures such as installing technical safety devices or optimizing actions of police and school attendants are supposed to reduce harm in case of emergency. Instead, scientifically founded and promising preventive approaches focus on secondary prevention and for this purpose employ the threat assessment approach, which is widespread within the USA. In this framework, responsible occupational groups such as teachers, school psychologists and police officers are to be trained in identifying students' warning signs, judging danger of these students for self and others in a systematic process and initiating suitable interventions.

  17. Association of achieved dialysis dose with mortality in the hemodialysis study: an example of "dose-targeting bias".

    PubMed

    Greene, Tom; Daugirdas, John; Depner, Thomas; Allon, Michael; Beck, Gerald; Chumlea, Cameron; Delmez, James; Gotch, Frank; Kusek, John W; Levin, Nathan; Owen, William; Schulman, Gerald; Star, Robert; Toto, Robert; Eknoyan, Garabed

    2005-11-01

    In the intention-to-treat analysis of the Hemodialysis Study, all-cause mortality did not differ significantly between the high versus standard hemodialysis dose groups. The association of mortality with delivered dose within each of the two randomized treatment groups was examined, and implications for observational studies were considered. Time-dependent Cox regression was used to relate the relative risk (RR) for mortality to the running mean of the achieved equilibrated Kt/V (eKt/V) over the preceding 4 mo. eKt/V was categorized by quintiles within each dose group. Analyses were controlled for case-mix factors and baseline anthropometric volume. Within each randomized dose group, mortality was elevated markedly when achieved eKt/V was in the lowest quintile (RR, 1.93; 95% confidence interval [CI], 1.40 to 2.66; P < 0.0001 in the standard-dose group; RR, 2.04; 95% CI, 1.50 to 2.76; P < 0.0001 in the high-dose group; RR relative to the middle quintiles). The mortality rate in the lowest eKt/V quintile of the high-dose group was higher than in the full standard-dose group (RR, 1.59; 95% CI, 1.29 to 1.96; P < 0.0001). Each 0.1 eKt/V unit below the group median was associated with a 58% higher mortality in the standard-dose group (P < 0.001) and a 37% higher mortality in the high-dose group (P < 0.001). The magnitude of these dose-mortality effects was seven- to 12-fold higher than the upper limit of the 95% CI from the intention-to-treat analysis. The effects were attenuated in lagged analyses but did not disappear. When dialysis dose is targeted closely, as under the controlled conditions of the Hemodialysis Study, patients with the lowest achieved dose relative to their target dose experience markedly increased mortality, to a degree that is not compatible with a biologic effect of dose. The possibility of similar (albeit smaller) biases should be considered when analyzing observational data sets relating mortality to achieved dose of dialysis. PMID:16192421

  18. Universality properties of school-based preventive intervention targeted at cannabis use.

    PubMed

    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. PMID:24420651

  19. New targets in the search for preventive and therapeutic agents for botulism.

    PubMed

    Anniballi, Fabrizio; Lonati, Davide; Fiore, Alfonsina; Auricchio, Bruna; De Medici, Dario; Locatelli, Carlo Alessandro

    2014-09-01

    Botulism is a severe neuroparalytic disease resulting from exposure to one of the most poisonous toxins to humans. Because of this high potency and the use of toxins as biological weapons, botulism is a public health concern and each case represents an emergency. Current therapy involves respiratory supportive care and anti-toxins administration. As a preventive measure, vaccination against toxins represents an effective strategy but is undesirable due the rarity of botulism and the effectiveness of toxins in treating several neuromuscular disorders. This paper summarizes the current issues in botulism treatment and prevention, highlighting the challenge for future researches.

  20. Incorporating Health and Behavioral Consequences of Child Abuse in Prevention Programs Targeting Female Adolescents.

    ERIC Educational Resources Information Center

    Buzi, Ruth S.; Weinman, Maxine L.; Smith, Peggy B.

    1998-01-01

    Examined the health and behavioral consequences of child abuse, comparing parenting and never-pregnant teens. Both groups identified major consequences of suicide, prostitution, school drop-out, crime, and substance abuse. Parenting teens expressed interest in prevention programs that would address these consequences. Recommendations for child…

  1. A Systematic Review of Universal Campaigns Targeting Child Physical Abuse Prevention

    ERIC Educational Resources Information Center

    Poole, Mary Kathryn; Seal, David W.; Taylor, Catherine A.

    2014-01-01

    The purpose of this review was to better understand the impact of universal campaign interventions with a media component aimed at preventing child physical abuse (CPA). The review included 17 studies featuring 15 campaigns conducted from 1989 to 2011 in five countries. Seven studies used experimental designs, but most were quasi-experimental. CPA…

  2. Building Evidence for a Prevention-Focused Education Program Targeting Parents of Infants and Toddlers

    ERIC Educational Resources Information Center

    Mendel, Whitney E.; Tomasello, Nicole M.; Nochajski, Thomas H.

    2012-01-01

    A lack of parenting skills puts young children at greater risk of maltreatment, and impedes healthy child development. Using a combination of a pre-post and post-only design, a prevention-focused parenting education workshop series was assessed to determine its influence on parenting knowledge and self-efficacy. Outcome measures indicated that…

  3. Early Life Viral Infections and the Development of Asthma – A Target for Asthma Prevention?

    PubMed Central

    Jackson, Daniel J.

    2014-01-01

    Purpose of the Review To discuss recent insights into the relationships between viral respiratory infections and asthma inception in the context of a long-term goal of moving towards prevention strategies for childhood asthma. Recent Findings There is strong evidence for respiratory syncytial virus (RSV) and human rhinovirus (RV) wheezing illnesses as important risk factors for asthma inception. The mechanisms underlying these relationships have been an intense area of study. Novel approaches for the prevention of virus infections and/or lessening the severity of associated illnesses are at various stages of development, and are important potential tools in efforts aimed at primary and secondary prevention of asthma. Summary Viral respiratory infections in early life are a major source of morbidity and critical in the development of asthma. Mechanisms by which these infections lead to asthma inception in susceptible individuals are emerging. Further, there are promising potential interventions currently available that should be tested in clinical trials. The goal of prevention of disease inception is clearly on the horizon. PMID:24569522

  4. Straight Talking for Targeted Pre-Schoolers: A Substance Abuse Prevention Manual.

    ERIC Educational Resources Information Center

    Heggins, Martha Jean; And Others

    This manual provides a substance abuse prevention curriculum for preschoolers that includes numerous activities that can be used in traditional learning centers. Unit One helps caregivers examine their style of interacting with young children and identify strategies that will facilitate children's problem solving, critical thinking, and decision…

  5. Outcomes of a pilot obesity prevention plus intervention targeting children and parenting practices

    Technology Transfer Automated Retrieval System (TEKTRAN)

    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...

  6. New Approaches to Prevent LEOPARD Syndrome-associated Cardiac Hypertrophy by Specifically Targeting Shp2-dependent Signaling*

    PubMed Central

    Schramm, Christine; Edwards, Michelle A.; Krenz, Maike

    2013-01-01

    In LEOPARD syndrome (LS) patients, mutations in the protein tyrosine phosphatase Shp2 cause hypertrophic cardiomyopathy. The prohypertrophic effects of mutant Shp2 are mediated downstream by hyperactivation of mammalian target of rapamycin. Our goal was to further define the signaling cascade that is essential for the underlying pathomechanism, thus expanding the list of potential future therapeutic targets. Using cultured neonatal rat cardiomyocytes with adenoviral gene delivery and pharmacological inhibitors, we found that hypertrophy induced by a particularly aggressive LS mutation in Shp2 depends on hyperactivation of Akt and focal adhesion kinase as well as mammalian target of rapamycin. Dissecting domain-specific functions of Shp2 using double and truncation mutants, we determined that the hypertrophic effects of mutant Shp2 depend on the two SH2 domains and on an intact catalytic center. The latter finding prompted us to test the efficacy of a Shp2 inhibitor targeted directly at the catalytic pocket. This compound, PHPS1, effectively prevented mutant Shp2-induced hypertrophy. In summary, we identified three novel targets for pharmacological therapy of LS-associated cardiac hypertrophy. Of particular importance is the finding that intervention directly at the mutant Shp2 protein is effective because this would facilitate custom-tailored therapeutic approaches for patients carrying LS mutations in Shp2. PMID:23673659

  7. Framework for Optimal Global Vaccine Stockpile Design for Vaccine-Preventable Diseases: Application to Measles and Cholera Vaccines as Contrasting Examples.

    PubMed

    Thompson, Kimberly M; Duintjer Tebbens, Radboud J

    2016-07-01

    Managing the dynamics of vaccine supply and demand represents a significant challenge with very high stakes. Insufficient vaccine supplies can necessitate rationing, lead to preventable adverse health outcomes, delay the achievements of elimination or eradication goals, and/or pose reputation risks for public health authorities and/or manufacturers. This article explores the dynamics of global vaccine supply and demand to consider the opportunities to develop and maintain optimal global vaccine stockpiles for universal vaccines, characterized by large global demand (for which we use measles vaccines as an example), and nonuniversal (including new and niche) vaccines (for which we use oral cholera vaccine as an example). We contrast our approach with other vaccine stockpile optimization frameworks previously developed for the United States pediatric vaccine stockpile to address disruptions in supply and global emergency response vaccine stockpiles to provide on-demand vaccines for use in outbreaks. For measles vaccine, we explore the complexity that arises due to different formulations and presentations of vaccines, consideration of rubella, and the context of regional elimination goals. We conclude that global health policy leaders and stakeholders should procure and maintain appropriate global vaccine rotating stocks for measles and rubella vaccine now to support current regional elimination goals, and should probably also do so for other vaccines to help prevent and control endemic or epidemic diseases. This work suggests the need to better model global vaccine supplies to improve efficiency in the vaccine supply chain, ensure adequate supplies to support elimination and eradication initiatives, and support progress toward the goals of the Global Vaccine Action Plan. PMID:25109229

  8. Framework for Optimal Global Vaccine Stockpile Design for Vaccine-Preventable Diseases: Application to Measles and Cholera Vaccines as Contrasting Examples.

    PubMed

    Thompson, Kimberly M; Duintjer Tebbens, Radboud J

    2016-07-01

    Managing the dynamics of vaccine supply and demand represents a significant challenge with very high stakes. Insufficient vaccine supplies can necessitate rationing, lead to preventable adverse health outcomes, delay the achievements of elimination or eradication goals, and/or pose reputation risks for public health authorities and/or manufacturers. This article explores the dynamics of global vaccine supply and demand to consider the opportunities to develop and maintain optimal global vaccine stockpiles for universal vaccines, characterized by large global demand (for which we use measles vaccines as an example), and nonuniversal (including new and niche) vaccines (for which we use oral cholera vaccine as an example). We contrast our approach with other vaccine stockpile optimization frameworks previously developed for the United States pediatric vaccine stockpile to address disruptions in supply and global emergency response vaccine stockpiles to provide on-demand vaccines for use in outbreaks. For measles vaccine, we explore the complexity that arises due to different formulations and presentations of vaccines, consideration of rubella, and the context of regional elimination goals. We conclude that global health policy leaders and stakeholders should procure and maintain appropriate global vaccine rotating stocks for measles and rubella vaccine now to support current regional elimination goals, and should probably also do so for other vaccines to help prevent and control endemic or epidemic diseases. This work suggests the need to better model global vaccine supplies to improve efficiency in the vaccine supply chain, ensure adequate supplies to support elimination and eradication initiatives, and support progress toward the goals of the Global Vaccine Action Plan.

  9. Heart disease education and prevention program targeting immigrant Latinos: using focus group responses to develop effective interventions.

    PubMed

    Moreno, C; Alvarado, M; Balcazar, H; Lane, C; Newman, E; Ortiz, G; Forrest, M

    1997-12-01

    Although research has provided considerable knowledge concerning the positive effects of behavioral change on morbidity and mortality from heart disease and related risk factors, some segments of the population have not benefited equitably from this information. In April 1995, the National Heart, Lung, and Blood Institute (NHLBI) conducted seven focus groups to determine knowledge and attitudes about heart disease and associated risk factors, identify media usage and preferences, and assess publications usage and preferences among Spanish-speaking Latino immigrants residing in the Washington, D.C., metropolitan area. This information was gathered to assist in the development of key messages and strategies for the NHLBI Latino Community Cardiovascular Disease Prevention and Outreach Initiative, Salud para su Corazón--a heart disease prevention and education campaign. Findings from these focus groups indicate that Latinos may not benefit from heart disease prevention messages developed for the general population because of language and cultural differences. The researchers concluded that health education and disease prevention programs targeting the Latino community should develop educational materials and interventions that address language preferences and cultural values. Furthermore, to be effective, these programs should show people how to make positive behavioral changes based on their current circumstances, while remaining sensitive to the fact that Latino immigrants face major life adjustments and many are still greatly influenced by their country of origin.

  10. Targeting Inflammatory Pathways by Triterpenoids for Prevention and Treatment of Cancer

    PubMed Central

    Yadav, Vivek R.; Prasad, Sahdeo; Sung, Bokyung; Kannappan, Ramaswamy; Aggarwal, Bharat B.

    2010-01-01

    Traditional medicine and diet has served mankind through the ages for prevention and treatment of most chronic diseases. Mounting evidence suggests that chronic inflammation mediates most chronic diseases, including cancer. More than other transcription factors, nuclear factor-kappaB (NF-κB) and STAT3 have emerged as major regulators of inflammation, cellular transformation, and tumor cell survival, proliferation, invasion, angiogenesis, and metastasis. Thus, agents that can inhibit NF-κB and STAT3 activation pathways have the potential to both prevent and treat cancer. In this review, we examine the potential of one group of compounds called triterpenes, derived from traditional medicine and diet for their ability to suppress inflammatory pathways linked to tumorigenesis. These triterpenes include avicins, betulinic acid, boswellic acid, celastrol, diosgenin, madecassic acid, maslinic acid, momordin, saikosaponins, platycodon, pristimerin, ursolic acid, and withanolide. This review thus supports the famous adage of Hippocrates, “Let food be thy medicine and medicine be thy food”. PMID:22069560

  11. Tanning, Skin Cancer Risk, and Prevention: A Content Analysis of Eight Popular Magazines that Target Female Readers, 1997–2006

    PubMed Central

    Cho, Hyunyi; Hall, Jennifer G.; Kosmoski, Carin; Fox, Rebekah L.; Mastin, Teresa

    2008-01-01

    The majority of tanning bed users in the U.S. are women. Previous health communication research frequently focused on the risk of skin cancer, but few studies assessed the mediated communication environment that may surround women’s beliefs and behaviors relevant to tanning. A content analysis of articles in eight magazines targeting girls, young women, older women, and women who are interested in fitness during the ten-year period of 1997–2006 was conducted. The amount of coverage of tanning bed use consequences was less than 50% of the coverage of tanning benefits. About 40% of the tanning benefits coverage touted looking healthy. The coverage of prevention methods focused on sunscreen use (55%), while the more important methods (e.g., protective clothing use) were rarely featured. Longitudinally, the coverage of the risk and prevention relevant issues increased between 1997 and 2006. The data indicate that the coverage of tanning benefits also increased during the same period. PMID:20228954

  12. Prior Knowledge of Potential School-Based Violence: Information Students Learn May Prevent a Targeted Attack

    ERIC Educational Resources Information Center

    Pollack, William S.; Modzeleski, William; Rooney, Georgeann

    2008-01-01

    In the wake of several high-profile shootings at schools in the United States, most notably the shootings that occurred at Columbine High School on April 20, 1999, the United States Secret Service (Secret Service) and the United States Department of Education (ED) embarked on a collaborative endeavor to study incidents of planned (or "targeted")…

  13. Targeting Inflammation to Prevent Bronchopulmonary Dysplasia: Can New Insights Be Translated Into Therapies?

    PubMed Central

    Kirpalani, Haresh

    2011-01-01

    Bronchopulmonary dysplasia (BPD) frequently complicates preterm birth and leads to significant long-term morbidity. Unfortunately, few therapies are known to effectively prevent or treat BPD. Ongoing research has been focusing on potential therapies to limit inflammation in the preterm lung. In this review we highlight recent bench and clinical research aimed at understanding the role of inflammation in the pathogenesis of BPD. We also critically assess currently used therapies and promising developments in the field. PMID:21646264

  14. A Novel Theranostic Platform for Targeted Cancer Therapy and Treatment Monitoring | Division of Cancer Prevention

    Cancer.gov

    DESCRIPTION (provided by applicant): Cancer treatment currently relies heavily upon administration of cytotoxic drugs that attack both cancerous and healthy cells due to limited selectivity of drugs. Therapeutic efficacy and systemic toxicity can be improved by employing a multifunctional drug delivery system that allows targeted drug delivery, controlled drug release and therapeutic effect monitoring. The integration of therapeutic and diagnostic treatments has created a new genre in patient care and personalized medicine termed theranostics. |

  15. EGFR blockade prevents glioma escape from BRAFV600E targeted therapy

    PubMed Central

    Prados, Michael; Weiss, William A.; James, C. David; Nicolaides, Theodore

    2015-01-01

    Mutational activation of BRAF (BRAFV600E) occurs in pediatric glioma and drives aberrant MAPK signaling independently of upstream cues. Targeted monotherapy against BRAFV600E displays efficacy in pre-clinical models of glioma, however xenograft tumors adapt rapidly and escape from the growth-inhibitory effects of BRAF-targeted therapy. Here, we show that intrinsic resistance to a BRAFV600E specific inhibitor stems, in part, from feedback activation of EGFR and downstream signaling pathways. BRAFV600E inhibition suppresses MAPK signaling, which in turn downregulates the EGFR phosphatase PTPN9, resulting in sustained EGFR phosphorylation and enhanced EGFR activity. We demonstrated that overexpression of PTPN9 reduces EGFR phosphorylation and cooperates with BRAFV600E inhibitor PLX4720 to reduce MAPK and Akt signaling, resulting in decreased glioma cell viability. Moreover, pharmacologic inhibition of EGFR combined with inhibition of BRAFV600E to reduce growth of glioma cell lines and orthotopic glioma xenograft by decreasing tumor cell proliferation while increasing apoptosis, with resultant significant extension of animal subject survival. Our data support clinical evaluation of BRAFV600E and EGFR targeted therapy in treating BRAFV600E glioma. PMID:26023796

  16. Informing HIV prevention efforts targeting Liberian youth: a study using the PLACE method in Liberia

    PubMed Central

    2013-01-01

    Background Preventing HIV infection among young people is a priority for the Liberian government. Data on the young people in Liberia are scarce but needed to guide HIV programming efforts. Methods We used the Priorities for Local AIDS Control Efforts (PLACE) method to gather information on risk behaviors that young people (ages 14 to 24) engage in or are exposed to that increase their vulnerability for HIV infection. Community informants identified 240 unique venues of which 150 were visited and verified by research staff. 89 of the 150 venues comprised our sampling frame and 571 females and 548 males were interviewed in 50 venues using a behavioral survey. Results Ninety-one percent of females and 86% of males reported being sexually active. 56% of females and 47% of males reported they initiated sexual activity before the age of 15. Among the sexually active females, 71% reported they had received money or a gift for sex and 56% of males reported they had given money or goods for sex. 20% of females and 6% males reported that their first sexual encounter was forced and 15% of females and 6% of males reported they had been forced to have sex in the past year. Multiple partnerships were common among both sexes with 81% females and 76% males reporting one or more sex partners in the past four weeks. Less than 1% reported having experiences with injecting drugs and only 1% of males reporting have sex with men. While knowledge of HIV/AIDS was high, prevention behaviors including HIV testing and condom use were low. Conclusion Youth-focused HIV efforts in Liberia need to address transactional sex and multiple and concurrent partnerships. HIV prevention interventions should include efforts to meet the economic needs of youth. PMID:24107301

  17. Targeting Toll-like receptor 4 prevents cobalt-mediated inflammation.

    PubMed

    Lawrence, Helen; Mawdesley, Amy Elizabeth; Holland, James Patrick; Kirby, John Andrew; Deehan, David John; Tyson-Capper, Alison Jane

    2016-02-16

    Cobalt-chrome alloy is a widely used biomaterial in joint replacements, dental implants and spinal rods. Although it is an effective and biocompatible material, adverse reactions to metal debris (ARMD) have arisen in a minority of patients, particularly in those with metal-on-metal bearing hip replacements. There is currently no treatment for ARMD and once progressive, early revision surgery of the implant is necessary. Therapeutic agents to prevent, halt or reverse ARMD would therefore be advantageous. Cobalt ions activate Toll-like receptor 4 (TLR4), an innate immune receptor responsible for inflammatory responses to bacterial lipopolysaccharide (LPS) resulting in the production of pro-inflammatory cytokines and chemokines. We hypothesised that anti-TLR4 neutralising antibodies, reported to inhibit TLR4-mediated inflammation, could prevent the inflammatory response to cobalt ions in an in vitro macrophage cell culture model. This study shows that a monoclonal anti-TLR4 antibody inhibited cobalt-mediated increases in pro-inflammatory IL8, CCL20 and IL1A expression, as well as IL-8 secretion. In contrast, a polyclonal antibody did not prevent the effect of cobalt ions on either IL-8 or IL1A expression, although it did have a small effect on the CCL20 response. Interestingly, both antibodies inhibited cobalt-mediated neutrophil migration although the greater effect was observed with the monoclonal antibody. In summary our data shows that a monoclonal anti-TLR4 antibody can inhibit cobalt-mediated inflammatory responses while a polyclonal antibody only inhibits the effect of specific cytokines. Anti-TLR4 antibodies have therapeutic potential in ARMD although careful antibody design is required to ensure that the LPS response is preserved. PMID:26840091

  18. Targeting Toll-like receptor 4 prevents cobalt-mediated inflammation

    PubMed Central

    Lawrence, Helen; Mawdesley, Amy Elizabeth; Holland, James Patrick; Kirby, John Andrew; Deehan, David John; Tyson-Capper, Alison Jane

    2016-01-01

    Cobalt-chrome alloy is a widely used biomaterial in joint replacements, dental implants and spinal rods. Although it is an effective and biocompatible material, adverse reactions to metal debris (ARMD) have arisen in a minority of patients, particularly in those with metal-on-metal bearing hip replacements. There is currently no treatment for ARMD and once progressive, early revision surgery of the implant is necessary. Therapeutic agents to prevent, halt or reverse ARMD would therefore be advantageous. Cobalt ions activate Toll-like receptor 4 (TLR4), an innate immune receptor responsible for inflammatory responses to bacterial lipopolysaccharide (LPS) resulting in the production of pro-inflammatory cytokines and chemokines. We hypothesised that anti-TLR4 neutralising antibodies, reported to inhibit TLR4-mediated inflammation, could prevent the inflammatory response to cobalt ions in an in vitro macrophagecell culture model. This study shows that a monoclonal anti-TLR4 antibody inhibited cobalt-mediated increases in pro-inflammatory IL8, CCL20 and IL1A expression, as well as IL-8 secretion. In contrast, a polyclonal antibody did not prevent the effect of cobalt ions on either IL-8 or IL1A expression, although it did have a small effect on the CCL20 response. Interestingly, both antibodies inhibited cobalt-mediated neutrophil migration although the greater effect was observed with the monoclonal antibody. In summary our data shows that a monoclonal anti-TLR4 antibody can inhibit cobalt-mediated inflammatory responses while a polyclonal antibody only inhibits the effect of specific cytokines. Anti-TLR4 antibodies have therapeutic potential in ARMD although careful antibody design is required to ensure that the LPS response is preserved. PMID:26840091

  19. Targeting Toll-like receptor 4 prevents cobalt-mediated inflammation.

    PubMed

    Lawrence, Helen; Mawdesley, Amy Elizabeth; Holland, James Patrick; Kirby, John Andrew; Deehan, David John; Tyson-Capper, Alison Jane

    2016-02-16

    Cobalt-chrome alloy is a widely used biomaterial in joint replacements, dental implants and spinal rods. Although it is an effective and biocompatible material, adverse reactions to metal debris (ARMD) have arisen in a minority of patients, particularly in those with metal-on-metal bearing hip replacements. There is currently no treatment for ARMD and once progressive, early revision surgery of the implant is necessary. Therapeutic agents to prevent, halt or reverse ARMD would therefore be advantageous. Cobalt ions activate Toll-like receptor 4 (TLR4), an innate immune receptor responsible for inflammatory responses to bacterial lipopolysaccharide (LPS) resulting in the production of pro-inflammatory cytokines and chemokines. We hypothesised that anti-TLR4 neutralising antibodies, reported to inhibit TLR4-mediated inflammation, could prevent the inflammatory response to cobalt ions in an in vitro macrophage cell culture model. This study shows that a monoclonal anti-TLR4 antibody inhibited cobalt-mediated increases in pro-inflammatory IL8, CCL20 and IL1A expression, as well as IL-8 secretion. In contrast, a polyclonal antibody did not prevent the effect of cobalt ions on either IL-8 or IL1A expression, although it did have a small effect on the CCL20 response. Interestingly, both antibodies inhibited cobalt-mediated neutrophil migration although the greater effect was observed with the monoclonal antibody. In summary our data shows that a monoclonal anti-TLR4 antibody can inhibit cobalt-mediated inflammatory responses while a polyclonal antibody only inhibits the effect of specific cytokines. Anti-TLR4 antibodies have therapeutic potential in ARMD although careful antibody design is required to ensure that the LPS response is preserved.

  20. Food and Play Preferences - Does Cancer Prevention Require Targeting the Child?

    PubMed

    Moore, Malcolm A; Tsuda, Hiroyuki

    2002-01-01

    Food preferences and habits regarding physical exercise and play regimens appear to become set relatively early in life, the mother being the major influence at this stage. Subsequently, the peer group takes on increasing importance, with continued roles for teachers and parents in providing an environment and guidance leading to adoption of a healthy or an unhealthy lifestyle. Since so many of the decisions that will determine exposure to risk and beneficial factors hinge on experience up to and through adolescence, the question arises as to whether more cancer prevention efforts should be directed at children and youths.

  1. Local microRNA delivery targets Palladin and prevents metastatic breast cancer.

    PubMed

    Gilam, Avital; Conde, João; Weissglas-Volkov, Daphna; Oliva, Nuria; Friedman, Eitan; Artzi, Natalie; Shomron, Noam

    2016-01-01

    Metastasis is the primary cause for mortality in breast cancer. MicroRNAs, gene expression master regulators, constitute an attractive candidate to control metastasis. Here we show that breast cancer metastasis can be prevented by miR-96 or miR-182 treatment, and decipher the mechanism of action. We found that miR-96/miR-182 downregulate Palladin protein levels, thereby reducing breast cancer cell migration and invasion. A common SNP, rs1071738, at the miR-96/miR-182-binding site within the Palladin 3'-UTR abolishes miRNA:mRNA binding, thus diminishing Palladin regulation by these miRNAs. Regulation is successfully restored by applying complimentary miRNAs. A hydrogel-embedded, gold-nanoparticle-based delivery vehicle provides efficient local, selective, and sustained release of miR-96/miR-182, markedly suppressing metastasis in a breast cancer mouse model. Combined delivery of the miRNAs with a chemotherapy drug, cisplatin, enables significant primary tumour shrinkage and metastasis prevention. Our data corroborate the role of miRNAs in metastasis, and suggest miR-96/miR-182 delivery as a potential anti-metastatic drug. PMID:27641360

  2. Evidence-based recommendations for the development of obesity prevention programs targeted at preschool children.

    PubMed

    Summerbell, C D; Moore, H J; Vögele, C; Kreichauf, S; Wildgruber, A; Manios, Y; Douthwaite, W; Nixon, C A; Gibson, E L

    2012-03-01

    The ToyBox intervention was developed using an evidence-based approach, using the findings of four reviews. These reviews included three critical and narrative reviews of educational strategies and psychological approaches explaining young children's acquisition and formation of energy-balance related behaviours, and the management of these behaviours, and also a systematic review of behavioural models underpinning school-based interventions in preschool and school settings for the prevention of obesity in children aged 4-6 years. This paper summarises and translates the findings from these reviews into practical evidence based recommendations for researchers and policy-makers to consider when developing and implementing interventions for the prevention of overweight and obesity in young (aged 4-6 years) children. The recommendations focus on two behaviours, physical activity and sedentary behaviour, and healthy eating, and include general recommendations, intervention approaches, interventions content, and simple messages. The review also briefly examines the role that the commercial sector plays in hindering or facilitating attempts to create healthy food environments for children. This paper also recognises that childhood obesity is not an issue for the education sector alone; it needs to be tackled at a multi sectoral level, recognizing the particularly important role of local governments, nongovernment organizations and the media.

  3. Childhood obesity prevention: an intervention targeting primary caregivers of school children.

    PubMed

    Bruss, Mozhdeh B; Michael, Timothy J; Morris, Joseph R; Applegate, Brooks; Dannison, Linda; Quitugua, Jackie A; Palacios, Rosa T; Klein, David J

    2010-01-01

    Community-based participatory research (CBPR) was used to design and evaluate the effectiveness of a culturally relevant, science-based intervention for the prevention of childhood obesity in the Commonwealth of the Northern Mariana Islands (CNMI), a US Commonwealth in the western Pacific. This cognitive behavioral lifestyle intervention, Project Familia Giya Marianas (PFGM), was offered during the 2005-2007 school years in all CNMI public elementary schools over eight sessions to primary caregivers of 3rd grade children (N = 407). A crossover design was utilized with half of the schools offering the intervention in the Fall term, while the other half delivered the sessions in the Spring term. The primary outcome measure was change in BMI z-score. There was an intervention-dependent effect on BMI z-score, with program impact being a function of baseline BMI and the number of lessons attended. This effect was most apparent in students whose baseline BMI z-score was in healthy range (>/=5 to <85 percentile). In both Asian and Pacific Island groups, children whose caregivers completed 5-8 lessons experienced a significant change in BMI z-score as compared to those with 0 lessons (P < 0.05). Research that integrates multidisciplinary and multimethod approaches is effective in identifying and/or devising solutions to address a complex condition such as childhood obesity. PFGM demonstrated that community participation can be successfully utilized in the development and implementation of childhood obesity prevention programs.

  4. Local microRNA delivery targets Palladin and prevents metastatic breast cancer

    PubMed Central

    Gilam, Avital; Conde, João; Weissglas-Volkov, Daphna; Oliva, Nuria; Friedman, Eitan; Artzi, Natalie; Shomron, Noam

    2016-01-01

    Metastasis is the primary cause for mortality in breast cancer. MicroRNAs, gene expression master regulators, constitute an attractive candidate to control metastasis. Here we show that breast cancer metastasis can be prevented by miR-96 or miR-182 treatment, and decipher the mechanism of action. We found that miR-96/miR-182 downregulate Palladin protein levels, thereby reducing breast cancer cell migration and invasion. A common SNP, rs1071738, at the miR-96/miR-182-binding site within the Palladin 3′-UTR abolishes miRNA:mRNA binding, thus diminishing Palladin regulation by these miRNAs. Regulation is successfully restored by applying complimentary miRNAs. A hydrogel-embedded, gold-nanoparticle-based delivery vehicle provides efficient local, selective, and sustained release of miR-96/miR-182, markedly suppressing metastasis in a breast cancer mouse model. Combined delivery of the miRNAs with a chemotherapy drug, cisplatin, enables significant primary tumour shrinkage and metastasis prevention. Our data corroborate the role of miRNAs in metastasis, and suggest miR-96/miR-182 delivery as a potential anti-metastatic drug. PMID:27641360

  5. Molecular approaches toward targeted cancer prevention with some food plants and their products: inflammatory and other signal pathways.

    PubMed

    Khuda-Bukhsh, Anisur Rahman; Das, Sreemanti; Saha, Santu Kumar

    2014-01-01

    In recent years, there has been growing interest in cancer prevention by food plants and their products. Although several plant parts have potentials for chemoprevention and other therapeutic use, their molecular mechanisms of action are not always well understood. Extensive research has identified several molecular targets that can potentially be used for the prevention and/or treatment of cancer. In this review, we accumulate evidences of modulating abilities of some dietary plants and their products on several signaling pathways, including the inflammatory and apoptotic ones, which may be targeted for cancer therapy. We have mainly focused on several phytochemicals like resveratrol (red grapes and peanuts), allicin (garlic), lycopene (tomato), indole-3-carbinol (cruciferous vegetables), vitamin C (citrus fruits), [6]-gingerol (ginger), emodin (aloe), natural antioxidant mixture (spinach), beta carotenoids (carrots), sulphoraphane (mustard), ellagic acid (pomegranate), myrecitin (cranberry), carnosol (rosemary), vanillin (vanilla) and eugenol (cloves). They act through one or more signaling pathways like nuclear factor kappa B, cyclooxygenase-2, signal transducer and activator of transcription 3, Akt, mitogen activated protein kinase/extracellular regulated kinase, Bcl-2, caspases, poly (ADP-ribose) polymerase, matrix metalloproteinase 2/9, and cyclin D1. Critical knowledge on these compounds and their signaling pathways may help in formulation of effective anticancer drugs.

  6. Transplant graft vasculopathy: an emerging target for prevention and treatment of renal allograft dysfunction.

    PubMed

    Kang, Duk-Hee; Kang, Shin-Wook; Jeong, Hyeon Joo; Kim, Yu Seun; Yang, Chul Woo; Johnson, Richard J

    2004-12-31

    Maintenance of healthy endothelium is essential to vascular homeostasis, and preservation of endothelial cell function is critical for transplant allograft function. Damage of microvascular endothelial cells is now regarded as a characteristic feature of acute vascular rejection and chronic allograft nephropathy, which is an important predictor of graft loss and is often associated with transplant vasculopathy. In this review, we will discuss the role of microvascular endothelium, in renal allograft dysfunction, particularly as it relates to markers of endothelial dysfunction and endothelial repair mechanisms. We also discuss the potential for therapies targeting endothelial dysfunction and transplant graft vasculopathy.

  7. Peripartum depression and anxiety as an integrative cross domain target for psychiatric preventative measures.

    PubMed

    Babb, Jessica A; Deligiannidis, Kristina M; Murgatroyd, Christopher A; Nephew, Benjamin C

    2015-01-01

    Exposure to high levels of early life stress has been identified as a potent risk factor for neurodevelopmental delays in infants, behavioral problems and autism in children, but also for several psychiatric illnesses in adulthood, such as depression, anxiety, autism, and posttraumatic stress disorder. Despite having robust adverse effects on both mother and infant, the pathophysiology of peripartum depression and anxiety are poorly understood. The objective of this review is to highlight the advantages of using an integrated approach addressing several behavioral domains in both animal and clinical studies of peripartum depression and anxiety. It is postulated that a greater focus on integrated cross domain studies will lead to advances in treatments and preventative measures for several disorders associated with peripartum depression and anxiety.

  8. Controlling Hypertension to Prevent Target Organ Damage: Perspectives from the World Hypertension League President.

    PubMed

    Lackland, Daniel T

    2016-01-01

    The evidence from epidemiological and observational studies over the past five decades consistently identify a significant association of blood pressure level and disease risks for both sexes, all races and cultures, as well as all age groups. The evidence is strong such that clinical guidelines and intervention programs focus on blood pressure management and lower blood pressure levels for primary and secondary stroke prevention supported and promoted by numerous organizations including the World Hypertension League. These comprehensive components of population risk reduction are ideal models for the clinical medicine and population health partnership, and timely for global implementation. The accelerated decline in blood pressure-related outcomes (eg, stroke mortality), which began in the 1970s in the US and Western countries, included models for aggressive detection, treatment and control strategies for hypertension. These strategies can be implemented on a global scale to respond to the global risks from blood pressure, which is developing in the most vulnerable populations. PMID:27440963

  9. Low Fitness in Midlife: A Novel Therapeutic Target for Heart Failure with Preserved Ejection Fraction Prevention.

    PubMed

    Pandey, Ambarish; Darden, Douglas; Berry, Jarett D

    2015-01-01

    Heart failure (HF) with preserved ejection fraction (HFpEF) is common and recalcitrant to any medical therapy, highlighting the need for novel strategies focused on its prevention. Recent studies have shown that low cardiorespiratory fitness (CRF) in middle age identifies a subgroup of individuals at particularly high risk for HF, particularly HFpEF. These findings suggest that low CRF in middle age represents an upstream marker for late-life HFpEF. Furthermore, evidence from recent epidemiological studies suggests that low CRF associated risk for HFpEF appears to be modifiable with improvement in CRF. The primary objective of this review is to provide an overview of the potential mechanisms through which exercise training and improvement in CRF may protect against the transition from a low fit stage to clinical HFpEF among at-risk sedentary, middle-age adults.

  10. PERIPARTUM DEPRESSION AND ANXIETY AS AN INTEGRATIVE CROSS DOMAIN TARGET FOR PSYCHIATRIC PREVENTATIVE MEASURES

    PubMed Central

    Babb, Jessica A.; Deligiannidis, Kristina M.; Murgatroyd, Christopher A.

    2014-01-01

    Exposure to high levels of early life stress has been identified as a potent risk factor for neurodevelopmental delays in infants, behavioral problems and autism in children, but also for several psychiatric illnesses in adulthood, such as depression, anxiety, autism, and posttraumatic stress disorder. Despite having robust adverse effects on both mother and infant, the pathophysiology of peripartum depression and anxiety are poorly understood. The objective of this review is to highlight the advantages of using an integrated approach addressing several behavioral domains in both animal and clinical studies of peripartum depression and anxiety. It is postulated that a greater focus on integrated cross domain studies will lead to advances in treatments and preventative measures for several disorders associated with peripartum depression and anxiety. PMID:24709228

  11. Targeting obesity-related adipose tissue dysfunction to prevent cancer development and progression.

    PubMed

    Gucalp, Ayca; Iyengar, Neil M; Hudis, Clifford A; Dannenberg, Andrew J

    2016-02-01

    The incidence of obesity, a leading modifiable risk factor for common solid tumors, is increasing. Effective interventions are needed to minimize the public health implications of obesity. Although the mechanisms linking increased adiposity to malignancy are incompletely understood, growing evidence points to complex interactions among multiple systemic and tissue-specific pathways including inflamed white adipose tissue. The metabolic and inflammatory consequences of white adipose tissue dysfunction collectively provide a plausible explanation for the link between overweight/obesity and carcinogenesis. Gaining a better understanding of these underlying molecular pathways and developing risk assessment tools that identify at-risk populations will be critical in implementing effective and novel cancer prevention and management strategies.

  12. New Targets for Prevention of Schizophrenia: Is It Time for Interventions in the Premorbid Phase?

    PubMed Central

    Seidman, Larry J.; Nordentoft, Merete

    2015-01-01

    A number of influences have converged that make this Special Theme Issue timely: “A New Direction: Considering Developmentally Sensitive Targets for Very Early Intervention in Schizophrenia”. These factors include: 1. the substantial knowledge about premorbid developmental vulnerabilities to psychosis, especially regarding schizophrenia; 2. the promising results emerging from interventions during the clinical high-risk (CHR) phase of psychosis and; 3. the recognition that the CHR period is a relatively late phase of developmental derailment. These factors have together led to a perspective that even earlier intervention is warranted. This paper briefly summarizes the articles comprising the Special Theme including new data on early neurocognitive development, proposed potential targets for psychosocial and psychopharmacological interventions during the premorbid period as early as pregnancy, and ethical challenges. These thought experiments must be empirically tested, and the ethical challenges overcome as posed by the various interventions, which range from relatively low risk, supportive, psychosocial to higher risk, experimental, pharmacological interventions. All of the interventions proposed require careful study of ethics, safety, potential stigma, feasibility, efficacy and tolerability, and the meaning to the people involved. PMID:25925393

  13. Targeting PPARγ Signaling Cascade for the Prevention and Treatment of Prostate Cancer

    PubMed Central

    Sikka, Sakshi; Chen, Luxi; Sethi, Gautam; Kumar, Alan Prem

    2012-01-01

    The peroxisome proliferator-activated receptor-gamma (PPARγ) is a member of the hormone-activated nuclear receptor superfamily. PPARγ can be activated by a diverse group of agents, such as endogenous polyunsaturated fatty acids, 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2), and thiazolidinedione (TZD) drugs. PPARγ induces antiproliferative, antiangiogenic, and prodifferentiation pathways in several tissue types, thus making it a highly useful target for downregulation of carcinogenesis. These TZD-derived novel therapeutic agents, alone or in combination with other anticancer drugs, have translational relevance in fostering effective strategies for cancer treatment. TZDs have been proven for antitumor activity in a wide variety of experimental cancer models, both in vitro and in vivo, by affecting the cell cycle, inducing cell differentiation and apoptosis, as well as by inhibiting tumor angiogenesis. Angiogenesis inhibition mechanisms of TZDs include direct inhibition of endothelial cell proliferation and migration, as well as reduction in tumor cell vascular endothelial growth factor production. In prostate cancer, PPARγ ligands such as troglitazone and 15d-PGJ2 have also shown to inhibit tumor growth. This paper will focus on current discoveries in PPARγ activation, targeting prostate carcinogenesis as well as the role of PPARγ as a possible anticancer therapeutic option. Here, we review PPARγ as an antitumor agent and summarize the antineoplastic effects of PPARγ agonists in prostate cancer. PMID:23213321

  14. Internet based HIV prevention research targeting rural MSM: feasibility, acceptability, and preliminary efficacy.

    PubMed

    Bowen, A M; Williams, M L; Daniel, C M; Clayton, S

    2008-12-01

    Internet delivered primary prevention interventions for HIV risk reduction present significant challenges. Changing lifestyle behaviors, such as beginning to use condoms, is difficult and men seeking dates on line may want to avoid thinking about HIV risk which may lead to low initiation and high dropout rates. Many Internet delivered HIV risk reduction programs have mimicked face-to-face outreach programs, failing to take advantage of the Internet's capabilities or did not conduct evaluation. This study focuses on examining the feasibility, acceptability, and efficacy of an Internet delivered HIV risk reduction program for rural men who have sex with men (MSM). The program included online recruiting, three intervention modules, each with two sessions, online questionnaires. The intervention was developed based on iterative research and the Information-Motivation-Behavioral skills model. Participants (N = 475) were randomly assigned to one of six module orders and data were collected automatically at pre-test and after each module. Data supports the feasibility and acceptability of the program as demonstrated by good retention and rapid program completion. Knowledge, self-efficacy, outcome expectancies and motivation increase in a dose response fashion. Post-intervention behavior changes included reduced anal sex and significant increases in condom use. Limitations include a short follow-up period, a predominantly young white rural sample, and the lack of an attention control. Overall the results of the study provide support for the efficacy of Internet-based interventions to reduce risk of HIV infection. Results also support traditional research methods to evaluate HIV prevention programs delivered exclusively through the Internet.

  15. Efficacy Trial of a Selective Prevention Program Targeting Both Eating Disorders and Obesity among Female College Students: 1- and 2-Year Follow-Up Effects

    ERIC Educational Resources Information Center

    Stice, Eric; Rohde, Paul; Shaw, Heather; Marti, C. Nathan

    2013-01-01

    Objective: Evaluate the effects of a prevention program targeting both eating disorders and obesity at 1- and 2-year follow-ups. Method: Female college students at risk for these outcomes because of body image concerns (N = 398) were randomized to the "Healthy Weight 2" group-based 4-hr prevention program, which promotes lasting healthy…

  16. Efficacy Trial of a Selective Prevention Program Targeting Both Eating Disorder Symptoms and Unhealthy Weight Gain among Female College Students

    ERIC Educational Resources Information Center

    Stice, Eric; Rohde, Paul; Shaw, Heather; Marti, C. Nathan

    2012-01-01

    Objective: Evaluate a selective prevention program targeting both eating disorder symptoms and unhealthy weight gain in young women. Method: Female college students at high-risk for these outcomes by virtue of body image concerns (N = 398; M age = 18.4 years, SD = 0.6) were randomized to the Healthy Weight group-based 4-hr prevention program,…

  17. RNA editing of microRNA prevents RNA-induced silencing complex recognition of target mRNA

    PubMed Central

    Cui, Yalei; Huang, Tianzhi; Zhang, Xiaobo

    2015-01-01

    MicroRNAs (miRNAs) integrate with Argonaut (Ago) to create the RNA-induced silencing complex, and regulate gene expression by silencing target mRNAs. RNA editing of miRNA may affect miRNA processing, assembly of the Ago complex and target mRNA binding. However, the function of edited miRNA, assembled within the Ago complex, has not been extensively investigated. In this study, sequence analysis of the Ago complex of Marsupenaeus japonicus shrimp infected with white spot syndrome virus (WSSV) revealed that host ADAR (adenosine deaminase acting on RNA) catalysed A-to-I RNA editing of a viral miRNA (WSSV-miR-N12) at the +16 site. This editing of the non-seed sequence did not affect association of the edited miRNA with the Ago protein, but inhibited interaction between the miRNA and its target gene (wsv399). The WSSV early gene wsv399 inhibited WSSV infection. As a result, the RNA editing of miRNA caused virus latency. Our results highlight a novel example of miRNA editing in the miRNA-induced silencing complex. PMID:26674414

  18. RNA editing of microRNA prevents RNA-induced silencing complex recognition of target mRNA.

    PubMed

    Cui, Yalei; Huang, Tianzhi; Zhang, Xiaobo

    2015-12-01

    MicroRNAs (miRNAs) integrate with Argonaut (Ago) to create the RNA-induced silencing complex, and regulate gene expression by silencing target mRNAs. RNA editing of miRNA may affect miRNA processing, assembly of the Ago complex and target mRNA binding. However, the function of edited miRNA, assembled within the Ago complex, has not been extensively investigated. In this study, sequence analysis of the Ago complex of Marsupenaeus japonicus shrimp infected with white spot syndrome virus (WSSV) revealed that host ADAR (adenosine deaminase acting on RNA) catalysed A-to-I RNA editing of a viral miRNA (WSSV-miR-N12) at the +16 site. This editing of the non-seed sequence did not affect association of the edited miRNA with the Ago protein, but inhibited interaction between the miRNA and its target gene (wsv399). The WSSV early gene wsv399 inhibited WSSV infection. As a result, the RNA editing of miRNA caused virus latency. Our results highlight a novel example of miRNA editing in the miRNA-induced silencing complex.

  19. Reservoir Targeted Vaccine Against Borrelia burgdorferi: A New Strategy to Prevent Lyme Disease Transmission

    PubMed Central

    Richer, Luciana Meirelles; Brisson, Dustin; Melo, Rita; Ostfeld, Richard S.; Zeidner, Nordin; Gomes-Solecki, Maria

    2014-01-01

    A high prevalence of infection with Borrelia burgdorferi in ixodid ticks is correlated with a high incidence of Lyme disease. The transmission of B. burgdorferi to humans can be disrupted by targeting 2 key elements in its enzootic cycle: the reservoir host and the tick vector. In a prospective 5-year field trial, we show that oral vaccination of wild white-footed mice resulted in outer surface protein A–specific seropositivity that led to reductions of 23% and 76% in the nymphal infection prevalence in a cumulative, time-dependent manner (2 and 5 years, respectively), whereas the proportion of infected ticks recovered from control plots varied randomly over time. Significant decreases in tick infection prevalence were observed within 3 years of vaccine deployment. Implementation of such a long-term public health measure could substantially reduce the risk of human exposure to Lyme disease. PMID:24523510

  20. Reservoir targeted vaccine against Borrelia burgdorferi: a new strategy to prevent Lyme disease transmission.

    PubMed

    Richer, Luciana Meirelles; Brisson, Dustin; Melo, Rita; Ostfeld, Richard S; Zeidner, Nordin; Gomes-Solecki, Maria

    2014-06-15

    A high prevalence of infection with Borrelia burgdorferi in ixodid ticks is correlated with a high incidence of Lyme disease. The transmission of B. burgdorferi to humans can be disrupted by targeting 2 key elements in its enzootic cycle: the reservoir host and the tick vector. In a prospective 5-year field trial, we show that oral vaccination of wild white-footed mice resulted in outer surface protein A-specific seropositivity that led to reductions of 23% and 76% in the nymphal infection prevalence in a cumulative, time-dependent manner (2 and 5 years, respectively), whereas the proportion of infected ticks recovered from control plots varied randomly over time. Significant decreases in tick infection prevalence were observed within 3 years of vaccine deployment. Implementation of such a long-term public health measure could substantially reduce the risk of human exposure to Lyme disease.

  1. siRNA Targeting the 2Apro Genomic Region Prevents Enterovirus 71 Replication In Vitro.

    PubMed

    Liu, Haibing; Qin, Yanyan; Kong, Zhenzhen; Shao, Qixiang; Su, Zhaoliang; Wang, Shengjun; Chen, Jianguo

    2016-01-01

    Enterovirus 71 (EV71) is the most important etiological agent of hand, foot, and mouth disease (HFMD) in young children, which is associated with severe neurological complications and has caused significant mortalities in recent HFMD outbreaks in Asia. However, there is no effective antiviral therapy against EV71. In this study, RNA interference (RNAi) was used as an antiviral strategy to inhibit EV71 replication. Three small interfering RNAs (siRNAs) targeting the 2Apro region of the EV71 genome were designed and synthesized. All the siRNAs were transfected individually into rhabdomyosarcoma (RD) cells, which were then infected with strain EV71-2006-52-9. The cytopathic effects (CPEs) in the infected RD cells, cell viability, viral titer, and viral RNA and protein expression were examined to evaluate the specific viral inhibition by the siRNAs. The results of cytopathogenicity and MTT tests indicated that the RD cells transfected with the three siRNAs showed slight CPEs and significantly high viability. The 50% tissue culture infective dose (TCID50) values demonstrated that the viral titer of the groups treated with three siRNAs were lower than those of the control groups. qRT-PCR and western blotting revealed that the levels of viral RNA and protein in the RD cells treated with the three siRNAs were lower than those in the controls. When RD cells transfected with siRNAs were also infected with strain EV71-2008-43-16, the expression of the VP1 protein was significantly inhibited. The levels of interferon α (IFN-α) and IFN-β did not differ significantly in any group. These results suggest that siRNAs targeting the 2Apro region of the EV71 genome exerted antiviral effects in vitro.

  2. siRNA Targeting the 2Apro Genomic Region Prevents Enterovirus 71 Replication In Vitro

    PubMed Central

    Kong, Zhenzhen; Shao, Qixiang; Su, Zhaoliang; Wang, Shengjun; Chen, Jianguo

    2016-01-01

    Enterovirus 71 (EV71) is the most important etiological agent of hand, foot, and mouth disease (HFMD) in young children, which is associated with severe neurological complications and has caused significant mortalities in recent HFMD outbreaks in Asia. However, there is no effective antiviral therapy against EV71. In this study, RNA interference (RNAi) was used as an antiviral strategy to inhibit EV71 replication. Three small interfering RNAs (siRNAs) targeting the 2Apro region of the EV71 genome were designed and synthesized. All the siRNAs were transfected individually into rhabdomyosarcoma (RD) cells, which were then infected with strain EV71-2006-52-9. The cytopathic effects (CPEs) in the infected RD cells, cell viability, viral titer, and viral RNA and protein expression were examined to evaluate the specific viral inhibition by the siRNAs. The results of cytopathogenicity and MTT tests indicated that the RD cells transfected with the three siRNAs showed slight CPEs and significantly high viability. The 50% tissue culture infective dose (TCID50) values demonstrated that the viral titer of the groups treated with three siRNAs were lower than those of the control groups. qRT–PCR and western blotting revealed that the levels of viral RNA and protein in the RD cells treated with the three siRNAs were lower than those in the controls. When RD cells transfected with siRNAs were also infected with strain EV71-2008-43-16, the expression of the VP1 protein was significantly inhibited. The levels of interferon α (IFN-α) and IFN-β did not differ significantly in any group. These results suggest that siRNAs targeting the 2Apro region of the EV71 genome exerted antiviral effects in vitro. PMID:26886455

  3. Tomato as a Source of Carotenoids and Polyphenols Targeted to Cancer Prevention.

    PubMed

    Martí, Raúl; Roselló, Salvador; Cebolla-Cornejo, Jaime

    2016-01-01

    A diet rich in vegetables has been associated with a reduced risk of many diseases related to aging and modern lifestyle. Over the past several decades, many researches have pointed out the direct relation between the intake of bioactive compounds present in tomato and a reduced risk of suffering different types of cancer. These bioactive constituents comprise phytochemicals such as carotenoids and polyphenols. The direct intake of these chemoprotective molecules seems to show higher efficiencies when they are ingested in its natural biological matrix than when they are ingested isolated or in dietary supplements. Consequently, there is a growing trend for improvement of the contents of these bioactive compounds in foods. The control of growing environment and processing conditions can ensure the maximum potential accumulation or moderate the loss of bioactive compounds, but the best results are obtained developing new varieties via plant breeding. The modification of single steps of metabolic pathways or their regulation via conventional breeding or genetic engineering has offered excellent results in crops such as tomato. In this review, we analyse the potential of tomato as source of the bioactive constituents with cancer-preventive properties and the result of modern breeding programs as a strategy to increase the levels of these compounds in the diet.

  4. Most at-risk populations: contextualising HIV prevention programmes targeting marginalised groups in Zanzibar, Tanzania.

    PubMed

    Ahmed, Naheed

    2014-09-01

    According to a 2009 UNAIDS report the HIV/AIDS prevalence rate in Zanzibar, Tanzania, is low in the general population (0.6%), but high among vulnerable groups, specifically sex workers (10.8%), injecting drug users (15.1%), and men who have sex with men (12.3%). In response to this concentrated epidemic, the Government of Zanzibar, international and local non-profit organisations have focused their prevention activities on these marginal populations. Although these efforts are beneficial in terms of disseminating information about HIV/AIDS and referring clients to health clinics, they fail to address how the socio-economic status of these groups places them at a greater risk for contracting and dying from the virus. Furthermore, there is an absence of qualitative research on these populations which is needed to understand the challenges these groups face and to improve the effectiveness of interventions. Through interviews with employees of government agencies and non-profit organisations, medical professionals, vulnerable populations and HIV/AIDS patients, this paper used a political economy of health and syndemic framework to examine how local realities inform and challenge HIV/AIDS programmes in Zanzibar.

  5. Tomato as a Source of Carotenoids and Polyphenols Targeted to Cancer Prevention

    PubMed Central

    Martí, Raúl; Roselló, Salvador; Cebolla-Cornejo, Jaime

    2016-01-01

    A diet rich in vegetables has been associated with a reduced risk of many diseases related to aging and modern lifestyle. Over the past several decades, many researches have pointed out the direct relation between the intake of bioactive compounds present in tomato and a reduced risk of suffering different types of cancer. These bioactive constituents comprise phytochemicals such as carotenoids and polyphenols. The direct intake of these chemoprotective molecules seems to show higher efficiencies when they are ingested in its natural biological matrix than when they are ingested isolated or in dietary supplements. Consequently, there is a growing trend for improvement of the contents of these bioactive compounds in foods. The control of growing environment and processing conditions can ensure the maximum potential accumulation or moderate the loss of bioactive compounds, but the best results are obtained developing new varieties via plant breeding. The modification of single steps of metabolic pathways or their regulation via conventional breeding or genetic engineering has offered excellent results in crops such as tomato. In this review, we analyse the potential of tomato as source of the bioactive constituents with cancer-preventive properties and the result of modern breeding programs as a strategy to increase the levels of these compounds in the diet. PMID:27331820

  6. Glycogen Synthase Kinase-3: A Potential Preventive Target for Prostate Cancer Management

    PubMed Central

    Li, Benyi; Thrasher, J. Brantley; Terranova, Paul

    2016-01-01

    Prostate cancers are the frequently diagnosed cancers in men and patients with metastatic disease only have 28% chance for 5-year survival. Patients with low risk tumors are subjected to active surveillance while high risk cases are actively treated. Unfortunately, there is no cure for late-stage patients. Glycogen synthase kinase-3 (GSK-3, α and β) is a protein serine/threonine kinase and has diverse cellular functions and numerous substrates. Accumulating evidence indicates that GSK-3α is mainly expressed in low-risk prostate cancers and is related to hormone-dependent androgen receptor (AR)-mediated gene expression, while GSK-3β is mainly expressed in high-risk prostate cancers and is related to hormone-independent AR-mediated gene expression. GSK-3 has been demonstrated as a positive regulator in AR transactivation and prostate cancer growth independent of the Wnt/β-catenin pathway. Different types of GSK-3 inhibitors including lithium show promising results in suppressing tumor growth in different animal models of prostate cancer. Importantly, clinical use of lithium is associated with reduced cancer incidence in psychiatric patients. Taken together, GSK-3 inhibition might be implicated in prostate cancer management as a preventive treatment. PMID:26051358

  7. Tomato as a Source of Carotenoids and Polyphenols Targeted to Cancer Prevention.

    PubMed

    Martí, Raúl; Roselló, Salvador; Cebolla-Cornejo, Jaime

    2016-01-01

    A diet rich in vegetables has been associated with a reduced risk of many diseases related to aging and modern lifestyle. Over the past several decades, many researches have pointed out the direct relation between the intake of bioactive compounds present in tomato and a reduced risk of suffering different types of cancer. These bioactive constituents comprise phytochemicals such as carotenoids and polyphenols. The direct intake of these chemoprotective molecules seems to show higher efficiencies when they are ingested in its natural biological matrix than when they are ingested isolated or in dietary supplements. Consequently, there is a growing trend for improvement of the contents of these bioactive compounds in foods. The control of growing environment and processing conditions can ensure the maximum potential accumulation or moderate the loss of bioactive compounds, but the best results are obtained developing new varieties via plant breeding. The modification of single steps of metabolic pathways or their regulation via conventional breeding or genetic engineering has offered excellent results in crops such as tomato. In this review, we analyse the potential of tomato as source of the bioactive constituents with cancer-preventive properties and the result of modern breeding programs as a strategy to increase the levels of these compounds in the diet. PMID:27331820

  8. Most at-risk populations: contextualising HIV prevention programmes targeting marginalised groups in Zanzibar, Tanzania.

    PubMed

    Ahmed, Naheed

    2014-09-01

    According to a 2009 UNAIDS report the HIV/AIDS prevalence rate in Zanzibar, Tanzania, is low in the general population (0.6%), but high among vulnerable groups, specifically sex workers (10.8%), injecting drug users (15.1%), and men who have sex with men (12.3%). In response to this concentrated epidemic, the Government of Zanzibar, international and local non-profit organisations have focused their prevention activities on these marginal populations. Although these efforts are beneficial in terms of disseminating information about HIV/AIDS and referring clients to health clinics, they fail to address how the socio-economic status of these groups places them at a greater risk for contracting and dying from the virus. Furthermore, there is an absence of qualitative research on these populations which is needed to understand the challenges these groups face and to improve the effectiveness of interventions. Through interviews with employees of government agencies and non-profit organisations, medical professionals, vulnerable populations and HIV/AIDS patients, this paper used a political economy of health and syndemic framework to examine how local realities inform and challenge HIV/AIDS programmes in Zanzibar. PMID:25388975

  9. Examining targets for HIV prevention: intravaginal practices in Urban Lusaka, Zambia.

    PubMed

    Alcaide, Maria L; Chisembele, Maureen; Mumbi, Miriam; Malupande, Emeria; Jones, Deborah

    2014-03-01

    Intravaginal practices (IVP) are the introduction of products inside the vagina for hygienic, health, or sexuality reasons. The influence of men and Alengizis, traditional marriage counselors for girls, in promoting IVP has not been explored. We conducted gender-concordant focus groups and key informant interviews with Alengizis. The responses were conducted grouped into three themes: (1) cultural norms, (2) types and reasons for IVP, and (3) health consequences. We found that IVP were used by all participants in our sample and were taught from generation to generation by friends, relatives, or Alengizis. The reasons for women to engage in IVP were hygienic, though men expect women to engage in IVP to enhance sexual pleasure. Approximately 40% of women are aware that IVP can facilitate genital infections, but felt they would not feel clean discontinuing IVP. All men were unaware of the vaginal damage caused by IVP, and were concerned about the loss of sexual pleasure if women discontinued IVP. Despite the health risks of IVP, IVP continue to be widespread in Zambia and an integral component of hygiene and sexuality. The frequency of IVP mandates exploration into methods to decrease or ameliorate their use as an essential component of HIV prevention. PMID:24568672

  10. The maternal womb: a novel target for cancer prevention in the era of the obesity pandemic?

    PubMed

    Simmen, Frank A; Simmen, Rosalia C M

    2011-11-01

    The dramatic rise in worldwide prevalence of obesity has necessitated the search for more efficacious antiobesity strategies to counter the increased cancer risks in overweight and obese individuals. The mechanistic pathways linking obesity status with adult chronic diseases such as cancer remain incompletely understood. A growing body of evidence suggests that novel approaches and interventional agents to disrupt the feed-forward cycle of maternal to offspring obesity transfer that is initiated in utero will be important for stemming both the obesity pandemic and the associated increase in cancer incidence. The convergence of multiple research areas including those encompassing the insulin and insulin-like growth factor systems, epigenetics, and stem cell biology is providing insights into the potential for cancer prevention in adult offspring previously exposed to the intrauterine environment of overweight/obese mothers. Here, we review the current state of this nascent research field, with a focus on three major cancers, namely breast, colorectal, and liver, and suggest some possible future directions to optimize its impact for the health of future generations.

  11. The Diabetes Prevention Program – Targeting the consequences of the Metabolic Syndrome

    PubMed Central

    Goldberg, Ronald B; Mather, Kieren

    2013-01-01

    This review describes the effect of lifestyle change or metformin compared to standard care on incident diabetes and cardiometabolic risk factors in the Diabetes Prevention Program (DPP) and its Outcome Study. The DPP was a randomized, controlled clinical trial of intensive lifestyle and metformin treatments versus standard care in 3234 subjects at high risk for diabetes. At baseline, hypertension was present in 28%, and 53% had the metabolic syndrome, with considerable variation in risk factors by age, gender and race. Over 2.8 years, diabetes incidence fell by 58% and 31% in the lifestyle and metformin groups respectively, and metabolic syndrome prevalence fell by a third with lifestyle change but was not reduced by metformin. In placebo- and metformin-treated subjects the prevalence of hypertension and dyslipidemia increased during the DPP, while lifestyle intervention slowed these increases significantly. During long term follow up using modified interventions, diabetes incidence decreased to about 5% per year in all groups. This was accompanied by significant improvement in CVD risk factors over time in all treatment groups, in part associated with increasing use of lipid lowering and antihypertensive medications. Thus a program of lifestyle change significantly reduced diabetes incidence and metabolic syndrome prevalence in subjects at high risk for diabetes. Metformin had more modest effects. PMID:22895669

  12. Nighttime assaults: using a national emergency department monitoring system to predict occurrence, target prevention and plan services

    PubMed Central

    2012-01-01

    Background Emergency department (ED) data have the potential to provide critical intelligence on when violence is most likely to occur and the characteristics of those who suffer the greatest health impacts. We use a national experimental ED monitoring system to examine how it could target violence prevention interventions towards at risk communities and optimise acute responses to calendar, holiday and other celebration-related changes in nighttime assaults. Methods A cross-sectional examination of nighttime assault presentations (6.01 pm to 6.00 am; n = 330,172) over a three-year period (31st March 2008 to 30th March 2011) to English EDs analysing changes by weekday, month, holidays, major sporting events, and demographics of those presenting. Results Males are at greater risk of assault presentation (adjusted odds ratio [AOR] 3.14, 95% confidence intervals [CIs] 3.11-3.16; P < 0.001); with male:female ratios increasing on more violent nights. Risks peak at age 18 years. Deprived individuals have greater risks of presenting across all ages (AOR 3.87, 95% CIs 3.82-3.92; P < 0.001). Proportions of assaults from deprived communities increase midweek. Female presentations in affluent areas peak aged 20 years. By age 13, females from deprived communities exceed this peak. Presentations peak on Friday and Saturday nights and the eves of public holidays; the largest peak is on New Year’s Eve. Assaults increase over summer with a nadir in January. Impacts of annual celebrations without holidays vary. Some (Halloween, Guy Fawkes and St Patrick’s nights) see increased assaults while others (St George’s and Valentine’s Day nights) do not. Home nation World Cup football matches are associated with nearly a three times increase in midweek assault presentation. Other football and rugby events examined show no impact. The 2008 Olympics saw assaults fall. The overall calendar model strongly predicts observed presentations (R2 = 0.918; P < 0

  13. Targeting Activation of Specific NF-κB Subunits Prevents Stress-Dependent Atherothrombotic Gene Expression

    PubMed Central

    Djuric, Zdenka; Kashif, Muhammed; Fleming, Thomas; Muhammad, Sajjad; Piel, David; von Bauer, Rüdiger; Bea, Florian; Herzig, Stephan; Zeier, Martin; Pizzi, Marina; Isermann, Berend; Hecker, Markus; Schwaninger, Markus; Bierhaus, Angelika; Nawroth, Peter P

    2012-01-01

    Psychosocial stress has been shown to be a contributing factor in the development of atherosclerosis. Although the underlying mechanisms have not been elucidated entirely, it has been shown previously that the transcription factor nuclear factor-κB (NF-κB) is an important component of stress-activated signaling pathway. In this study, we aimed to decipher the mechanisms of stress-induced NF-κB-mediated gene expression, using an in vitro and in vivo model of psychosocial stress. Induction of stress led to NF-κB-dependent expression of proinflammatory (tissue factor, intracellular adhesive molecule 1 [ICAM-1]) and protective genes (manganese superoxide dismutase [MnSOD]) via p50, p65 or cRel. Selective inhibition of the different subunits and the respective kinases showed that inhibition of cRel leads to the reduction of atherosclerotic lesions in apolipoprotein−/− (ApoE−/−) mice via suppression of proinflammatory gene expression. This observation may therefore provide a possible explanation for ineffectiveness of antioxidant therapies and suggests that selective targeting of cRel activation may provide a novel approach for the treatment of stress-related inflammatory vascular disease. PMID:23114885

  14. Targeting Sleep Disordered Breathing to Prevent Heart Failure: What is the Evidence?

    PubMed Central

    Kusunose, Kenya; Mehra, Reena

    2014-01-01

    The inter-relationships of sleep disordered breathing (SDB) and heart failure (HF) are becoming increasingly well-characterized. The pathways linking the two entities are likely bi-directional and key underlying pathophysiological mechanisms at play include autonomic nervous system fluctuations, intermittent hypoxia, intrathoracic cardiac mechanical influences, rostral fluid shifts and up-regulation of systemic inflammation and oxidative stress. Given the increased morbidity and mortality which accompanies heart failure, the recognition and treatment of factors such as sleep disordered breathing is paramount in order to mitigate these untoward downstream health consequences. Recently, the management of HF requires combining several treatments including pharmacotherapy, electrophysiologic therapy, and cardiac surgery to target the various complex facets of HF. Despite the development of HF treatments, HF remains to pose a great challenge to the general cardiologist. Herein we review several interventional studies highlighting the effects of treating SDB on HF morbidity and mortality with a notable predominance of literature focusing on HF reduced ejection fraction (HF-REF) as well as emerging data describing SDB treatment effects in HF preserved EF (HF-PEF). These data are compelling yet with intrinsic limitations which underscore the need for appropriately powered clinical trials employing rigorous clinical trials methodology to examine the effect of SDB treatment on HF progression and associated adverse outcomes. PMID:25215169

  15. Prevention against diffuse spinal cord astrocytoma: can the Notch pathway be a novel treatment target?

    PubMed Central

    Sun, Jian-jun; Wang, Zhen-yu; Li, Ling-song; Yu, Hai-yan; Xu, Yong-sheng; Wu, Hai-bo; Luo, Yi; Liu, Bin; Zheng, Mei; Mao, Jin-long; Lou, Xiao-hui

    2015-01-01

    This study was designed to investigate whether the Notch pathway is involved in the development of diffuse spinal cord astrocytomas. BALB/c nude mice received injections of CD133+ and CD133− cell suspensions prepared using human recurrent diffuse spinal cord astrocytoma tissue through administration into the right parietal lobe. After 7–11 weeks, magnetic resonance imaging was performed weekly. Xenografts were observed on the surfaces of the brains of mice receiving the CD133+ cell suspension, and Notch-immunopositive expression was observed in the xenografts. By contrast, no xenografts appeared in the identical position on the surfaces of the brains of mice receiving the CD133− cell suspension, and Notch-immunopositive expression was hardly detected either. Hematoxylin-eosin staining and immunohistochemical staining revealed xenografts on the convex surfaces of the brains of mice that underwent CD133+ astrocytoma transplantation. Some sporadic astroglioma cells showed pseudopodium-like structures, which extended into the cerebral white matter. However, it should be emphasized that the subcortex xenograft with Notch-immunopositive expression was found in the fourth mouse received injection of CD133− astrocytoma cells. However, these findings suggest that the Notch pathway plays an important role in the formation of astrocytomas, and can be considered a novel treatment target for diffuse spinal cord astrocytoma. PMID:25883623

  16. Prevention of cytosolic IAPs degradation: a potential pharmacological target in Huntington's Disease.

    PubMed

    Goffredo, Donato; Rigamonti, Dorotea; Zuccato, Chiara; Tartari, Marzia; Valenza, Marta; Cattaneo, Elena

    2005-08-01

    Huntington's Disease (HD) is a neurodegenerative disorder caused by an abnormally expanded polyglutamine trait in the amino-terminal region of huntingtin. Pathogenic mechanisms involve a gained toxicity of mutant huntingtin and a potentially reduced neuroprotective function of the wild-type allele. Among the molecular abnormalities reported, HD cells are characterized by the presence of aggregates, transcriptional dysregulation, altered mitochondrial membrane potential and aberrant Ca++ handling. In addition, upon exposure to toxic stimuli, increased mitochondrial release of cytochrome C and activation of caspase-9 and caspase-3 are found in HD cells and tissue. Here we report that HTRA2 and Smac/DIABLO, two additional mitochondrial pro-apoptotic factors, are aberrantly released from brain-derived cells expressing mutant huntingtin. This event causes a reduction in levels of the cytosolic IAP1 (Inhibitor of Apoptosis Protein-1) and XIAP (X-linked inhibitor apoptosis) antiapoptotic IAP family members. Reduced IAP levels are also found in post-mortem HD brain tissue. Treatment with ucf101, a serine protease HTRA2 specific inhibitor, counteracts IAPs degradation in HD cells and increases their survival. These results point to the IAPs as potential pharmacological targets in Huntington's Disease. PMID:15967379

  17. Targeted disruption of CD1d prevents NKT cell development in pigs

    PubMed Central

    Yang, Guan; Artiaga, Bianca L.; Hackmann, Timothy J.; Samuel, Melissa S.; Walters, Eric M; Salek-Ardakani, Shahram; Driver, John P.

    2016-01-01

    Studies in mice genetically lacking natural killer T (NKT) cells show that these lymphocytes make important contributions to both innate and adaptive immune responses. However, the usefulness of murine models to study human NKT cells is limited by the many differences between mice and humans, including that their NKT cell frequencies, subsets and distribution are dissimilar. A more suitable model may be swine that share many metabolic, physiological and growth characteristics with humans and are also similar for NKT cells. Thus, we analyzed genetically modified pigs made deficient for CD1d that is required for the development of Type I invariant NKT (iNKT) cells that express a semi-invariant T cell receptor (TCR) and Type II NKT cells that use variable TCRs. Peripheral blood analyzed by flow cytometry and interferon-γ (IFNγ) enzyme-linked immuno spot (ELISPOT) assays demonstrated that CD1d-knockout pigs completely lack iNKT cells while other leukocyte populations remain intact. CD1d and NKT cells have been shown to be involved in shaping the composition of the commensal microbiota in mice. Therefore, we also compared the fecal microbiota profile between pigs expressing and lacking NKT cells. However, no differences were found between pigs lacking or expressing CD1d. Our results are the first to show that knocking-out CD1d prevents the development of iNKT cells in a non-rodent species. CD1d-deficient pigs should offer a useful model to more accurately determine the contribution of NKT cells for human immune responses. They also have potential for understanding how NKT cells impact the health of commercial swine. PMID:25930071

  18. Where are the men? Targeting male partners in preventing mother-to-child HIV transmission.

    PubMed

    Koo, Kevin; Makin, Jennifer D; Forsyth, Brian W C

    2013-01-01

    Involvement of male partners may increase adherence to and improve outcomes of programs to prevent mother-to-child HIV transmission (PMTCT). Greater understanding of factors impeding male voluntary HIV counseling and testing (VCT) is needed. A cross-sectional study was conducted in Tshwane, South Africa. Semi-structured interviews were completed with men whose partners had recently been pregnant. Of 124 men who participated, 94% believed male HIV testing was important, but 40% had never been tested. Of those tested, 32% were tested during the pregnancy, while 37% were tested afterward. Fifty-eight percent of men reported that their female partners had disclosed their test results during pregnancy. A man's likelihood of testing during pregnancy was associated with prior discussion of testing in PMTCT, knowing the female partner had tested, and her disclosure of the test result (all p<0.05). In terms of increasing male-partner HIV testing rates, 74% of the men reported they would respond favorably to a written invitation for VCT from their partners. Based on themes that emerged during the interviews, six partner invitation cards to encourage male involvement in PMTCT were designed. Responses to the cards were elicited from 158 men and 409 women. One invitation card framed by the themes of fatherhood and the baby was selected by 41% of men and 31% of women as the most likely for women undergoing PMTCT to bring to their male partners and the most successful at encouraging men to be tested. In conclusion, this study found that a substantial proportion of men whose partners were recently pregnant had never been tested themselves; of those who had tested, most had done so only after the pregnancy. Encouraging partner communication and clinic attendance using an invitation card could facilitate increased male testing and participation in PMTCT. PMID:22670795

  19. Sedentary behaviour as a new behavioural target in the prevention and treatment of type 2 diabetes.

    PubMed

    Henson, Joseph; Dunstan, David W; Davies, Melanie J; Yates, Thomas

    2016-01-01

    Our modern day society encompasses an ecological niche in which sedentary behaviour, labour-saving devices and energy dense foods have become the new reference of living. We now spend more time sedentary, defined as sitting, than in all other activities combined. It has recently been confirmed that the consequences of our modern chair dependency are substantial and a direct contributing factor to the ever increasing epidemic of chronic diseases witnessed within industrialized environments. Epidemiological evidence--from both cross-sectional and prospective observational studies--has indicated that the time spent in sedentary behaviour is a distinct risk factor for several health outcomes, including type 2 diabetes mellitus, insulin resistance, all-cause and cardiovascular disease mortality, depression and some types of cancer. Importantly, these detrimental associations remain even after accounting for time spent in moderate-to-vigorous physical activity, with the strongest and most persistent associations seen between sedentary time and type 2 diabetes mellitus. Importantly, experimental studies have started to confirm the observational associations, with mounting evidence showing that breaking prolonged sitting time with light ambulation is an effective strategy for improving postprandial glucose regulation. Indeed, there is even emerging evidence showing that simply substituting sitting for standing regularly throughout the day may be of sufficient stimulus to improve glucose regulation. We highlight some of the key definitions, issues and evidence underpinning the link between sedentary behaviour and chronic disease in order to better inform clinicians and patients about the importance of incorporating reduced sitting time into type 2 diabetes mellitus management and prevention pathways.

  20. Targeted Overexpression of Mitochondrial Catalase Prevents Radiation-Induced Cognitive Dysfunction

    PubMed Central

    Parihar, Vipan K.; Allen, Barrett D.; Tran, Katherine K.; Chmielewski, Nicole N.; Craver, Brianna M.; Martirosian, Vahan; Morganti, Josh M.; Rosi, Susanna; Vlkolinsky, Roman; Acharya, Munjal M.; Nelson, Gregory A.; Allen, Antiño R.

    2015-01-01

    Abstract Aims: Radiation-induced disruption of mitochondrial function can elevate oxidative stress and contribute to the metabolic perturbations believed to compromise the functionality of the central nervous system. To clarify the role of mitochondrial oxidative stress in mediating the adverse effects of radiation in the brain, we analyzed transgenic (mitochondrial catalase [MCAT]) mice that overexpress human catalase localized to the mitochondria. Results: Compared with wild-type (WT) controls, overexpression of the MCAT transgene significantly decreased cognitive dysfunction after proton irradiation. Significant improvements in behavioral performance found on novel object recognition and object recognition in place tasks were associated with a preservation of neuronal morphology. While the architecture of hippocampal CA1 neurons was significantly compromised in irradiated WT mice, the same neurons in MCAT mice did not exhibit extensive and significant radiation-induced reductions in dendritic complexity. Irradiated neurons from MCAT mice maintained dendritic branching and length compared with WT mice. Protected neuronal morphology in irradiated MCAT mice was also associated with a stabilization of radiation-induced variations in long-term potentiation. Stabilized synaptic activity in MCAT mice coincided with an altered composition of the synaptic AMPA receptor subunits GluR1/2. Innovation: Our findings provide the first evidence that neurocognitive sequelae associated with radiation exposure can be reduced by overexpression of MCAT, operating through a mechanism involving the preservation of neuronal morphology. Conclusion: Our article documents the neuroprotective properties of reducing mitochondrial reactive oxygen species through the targeted overexpression of catalase and how this ameliorates the adverse effects of proton irradiation in the brain. Antioxid. Redox Signal. 22, 78–91. PMID:24949841

  1. The histaminergic system as a target for the prevention of obesity and metabolic syndrome.

    PubMed

    Provensi, Gustavo; Blandina, Patrizio; Passani, Maria Beatrice

    2016-07-01

    The control of food intake and body weight is very complex. Key factors driving eating behavior are hunger and satiety that are controlled by an interplay of several central and peripheral neuroendocrine systems, environmental factors, the behavioral state and circadian rhythm, which all concur to alter homeostatic aspects of appetite and energy expenditure. Brain histamine plays a fundamental role in eating behavior as it induces loss of appetite and has long been considered a satiety signal that is released during food intake (Sakata et al., 1997). Animal studies have shown that brain histamine is released during the appetitive phase to provide a high level of arousal preparatory to feeding, but also mediates satiety. Furthermore, histamine regulates peripheral mechanisms such as glucose uptake and insulin function. Preclinical research indicates that activation of H1 and H3 receptors is crucial for the regulation of the diurnal rhythm of food consumption; furthermore, these receptors have been specifically recognized as mediators of energy intake and expenditure. Despite encouraging preclinical data, though, no brain penetrating H1 receptor agonists have been identified that would have anti-obesity effects. The potential role of the H3 receptor as a target of anti-obesity therapeutics was explored in clinical trials that did not meet up to the expectations or were interrupted (clinicaltrials.gov). Nonetheless, interesting results are emerging from clinical trials that evaluated the attenuating effect of betahistine (an H1 agonist/H3 antagonist) on metabolic side effects associated with chronic antipsychotics treatment. Aim of this review is to summarize recent results that suggest the clinical relevance of the histaminergic system for the treatment of feeding disorders and provide an up-to-date summary of preclinical research. This article is part of the Special Issue entitled 'Histamine Receptors'.

  2. TCF4 Is a Molecular Target of Resveratrol in the Prevention of Colorectal Cancer

    PubMed Central

    Jeong, Jin Boo; Lee, Jihye; Lee, Seong-Ho

    2015-01-01

    The Wnt/β-catenin pathway plays an essential role in the tumorigenesis of colorectal cancer. T-cell factor-4 (TCF4) is a member of the TCF/LEF (lymphoid enhancer factor) family of transcription factors, and dysregulation of β-catenin is decisive for the initiation and progression of colorectal cancer. However, the role of TCF4 in the transcriptional regulation of its target gene remained poorly understood. Resveratrol is a dietary phytoalexin and present in many plants, including grape skin, nuts and fruits. Although resveratrol has been widely implicated in anti-tumorigenic and pro-apoptotic properties in several cancer models, the underlying cellular mechanisms are only partially understood. The current study was performed to elucidate the molecular mechanism of the anti-cancer activity of resveratrol in human colorectal cancer cells. The treatment of resveratrol and other phytochemicals decreased the expression of TCF4. Resveratrol decreases cellular accumulation of exogenously-introduced TCF4 protein, but did not change the TCF4 transcription. The inhibition of proteasomal degradation using MG132 (carbobenzoxy-Leu-Leu-leucinal) and lactacystin ameliorates resveratrol-stimulated down-regulation of TCF4. The half-life of TCF4 was decreased in the cells exposed to resveratrol. Resveratrol increased phosphorylation of TCF4 at serine/threonine residues through ERK (extracellular signal-regulated kinases) and p38-dependent pathways. The TCF4 knockdown decreased TCF/β-catenin-mediated transcriptional activity and sensitized resveratrol-induced apoptosis. The current study provides a new mechanistic link between resveratrol and TCF4 down-regulation and significant benefits for further preclinical and clinical practice. PMID:25961950

  3. Voluntary Medical Male Circumcision for HIV Prevention in Swaziland: Modeling the Impact of Age Targeting

    PubMed Central

    Kripke, Katharine; Okello, Velephi; Maziya, Vusi; Benzerga, Wendy; Mirira, Munamato; Gold, Elizabeth; Schnure, Melissa; Sgaier, Sema; Castor, Delivette; Reed, Jason

    2016-01-01

    Background Voluntary medical male circumcision (VMMC) for HIV prevention has been a priority for Swaziland since 2009. Initially focusing on men ages 15–49, the Ministry of Health reduced the minimum age for VMMC from 15 to 10 years in 2012, given the existing demand among 10- to 15-year-olds. To understand the implications of focusing VMMC service delivery on specific age groups, the MOH undertook a modeling exercise to inform policy and implementation in 2013–2014. Methods and Findings The impact and cost of circumcising specific age groups were assessed using the Decision Makers’ Program Planning Tool, Version 2.0 (DMPPT 2.0), a simple compartmental model. We used age-specific HIV incidence from the Swaziland HIV Incidence Measurement Survey (SHIMS). Population, mortality, births, and HIV prevalence were imported from a national Spectrum/Goals model recently updated in consultation with country stakeholders. Baseline male circumcision prevalence was derived from the most recent Swaziland Demographic and Health Survey. The lowest numbers of VMMCs per HIV infection averted are achieved when males ages 15–19, 20–24, 25–29, and 30–34 are circumcised, although the uncertainty bounds for the estimates overlap. Circumcising males ages 25–29 and 20–24 provides the most immediate reduction in HIV incidence. Circumcising males ages 15–19, 20–24, and 25–29 provides the greatest magnitude incidence reduction within 15 years. The lowest cost per HIV infection averted is achieved by circumcising males ages 15–34: $870 U.S. dollars (USD). Conclusions The potential impact, cost, and cost-effectiveness of VMMC scale-up in Swaziland are not uniform. They vary by the age group of males circumcised. Based on the results of this modeling exercise, the Ministry of Health’s Swaziland Male Circumcision Strategic and Operational Plan 2014–2018 adopted an implementation strategy that calls for circumcision to be scaled up to 50% coverage for neonates, 80

  4. A geranyl acetophenone targeting cysteinyl leukotriene synthesis prevents allergic airway inflammation in ovalbumin-sensitized mice

    SciTech Connect

    Ismail, Norazren; Jambari, Nuzul Nurahya; Zareen, Seema; Akhtar, Mohamad Nadeem; Shaari, Khozirah; Zamri-Saad, Mohamad; Tham, Chau Ling; Sulaiman, Mohd Roslan; Lajis, Nordin Hj; Israf, Daud Ahmad

    2012-03-01

    Asthma is associated with increased pulmonary inflammation and airway hyperresponsiveness. The current use of corticosteroids in the management of asthma has recently raised issues regarding safety and lack of responsiveness in 5–10% of asthmatic individuals. The aim of the present study was to investigate the therapeutic effect of a non-steroidal small molecule that has cysteinyl leukotriene (cysLT) inhibitory activity, upon attenuation of allergic lung inflammation in an acute murine model. Mice were sensitized with ovalbumin (OVA) and treated with several intraperitoneal doses (100, 20, 2 and 0.2 mg/kg) of 2,4,6,-trihydroxy-3-geranylacetophenone (tHGA). Bronchoalveolar lavage was performed, blood and lung samples were obtained and respiratory function was measured. OVA sensitization increased pulmonary inflammation and pulmonary allergic inflammation was significantly reduced at doses of 100, 20 and 2 mg/kg with no effect at the lowest dose of 0.2 mg/kg. The beneficial effects in the lung were associated with reduced eosinophilic infiltration and reduced secretion of Th2 cytokines and cysLTs. Peripheral blood reduction of total IgE was also a prominent feature. Treatment with tHGA significantly attenuated altered airway hyperresponsiveness as measured by the enhanced pause (Penh) response to incremental doses of methacholine. These data demonstrate that tHGA, a synthetic non-steroidal small molecule, can prevent acute allergic inflammation. This proof of concept opens further avenues of research and development of tHGA as an additional option to the current armamentarium of anti-asthma therapeutics. -- Highlights: ► Safer and effective anti-asthmatic drugs are in great demand. ► tHGA is a new 5-LO/cysLT inhibitor that inhibits allergic asthma in mice. ► tHGA is a natural compound that can be synthesized. ► Doses as low as 2 mg/kg alleviate lung pathology in experimental asthma. ► tHGA is a potential drug lead for the treatment of allergic asthma.

  5. Evaluation of a targeted AIDS prevention intervention to increase condom use among prostitutes in Ghana.

    PubMed

    Asamoah-Adu, A; Weir, S; Pappoe, M; Kanlisi, N; Neequaye, A; Lamptey, P

    1994-02-01

    Findings of a prospective study of condom use among prostitutes in Ghana provided support for acquired immunodeficiency syndrome (AIDS) prevention educational interventions with this high risk populating and evidence of informal program diffusion. 382 self-identified prostitutes voluntarily entered the study in three waves (a pilot group of 72 recruited in June 1987, another 176 prostitutes who were admitted at their request in January 1988, and 106 who entered in September 1991). From this group, selected prostitutes were trained to educate their peers about AIDS risk factors through meetings and printed materials and to distribute free condoms. Self-reported condom use in 1991 was correlated with contact with these peer educators. During the 6-month pilot study, the proportion of prostitutes who always used condom increased from 6% at baseline to 71%. 48% of prostitutes entering the study in January 1988 were already always using condoms, suggesting a diffusion effect. In 1991, consistent condom use was reported by 56% of women from the pilot group available for follow-up and 66% of those interviewed from the 1988 wave; however, these rates were not appreciably higher than the 55% rate reported at baseline by the 1991 wave of recruits. (This convergence is assumed to reflect both suspension of the educational program in 1988-91 and increased social acceptance of condom use given the spread of AIDS.) Of the 107 women from the pilot and expanded groups available for interview in 1991, 24% identified peer outreach workers as their source of AIDS information. Women who had contact with staff were 2.63 times more likely than non-exposed women to report consistent condom use. The interaction model revealed that women who maintained contact with project staff were 3.17 times more likely to be consistent users, those who knew that healthy appearing men could transmit AIDS were 2.68 times more likely to fall into this use category, and prostitutes who had clients who

  6. Intestinal permeability--a new target for disease prevention and therapy.

    PubMed

    Bischoff, Stephan C; Barbara, Giovanni; Buurman, Wim; Ockhuizen, Theo; Schulzke, Jörg-Dieter; Serino, Matteo; Tilg, Herbert; Watson, Alastair; Wells, Jerry M

    2014-11-18

    Data are accumulating that emphasize the important role of the intestinal barrier and intestinal permeability for health and disease. However, these terms are poorly defined, their assessment is a matter of debate, and their clinical significance is not clearly established. In the present review, current knowledge on mucosal barrier and its role in disease prevention and therapy is summarized. First, the relevant terms 'intestinal barrier' and 'intestinal permeability' are defined. Secondly, the key element of the intestinal barrier affecting permeability are described. This barrier represents a huge mucosal surface, where billions of bacteria face the largest immune system of our body. On the one hand, an intact intestinal barrier protects the human organism against invasion of microorganisms and toxins, on the other hand, this barrier must be open to absorb essential fluids and nutrients. Such opposing goals are achieved by a complex anatomical and functional structure the intestinal barrier consists of, the functional status of which is described by 'intestinal permeability'. Third, the regulation of intestinal permeability by diet and bacteria is depicted. In particular, potential barrier disruptors such as hypoperfusion of the gut, infections and toxins, but also selected over-dosed nutrients, drugs, and other lifestyle factors have to be considered. In the fourth part, the means to assess intestinal permeability are presented and critically discussed. The means vary enormously and probably assess different functional components of the barrier. The barrier assessments are further hindered by the natural variability of this functional entity depending on species and genes as well as on diet and other environmental factors. In the final part, we discuss selected diseases associated with increased intestinal permeability such as critically illness, inflammatory bowel diseases, celiac disease, food allergy, irritable bowel syndrome, and--more recently recognized

  7. Interventions among male clients of female sex workers in Benin, West Africa: an essential component of targeted HIV preventive interventions

    PubMed Central

    Lowndes, C M; Alary, M; Labbé, A‐C; Gnintoungbè, C; Belleau, M; Mukenge, L; Meda, H; Ndour, M; Anagonou, S; Gbaguidi, A

    2007-01-01

    Objectives To assess the impact of interventions targeted towards female sex workers (FSWs) and their male clients on client HIV/STI prevalence and sexual behaviour. Methods From 1993 to 2006, an HIV/STI preventive intervention focusing on condom promotion and STI care was implemented among FSWs in Cotonou, Benin, and then expanded to cover their male sexual partners in 2000. The interventions were scaled up to five other cities of Benin in 2001–2002. Serial cross‐sectional surveys of HIV/STI prevalence and sexual behaviour were carried out among clients in Cotonou in 1998, 2002 and 2005; and in the five other cities (O/Cotonou) in 2002 and 2005. Results Significant declines in gonorrhoea prevalence among clients of FSWs: Cotonou, from 5.4% in 1998 to 1.6% in 2005; O/Cotonou: from 3.5% in 2002 to 0.59% in 2005. Chlamydia prevalence also declined O/Cotonou, from 4.8% to 1.8%, while HIV prevalence remained stable. Reported condom use by clients with both FSWs and casual non‐FSW partners, but not regular partners, increased significantly. While condom use at last sex with an FSW was similar in Cotonou to O/Cotonou around the time of implementation of the interventions (56% in 1998 vs 49% in 2002, respectively), it had risen to similar levels by 2005 (95% and 96%, respectively). Conclusions These results demonstrate that it is possible to implement preventive and clinical services for clients of FSWs, and suggest that such interventions, integrated with those targeted towards FSWs, can have a significant effect on sexual behaviour and STI prevalence (particularly gonorrhoea) among this population. PMID:17942573

  8. Pharmacological targeting of CSF1R inhibits microglial proliferation and prevents the progression of Alzheimer’s-like pathology

    PubMed Central

    Olmos-Alonso, Adrian; Schetters, Sjoerd T. T.; Sri, Sarmi; Askew, Katharine; Mancuso, Renzo; Vargas-Caballero, Mariana; Holscher, Christian; Perry, V. Hugh

    2016-01-01

    The proliferation and activation of microglial cells is a hallmark of several neurodegenerative conditions. This mechanism is regulated by the activation of the colony-stimulating factor 1 receptor (CSF1R), thus providing a target that may prevent the progression of conditions such as Alzheimer’s disease. However, the study of microglial proliferation in Alzheimer’s disease and validation of the efficacy of CSF1R-inhibiting strategies have not yet been reported. In this study we found increased proliferation of microglial cells in human Alzheimer’s disease, in line with an increased upregulation of the CSF1R-dependent pro-mitogenic cascade, correlating with disease severity. Using a transgenic model of Alzheimer’s-like pathology (APPswe, PSEN1dE9; APP/PS1 mice) we define a CSF1R-dependent progressive increase in microglial proliferation, in the proximity of amyloid-β plaques. Prolonged inhibition of CSF1R in APP/PS1 mice by an orally available tyrosine kinase inhibitor (GW2580) resulted in the blockade of microglial proliferation and the shifting of the microglial inflammatory profile to an anti-inflammatory phenotype. Pharmacological targeting of CSF1R in APP/PS1 mice resulted in an improved performance in memory and behavioural tasks and a prevention of synaptic degeneration, although these changes were not correlated with a change in the number of amyloid-β plaques. Our results provide the first proof of the efficacy of CSF1R inhibition in models of Alzheimer’s disease, and validate the application of a therapeutic strategy aimed at modifying CSF1R activation as a promising approach to tackle microglial activation and the progression of Alzheimer’s disease. PMID:26747862

  9. Pharmacological targeting of CSF1R inhibits microglial proliferation and prevents the progression of Alzheimer's-like pathology.

    PubMed

    Olmos-Alonso, Adrian; Schetters, Sjoerd T T; Sri, Sarmi; Askew, Katharine; Mancuso, Renzo; Vargas-Caballero, Mariana; Holscher, Christian; Perry, V Hugh; Gomez-Nicola, Diego

    2016-03-01

    The proliferation and activation of microglial cells is a hallmark of several neurodegenerative conditions. This mechanism is regulated by the activation of the colony-stimulating factor 1 receptor (CSF1R), thus providing a target that may prevent the progression of conditions such as Alzheimer's disease. However, the study of microglial proliferation in Alzheimer's disease and validation of the efficacy of CSF1R-inhibiting strategies have not yet been reported. In this study we found increased proliferation of microglial cells in human Alzheimer's disease, in line with an increased upregulation of the CSF1R-dependent pro-mitogenic cascade, correlating with disease severity. Using a transgenic model of Alzheimer's-like pathology (APPswe, PSEN1dE9; APP/PS1 mice) we define a CSF1R-dependent progressive increase in microglial proliferation, in the proximity of amyloid-β plaques. Prolonged inhibition of CSF1R in APP/PS1 mice by an orally available tyrosine kinase inhibitor (GW2580) resulted in the blockade of microglial proliferation and the shifting of the microglial inflammatory profile to an anti-inflammatory phenotype. Pharmacological targeting of CSF1R in APP/PS1 mice resulted in an improved performance in memory and behavioural tasks and a prevention of synaptic degeneration, although these changes were not correlated with a change in the number of amyloid-β plaques. Our results provide the first proof of the efficacy of CSF1R inhibition in models of Alzheimer's disease, and validate the application of a therapeutic strategy aimed at modifying CSF1R activation as a promising approach to tackle microglial activation and the progression of Alzheimer's disease.

  10. A Targeted Infection Prevention Intervention in Nursing Home Residents With Indwelling Devices

    PubMed Central

    Mody, Lona; Krein, Sarah L.; Saint, Sanjay K.; Min, Lillian C.; Montoya, Ana; Lansing, Bonnie; McNamara, Sara E.; Symons, Kathleen; Fisch, Jay; Koo, Evonne; Rye, Ruth Anne; Galecki, Andrzej; Kabeto, Mohammed U.; Fitzgerald, James T.; Olmsted, Russell N.; Kauffman, Carol A.; Bradley, Suzanne F.

    2015-01-01

    IMPORTANCE Indwelling devices (eg, urinary catheters and feeding tubes) are often used in nursing homes (NHs). Inadequate care of residents with these devices contributes to high rates of multidrug-resistant organisms (MDROs) and device-related infections in NHs. OBJECTIVE To test whether a multimodal targeted infection program (TIP) reduces the prevalence of MDROs and incident device-related infections. DESIGN, SETTING, AND PARTICIPANTS Randomized clinical trial at 12 community-based NHs from May 2010 to April 2013. Participants were high-risk NH residents with urinary catheters, feeding tubes, or both. INTERVENTIONS Multimodal, including preemptive barrier precautions, active surveillance for MDROs and infections, and NH staff education. MAIN OUTCOMES AND MEASURES The primary outcome was the prevalence density rate of MDROs, defined as the total number of MDROs isolated per visit averaged over the duration of a resident's participation. Secondary outcomes included new MDRO acquisitions and new clinically defined device-associated infections. Data were analyzed using a mixed-effects multilevel Poisson regression model (primary outcome) and a Cox proportional hazards model (secondary outcome), adjusting for facility-level clustering and resident-level variables. RESULTS In total, 418 NH residents with indwelling devices were enrolled, with 34 174 device-days and 6557 anatomic sites sampled. Intervention NHs had a decrease in the overall MDRO prevalence density (rate ratio, 0.77; 95% CI, 0.62–0.94). The rate of new methicillin-resistant Staphylococcus aureus acquisitions was lower in the intervention group than in the control group (rate ratio, 0.78; 95% CI, 0.64–0.96). Hazard ratios for the first and all (including recurrent) clinically defined catheter-associated urinary tract infections were 0.54 (95% CI, 0.30–0.97) and 0.69 (95% CI, 0.49–0.99), respectively, in the intervention group and the control group. There were no reductions in new vancomycin

  11. Glutathione prevents preterm parturition and fetal death by targeting macrophage-induced reactive oxygen species production in the myometrium.

    PubMed

    Hadi, Tarik; Bardou, Marc; Mace, Guillaume; Sicard, Pierre; Wendremaire, Maeva; Barrichon, Marina; Richaud, Sarah; Demidov, Oleg; Sagot, Paul; Garrido, Carmen; Lirussi, Frédéric

    2015-06-01

    Preterm birth is an inflammatory process resulting from the massive infiltration of innate immune cells and the production of proinflammatory cytokines in the myometrium. However, proinflammatory cytokines, which induce labor in vivo, fail to induce labor-associated features in human myometrial cells (MCs). We thus aimed to investigate if reactive oxygen species (ROS) production could be the missing step between immune cell activation and MC response. Indeed, we found that ROS production is increased in the human preterm laboring myometrium (27% ROS producing cells, respectively, versus 2% in nonlaboring controls), with 90% ROS production in macrophages. Using LPS-stimulated myometrial samples and cell coculture experiments, we demonstrated that ROS production is required for labor onset. Furthermore, we showed that ROS are required first in the NADPH oxidase (NADPHox)-2/NF-κB-dependent macrophage response to inflammatory stimuli but, more importantly, to trigger macrophage-induced MCs transactivation. Remarkably, in a murine model of LPS-induced preterm labor (inducing delivery within 17 hours, with no pup survival), cotreatment with glutathione delayed labor onset up to 94 hours and prevented in utero fetal distress, allowing 46% pups to survive. These results suggest that targeting ROS production with the macrophage-permeable antioxidant glutathione could constitute a promising strategy to prevent preterm birth. PMID:25757563

  12. NRF2 Is a Key Target for Prevention of Noise-Induced Hearing Loss by Reducing Oxidative Damage of Cochlea

    PubMed Central

    Honkura, Yohei; Matsuo, Hirotaka; Murakami, Shohei; Sakiyama, Masayuki; Mizutari, Kunio; Shiotani, Akihiro; Yamamoto, Masayuki; Morita, Ichiro; Shinomiya, Nariyoshi; Kawase, Tetsuaki; Katori, Yukio; Motohashi, Hozumi

    2016-01-01

    Noise-induced hearing loss (NIHL) is one of the most common sensorineural hearing deficits. Recent studies have demonstrated that the pathogenesis of NIHL is closely related to ischemia-reperfusion injury of cochlea, which is caused by blood flow decrease and free radical production due to excessive noise. This suggests that protecting the cochlea from oxidative stress is an effective therapeutic approach for NIHL. NRF2 is a transcriptional activator playing an essential role in the defense mechanism against oxidative stress. To clarify the contribution of NRF2 to cochlear protection, we examined Nrf2–/– mice for susceptibility to NIHL. Threshold shifts of the auditory brainstem response at 7 days post-exposure were significantly larger in Nrf2–/– mice than wild-type mice. Treatment with CDDO-Im, a potent NRF2-activating drug, before but not after the noise exposure preserved the integrity of hair cells and improved post-exposure hearing levels in wild-type mice, but not in Nrf2–/– mice. Therefore, NRF2 activation is effective for NIHL prevention. Consistently, a human NRF2 SNP was significantly associated with impaired sensorineural hearing levels in a cohort subjected to occupational noise exposure. Thus, high NRF2 activity is advantageous for cochlear protection from noise-induced injury, and NRF2 is a promising target for NIHL prevention. PMID:26776972

  13. NRF2 Is a Key Target for Prevention of Noise-Induced Hearing Loss by Reducing Oxidative Damage of Cochlea.

    PubMed

    Honkura, Yohei; Matsuo, Hirotaka; Murakami, Shohei; Sakiyama, Masayuki; Mizutari, Kunio; Shiotani, Akihiro; Yamamoto, Masayuki; Morita, Ichiro; Shinomiya, Nariyoshi; Kawase, Tetsuaki; Katori, Yukio; Motohashi, Hozumi

    2016-01-18

    Noise-induced hearing loss (NIHL) is one of the most common sensorineural hearing deficits. Recent studies have demonstrated that the pathogenesis of NIHL is closely related to ischemia-reperfusion injury of cochlea, which is caused by blood flow decrease and free radical production due to excessive noise. This suggests that protecting the cochlea from oxidative stress is an effective therapeutic approach for NIHL. NRF2 is a transcriptional activator playing an essential role in the defense mechanism against oxidative stress. To clarify the contribution of NRF2 to cochlear protection, we examined Nrf2(-/-) mice for susceptibility to NIHL. Threshold shifts of the auditory brainstem response at 7 days post-exposure were significantly larger in Nrf2(-/-) mice than wild-type mice. Treatment with CDDO-Im, a potent NRF2-activating drug, before but not after the noise exposure preserved the integrity of hair cells and improved post-exposure hearing levels in wild-type mice, but not in Nrf2(-/-) mice. Therefore, NRF2 activation is effective for NIHL prevention. Consistently, a human NRF2 SNP was significantly associated with impaired sensorineural hearing levels in a cohort subjected to occupational noise exposure. Thus, high NRF2 activity is advantageous for cochlear protection from noise-induced injury, and NRF2 is a promising target for NIHL prevention.

  14. Lipoprotein-associated phospholipase A2 (Lp-PLA2) as a therapeutic target to prevent retinal vasopermeability during diabetes

    PubMed Central

    Canning, Paul; Kenny, Bridget-Ann; Prise, Vivien; Glenn, Josephine; Sarker, Mosharraf H.; Hudson, Natalie; Brandt, Martin; Lopez, Francisco J.; Gale, David; Luthert, Philip J.; Adamson, Peter; Turowski, Patric; Stitt, Alan W.

    2016-01-01

    Lipoprotein-associated phospholipase A2 (Lp-PLA2) hydrolyses oxidized low-density lipoproteins into proinflammatory products, which can have detrimental effects on vascular function. As a specific inhibitor of Lp-PLA2, darapladib has been shown to be protective against atherogenesis and vascular leakage in diabetic and hypercholesterolemic animal models. This study has investigated whether Lp-PLA2 and its major enzymatic product, lysophosphatidylcholine (LPC), are involved in blood–retinal barrier (BRB) damage during diabetic retinopathy. We assessed BRB protection in diabetic rats through use of species-specific analogs of darapladib. Systemic Lp-PLA2 inhibition using SB-435495 at 10 mg/kg (i.p.) effectively suppressed BRB breakdown in streptozotocin-diabetic Brown Norway rats. This inhibitory effect was comparable to intravitreal VEGF neutralization, and the protection against BRB dysfunction was additive when both targets were inhibited simultaneously. Mechanistic studies in primary brain and retinal microvascular endothelial cells, as well as occluded rat pial microvessels, showed that luminal but not abluminal LPC potently induced permeability, and that this required signaling by the VEGF receptor 2 (VEGFR2). Taken together, this study demonstrates that Lp-PLA2 inhibition can effectively prevent diabetes-mediated BRB dysfunction and that LPC impacts on the retinal vascular endothelium to induce vasopermeability via VEGFR2. Thus, Lp-PLA2 may be a useful therapeutic target for patients with diabetic macular edema (DME), perhaps in combination with currently administered anti-VEGF agents. PMID:27298369

  15. Using Risk Group Profiles as a Lightweight Qualitative Approach for Intervention Development: An Example of Prevention of Tick Bites and Lyme Disease

    PubMed Central

    van Velsen, Lex; van Gemert - Pijnen, Julia EWC; Maat, Angelique; van Steenbergen, Jim E; Crutzen, Rik

    2013-01-01

    groups were as follows: (1) outdoor people that check for tick bites, (2) outdoor people that do not check for tick bites, (3) parents that check their children for tick bites, and (4) parents that do not check their children for tick bites. Previous experience with ticks or LD was the main denominator between the groups. Checking for tick bites is a more easily adopted measure than preventing tick bites. Therefore, for all groups, public health efforts in the future should primarily emphasize on the importance of checking for tick bites. Conclusions The lightweight qualitative approach presented in this paper is highly relevant in tailoring public health efforts toward specific groups. The profiles of members in each risk group and the motivations underlying the behaviors of the members in each risk group can be used to determine the features and content of a targeted communication strategy about ticks and LD. PMID:24172875

  16. Aiming at a moving target: research ethics in the context of evolving standards of care and prevention.

    PubMed

    Shah, Seema; Lie, Reidar K

    2013-11-01

    In rapidly evolving medical fields where the standard of care or prevention changes frequently, guidelines are increasingly likely to conflict with what participants receive in research. Although guidelines typically set the standard of care, there are some cases in which research can justifiably deviate from guidelines. When guidelines conflict with research, an ethical issue only arises if guidelines are rigorous and should be followed. Next, it is important that the cumulative evidence and the conclusions reached by the guidelines do not eliminate the need for further research. Even when guidelines are rigorous and the study still asks an important question, we argue that there may be good reasons for deviations in three cases: (1) when research poses no greater net risk than the standard of care; (2) when there is a continued need for additional evidence, for example, when subpopulations are not covered by the guidelines; and (3) less frequently, when clinical practice guidelines can be justified by the evidence, but practitioners disagree about the guidelines, and the guidelines are not consistently followed as a result. We suggest that procedural protections may be especially useful in deciding when studies in the third category can proceed.

  17. Radiotherapy-induced miR-223 prevents relapse of breast cancer by targeting the EGF pathway

    PubMed Central

    Fabris, L; Berton, S; Citron, F; D'Andrea, S; Segatto, I; Nicoloso, M S; Massarut, S; Armenia, J; Zafarana, G; Rossi, S; Ivan, C; Perin, T; Vaidya, J S; Avanzo, M; Roncadin, M; Schiappacassi, M; Bristow, R G; Calin, G; Baldassarre, G; Belletti, B

    2016-01-01

    In breast cancer (BC) patients, local recurrences often arise in proximity of the surgical scar, suggesting that response to surgery may have a causative role. Radiotherapy (RT) after lumpectomy significantly reduces the risk of recurrence. We investigated the direct effects of surgery and of RT delivered intraoperatively (IORT), by collecting irradiated and non-irradiated breast tissues from BC patients, after tumor removal. These breast tissue specimens have been profiled for their microRNA (miR) expression, in search of differentially expressed miR among patients treated or not with IORT. Our results demonstrate that IORT elicits effects that go beyond the direct killing of residual tumor cells. IORT altered the wound response, inducing the expression of miR-223 in the peri-tumoral breast tissue. miR-223 downregulated the local expression of epidermal growth factor (EGF), leading to decreased activation of EGF receptor (EGFR) on target cells and, eventually, dampening a positive EGF–EGFR autocrine/paracrine stimulation loop induced by the post-surgical wound-healing response. Accordingly, both RT-induced miR-223 and peri-operative inhibition of EGFR efficiently prevented BC cell growth and reduced recurrence formation in mouse models of BC. Our study uncovers unknown effects of RT delivered on a wounded tissue and prompts to the use of anti-EGFR treatments, in a peri-operative treatment schedule, aimed to timely treat BC patients and restrain recurrence formation. PMID:26876200

  18. Obesity Prevention from Conception: A Workshop to Guide the Development of a Pan-Canadian Trial Targeting the Gestational Period

    PubMed Central

    Adamo, Kristi B; Shen, Garry X; Mottola, Michelle; Nascimento, Simony; Jean-Philippe, Sonia; Ferraro, Zachary M; Nerenberg, Kara; Smith, Graeme; Chari, Radha; Gaudet, Laura; Piccinini-Vallis, Helena; McDonald, Sarah; Atkinson, Stephanie; Godbout, Ariane; Robitaille, Julie; Davidge, Sandra T; Gruslin, Andrée; Prud’homme, Denis; Stacey, Dawn; Rossiter, Melissa; Goldfield, Gary S; Dodd, Jodie

    2014-01-01

    This report summarizes a meeting, Obesity Prevention from Conception, held in Ottawa in 2012. This planning workshop was funded by the Canadian Institutes of Health Research (CIHR) to bring together researchers with expertise in the area of maternal obesity (OB) and weight gain in pregnancy and pregnancy-related disease to attend a one-day workshop and symposium to discuss the development of a cross-Canada lifestyle intervention trial for targeting pregnant women. This future intervention will aim to reduce downstream OB in children through encouraging appropriate weight gain during the mother’s pregnancy. The workshop served to (i) inform the development of a lifestyle intervention for women with a high pre-pregnancy body mass index (BMI), (ii) identify site investigators across Canada, and (iii) guide the development of a grant proposal focusing on the health of mom and baby. A brief summary of the presentations as well as the focus groups is presented for use in planning future research.

  19. The Long-Term Effectiveness of a Selective, Personality-Targeted Prevention Program in Reducing Alcohol Use and Related Harms: A Cluster Randomized Controlled Trial

    ERIC Educational Resources Information Center

    Newton, Nicola C.; Conrod, Patricia J.; Slade, Tim; Carragher, Natacha; Champion, Katrina E.; Barrett, Emma L.; Kelly, Erin V.; Nair, Natasha K.; Stapinski, Lexine; Teesson, Maree

    2016-01-01

    Background: This study investigated the long-term effectiveness of Preventure, a selective personality-targeted prevention program, in reducing the uptake of alcohol, harmful use of alcohol, and alcohol-related harms over a 3-year period. Methods: A cluster randomized controlled trial was conducted to assess the effectiveness of Preventure.…

  20. HIV prevention and care services for female sex workers: efficacy of a targeted community-based intervention in Burkina Faso

    PubMed Central

    Traore, Isidore T; Meda, Nicolas; Hema, Noelie M; Ouedraogo, Djeneba; Some, Felicien; Some, Roselyne; Niessougou, Josiane; Sanon, Anselme; Konate, Issouf; Van De Perre, Philippe; Mayaud, Philippe; Nagot, Nicolas

    2015-01-01

    Introduction Although interventions to control HIV among high-risk groups such as female sex workers (FSW) are highly recommended in Africa, the contents and efficacy of these interventions are unclear. We therefore designed a comprehensive dedicated intervention targeting young FSW and assessed its impact on HIV incidence in Burkina Faso. Methods Between September 2009 and September 2011 we conducted a prospective, interventional cohort study of FSW aged 18 to 25 years in Ouagadougou, with quarterly follow-up for a maximum of 21 months. The intervention combined prevention and care within the same setting, consisting of peer-led education sessions, psychological support, sexually transmitted infections and HIV care, general routine health care and reproductive health services. At each visit, behavioural characteristics were collected and HIV, HSV-2 and pregnancy were tested. We compared the cohort HIV incidence with a modelled expected incidence in the study population in the absence of intervention, using data collected at the same time from FSW clients. Results The 321 HIV-uninfected FSW enrolled in the cohort completed 409 person-years of follow-up. No participant seroconverted for HIV during the study (0/409 person-years), whereas the expected modelled number of HIV infections were 5.05/409 person-years (95% CI, 5.01–5.08) or 1.23 infections per 100 person-years (p=0.005). This null incidence was related to a reduction in the number of regular partners and regular clients, and by an increase in consistent condom use with casual clients (adjusted odds ratio (aOR)=2.19; 95% CI, 1.16–4.14, p=0.01) and with regular clients (aOR=2.18; 95% CI, 1.26–3.76, p=0.005). Conclusions Combining peer-based prevention and care within the same setting markedly reduced the HIV incidence among young FSW in Burkina Faso, through reduced risky behaviours. PMID:26374604

  1. HIV among immigrants living in high-income countries: a realist review of evidence to guide targeted approaches to behavioural HIV prevention

    PubMed Central

    2012-01-01

    Background Immigrants from developing and middle-income countries are an emerging priority in HIV prevention in high-income countries. This may be explained in part by accelerating international migration and population mobility. However, it may also be due to the vulnerabilities of immigrants including social exclusion along with socioeconomic, cultural and language barriers to HIV prevention. Contemporary thinking on effective HIV prevention stresses the need for targeted approaches that adapt HIV prevention interventions according to the cultural context and population being addressed. This review of evidence sought to generate insights into targeted approaches in this emerging area of HIV prevention. Methods We undertook a realist review to answer the research question: ‘How are HIV prevention interventions in high-income countries adapted to suit immigrants’ needs?’ A key goal was to uncover underlying theories or mechanisms operating in behavioural HIV prevention interventions with immigrants, to uncover explanations as how and why they work (or not) for particular groups in particular contexts, and thus to refine the underlying theories. The realist review mapped seven initial mechanisms underlying culturally appropriate HIV prevention with immigrants. Evidence from intervention studies and qualitative studies found in systematic searches was then used to test and refine these seven mechanisms. Results Thirty-four intervention studies and 40 qualitative studies contributed to the analysis and synthesis of evidence. The strongest evidence supported the role of ‘consonance’ mechanisms, indicating the pivotal need to incorporate cultural values into the intervention content. Moderate evidence was found to support the role of three other mechanisms – ‘understanding’, ‘specificity’ and ‘embeddedness’ – which indicated that using the language of immigrants, usually the ‘mother tongue’, targeting (in terms of ethnicity) and the use of

  2. A Mitochondrial-Targeted Coenzyme Q Analog Prevents Weight Gain and Ameliorates Hepatic Dysfunction in High-Fat–Fed Mice

    PubMed Central

    Fink, Brian D.; Herlein, Judith A.; Guo, Deng Fu; Kulkarni, Chaitanya; Weidemann, Benjamin J.; Yu, Liping; Grobe, Justin L.; Rahmouni, Kamal; Kerns, Robert J.

    2014-01-01

    We hypothesized that the mitochondrial-targeted antioxidant, mitoquinone (mitoQ), known to have mitochondrial uncoupling properties, might prevent the development of obesity and mitigate liver dysfunction by increasing energy expenditure, as opposed to reducing energy intake. We administered mitoQ or vehicle (ethanol) to obesity-prone C57BL/6 mice fed high-fat (HF) or normal-fat (NF) diets. MitoQ (500 µM) or vehicle (ethanol) was added to the drinking water for 28 weeks. MitoQ significantly reduced total body mass and fat mass in the HF-fed mice but had no effect on these parameters in NF mice. Food intake was reduced by mitoQ in the HF-fed but not in the NF-fed mice. Average daily water intake was reduced by mitoQ in both the NF- and HF-fed mice. Hypothalamic expression of neuropeptide Y, agouti-related peptide, and the long form of the leptin receptor were reduced in the HF but not in the NF mice. Hepatic total fat and triglyceride content did not differ between the mitoQ-treated and control HF-fed mice. However, mitoQ markedly reduced hepatic lipid hydroperoxides and reduced circulating alanine aminotransferase, a marker of liver function. MitoQ did not alter whole-body oxygen consumption or liver mitochondrial oxygen utilization, membrane potential, ATP production, or production of reactive oxygen species. In summary, mitoQ added to drinking water mitigated the development of obesity. Contrary to our hypothesis, the mechanism involved decreased energy intake likely mediated at the hypothalamic level. MitoQ also ameliorated HF-induced liver dysfunction by virtue of its antioxidant properties without altering liver fat or mitochondrial bioenergetics. PMID:25301169

  3. Targeting Apoptosis Signalling Kinase-1 (ASK-1) Does Not Prevent the Development of Neuropathy in Streptozotocin-Induced Diabetic Mice

    PubMed Central

    Newton, Victoria L.; Ali, Sumia; Duddy, Graham; Whitmarsh, Alan J.; Gardiner, Natalie J.

    2014-01-01

    Apoptosis signal-regulating kinase-1 (ASK1) is a mitogen-activated protein 3 kinase (MAPKKK/MAP3K) which lies upstream of the stress-activated MAPKs, JNK and p38. ASK1 may be activated by a variety of extracellular and intracellular stimuli. MAP kinase activation in the sensory nervous system as a result of diabetes has been shown in numerous preclinical and clinical studies. As a common upstream activator of both p38 and JNK, we hypothesised that activation of ASK1 contributes to nerve dysfunction in diabetic neuropathy. We therefore wanted to characterize the expression of ASK1 in sensory neurons, and determine whether the absence of functional ASK1 would protect against the development of neuropathy in a mouse model of experimental diabetes. ASK1 mRNA and protein is constitutively expressed by multiple populations of sensory neurons of the adult mouse lumbar DRG. Diabetes was induced in male C57BL/6 and transgenic ASK1 kinase-inactive (ASK1n) mice using streptozotocin. Levels of ASK1 do not change in the DRG, spinal cord, or sciatic nerve following induction of diabetes. However, levels of ASK2 mRNA increase in the spinal cord at 4 weeks of diabetes, which could represent a future target for this field. Neither motor nerve conduction velocity deficits, nor thermal or mechanical hypoalgesia were prevented or ameliorated in diabetic ASK1n mice. These results suggest that activation of ASK1 is not responsible for the nerve deficits observed in this mouse model of diabetic neuropathy. PMID:25329046

  4. [Differentiated structures of early prevention measures for families at risk using the example of the project "nobody slips through the net"].

    PubMed

    Eickhorst, Andreas; Borchardt, Silke; Cierpka, Manfred

    2012-01-01

    Against the background of practical experiences from the Early Prevention model project "Nobody slips through the net" (in three counties of Germany) the necessity of differentiated structures of preventive measures for different groups of families will be discussed. Therefore a distribution in three types of families the visiting qualified person could be confronted with during their work in the families' homes is proposed, especially with respect to the degree of risk and available resources. We conclude by illustrating the implications of this approach by means of a case vignette. PMID:23367809

  5. In Our Own Words: Community Story Traditions To Prevent and Heal Substance Abuse. A Teacher's Guide with Examples from Native American and Rural Contexts.

    ERIC Educational Resources Information Center

    Tierney, Michael

    As the national war on drugs continues, children and youth are told to "just say no" but are seldom given the information and skills to sort out the mixed signals coming from peers, adults, and the mass media. This guidebook presents examples of three approaches to community "storytelling" projects through which children and youth can explore…

  6. Population-based analysis of health care contacts among suicide decedents: identifying opportunities for more targeted suicide prevention strategies.

    PubMed

    Schaffer, Ayal; Sinyor, Mark; Kurdyak, Paul; Vigod, Simone; Sareen, Jitender; Reis, Catherine; Green, Diane; Bolton, James; Rhodes, Anne; Grigoriadis, Sophie; Cairney, John; Cheung, Amy

    2016-06-01

    The objective of this study was to detail the nature and correlates of mental health and non-mental health care contacts prior to suicide death. We conducted a systematic extraction of data from records at the Office of the Chief Coroner of Ontario of each person who died by suicide in the city of Toronto from 1998 to 2011. Data on 2,835 suicide deaths were linked with provincial health administrative data to identify health care contacts during the 12 months prior to suicide. Sub-populations of suicide decedents based on the presence and type of mental health care contact were described and compared across socio-demographic, clinical and suicide-specific variables. Time periods from last mental health contact to date of death were calculated and a Cox proportional hazards model examined covariates. Among suicide decedents, 91.7% had some type of past-year health care contact prior to death, 66.4% had a mental health care contact, and 25.3% had only non-mental health contacts. The most common type of mental health contact was an outpatient primary care visit (54.0%), followed by an outpatient psychiatric visit (39.8%), an emergency department visit (31.1%), and a psychiatric hospitalization (21.0%). The median time from last mental health contact to death was 18 days (interquartile range 5-63). Mental health contact was significantly associated with female gender, age 25-64, absence of a psychosocial stressor, diagnosis of schizophrenia or bipolar disorder, past suicide attempt, self-poisoning method and absence of a suicide note. Significant differences between sub-populations of suicide decedents based on the presence and nature of their health care contacts suggest the need for targeting of community and clinical-based suicide prevention strategies. The predominance of ambulatory mental health care contacts, often close to the time of death, reinforce the importance of concentrating efforts on embedding risk assessment and care pathways into all routine primary

  7. Population‐based analysis of health care contacts among suicide decedents: identifying opportunities for more targeted suicide prevention strategies

    PubMed Central

    Schaffer, Ayal; Sinyor, Mark; Kurdyak, Paul; Vigod, Simone; Sareen, Jitender; Reis, Catherine; Green, Diane; Bolton, James; Rhodes, Anne; Grigoriadis, Sophie; Cairney, John; Cheung, Amy

    2016-01-01

    The objective of this study was to detail the nature and correlates of mental health and non‐mental health care contacts prior to suicide death. We conducted a systematic extraction of data from records at the Office of the Chief Coroner of Ontario of each person who died by suicide in the city of Toronto from 1998 to 2011. Data on 2,835 suicide deaths were linked with provincial health administrative data to identify health care contacts during the 12 months prior to suicide. Sub‐populations of suicide decedents based on the presence and type of mental health care contact were described and compared across socio‐demographic, clinical and suicide‐specific variables. Time periods from last mental health contact to date of death were calculated and a Cox proportional hazards model examined covariates. Among suicide decedents, 91.7% had some type of past‐year health care contact prior to death, 66.4% had a mental health care contact, and 25.3% had only non‐mental health contacts. The most common type of mental health contact was an outpatient primary care visit (54.0%), followed by an outpatient psychiatric visit (39.8%), an emergency department visit (31.1%), and a psychiatric hospitalization (21.0%). The median time from last mental health contact to death was 18 days (interquartile range 5‐63). Mental health contact was significantly associated with female gender, age 25‐64, absence of a psychosocial stressor, diagnosis of schizophrenia or bipolar disorder, past suicide attempt, self‐poisoning method and absence of a suicide note. Significant differences between sub‐populations of suicide decedents based on the presence and nature of their health care contacts suggest the need for targeting of community and clinical‐based suicide prevention strategies. The predominance of ambulatory mental health care contacts, often close to the time of death, reinforce the importance of concentrating efforts on embedding risk assessment and care pathways

  8. Comparing Perceived and Test-Based Knowledge of Cancer Risk and Prevention among Hispanic and African Americans: An Example of Community Participatory Research

    PubMed Central

    Jones, Loretta; Bazargan, Mohsen; Lucas-Wright, Anna; Vadgama, Jaydutt V.; Vargas, Roberto; Smith, James; Otoukesh, Salman; Maxwell, Annette E.

    2013-01-01

    Background Most theoretical formulations acknowledge that knowledge and awareness of cancer screening and prevention recommendations significantly influence health behaviors. This study compares perceived knowledge of cancer prevention and screening with test-based knowledge in a community sample. We also examine demographic variables and self-reported cancer screening and prevention behaviors as correlates of both knowledge scores, and consider whether cancer related knowledge can be accurately assessed using just a few, simple questions in a short and easy-to-complete survey. Methods We used a community-partnered participatory research approach to develop our study aims and a survey. The study sample was composed of 180 predominantly African American and Hispanic community individuals who participated in a full-day cancer prevention and screening promotion conference in South Los Angeles, California, on July 2011. Participants completed a self-administered survey in English or Spanish at the beginning of the conference. Results Our data indicate that perceived and test-based knowledge scores are only moderately correlated. Perceived knowledge score shows a stronger association with demographic characteristics and other cancer related variables than the test-based score. Thirteen out of twenty variables that are examined in our study showed a statistically significant correlation with the perceived knowledge score, however, only four variables demonstrated a statistically significant correlation with the test-based knowledge score. Conclusion Perceived knowledge of cancer prevention and screening was assessed with fewer items than test-based knowledge. Thus, using this assessment could potentially reduce respondent burden. However, our data demonstrate that perceived and test-based knowledge are separate constructs. PMID:23530303

  9. C1q-targeted monoclonal antibody prevents complement-dependent cytotoxicity and neuropathology in in vitro and mouse models of neuromyelitis optica

    PubMed Central

    Phuan, Puay-Wah; Zhang, Hua; Asavapanumas, Nithi; Leviten, Michael; Rosenthal, Arnon; Tradtrantip, Lukmanee

    2014-01-01

    Neuromyelitis optica (NMO) is an autoimmune disorder with inflammatory demyelinating lesions in the central nervous system, particularly in the spinal cord and optic nerve. NMO pathogenesis is thought to involve binding of anti-aquaporin-4 (AQP4) autoantibodies to astrocytes, which causes complement-dependent cytotoxicity (CDC) and downstream inflammation leading to oligo-dendrocyte and neuronal injury. Vasculocentric deposition of activated complement is a prominent feature of NMO pathology. Here, we show that a neutralizing monoclonal antibody against the C1q protein in the classical complement pathway prevents AQP4 autoantibody-dependent CDC in cell cultures and NMO lesions in ex vivo spinal cord slice cultures and in mice. A monoclonal antibody against human C1q with 11 nM binding affinity prevented CDC caused by NMO patient serum in AQP4-transfected cells and primary astrocyte cultures, and prevented complement-dependent cell-mediated cytotoxicity (CDCC) produced by natural killer cells. The anti-C1q antibody prevented astrocyte damage and demyelination in mouse spinal cord slice cultures exposed to AQP4 autoantibody and human complement. In a mouse model of NMO produced by intracerebral injection of AQP4 autoantibody and human complement, the inflammatory demyelinating lesions were greatly reduced by intracerebral administration of the anti-C1q antibody. These results provide proof-of-concept for C1q-targeted monoclonal antibody therapy in NMO. Targeting of C1q inhibits the classical complement pathway directly and causes secondary inhibition of CDCC and the alternative complement pathway. As C1q-targeted therapy leaves the lectin complement activation pathway largely intact, its side-effect profile is predicted to differ from that of therapies targeting downstream complement proteins. PMID:23677375

  10. The Use of Profiling To Target Services in State Welfare-to-Work Programs: An Example of Process and Implementation. Upjohn Institute Staff Working Paper.

    ERIC Educational Resources Information Center

    Eberts, Randall W.

    A pilot project was designed to test the efficacy of profiling welfare recipients and referring them to welfare-to-work services targeted toward their specific work histories and skills. The general framework of Michigan's Work First program was used to illustrate how profiling can be designed and administered. A profiling model was proposed that…

  11. Novel Kinase Inhibitors Targeting the PH Domain of AKT for Preventing and Treating Cancer | NCI Technology Transfer Center | TTC

    Cancer.gov

    The National Cancer Institute's Medical Oncology Branch is seeking statements of capability or interest from parties interested in licensing and co-development collaborative research to further develop, evaluate, or commercialize novel kinase inhibitors targeting the PH domain of AKT.

  12. Gamma (γ)-Ray Activity as a Tool for Identification of Hidden Ejecta Deposits Around Impact Crater on Basaltic Target: Example from Lonar Crater, India

    NASA Astrophysics Data System (ADS)

    Bose, T.; Misra, S.; Chakraborty, S.; Reddy, K.

    2013-11-01

    Geophysical techniques based on radioactivity measurements are not generally used for exploration of asteroid impact craters. Our studies on the field and laboratory measurements of radioactivity on samples from the Lonar crater, India, show that this technique could be an important method for mapping the distribution of ejecta around the deeply excavated impact craters particularly when these structures are formed on relatively old target rocks/palaeosol. The Lonar ejecta shows ~1.3 times higher γ-ray count rates in the field on average compared to the underlying palaeosol and ~1.9 times higher values over the target basalt while measured by a portable Geiger-Müller pulse counter. The absorbed γ-dose rate (D) of the Lonar samples, computed from 232Th, 238U, and 40K abundances in these samples, also show that the ejecta has distinct bulk dose rates (average ~8.42 nGy h-1) as compared to those of the palaeosol (~18.34 nGy h-1), target basalt (~11.97 nGy h-1), and the impact-melts and spherules (~14 nGy h-1). Therefore, radioactivity mapping of the terrestrial and planetary impact craters by direct methods has importance in mapping ejecta distributions around these structures.

  13. A Targeted E-Learning Program for Surgical Trainees to Enhance Patient Safety in Preventing Surgical Infection

    ERIC Educational Resources Information Center

    McHugh, Seamus Mark; Corrigan, Mark; Dimitrov, Borislav; Cowman, Seamus; Tierney, Sean; Humphreys, Hilary; Hill, Arnold

    2010-01-01

    Introduction: Surgical site infection accounts for 20% of all health care-associated infections (HCAIs); however, a program incorporating the education of surgeons has yet to be established across the specialty. Methods: An audit of surgical practice in infection prevention was carried out in Beaumont Hospital from July to November 2009. An…

  14. Targeted Routine Antenatal Anti-D Prophylaxis in the Prevention of RhD Immunisation - Outcome of a New Antenatal Screening and Prevention Program

    PubMed Central

    Tiblad, Eleonor; Taune Wikman, Agneta; Ajne, Gunilla; Blanck, Agneta; Jansson, Yvonne; Karlsson, Anita; Nordlander, Elisabeth; Holländer, Bibi Shassti; Westgren, Magnus

    2013-01-01

    Objective To estimate the incidence of RhD immunisation after implementation of first trimester non-invasive fetal RHD screening to select only RhD negative women carrying RHD positive fetuses for routine antenatal anti-D prophylaxis (RAADP). Materials and Methods We present a population-based prospective observational cohort study with historic controls including all maternity care centres and delivery hospitals in the Stockholm region, Sweden. All RhD negative pregnant women were screened for fetal RHD genotype in the first trimester of pregnancy. Anti-D immunoglobulin (250–300 µg) was administered intramuscularly in gestational week 28–30 to participants with RHD positive fetuses. Main outcome measure was the incidence of RhD immunisation developing during or after pregnancy. Results During the study period 9380 RhD negative women gave birth in Stockholm. Non-invasive fetal RHD genotyping using cell-free fetal DNA in maternal plasma was performed in 8374 pregnancies of which 5104 (61%) were RHD positive and 3270 (39%) RHD negative. In 4590 pregnancies with an RHD positive test the women received antenatal anti-D prophylaxis. The incidence of RhD immunisation in the study cohort was 0.26 percent (24/9380) (95% CI 0.15–0.36%) compared to 0.46 percent (86/18546) (95% CI 0.37 to 0.56%) in the reference cohort. The risk ratio (RR) for sensitisation was 0.55 (95% CI 0.35 to 0.87) and the risk reduction was statistically significant (p = 0.009). The absolute risk difference was 0.20 percent, corresponding to a number needed to treat (NNT) of 500. Conclusions Using first trimester non-invasive antenatal screening for fetal RHD to target routine antenatal anti-D prophylaxis selectively to RhD negative women with RHD positive fetuses significantly reduces the incidence of new RhD immunisation. The risk reduction is comparable to that reported in studies evaluating the outcome of non selective RAADP to all RhD negative women. The cost-effectiveness of this

  15. Carboxylic acid functionalization prevents the translocation of multi-walled carbon nanotubes at predicted environmentally relevant concentrations into targeted organs of nematode Caenorhabditis elegans

    NASA Astrophysics Data System (ADS)

    Nouara, Abdelli; Wu, Qiuli; Li, Yinxia; Tang, Meng; Wang, Haifang; Zhao, Yuliang; Wang, Dayong

    2013-06-01

    Carboxyl (-COOH) surface modified multi-walled carbon nanotubes (MWCNTs-COOH) can be used for targeted delivery of drugs and imaging. However, whether MWCNTs-COOH at environmentally relevant concentrations exert certain toxic effects on multicellular organisms and the underlying mechanisms are still largely unclear. In the present study, we applied the nematode Caenorhabditis elegans to evaluate the properties of MWCNTs-COOH at environmentally relevant concentrations by comparing the effects of MWCNTs and MWCNTs-COOH exposure on C. elegans from L1-larvae to adult at concentrations of 0.001-1000 μg L-1. Exposure to MWCNTs could potentially damage the intestine (primary targeted organ) at concentrations greater than 0.1 μg L-1 and functions of neurons and reproductive organ (secondary targeted organs) at concentrations greater than 0.001 μg L-1. Carboxyl modification prevented the toxicity of MWCNTs on the primary and the secondary targeted organs at concentrations less than 100 μg L-1, suggesting that carboxyl modification can effectively prevent the adverse effects of MWCNTs at environmentally relevant concentrations. After exposure, MWCNTs-COOH (1 mg L-1) were translocated into the spermatheca and embryos in the body through the primary targeted organs. However, MWCNTs-COOH (10 μg L-1) were not observed in spermatheca and embryos in the body of nematodes. Moreover, relatively high concentrations of MWCNTs-COOH exposed nematodes might have a hyper-permeable intestinal barrier, whereas MWCNTs-COOH at environmentally relevant concentrations effectively sustained the normally permeable state for the intestinal barrier. Therefore, we elucidated the cellular basis of carboxyl modification to prevent toxicity of MWCNTs at environmentally relevant concentrations. Our data highlights the key role of biological barriers in the primary targeted organs to block toxicity formation from MWCNTs, which will be useful for the design of effective prevention strategies against

  16. Age-targeted HIV treatment and primary prevention as a ‘ring fence’ to efficiently interrupt the age patterns of transmission in generalized epidemic settings in South Africa

    PubMed Central

    Bershteyn, Anna; Klein, Daniel J.; Eckhoff, Philip A.

    2016-01-01

    Background Generalized HIV epidemics propagate to future generations according to the age patterns of transmission. We hypothesized that future generations could be protected from infection using age-targeted prevention, analogous to the ring-fencing strategies used to control the spread of smallpox. Methods We modeled age-targeted or cohort-targeted outreach with HIV treatment and/or prevention using EMOD-HIV v0·8, an individual-based network model of HIV transmission in South Africa. Results Targeting ages 20 to 30 with intensified outreach, linkage, and eligibility for antiretroviral therapy (ART) averted 45% as many infections as universal outreach for approximately one-fifth the cost beyond existing HIV services. Though cost-effective, targeting failed to eliminate all infections to those under 20 due to vertical and inter-generational transmission. Cost-effectiveness of optimal prevention strategies included US$6238 per infection averted targeting ages 10–30, US$5031 targeting 20–30, US$4279 targeting 22–27, and US$3967 targeting 25–27, compared to US$10 812 for full-population test-and-treat. Minimizing burden (disability-adjusted life years [DALYs]) rather than infections resulted in older target age ranges because older adults were more likely to receive a direct health benefit from treatment. Conclusions Age-targeted treatment for HIV prevention is unlikely to eliminate HIV epidemics, but is an efficient strategy for reducing new infections in generalized epidemics settings. PMID:27008897

  17. Epigallocatechin-3-gallate: a useful, effective and safe clinical approach for targeted prevention and individualised treatment of neurological diseases?

    PubMed Central

    2013-01-01

    Neurodegenerative disorders show an increasing prevalence in a number of highly developed countries. Often, these diseases require life-long treatment mostly with drugs which are costly and mostly accompanied by more or less serious side-effects. Their heterogeneous manifestation, severity and outcome pose the need for individualised treatment options. There is an intensive search for new strategies not only for treating but also for preventing these diseases. Green tea and green tea extracts seem to be such a promising and safe alternative. However, data regarding the beneficial effects and possible underlying mechanism, specifically in clinical trials, are rare and rather controversial or non-conclusive. This review outlines the existing evidence from preclinical studies (cell and tissue cultures and animal models) and clinical trials regarding preventive and therapeutic effects of epigallcatechin-3-gallate in neurodegenerative diseases and considers antioxidative vs. pro-oxidative properties of the tea catechin important for dosage recommendations. PMID:23418936

  18. Apurinic/apyrimidinic endonuclease/redox effector factor-1(APE/Ref-1): a unique target for the prevention and treatment of human melanoma.

    PubMed

    Yang, Sun; Meyskens, Frank L

    2009-03-01

    Management of melanoma is a growing and challenging public health issue requiring novel and multidisciplinary approaches to achieve more efficient prevention and therapeutic benefits. The aim of this article is to show the critical role of APE/Ref-1 on melanomagenesis and progression. APE/Ref-1 serves as a redox-sensitive node of convergence of various signals as well as a DNA-repair enzyme, and its activation protects melanocytes and melanoma cells from chronic oxidative stress and promotes cell survival via mediation of downstream pathways. APE/Ref-1 is a strong candidate as a potential drug-treatable target for the prevention and treatment of human melanoma. Lead compounds exhibiting inhibitory effects on APE/Ref-1 are also reviewed. We anticipate potential clinical benefit in the future through inhibition of APE/Ref-1 and/or Ref-1-mediated signaling.

  19. Nipping early risk factors in the bud: preventing substance abuse, delinquency, and violence in adolescence through interventions targeted at young children (0-8 years).

    PubMed

    Webster-Stratton, C; Taylor, T

    2001-09-01

    This bulletin describes state-of-the-art universal and selective prevention programs designed to promote parent and teacher competencies and to prevent conduct problems. In addition, it describes indicated interventions designed for children who already have been diagnosed with oppositional defiant disorder and/or conduct disorder. Emphasis is placed on empirically supported programs that have identified key malleable risk factors in children, families, and schools, which have been shown in longitudinal research to be related to later development of substance abuse, delinquency, and violence. We have targeted preschool and primary grade children, ages 0-8 years, in this review because research suggests that the most effective interventions can nip in the bud risk behaviors in the early years, before antisocial behaviors become crystallized. Guidelines for selecting effective interventions are provided.

  20. Effects of ethnic targeting on the perceived effectiveness of cancer prevention messages among latinas and non-latina white women.

    PubMed

    Ramírez, A Susana

    2013-01-01

    In general, efforts to target Latinos are made through Spanish-language messages, yet 75% of U.S. Latinos are bilingual or English dominant. Acculturation (adapting mainstream traits) is associated with increased lifestyle-related risk behaviors. Latinos maintain cultural traits and ethnic identification even as they appear to acculturate (e.g., through language). This raises questions about how to communicate health information to more-acculturated Latinos who are not reached by traditional Spanish outreach yet may not identify with general-market messages. This study tested the relative efficacy of English-language messages targeted to Latinas, compared with general-market messages, among highly acculturated Latina women and non-Latina White women. In this pair of online experiments, Latinas (n = 715) and non-Latina White women (n = 704) rated the perceived effectiveness of general-market versus Latina-targeted Pap smear and mammogram public service announcements. In 1 of 2 experiments ethnically targeted messages were rated relatively more effective for the intended audience and equally effective for the general audience. The author discusses implications for how campaigns reach U.S. Latinos across the acculturation spectrum.

  1. Comprehensive STD/HIV prevention education targeting US adolescents: review of an ethical dilemma and proposed ethical framework.

    PubMed

    Brown, E J; Simpson, E M

    2000-07-01

    Adolescents are increasingly at risk for sexually transmitted diseases (STDs), including human immunodeficiency virus (HIV) infection. The prolonged latency period, sometimes in excess of five years, and the incubation period of up to 10 years before the manifestation of symptoms, may foster adolescents' false sense of invincibility and denial as they often do not see the devastating effects of the disease in their peers until they are older. In turn, their practice of safer sex may be hindered and thereby contribute to the escalation of this public health crisis among sexually active adolescents. Prevention-focused recommendations were made in the USA as a result of this crisis. Recommendations were made to: (1) include STD/HIV education in the curricula of grades kindergarten to 12; (2) increase to at least 75% the proportion of primary care and mental health professionals who provide age-appropriate STD/HIV prevention counselling to adolescents; and (3) expand HIV prevention services to include age-appropriate HIV education curricula for students in grades 4-12 in 95% of schools. Yet, in the USA, the provision of school-based comprehensive STD/HIV education has been difficult to achieve owing to certain limitations and, in some instances, legal action. These limitations include: limited student access; restricted content; and the implementation of sporadic and/or brief educational programmes. Given these recommendations and the fact that adolescents are acquiring STDs and HIV infections at increasing rates, and despite the limitations and legal actions, do health care professionals not have an ethical obligation to provide adolescents with comprehensive STD/HIV prevention education? This ethical dilemma will be discussed using the ethical decision-making principles of 'autonomy' and 'beneficence', and a decision-making model proposed by Thompson and Thompson, and by Chally and Loric.

  2. Who to target in sudden unexpected death in epilepsy prevention and how? Risk factors, biomarkers, and intervention study designs.

    PubMed

    Tomson, Torbjörn; Surges, Rainer; Delamont, Robert; Haywood, Serena; Hesdorffer, Dale C

    2016-01-01

    The risk of dying suddenly and unexpectedly is increased 24- to 28-fold among young people with epilepsy compared to the general population, but the incidence of sudden unexpected death in epilepsy (SUDEP) varies markedly depending on the epilepsy population. This article first reviews risk factors and biomarkers for SUDEP with the overall aim of enabling identification of epilepsy populations with different risk levels as a background for a discussion of possible intervention strategies. The by far most important clinical risk factor is frequency of generalized tonic-clonic seizures (GTCS), but nocturnal seizures, early age at onset, and long duration of epilepsy have been identified as additional risk factors. Lack of antiepileptic drug (AED) treatment or, in the context of clinical trials, adjunctive placebo versus active treatment is associated with increased risks. Despite considerable research, reliable electrophysiologic (electrocardiography [ECG] or electroencephalography [EEG]) biomarkers of SUDEP risk remain to be established. This is an important limitation for prevention strategies and intervention studies. There is a lack of biomarkers for SUDEP, and until validated biomarkers are found, the endpoint of interventions to prevent SUDEP must be SUDEP itself. These interventions, be they pharmacologic, seizure-detection devices, or nocturnal supervision, require large numbers. Possible methods for assessing prevention measures include public health community interventions, self-management, and more traditional (and much more expensive) randomized clinical trials.

  3. Silibinin prevents prostate cancer cell-mediated differentiation of naïve fibroblasts into cancer-associated fibroblast phenotype by targeting TGF β2.

    PubMed

    Ting, Harold J; Deep, Gagan; Jain, Anil K; Cimic, Adela; Sirintrapun, Joseph; Romero, Lina M; Cramer, Scott D; Agarwal, Chapla; Agarwal, Rajesh

    2015-09-01

    Tumor microenvironment (TM) is an essential element in prostate cancer (PCA), offering unique opportunities for its prevention. TM includes naïve fibroblasts that are recruited by nascent neoplastic lesion and altered into 'cancer-associated fibroblasts' (CAFs) that promote PCA. A better understanding and targeting of interaction between PCA cells and fibroblasts and inhibiting CAF phenotype through non-toxic agents are novel approaches to prevent PCA progression. One well-studied cancer chemopreventive agent is silibinin, and thus, we examined its efficacy against PCA cells-mediated differentiation of naïve fibroblasts into a myofibroblastic-phenotype similar to that found in CAFs. Silibinin's direct inhibitory effect on the phenotype of CAFs derived directly from PCA patients was also assessed. Human prostate stromal cells (PrSCs) exposed to control conditioned media (CCM) from human PCA PC3 cells showed more invasiveness, with increased alpha-smooth muscle actin (α-SMA) and vimentin expression, and differentiation into a phenotype we identified in CAFs. Importantly, silibinin (at physiologically achievable concentrations) inhibited α-SMA expression and invasiveness in differentiated fibroblasts and prostate CAFs directly, as well as indirectly by targeting PCA cells. The observed increase in α-SMA and CAF-like phenotype was transforming growth factor (TGF) β2 dependent, which was strongly inhibited by silibinin. Furthermore, induction of α-SMA and CAF phenotype by CCM were also strongly inhibited by a TGFβ2-neutralizing antibody. The inhibitory effect of silibinin on TGFβ2 expression and CAF-like biomarkers was also observed in PC3 tumors. Together, these findings highlight the potential usefulness of silibinin in PCA prevention through targeting the CAF phenotype in the prostate TM.

  4. Silibinin Prevents Prostate Cancer Cell-Mediated Differentiation of Naïve Fibroblasts into Cancer-Associated Fibroblast Phenotype by Targeting TGF β2

    PubMed Central

    Ting, Harold; Deep, Gagan; Jain, Anil K.; Cimic, Adela; Sirintrapun, Joseph; Romero, Lina M.; Cramer, Scott D.; Agarwal, Chapla; Agarwal, Rajesh

    2014-01-01

    Tumor microenvironment is an essential element in prostate cancer (PCA), offering unique opportunities for its prevention. Tumor microenvironment includes naïve fibroblasts that are recruited by nascent neoplastic lesion and altered into ‘cancer-associated fibroblasts’ (CAFs) that promote PCA. A better understanding and targeting of interaction between PCA cells and fibroblasts and inhibiting CAF phenotype through non-toxic agents are novel approaches to prevent PCA progression. One well-studied cancer chemopreventive agent is silibinin, and thus, we examined its efficacy against PCA cells-mediated differentiation of naïve fibroblasts into a myofibroblastic-phenotype similar to that found in CAFs. Silibinin’s direct inhibitory effect on the phenotype of CAFs derived directly from PCA patients was also assessed. Human prostate stromal cells (PrSCs) exposed to control conditioned media (CCM) from human PCA PC3 cells showed more invasiveness, with increased α-SMA (alpha-smooth muscle actin) and vimentin expression, and differentiation into a phenotype we identified in CAFs. Importantly, silibinin (at physiologically-achievable concentrations) inhibited α-SMA expression and invasiveness in differentiated fibroblasts and prostate CAFs directly, as well as indirectly by targeting PCA cells. The observed increase in α-SMA and CAF-like phenotype was transforming growth factor (TGF) β2 dependent, which was strongly inhibited by silibinin. Furthermore, induction of ±-SMA and CAF phenotype by CCM were also strongly inhibited by a TGFβ2-neutralizing antibody. The inhibitory effect of silibinin on TGFβ2 expression and CAF-like biomarkers was also observed in PC3 tumors. Together, these findings highlight the potential usefulness of silibinin in PCA prevention through targeting the CAF phenotype in the prostate tumor microenvironment. PMID:24615813

  5. Shining examples

    SciTech Connect

    Flavin, C.; O`Meara, M.

    1997-05-01

    Creative financing for setting up individual solar power systems and energy efficient appliances is beginning to come of age in developing countries. This article describes the practical implementation of such solar energy financing as well as the broader implications, using India, Indonesia and the Dominican Republic as examples. Also included is a discussion of the government and publically supported organizations which are encouraging solar energy use and realistic financing.

  6. Communication Skills for Patient Engagement: Argumentation Competencies As Means to Prevent or Limit Reactance Arousal, with an Example from the Italian Healthcare System

    PubMed Central

    Bigi, Sarah

    2016-01-01

    The paper discusses the role of argumentative competencies for the achievement of patient engagement through communication in doctor-patient consultations. The achievement of patient engagement is being proposed by recent studies as a condition that can facilitate in particular patient adherence, which involves behavior change. One obstacle to behavior change that has been observed is reactance, i.e., resistance to persuasive messages when a threat to freedom is perceived. In the medical field, reactance theory has been mostly applied in the field of mental health, less frequently to understand non-adherence in general. However, a few studies have revealed that reactance can actually explain in part the motives behind non-adherence. These studies propose that the arousal of reactance could be limited or prevented by adopting relational measures aimed at giving patients the feeling that they still hold some control over the process of care and that the “impositions” on their freedoms are acceptable because they have had the opportunity to decide about them. However, they do not discuss how these strategies should be operationalized at the dialogical level. A debated issue in the study of reactance is the role played by knowledge. It seems that pure information regarding an issue is likely to represent a threat in itself. Complementary to this is the finding that quality of argument does not impact on the degree of reactance. These findings pose a problem in view of the goal of patient education, itself considered as a necessary premise for any process of patient engagement and adherence. It seems necessary to move away from a conception of education as mere transmission of information and look for more effective ways of transferring knowledge to patients. With regard to this issue, the paper argues that useful insights can be found in studies on science education, in which it is shown experimentally that argumentative processes favor learning and understanding

  7. Nitric oxide as a target of complementary and alternative medicines to prevent and treat inflammation and cancer

    PubMed Central

    Hofseth, Lorne J.

    2009-01-01

    Nitric oxide (NO) and associated reactive nitrogen species (RNS) are involved in many physiological functions. There has been an ongoing debate to whether RNS can inhibit or perpetuate chronic inflammation and associated carcinogenesis. Although the final outcome depends on the genetic make-up of its target, the surrounding microenvironment, the activity and localization of nitric oxide synthase (NOS) isoforms, and overall levels of NO/RNS, evidence is accumulating that in general, RNS drive inflammation and cancers associated with inflammation. To this end, many complementary and alternative medicines (CAMs) that work in chemoprevention associated with chronic inflammation, are inhibitors of excessive NO observed in inflammatory conditions. Here we review recent literature outlining a role of NO/RNS in chronic inflammation and cancer, and point toward NO as one of several targets for the success of CAMs in treating chronic inflammation and cancer associated with this inflammation. PMID:18440130

  8. Peptidylarginine deiminases: novel drug targets for prevention of neuronal damage following hypoxic ischemic insult (HI) in neonates.

    PubMed

    Lange, Sigrun; Rocha-Ferreira, Eridan; Thei, Laura; Mawjee, Priyanka; Bennett, Kate; Thompson, Paul R; Subramanian, Venkataraman; Nicholas, Anthony P; Peebles, Donald; Hristova, Mariya; Raivich, Gennadij

    2014-08-01

    Neonatal hypoxic ischaemic (HI) injury frequently causes neural impairment in surviving infants. Our knowledge of the underlying molecular mechanisms is still limited. Protein deimination is a post-translational modification caused by Ca(+2) -regulated peptidylarginine deiminases (PADs), a group of five isozymes that display tissue-specific expression and different preference for target proteins. Protein deimination results in altered protein conformation and function of target proteins, and is associated with neurodegenerative diseases, gene regulation and autoimmunity. In this study, we used the neonatal HI and HI/infection [lipopolysaccharide (LPS) stimulation] murine models to investigate changes in protein deimination. Brains showed increases in deiminated proteins, cell death, activated microglia and neuronal loss in affected brain areas at 48 h after hypoxic ischaemic insult. Upon treatment with the pan-PAD inhibitor Cl-amidine, a significant reduction was seen in microglial activation, cell death and infarct size compared with control saline or LPS-treated animals. Deimination of histone 3, a target protein of the PAD4 isozyme, was increased in hippocampus and cortex specifically upon LPS stimulation and markedly reduced following Cl-amidine treatment. Here, we demonstrate a novel role for PAD enzymes in neural impairment in neonatal HI Encephalopathy, highlighting their role as promising new candidates for drug-directed intervention in neurotrauma. Hypoxic Ischaemic Insult (HI) results in activation of peptidylarginine deiminases (PADs) because of calcium dysregulation. Target proteins undergo irreversible changes of protein bound arginine to citrulline, resulting in protein misfolding. Infection in synergy with HI causes up-regulation of TNFα, nuclear translocation of PAD4 and change in gene regulation as a result of histone deimination. Pharmacological PAD inhibition significantly reduced HI brain damage.

  9. VEGFA/VEGFR2-targeted therapies prevent the VEGFA-induced proliferation of regulatory T cells in cancer

    PubMed Central

    Terme, Magali; Tartour, Eric; Taieb, Julien

    2013-01-01

    Some of the anti-angiogenic agents currently used to treat solid malignancies have effects on tumor endothelial cells as well as on immune cells. We have recently demonstrated that targeting the vascular endothelial growth factor A (VEGFA)/VEGF receptor 2 (VEGFR2) signaling pathway reduces the proportion of regulatory T cells (Treg) in a mouse model of colorectal cancer (CRC) and in metastatic CRC patients as it inhibits tumor-induced Treg proliferation. PMID:24083078

  10. Differential subcellular mRNA targeting: deletion of a single nucleotide prevents the transport to axons but not to dendrites of rat hypothalamic magnocellular neurons.

    PubMed Central

    Mohr, E; Morris, J F; Richter, D

    1995-01-01

    It has previously been shown that mRNA encoding the arginine vasopressin (AVP) precursor is targeted to axons of rat magnocellular neurons of the hypothalamo-neurohypophyseal tract. In the homozygous Brattle-boro rat, which has a G nucleotide deletion in the coding region of the AVP gene, no such targeting is observed although the gene is transcribed. RNase protection and heteroduplex analyses demonstrate that, in heterozygous animals, which express both alleles of the AVP gene, the wild-type but not the mutant transcript is subject to axonal compartmentation. In contrast, wild-type and mutant AVP mRNAs are present in dendrites. These data suggest the existence of different mechanisms for mRNA targeting to the two subcellular compartments. Axonal mRNA localization appears to take place after protein synthesis; the mutant transcript is not available for axonal targeting because it lacks a stop codon preventing its release from ribosomes. Dendritic compartmentation, on the other hand, is likely to precede translation and, thus, would be unable to discriminate between the two mRNAs. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4 Fig. 5 Fig. 6 PMID:7753814

  11. Prevention of Liver Fibrosis by Triple Helix-Forming Oligodeoxyribonucleotides Targeted to the Promoter Region of Type I Collagen Gene

    PubMed Central

    Koilan, Subramaniyan; Hamilton, David; Baburyan, Narina; Padala, Mythili K.; Weber, Karl T.

    2010-01-01

    Hepatic fibrosis leading to cirrhosis remains a global health problem. The most common etiologies are alcoholism and viral infections. Liver fibrosis is associated with major changes in both quantity and composition of extracellular matix and leads to disorganization of the liver architecture and irreversible damage to the liver function. As of now there is no effective therapy to control fibrosis. The end product of fibrosis is abnormal synthesis and accumulation of type I collagen in the extracellular matrix, which is produced by activated stellate or Ito cells in the damaged liver. Therefore, inhibition of transcription of type I collagen should in principle inhibit its production and accumulation in liver. Normally, DNA exists in a duplex form. However, under some circumstances, DNA can assume triple helical (triplex) structures. Intermolecular triplexes, formed by the addition of a sequence-specific third strand to the major groove of the duplex DNA, have the potential to serve as selective gene regulators. Earlier, we demonstrated efficient triplex formation between the exogenously added triplex-forming oligodeoxyribonucleotides (TFOs) and a specific sequence in the promoter region of the COL1A1 gene. In this study we used a rat model of liver fibrosis, induced by dimethylnitrosamine, to test whether these TFOs prevent liver fibrosis. Our results indicate that both the 25-mer and 18-mer TFOs, specific for the upstream nucleotide sequence from −141 to −165 (relative to the transcription start site) in the 5′ end of collagen gene promoter, effectively prevented accumulation of liver collagen and fibrosis. We also observed improvement in liver function tests. However, mutations in the TFO that eliminated formation of triplexes are ineffective in preventing fibrosis. We believe that these TFOs can be used as potential antifibrotic therapeutic molecules. PMID:20818932

  12. The role of nutraceuticals in pancreatic cancer prevention and therapy: Targeting cellular signaling, miRNAs and epigenome

    PubMed Central

    Li, Yiwei; Go, Vay Liang W.; Sarkar, Fazlul H.

    2014-01-01

    Pancreatic cancer is one of the most aggressive malignancies in US adults. The experimental studies have found that antioxidant nutrients could reduce oxidative DNA damage, suggesting that these antioxidants may protect against pancreatic carcinogenesis. Several epidemiologic studies showed that dietary intake of antioxidants was inversely associated with the risk of pancreatic cancer, demonstrating the inhibitory effects of antioxidants on pancreatic carcinogenesis. Moreover, nutraceuticals, the anti-cancer agents from diet or natural plants, have been found to inhibit the development and progression of pancreatic cancer through the regulation of cellular signaling pathways. Importantly, nutraceuticals also up-regulate the expression of tumor suppressive miRNAs and down-regulate the expression of oncogenic miRNAs, leading to the inhibition of pancreatic cancer cell growth and pancreatic Cancer Stem Cell (CSC) self-renewal through modulation of cellular signaling network. Furthermore, nutraceuticals also regulate epigenetically deregulated DNAs and miRNAs, leading to the normalization of altered cellular signaling in pancreatic cancer cells. Therefore, nutraceuticals could have much broader use in the prevention and/or treatment of pancreatic cancer in combination with conventional chemotherapeutics. However, more in vitro mechanistic experiments, in vivo animal studies, and clinical trials are needed to realize the true value of nutraceuticals in the prevention and/or treatment of pancreatic cancer. PMID:25493373

  13. The Jak-STAT target Chinmo prevents sex transformation of adult stem cells in the Drosophila testis niche

    PubMed Central

    Ma, Qing; Wawersik, Matthew; Matunis, Erika L.

    2014-01-01

    Local signals maintain adult stem cells in many tissues. Whether the sexual identity of adult stem cells must also be maintained was not known. In the adult Drosophila testis niche, local Jak-STAT signaling promotes somatic cyst stem cell (CySC) renewal through several effectors, including the putative transcription factor Chronologically inappropriate morphogenesis (Chinmo). Here, we find that Chinmo also prevents feminization of CySCs. Chinmo promotes expression of the canonical male sex determination factor DoublesexM (DsxM) within CySCs and their progeny, and ectopic expression of DsxM in the CySC lineage partially rescues the chinmo sex transformation phenotype, placing Chinmo upstream of DsxM. The Dsx homologue DMRT1 prevents the male-to female conversion of differentiated somatic cells in the adult mammalian testis, but its regulation is not well understood. Our work indicates that sex maintenance occurs in adult somatic stem cells, and that this highly conserved process is governed by effectors of niche signals. PMID:25453558

  14. A protocol for targeted enrichment of intron-containing sequence markers for recent radiations: A phylogenomic example from Heuchera (Saxifragaceae)1

    PubMed Central

    Folk, Ryan A.; Mandel, Jennifer R.; Freudenstein, John V.

    2015-01-01

    Premise of the study: Phylogenetic inference is moving to large multilocus data sets, yet there remains uncertainty in the choice of marker and sequencing method at low taxonomic levels. To address this gap, we present a method for enriching long loci spanning intron-exon boundaries in the genus Heuchera. Methods: Two hundred seventy-eight loci were designed using a splice-site prediction method combining transcriptomic and genomic data. Biotinylated probes were designed for enrichment of these loci. Reference-based assembly was performed using genomic references; additionally, chloroplast and mitochondrial genomes were used as references for off-target reads. The data were aligned and subjected to coalescent and concatenated phylogenetic analyses to demonstrate support for major relationships. Results: Complete or nearly complete (>99%) sequences were assembled from essentially all loci from all taxa. Aligned introns showed a fourfold increase in divergence as opposed to exons. Concatenated analysis gave decisive support to all nodes, and support was also high and relationships mostly similar in the coalescent analysis. Organellar phylogenies were also well-supported and conflicted with the nuclear signal. Discussion: Our approach shows promise for resolving a recent radiation. Enrichment for introns is highly successful with little or no sequencing dropout at low taxonomic levels despite higher substitution and indel frequencies, and should be exploited in studies of species complexes. PMID:26312196

  15. Development and early implementation of the bigger picture, a youth-targeted public health literacy campaign to prevent type 2 diabetes.

    PubMed

    Rogers, Elizabeth A; Fine, Sarah; Handley, Margaret A; Davis, Hodari; Kass, James; Schillinger, Dean

    2014-01-01

    The prevalence of type 2 diabetes is rapidly rising, especially among minority and low-income youth. There is an unmet need to engage youth in identifying solutions to reverse this trajectory. Social marketing campaigns and entertainment education are effective forms of health communication for engaging populations in health-promoting behaviors. Critical to curbing the epidemic is moving the diabetes conversation away from individual behavior alone and toward a socioecologic perspective using a public health literacy framework. The authors developed an academic-community partnership to develop, implement, and evaluate a type 2 diabetes prevention campaign targeting minority and low-income youth. The Bigger Picture campaign uses hard-hitting, youth-generated spoken-word messages around key environmental and social drivers of the type 2 diabetes epidemic. Campaign goals included promoting health capacity and civic engagement. This article focuses on the development and implementation of the campaign, including (a) rationale and theoretical underpinnings, (b) steps in campaign creation, (c) testing the campaign messaging, and (d) campaign dissemination and evaluation planning. A youth-created health communication campaign using a public health literacy framework with targeted, relevant, and compelling messaging appears to be a promising vehicle for reaching at-risk youth to increase knowledge of and attitudes about preventing type 2 diabetes, change social norms, and motivate participation in health-promoting initiatives. PMID:25315590

  16. Effective Prevention of Liver Fibrosis by Liver-targeted Hydrodynamic Gene Delivery of Matrix Metalloproteinase-13 in a Rat Liver Fibrosis Model

    PubMed Central

    Abe, Hiroyuki; Kamimura, Kenya; Kobayashi, Yuji; Ohtsuka, Masato; Miura, Hiromi; Ohashi, Riuko; Yokoo, Takeshi; Kanefuji, Tsutomu; Suda, Takeshi; Tsuchida, Masanori; Aoyagi, Yutaka; Zhang, Guisheng; Liu, Dexi; Terai, Shuji

    2016-01-01

    Liver fibrosis is the final stage of liver diseases that lead to liver failure and cancer. While various diagnostic methods, including the use of serum marker, have been established, no standard therapy has been developed. The objective of this study was to assess the approach of overexpressing matrix metalloproteinase-13 gene (MMP13) in rat liver to prevent liver fibrosis progression. A rat liver fibrosis model was established by ligating the bile duct, followed by liver-targeted hydrodynamic gene delivery of a MMP13 expression vector, containing a CAG promoter-MMP13-IRES-tdTomato-polyA cassette. After 14 days, the serum level of MMP13 peaked at 71.7 pg/ml in MMP13-treated group, whereas the nontreated group only showed a level of ~5 pg/ml (P < 0.001). These levels were sustained for the next 60 days. The statistically lower level of the hyaluronic acids in treated group versus the nontreated group (P < 0.05) reveals the therapeutic effect of MMP13 overexpression. Quantitative analysis of tissue stained with sirius red showed a statistically larger volume of fibrotic tissue in the nontreated group compared to that of MMP13-treated rats (P < 0.05). These results suggest that the liver-targeted hydrodynamic delivery of MMP13 gene could be effective in the prevention of liver fibrosis. PMID:26730813

  17. Development and Early Implementation of The Bigger Picture, a Youth-Targeted Public Health Literacy Campaign to Prevent Type 2 Diabetes

    PubMed Central

    ROGERS, ELIZABETH; FINE, SARAH; HANDLEY, MARGARET A.; DAVIS, HODARI; KASS, JAMES; SCHILLINGER, DEAN

    2014-01-01

    The prevalence of Type 2 diabetes (DM2) is rapidly rising, especially among minority and low-income youth. There is an unmet need to engage youth in identifying solutions to reverse this trajectory. Social marketing campaigns and entertainment education are effective forms of health communication for engaging populations in health-promoting behaviors. Critical to curbing the epidemic is moving the diabetes conversation away from individual behavior alone and toward a socio-ecologic perspective using a public health literacy framework. We developed an academic-community partnership to develop, implement, and evaluate a DM2 prevention campaign targeting minority and low-income youth. The Bigger Picture uses hard-hitting, youth-generated “spoken-word” messages around key environmental and social drivers of the DM2 epidemic. Campaign goals included promoting health capacity and civic engagement. This paper focuses on the development and implementation of the campaign, including (a) rationale and theoretical underpinnings; (b) steps in campaign creation; (c) testing the campaign messaging; and (d) campaign dissemination and evaluation planning. A youth-created health communication campaign using a public health literacy framework with targeted, relevant, and compelling messaging appears to be a promising vehicle for reaching at-risk youth to increase knowledge of and attitudes about preventing DM2, change social norms, and motivate participation in health promotion initiatives. PMID:25315590

  18. A pebble in the pond: the ripple effect of an obesity prevention intervention targeting the child care environment.

    PubMed

    Drummond, Rebecca L; Staten, Lisa K; Sanford, Mary Reyes; Davidson, Christopher L; Magda Ciocazan, Maria; Khor, Kai-Ning; Kaplan, Frances

    2009-04-01

    Through Steps to a Healthier Arizona, a unique partnership was developed to reach the culturally diverse, rural communities of Southern Arizona. This partnership included local, regional, and state agencies and coalitions focused on reducing the burden of chronic disease and health disparities. This article describes the success of a program aimed at preventing childhood obesity and diabetes. Partners in Yuma County worked with child care providers to implement organizational best practices which promote positive nutrition and physical activity behaviors in young children. As a result of this project, the number of child care centers in Yuma County implementing best practices increased. Additionally a ripple effect has reached beyond the individual child care setting, into broader local and state early childhood development systems. Taking place against the backdrop of state-wide initiatives in early childhood development and health, the Steps to a Healthier Arizona's NAP SACC program positioned stakeholders to integrate with these advances.

  19. Recent progress in defining mechanisms and potential targets for prevention of normal tissue injury after radiation therapy

    SciTech Connect

    Anscher, Mitchell S. . E-mail: anscher@radonc.duke.edu; Chen, Liguang; Rabbani, Zahid; Kang Song; Larrier, Nicole; Huang Hong; Samulski, Thaddeus V.; Dewhirst, Mark W.; Brizel, David M.; Folz, Rodney J.; Vujaskovic, Zeljko

    2005-05-01

    The ability to optimize treatments for cancer on the basis of relative risks for normal tissue injury has important implications in oncology, because higher doses of radiation might, in some diseases, improve both local control and survival. To achieve this goal, a thorough understanding of the molecular mechanisms responsible for radiation-induced toxicity will be essential. Recent research has demonstrated that ionizing radiation triggers a series of genetic and molecular events, which might lead to chronic persistent alterations in the microenvironment and an aberrant wound-healing response. Disrupted epithelial-stromal cell communication might also be important. With the application of a better understanding of fundamental biology to clinical practice, new approaches to treating and preventing normal tissue injury can focus on correcting these disturbed molecular processes.

  20. Targeting α-7 nicotinic acetylcholine receptor in the enteric nervous system: a cholinergic agonist prevents gut barrier failure after severe burn injury.

    PubMed

    Costantini, Todd W; Krzyzaniak, Michael; Cheadle, Gerald A; Putnam, James G; Hageny, Ann-Marie; Lopez, Nicole; Eliceiri, Brian P; Bansal, Vishal; Coimbra, Raul

    2012-08-01

    We have previously shown that vagal nerve stimulation prevents intestinal barrier loss in a model of severe burn injury in which injury was associated with decreased expression and altered localization of intestinal tight junction proteins. α-7 Nicotinic acetylcholine receptor (α-7 nAchR) has been shown to be necessary for the vagus nerve to modulate the systemic inflammatory response, but the role of α-7 nAchR in mediating gut protection remained unknown. We hypothesized that α-7 nAchR would be present in the gastrointestinal tract and that treatment with a pharmacological agonist of α-7 nAchR would protect against burn-induced gut barrier injury. The effects of a pharmacological cholinergic agonist on gut barrier integrity were studied using an intraperitoneal injection of nicotine 30 minutes after injury. Intestinal barrier integrity was examined by measuring permeability to 4-kDa fluorescein isothiocyanate-dextran and by examining changes in expression and localization of the intestinal tight junction proteins occludin and ZO-1. Nicotine injection after injury prevented burn-induced intestinal permeability and limited histological gut injury. Treatment with nicotine prevented decreased expression and altered localization of occludin and ZO-1, as seen in animals undergoing burn alone. Defining the interactions among the vagus nerve, the enteric nervous system, and the intestinal epithelium may lead to development of targeted therapeutics aimed at reducing gut barrier failure and intestinal inflammation after severe injury.

  1. Targeting miR-23a in CD8+ cytotoxic T lymphocytes prevents tumor-dependent immunosuppression

    PubMed Central

    Lin, Regina; Chen, Ling; Chen, Gang; Hu, Chunyan; Jiang, Shan; Sevilla, Jose; Wan, Ying; Sampson, John H.; Zhu, Bo; Li, Qi-Jing

    2014-01-01

    CD8+ cytotoxic T lymphocytes (CTLs) have potent antitumor activity and therefore are leading candidates for use in tumor immunotherapy. The application of CTLs for clinical use has been limited by the susceptibility of ex vivo–expanded CTLs to become dysfunctional in response to immunosuppressive microenvironments. Here, we developed a microRNA-targeting (miRNA-targeting) approach that augments CTL cytotoxicity and preserves immunocompetence. Specifically, we screened for miRNAs that modulate cytotoxicity and identified miR-23a as a strong functional repressor of the transcription factor BLIMP-1, which promotes CTL cytotoxicity and effector cell differentiation. In a cohort of advanced lung cancer patients, miR-23a was upregulated in tumor-infiltrating CTLs, and expression correlated with impaired antitumor potential of patient CTLs. We determined that tumor-derived TGF-β directly suppresses CTL immune function by elevating miR-23a and downregulating BLIMP-1. Functional blocking of miR-23a in human CTLs enhanced granzyme B expression, and in mice with established tumors, immunotherapy with just a small number of tumor-specific CTLs in which miR-23a was inhibited robustly hindered tumor progression. Together, our findings provide a miRNA-based strategy that subverts the immunosuppression of CTLs that is often observed during adoptive cell transfer tumor immunotherapy and identify a TGF-β–mediated tumor immune-evasion pathway. PMID:25347474

  2. An empiric risk scoring tool for identifying high-risk heterosexual HIV-1 serodiscordant couples for targeted HIV-1 prevention

    PubMed Central

    KAHLE, Erin M.; HUGHES, James P.; LINGAPPA, Jairam R.; JOHN-STEWART, Grace; CELUM, Connie; NAKKU-JOLOBA, Edith; NJUGUNA, Stella; MUGO, Nelly; BUKUSI, Elizabeth; MANONGI, Rachel; BAETEN, Jared M.

    2012-01-01

    Background and objectives Heterosexual HIV-1 serodiscordant couples are increasingly recognized as an important source of new HIV-1 infections in sub-Saharan Africa. A simple risk assessment tool could be useful for identifying couples at highest risk for HIV-1 transmission. Methods Using data from three prospective studies of HIV-1 serodiscordant couples from seven African countries and standard methods for development of clinical prediction rules, we derived and validated a risk scoring tool developed from multivariate modeling and composed of key predictors for HIV-1 risk that could be measured in standard research and clinical settings. Results The final risk score included age of the HIV-1 uninfected partner, married and/or cohabiting partnership, number of children, unprotected sex, uncircumcised male HIV-1 uninfected partner, and plasma HIV-1 RNA in the HIV-1 infected partner. The maximum risk score was 12, scores ≥5 were associated with an annual HIV-1 incidence of >3%, and couples with a score ≥6 accounted for only 28% of the population but 67% of HIV-1 transmissions. The area under the curve for predictive ability of the score was 0.74 (95% CI 0.70–0.78). Internal and external validation showed similar predictive ability of the risk score, even when plasma viral load was excluded from the risk score. Conclusions A discrete combination of clinical and behavioral characteristics defines highest-risk HIV-1 serodiscordant couples. Discriminating highest-risk couples for HIV-1 prevention programs and clinical trials using a validated risk score could improve research efficiency and maximize the impact of prevention strategies for reducing HIV-1 transmission. PMID:23187945

  3. Tacrolimus (FK506) prevents early stages of ethanol induced hepatic fibrosis by targeting LARP6 dependent mechanism of collagen synthesis.

    PubMed

    Manojlovic, Zarko; Blackmon, John; Stefanovic, Branko

    2013-01-01

    Tacrolimus (FK506) is a widely used immunosuppressive drug. Its effects on hepatic fibrosis have been controversial and attributed to immunosuppression. We show that in vitro FK506, inhibited synthesis of type I collagen polypeptides, without affecting expression of collagen mRNAs. In vivo, administration of FK506 at a dose of 4 mg/kg completely prevented development of alcohol/carbon tetrachloride induced liver fibrosis in rats. Activation of hepatic stellate cells (HSCs) was absent in the FK506 treated livers and expression of collagen α2(I) mRNA was at normal levels. Collagen α1(I) mRNA was increased in the FK506 treated livers, but this mRNA was not translated into α1(I) polypeptide. No significant inflammation was associated with the fibrosis model used. FK506 binding protein 3 (FKBP3) is one of cellular proteins which binds FK506 with high affinity. We discovered that FKBP3 interacts with LARP6 and LARP6 is the major regulator of translation and stability of collagen mRNAs. In the presence of FK506 the interaction between FKBP3 and LARP6 is weakened and so is the pull down of collagen mRNAs with FKBP3. We postulate that FK506 inactivates FKBP3 and that lack of interaction of LARP6 and FKBP3 results in aberrant translation of collagen mRNAs and prevention of fibrosis. This is the first report of such activity of FK506 and may renew the interest in using this drug to alleviate hepatic fibrosis.

  4. Tacrolimus (FK506) Prevents Early Stages of Ethanol Induced Hepatic Fibrosis by Targeting LARP6 Dependent Mechanism of Collagen Synthesis

    PubMed Central

    Manojlovic, Zarko; Blackmon, John; Stefanovic, Branko

    2013-01-01

    Tacrolimus (FK506) is a widely used immunosuppressive drug. Its effects on hepatic fibrosis have been controversial and attributed to immunosuppression. We show that in vitro FK506, inhibited synthesis of type I collagen polypeptides, without affecting expression of collagen mRNAs. In vivo, administration of FK506 at a dose of 4 mg/kg completely prevented development of alcohol/carbon tetrachloride induced liver fibrosis in rats. Activation of hepatic stellate cells (HSCs) was absent in the FK506 treated livers and expression of collagen α2(I) mRNA was at normal levels. Collagen α1(I) mRNA was increased in the FK506 treated livers, but this mRNA was not translated into α1(I) polypeptide. No significant inflammation was associated with the fibrosis model used. FK506 binding protein 3 (FKBP3) is one of cellular proteins which binds FK506 with high affinity. We discovered that FKBP3 interacts with LARP6 and LARP6 is the major regulator of translation and stability of collagen mRNAs. In the presence of FK506 the interaction between FKBP3 and LARP6 is weakened and so is the pull down of collagen mRNAs with FKBP3. We postulate that FK506 inactivates FKBP3 and that lack of interaction of LARP6 and FKBP3 results in aberrant translation of collagen mRNAs and prevention of fibrosis. This is the first report of such activity of FK506 and may renew the interest in using this drug to alleviate hepatic fibrosis. PMID:23755290

  5. Bioavailability of Phytochemical Constituents From a Novel Soy Fortified Lycopene Rich Tomato Juice Developed for Targeted Cancer Prevention Trials

    PubMed Central

    Bohn, Torsten; Blackwood, Michelle; Francis, David; Tian, Qingguo; Schwartz, Steven J.; Clinton, Steven K.

    2013-01-01

    Studies suggest that tomato and soy foods may contribute to a lower risk of certain cancers. We developed a novel soy germ tomato juice to be used in controlled cancer prevention trials. This study describes an initial test of compliance, phytochemical bioavailability, and effects on biomarkers of blood lipids. Healthy men and women (n = 18) consumed a soy germ-fortified juice daily (300 mL supplying 66 mg isoflavones and 22 mg lycopene) for 8 wk. A single-dose bioavailability study was completed on day 1 and isoflavones in plasma and urine, and lycopene in the plasma, were measured. All subjects completed the trial, with 97.7% ± 3.5% (mean ± SD) of the scheduled juice consumed. No adverse effects were documented. The postprandial study indicated that 3.1% ± 2.3% of lycopene was absorbed and that 49.3% ± 12.1% isoflavones ingested were recovered in 24-h urines. Lycopene plasma concentration changed from 0.60 ± 0.22 to 1.24 ± 0.30 μmol/L during 8 wk of consumption. Juice consumption significantly improved resistance of LDL+VLDL-C to Cu2+-mediated oxidation (P = 0.039), HDL-C (47.3 ± 15.8 to 51.7 ± 14.8 mg/dL, P < 0.001), and the ratio of total-C/HDL-C (4.25 ± 1.59 to 3.63 ± 1.16, P < 0.001) at 8 wk. A well-characterized soy-fortified tomato juice can be produced in large scale for multiinstitutional long-term cancer prevention trials and showed excellent compliance with no toxicity, while demonstrating absorption of biologically active phytochemicals. PMID:22098224

  6. Targeting tumour hypoxia to prevent cancer metastasis. From biology, biosensing and technology to drug development: the METOXIA consortium.

    PubMed

    Pettersen, Erik O; Ebbesen, Peter; Gieling, Roben G; Williams, Kaye J; Dubois, Ludwig; Lambin, Philippe; Ward, Carol; Meehan, James; Kunkler, Ian H; Langdon, Simon P; Ree, Anne H; Flatmark, Kjersti; Lyng, Heidi; Calzada, Maria J; Peso, Luis Del; Landazuri, Manuel O; Görlach, Agnes; Flamm, Hubert; Kieninger, Jochen; Urban, Gerald; Weltin, Andreas; Singleton, Dean C; Haider, Syed; Buffa, Francesca M; Harris, Adrian L; Scozzafava, Andrea; Supuran, Claudiu T; Moser, Isabella; Jobst, Gerhard; Busk, Morten; Toustrup, Kasper; Overgaard, Jens; Alsner, Jan; Pouyssegur, Jacques; Chiche, Johanna; Mazure, Nathalie; Marchiq, Ibtissam; Parks, Scott; Ahmed, Afshan; Ashcroft, Margaret; Pastorekova, Silvia; Cao, Yihai; Rouschop, Kasper M; Wouters, Brad G; Koritzinsky, Marianne; Mujcic, Hilda; Cojocari, Dan

    2015-01-01

    The hypoxic areas of solid cancers represent a negative prognostic factor irrespective of which treatment modality is chosen for the patient. Still, after almost 80 years of focus on the problems created by hypoxia in solid tumours, we still largely lack methods to deal efficiently with these treatment-resistant cells. The consequences of this lack may be serious for many patients: Not only is there a negative correlation between the hypoxic fraction in tumours and the outcome of radiotherapy as well as many types of chemotherapy, a correlation has been shown between the hypoxic fraction in tumours and cancer metastasis. Thus, on a fundamental basis the great variety of problems related to hypoxia in cancer treatment has to do with the broad range of functions oxygen (and lack of oxygen) have in cells and tissues. Therefore, activation-deactivation of oxygen-regulated cascades related to metabolism or external signalling are important areas for the identification of mechanisms as potential targets for hypoxia-specific treatment. Also the chemistry related to reactive oxygen radicals (ROS) and the biological handling of ROS are part of the problem complex. The problem is further complicated by the great variety in oxygen concentrations found in tissues. For tumour hypoxia to be used as a marker for individualisation of treatment there is a need for non-invasive methods to measure oxygen routinely in patient tumours. A large-scale collaborative EU-financed project 2009-2014 denoted METOXIA has studied all the mentioned aspects of hypoxia with the aim of selecting potential targets for new hypoxia-specific therapy and develop the first stage of tests for this therapy. A new non-invasive PET-imaging method based on the 2-nitroimidazole [(18)F]-HX4 was found to be promising in a clinical trial on NSCLC patients. New preclinical models for testing of the metastatic potential of cells were developed, both in vitro (2D as well as 3D models) and in mice (orthotopic grafting

  7. Nrf2 signaling and redox homeostasis in the aging heart: A potential target to prevent cardiovascular diseases?

    PubMed

    Silva-Palacios, Alejandro; Königsberg, Mina; Zazueta, Cecilia

    2016-03-01

    Aging process is often accompanied with a high incidence of cardiovascular diseases (CVD) due to the synergistic effects of age-related changes in heart morphology/function and prolonged exposure to injurious effects of CVD risk factors. Oxidative stress, considered a hallmark of aging, is also an important feature in pathologies that predispose to CVD development, like hypertension, diabetes and obesity. Approaches directed to prevent the occurrence of CVD during aging have been explored both in experimental models and in controlled clinical trials, in order to improve health span, reduce hospitalizations and increase life quality during elderly. In this review we discuss oxidative stress role as a main risk factor that relates CVD with aging. As well as interventions that aim to reduce oxidative stress by supplementing with exogenous antioxidants. In particular, strategies of improving the endogenous antioxidant defenses through activating the nuclear factor related-2 factor (Nrf2) pathway; one of the best studied molecules in cellular redox homeostasis and a master regulator of the antioxidant and phase II detoxification response.

  8. Stroke risk factor knowledge in Hispanic and non-Hispanic white women in New Mexico: implications for targeted prevention strategies.

    PubMed

    Kattapong, V J; Longstreth, W T; Kukull, W A; Howard, D B; Bowes, J I; Wilson, B E; Bigney, J B; Becker, T M

    1998-01-01

    Hispanic women in New Mexico have recently experienced an increase in age-adjusted mortality compared with non-Hispanic white women. Since patients' knowledge of stroke risk factors may affect risk factor control, the present study was undertaken to characterize stroke risk factor understanding in Hispanic and non-Hispanic white women in New Mexico. We administered a stroke risk factor knowledge survey to 215 women hospitalized in Albuquerque, New Mexico. Patients were classified by each of three dichotomous groupings: stroke or nonstroke diagnosis; Hispanic or non-Hispanic white ethnicity; history of cardiovascular risk factors. The frequency of specific item responses was determined for each patient grouping. Two-way analysis of variance was used to determine whether composite knowledge score differed among patient groups. Stress was the attribute most commonly thought to be a risk factor for stroke. Although no ethnic differences were found on composite knowledge score, Hispanic women were significantly less likely to report hypertension as a stroke risk factor than non-Hispanic white women. We suggest that stroke risk factor understanding in Hispanic and non-Hispanic white women in New Mexico is inadequate. Insufficient understanding of the consequences of hypertension, including stroke, may diminish the degree of hypertension control that patients achieve. Further study of the relationship between stroke risk factor understanding and health behavior could enhance prevention efforts.

  9. The Epigenome as a Potential Mediator of Cancer Prevention by Dietary Phytochemicals: the Fetus as a Target

    PubMed Central

    Kaur, Pushpinder; Shorey, Lyndsey E.; Ho, Emily; Dashwood, Roderick H.; Williams, David E.

    2013-01-01

    Epigenetic events establish a particular gene expression signature for each cell type during differentiation and fertilization. Disruption of these epigenetic programs in response to environmental stimuli during prenatal exposure dysregulates the fetal epigenome, potentially impacting susceptibility to disease later in life (the fetal basis of adult disease). Maternal dietary modifications during gestation and lactation play a pivotal role in the period of fetal (re)programming. Recently, many studies have demonstrated the impact of maternal nutrition on the fetal epigenome. In this review, we discuss the complex interplay between various environmental factors and epigenetic mechanisms which have been found to affect the human and animal models. We summarize here the impact of various dietary phytochemicals capable of modulating the epigenome in diverse human cancers and childhood cancer with potential environmental etiology through maternal consumption during pregnancy and lactation and discuss other dietary agents that are still untested as to their effectiveness in transplacental studies. Recent developments discussed here enhance our understanding of how chemopreventive agents act, their potential to impact the prenatal epigenome and to identify dietary interventions that can be beneficial in treating and preventing disease. PMID:23815143

  10. Targeting cultural changes supportive of the healthiest lifestyle patterns. A biosocial evidence-base for prevention of obesity.

    PubMed

    Booth, David A; Booth, Phil

    2011-02-01

    This paper argues that the rise in obesity can be slowed only by universal education based on a type of evidence that does not yet exist. On top of literacy and numeracy, people need the ability to preempt the fattening effect of a decrease in habitual physical activity by altering familiar patterns of eating, drinking and exercise in ways that are both maintainable within the individual's social and physical environment and also effective at decreasing weight to the asymptote for each sustained change. Hence the prevention of obesity requires locally valid evidence on which changes to specific customary habits actually do avoid unhealthy fattening. Interventions need to focus on antecedents to individuals' common lapses from the healthy changes in these customs. Yet no research has been funded into the public's descriptions of feasible changes that cause a step down in weight, let alone into the environmental conditions for individuals' maintenance of those changes. As a result, public health policies on obesity lack scientific basis. When will a start be made on systematic identification of cultural supports to readily executed patterns of lifestyle behaviour which improve health to extents that have been directly measured?

  11. Comparing a marginal structural model with a Cox proportional hazard model to estimate the effect of time-dependent drug use in observational studies: statin use for primary prevention of cardiovascular disease as an example from the Rotterdam Study.

    PubMed

    de Keyser, Catherine E; Leening, Maarten J G; Romio, Silvana A; Jukema, J Wouter; Hofman, Albert; Ikram, M Arfan; Franco, Oscar H; Stijnen, Theo; Stricker, Bruno H

    2014-11-01

    When studying the causal effect of drug use in observational data, marginal structural modeling (MSM) can be used to adjust for time-dependent confounders that are affected by previous treatment. The objective of this study was to compare traditional Cox proportional hazard models (with and without time-dependent covariates) with MSM to study causal effects of time-dependent drug use. The example of primary prevention of cardiovascular disease (CVD) with statins was examined using up to 17.7 years of follow-up from 4,654 participants of the observational prospective population-based Rotterdam Study. In the MSM model, the weight was based on measurements of established cardiovascular risk factors and co-morbidity. In general, we could not demonstrate important differences in results from the Cox models and MSM. Results from analysis on duration of statin use suggested that substantial residual confounding by indication was not accounted for during the period shortly after statin initiation. In conclusion, although on theoretical grounds MSM is an elegant technique, lack of data on the precise time-dependent confounders, such as indication of treatment or other considerations of the prescribing physician jeopardizes the calculation of valid weights. Confounding remains a hurdle in observational effectiveness research on preventive drugs with a multitude of prescription determinants.

  12. Preventing Damage Limitation: Targeting DNA-PKcs and DNA Double-Strand Break Repair Pathways for Ovarian Cancer Therapy

    PubMed Central

    Dungl, Daniela A.; Maginn, Elaina N.; Stronach, Euan A.

    2015-01-01

    Platinum-based chemotherapy is the cornerstone of ovarian cancer treatment, and its efficacy is dependent on the generation of DNA damage, with subsequent induction of apoptosis. Inappropriate or aberrant activation of the DNA damage response network is associated with resistance to platinum, and defects in DNA repair pathways play critical roles in determining patient response to chemotherapy. In ovarian cancer, tumor cell defects in homologous recombination – a repair pathway activated in response to double-strand DNA breaks (DSB) – are most commonly associated with platinum-sensitive disease. However, despite initial sensitivity, the emergence of resistance is frequent. Here, we review strategies for directly interfering with DNA repair pathways, with particular focus on direct inhibition of non-homologous end joining (NHEJ), another DSB repair pathway. DNA-dependent protein kinase catalytic subunit (DNA-PKcs) is a core component of NHEJ and it has shown considerable promise as a chemosensitization target in numerous cancer types, including ovarian cancer where it functions to promote platinum-induced survival signaling, via AKT activation. The development of pharmacological inhibitors of DNA-PKcs is on-going, and clinic-ready agents offer real hope to patients with chemoresistant disease. PMID:26579492

  13. MicroRNA-26a prevents endothelial cell apoptosis by directly targeting TRPC6 in the setting of atherosclerosis

    PubMed Central

    Zhang, Yong; Qin, Wei; Zhang, Longyin; Wu, Xianxian; Du, Ning; Hu, Yingying; Li, Xiaoguang; Shen, Nannan; Xiao, Dan; Zhang, Haiying; Li, Zhange; Zhang, Yue; Yang, Huan; Gao, Feng; Du, Zhimin; Xu, Chaoqian; Yang, Baofeng

    2015-01-01

    Atherosclerosis, a chronic inflammatory disease, is the major cause of life-threatening complications such as myocardial infarction and stroke. Endothelial apoptosis plays a vital role in the initiation and progression of atherosclerotic lesions. Although a subset of microRNAs (miRs) have been identified as critical regulators of atherosclerosis, studies on their participation in endothelial apoptosis in atherosclerosis have been limited. In our study, we found that miR-26a expression was substantially reduced in the aortic intima of ApoE−/− mice fed with a high-fat diet (HFD). Treatment of human aortic endothelial cells (HAECs) with oxidized low-density lipoprotein (ox-LDL) suppressed miR-26a expression. Forced expression of miR-26a inhibited endothelial apoptosis as evidenced by MTT assay and TUNEL staining results. Further analysis identified TRPC6 as a target of miR-26a, and TRPC6 overexpression abolished the anti-apoptotic effect of miR-26a. Moreover, the cytosolic calcium and the mitochondrial apoptotic pathway were found to mediate the beneficial effects of miR-26a on endothelial apoptosis. Taken together, our study reveals a novel role of miR-26a in endothelial apoptosis and indicates a therapeutic potential of miR-26a for atherosclerosis associated with apoptotic cell death. PMID:25801675

  14. MicroRNA-26a prevents endothelial cell apoptosis by directly targeting TRPC6 in the setting of atherosclerosis

    NASA Astrophysics Data System (ADS)

    Zhang, Yong; Qin, Wei; Zhang, Longyin; Wu, Xianxian; Du, Ning; Hu, Yingying; Li, Xiaoguang; Shen, Nannan; Xiao, Dan; Zhang, Haiying; Li, Zhange; Zhang, Yue; Yang, Huan; Gao, Feng; Du, Zhimin; Xu, Chaoqian; Yang, Baofeng

    2015-03-01

    Atherosclerosis, a chronic inflammatory disease, is the major cause of life-threatening complications such as myocardial infarction and stroke. Endothelial apoptosis plays a vital role in the initiation and progression of atherosclerotic lesions. Although a subset of microRNAs (miRs) have been identified as critical regulators of atherosclerosis, studies on their participation in endothelial apoptosis in atherosclerosis have been limited. In our study, we found that miR-26a expression was substantially reduced in the aortic intima of ApoE-/- mice fed with a high-fat diet (HFD). Treatment of human aortic endothelial cells (HAECs) with oxidized low-density lipoprotein (ox-LDL) suppressed miR-26a expression. Forced expression of miR-26a inhibited endothelial apoptosis as evidenced by MTT assay and TUNEL staining results. Further analysis identified TRPC6 as a target of miR-26a, and TRPC6 overexpression abolished the anti-apoptotic effect of miR-26a. Moreover, the cytosolic calcium and the mitochondrial apoptotic pathway were found to mediate the beneficial effects of miR-26a on endothelial apoptosis. Taken together, our study reveals a novel role of miR-26a in endothelial apoptosis and indicates a therapeutic potential of miR-26a for atherosclerosis associated with apoptotic cell death.

  15. Bullying prevention in schools by targeting cognitions, emotions, and behavior: Evaluating the effectiveness of the REBE-ViSC program.

    PubMed

    Trip, Simona; Bora, Carmen; Sipos-Gug, Sebastian; Tocai, Ioana; Gradinger, Petra; Yanagida, Takuya; Strohmeier, Dagmar

    2015-10-01

    The effectiveness of a class-based antibullying prevention program on cognitions, emotions, and behaviors was investigated. The program consists of a cognitive-behavioral (Rational Emotive Behavioral Education; REBE) and a behavioral (Viennese Social Competence; ViSC) component. The REBE program is based on rational emotive behavioral theory and contains 9 student lessons. The ViSC program is based on social learning theory and comprises 10 student lessons. The order of the programs was experimentally manipulated. The REBE-ViSC program was implemented in 5 schools (14 classes), the ViSC-REBE program was implemented in 3 schools (9 classes), and 3 schools (11 classes) served as an untreated control group. Data were collected during 1 school year at pretest, midpoint, and posttest. Emotions (overt and internalizing anger), cognitions (learning and entitlement), and behaviors (bullying perpetration and bullying victimization) were measured with self-assessments. To examine the effectiveness of the REBE-ViSC/ViSC-REBE program, multilevel growth models were applied (time points at Level 1, individuals at Level 2, and classes at Level 3). The analyses revealed that the program effects differed depending on the order of the programs. The REBE-ViSC condition was more effective in changing negative emotions than the ViSC-REBE condition; both experimental conditions were effective in reducing dysfunctional cognitions, whereas no behavioral change was found in the 2 experimental groups when compared with the control group. To improve program effectiveness regarding behavioral changes, a multilevel whole-school approach including a teacher component is recommended. PMID:26376177

  16. Bullying prevention in schools by targeting cognitions, emotions, and behavior: Evaluating the effectiveness of the REBE-ViSC program.

    PubMed

    Trip, Simona; Bora, Carmen; Sipos-Gug, Sebastian; Tocai, Ioana; Gradinger, Petra; Yanagida, Takuya; Strohmeier, Dagmar

    2015-10-01

    The effectiveness of a class-based antibullying prevention program on cognitions, emotions, and behaviors was investigated. The program consists of a cognitive-behavioral (Rational Emotive Behavioral Education; REBE) and a behavioral (Viennese Social Competence; ViSC) component. The REBE program is based on rational emotive behavioral theory and contains 9 student lessons. The ViSC program is based on social learning theory and comprises 10 student lessons. The order of the programs was experimentally manipulated. The REBE-ViSC program was implemented in 5 schools (14 classes), the ViSC-REBE program was implemented in 3 schools (9 classes), and 3 schools (11 classes) served as an untreated control group. Data were collected during 1 school year at pretest, midpoint, and posttest. Emotions (overt and internalizing anger), cognitions (learning and entitlement), and behaviors (bullying perpetration and bullying victimization) were measured with self-assessments. To examine the effectiveness of the REBE-ViSC/ViSC-REBE program, multilevel growth models were applied (time points at Level 1, individuals at Level 2, and classes at Level 3). The analyses revealed that the program effects differed depending on the order of the programs. The REBE-ViSC condition was more effective in changing negative emotions than the ViSC-REBE condition; both experimental conditions were effective in reducing dysfunctional cognitions, whereas no behavioral change was found in the 2 experimental groups when compared with the control group. To improve program effectiveness regarding behavioral changes, a multilevel whole-school approach including a teacher component is recommended.

  17. Chitosan-based nanoparticles for survivin targeted siRNA delivery in breast tumor therapy and preventing its metastasis

    PubMed Central

    Sun, Ping; Huang, Wei; Jin, Mingji; Wang, Qiming; Fan, Bo; Kang, Lin; Gao, Zhonggao

    2016-01-01

    Nanoparticle-mediated small interfering RNA (siRNA) delivery is a promising therapeutic strategy in various cancers. However, it is difficult to deliver degradative siRNA to tumor tissue, and thus a safe and efficient vector for siRNA delivery is essential for cancer therapy. In this study, poly(ethylene glycol)-modified chitosan (PEG-CS) was synthesized successfully for delivering nucleic acid drug. We deemed that PEGylated CS could improve its solubility by forming a stable siRNA loaded in nanoparticles, and enhancing transfection efficiency of siRNA-loaded CS nanoparticles in cancer cell line. The research results showed that siRNA loaded in PEGylated CS (PEG-CS/siRNA) nanoparticles with smaller particle size had superior structural stability in the physical environment compared to CS nanoparticles. The data of in vitro antitumor activity revealed that 4T1 tumor cell growth was significantly inhibited and cellular uptake of PEG-CS/siRNA nanoparticles in 4T1 cells was dramatically enhanced compared to naked siRNA groups. The results from flow cytometry and confocal laser scanning microscopy showed that PEG-CS/siRNA nanoparticles were more easily taken up than naked siRNA. Importantly, PEG-CS/siRNA nanoparticles significantly reduced the growth of xenograft tumors of 4T1 cells in vivo. It has been demonstrated that the PEG-CS is a safe and efficient vector for siRNA delivery, and it can effectively reduce tumor growth and prevent metastasis. PMID:27729789

  18. Homocysteine-lowering is not a primary target for cardiovascular disease prevention in chronic kidney disease patients.

    PubMed

    Suliman, Mohamed E; Lindholm, Bengt; Bárány, Peter; Qureshi, Abdul Rashid; Stenvinkel, Peter

    2007-01-01

    The homocysteine (Hcy) theory states that total homocysteine (tHcy) is a risk factor for atherosclerosis. Chronic kidney disease (CKD) is one of the most frequent causes of hyperhomocysteinemia in the presence of high prevalence of cardiovascular disease (CVD). However, there is not yet any conclusive answer to the question whether Hcy may contribute to, or predict, cardiovascular events or mortality in CKD patients or whether it is just an innocent bystander biologically related to other potential risk factors for CVD. Moreover, tHcy levels in CKD are influenced by several commonly occurring confounding factors, such as inflammation and protein-energy wasting (PEW). These factors are also associated with morbidity and mortality and altogether this may explain why Hcy does not show up as a cardiovascular risk but in fact is reversely associated with clinical outcome. Thorough evaluation of such reverse association may not necessarily imply that the principles of Hcy being a contributor to vascular pathophysiology are different in CKD patients but rather indicate that other superimposed factors, such as PEW and inflammation, are more important. These confounders contribute significantly to the unacceptably high mortality rate in this patient population and may require nutritional and anti-inflammatory interventions to improve clinical outcome. So far, the results of recent folic acid intervention trials do not support the use of folic acid supplementation for lowering tHcy and improving survival in CKD patients. Although we are still waiting for the results from several ongoing controlled randomized trials in this area, future studies are needed to evaluate if thiol-exchange agents, besides folic acid, as part of a future multifactorial intervention regime targeting inflammation, PEW, oxidative stress as well as hyperhomocysteinemia may decrease CVD risk in this high-risk patient population.

  19. Considering J.Lo and Ugly Betty: a qualitative examination of risk factors and prevention targets for body dissatisfaction, eating disorders, and obesity in young Latina women.

    PubMed

    Franko, Debra L; Coen, Emilie J; Roehrig, James P; Rodgers, Rachel F; Jenkins, Amy; Lovering, Meghan E; Dela Cruz, Stephanie

    2012-06-01

    Latina women are vulnerable to poor body image, eating disorders, and obesity, particularly during the college years. This study sought to identify common cultural antecedents of these concerns in order to inform the development of prevention programs for this population. Six groups of university students who identified as Latina (N=27) discussed cultural aspects of body image, eating disorders, and obesity. Thematic analysis identified four main themes: (a) cultural disparities in body-ideal, including the influence of the media and acculturation issues; (b) messages about body shape and weight received by family, peers, and society; (c) difficulties making healthy eating and physical activity choices as a function of college life; and (d) the influence of peers and potential male partners on body satisfaction and body-ideals. These results have implications for the development of programs targeting body dissatisfaction and risk for eating disorders and obesity in Latina college women. PMID:22609033

  20. Carbon nanoparticles induce ceramide- and lipid raft-dependent signalling in lung epithelial cells: a target for a preventive strategy against environmentally-induced lung inflammation

    PubMed Central

    2012-01-01

    Background Particulate air pollution in lung epithelial cells induces pathogenic endpoints like proliferation, apoptosis, and pro-inflammatory reactions. The activation of the epidermal growth factor receptor (EGFR) is a key event responsible for signalling events involving mitogen activated protein kinases specific for these endpoints. The molecular events leading to receptor activation however are not well understood. These events are relevant for the toxicological evaluation of inhalable particles as well as for potential preventive strategies in situations when particulate air pollution cannot be avoided. The current study therefore had the objective to elucidate membrane-coupled events leading to EGFR activation and the subsequent signalling cascade in lung epithelial cells. Furthermore, we aimed to identify the molecular target of ectoine, a biophysical active substance which we described to prevent carbon nanoparticle-induced lung inflammation. Methods Membrane signalling events were investigated in isolated lipid rafts from lung epithelial cells with regard to lipid and protein content of the signalling platforms. Using positive and negative intervention approaches, lipid raft changes, subsequent signalling events, and lung inflammation were investigated in vitro in lung epithelial cells (RLE-6TN) and in vivo in exposed animals. Results Carbon nanoparticle treatment specifically led to an accumulation of ceramides in lipid rafts. Detailed analyses demonstrated a causal link of ceramides and subsequent EGFR activation coupled with a loss of the receptor in the lipid raft fractions. In vitro and in vivo investigations demonstrate the relevance of these events for carbon nanoparticle-induced lung inflammation. Moreover, the compatible solute ectoine was able to prevent ceramide-mediated EGFR phosphorylation and subsequent signalling as well as lung inflammation in vivo. Conclusion The data identify a so far unknown event in pro-inflammatory signalling and

  1. Youth Whose Weight Exceeds Healthy Guidelines Are High-Risk Targets for Tobacco Prevention Messaging and Close Monitoring of Cigarette Use

    PubMed Central

    Reiter-Purtill, Jennifer; Peugh, James L.; Wu, Yelena; Becnel, Jennifer N.

    2015-01-01

    Abstract Background: Adolescents are long-standing tobacco prevention targets, given that smoking patterns typically originate before adulthood. Pediatric overweight/obesity remains at epidemic levels. Links between these two biobehavioral risks are not well understood, yet of keen public health and pediatric care relevance. The aims of the present study were to examine smoking behaviors and attitudes of overweight (OV), obese (OB), and severely obese (SO) adolescents, compared to healthy weight (HW), utilizing the nationally representative sample, Monitoring the Future. Methods: Smoking behavior prevalence (ever, current, or age of initiation), perceived risk of harm, disapproval of others smoking, and peer smoking were determined for a pooled 2008–2009 sample of 19,678 10th graders (Mage=16.09±0.47 years) by CDC-defined BMI percentile-based categories within race/ethnic group (69.5% white, 14.5% African American, and 16.0% Hispanic). Logistic regression examined the impact of excess weight status on smoking behaviors and attitudes relative to HW. Results: Relative to HW of same race/ethnicity, white or African American OV, OB, and SO had higher odds of recent smoking, with the highest prevalence among SO. For white youth, excess weight increased odds of ever smoking, early daily smoking (before grade 9), perceiving low risk of harm, and not disapproving of others smoking. Findings varied for African American or Hispanic youth. Conclusions: As we move toward fostering a tobacco-free generation, youth whose weight exceeds healthy guidelines are high-risk targets for tobacco prevention messaging and close monitoring of cigarette use, particularly those who are severely obese as well as white youth of excess weight, starting before adolescence. PMID:26172423

  2. Cardiac progenitor cell-derived exosomes prevent cardiomyocytes apoptosis through exosomal miR-21 by targeting PDCD4.

    PubMed

    Xiao, J; Pan, Y; Li, X H; Yang, X Y; Feng, Y L; Tan, H H; Jiang, L; Feng, J; Yu, X Y

    2016-01-01

    Cardiac progenitor cells derived from adult heart have emerged as one of the most promising stem cell types for cardiac protection and repair. Exosomes are known to mediate cell-cell communication by transporting cell-derived proteins and nucleic acids, including various microRNAs (miRNAs). Here we investigated the cardiac progenitor cell (CPC)-derived exosomal miRNAs on protecting myocardium under oxidative stress. Sca1(+)CPCs-derived exosomes were purified from conditional medium, and identified by nanoparticle trafficking analysis (NTA), transmission electron microscopy and western blotting using CD63, CD9 and Alix as markers. Exosomes production was measured by NTA, the result showed that oxidative stress-induced CPCs secrete more exosomes compared with normal condition. Although six apoptosis-related miRNAs could be detected in two different treatment-derived exosomes, only miR-21 was significantly upregulated in oxidative stress-induced exosomes compared with normal exosomes. The same oxidative stress could cause low miR-21 and high cleaved caspase-3 expression in H9C2 cardiac cells. But the cleaved caspase-3 was significantly decreased when miR-21 was overexpressed by transfecting miR-21 mimic. Furthermore, miR-21 mimic or inhibitor transfection and luciferase activity assay confirmed that programmed cell death 4 (PDCD4) was a target gene of miR-21, and miR-21/PDCD4 axis has an important role in anti-apoptotic effect of H9C2 cell. Western blotting and Annexin V/PI results demonstrated that exosomes pre-treated H9C2 exhibited increased miR-21 whereas decreased PDCD4, and had more resistant potential to the apoptosis induced by the oxidative stress, compared with non-treated cells. These findings revealed that CPC-derived exosomal miR-21 had an inhibiting role in the apoptosis pathway through downregulating PDCD4. Restored miR-21/PDCD4 pathway using CPC-derived exosomes could protect myocardial cells against oxidative stress-related apoptosis. Therefore

  3. Target cell extraction coupled with LC-MS/MS analysis for screening potential bioactive components in Ginkgo biloba extract with preventive effect against diabetic nephropathy.

    PubMed

    Qiu, Jing-ying; Chen, Xu; Zheng, Xiao-xiao; Jiang, Xiang-lan; Yang, Dong-zhi; Yu, Yan-yan; Du, Qian; Tang, Dao-quan; Yin, Xiao-xing

    2015-02-01

    A rapid and useful approach for screening potential bioactive components in Ginkgo biloba extract (GBE) with preventive effect against diabetic nephropathy (DN) was developed using mesangial cells extraction coupled with high-performance liquid chromatography tandem mass spectrometry (LC-MS/MS) analysis. Mesangial cells were first divided into two groups according to their treatments with high glucose or high glucose plus GBE. After incubation for 4, 8, 12, 16, 24 and 48 h, the cells were harvested and extracted with 40% acetic acid in water before LC-MS/MS analysis. Then, 19 compounds and five metabolites were found to selectively combine with mesangial cells. Notably, compounds including quercetin and rutin were identified or tentatively characterized according to the results of retention time and MS spectra, which is highly consistent with our previous reports that quercetin and rutin are potent protective agents against glomerulosclerosis in DN. Therefore, all these results indicate that target cell extraction coupled with LC-MS/MS analysis can be successfully applied for predicting the bioactive components in GBE with preventive effect against DN.

  4. Context-dependent differences in miR-10b breast oncogenesis can be targeted for the prevention and arrest of lymph node metastasis

    PubMed Central

    Yigit, MV; Ghosh, SK; Kumar, M; Petkova, V; Kavishwar, A; Moore, A; Medarova, Z

    2013-01-01

    Metastases, and not the primary tumor from which they originate, are the main reason for mortality from carcinoma. Although the molecular mechanisms behind metastasis are poorly understood, it is clear that epigenetic dysregulation at the level of microRNA expression is a key characteristic of the metastatic process that can be exploited for therapy. Here, we describe an miRNA-targeted therapeutic approach for the prevention and arrest of lymph node metastasis. Therapy relies on the inhibition of the pro-metastatic microRNA-10b. It is delivered to primary and lymph node metastatic tumor cells using an imaging-capable nanodrug that is designed to specifically home to these tissues. Treatment of invasive human breast tumor cells (MDA-MB-231) with the nanodrug in vitro downregulates miR-10b and abolishes the invasion and migration of the tumor cells. After intravenous delivery to mice bearing orthotopic MDA-MB-231-luc-D3H2LN tumors, the nanodrug accumulates in the primary tumor and lymph nodes. When treatment is initiated before metastasis to lymph nodes, metastasis is prevented. Treatment after the formation of lymph node metastases arrests the metastatic process without a concomitant effect on primary tumor growth raising the possibility of a context-dependent variation in miR-10b breast oncogenesis. PMID:22580603

  5. The evaluation of the JEWEL project: an innovative economic enhancement and HIV prevention intervention study targeting drug using women involved in prostitution.

    PubMed

    Sherman, S G; German, D; Cheng, Y; Marks, M; Bailey-Kloche, M

    2006-01-01

    The JEWEL (Jewellery Education for Women Empowering Their Lives) pilot study examined the efficacy of an economic empowerment and HIV prevention intervention targeting illicit drug-using women (n=50) who were involved in prostitution in Baltimore, Maryland. The intervention was comprised of six 2-hour sessions that taught HIV prevention risk reduction and the making, marketing and selling of jewellery. Bivariate comparisons examined behaviour change pre- and 3-months post-intervention. The intervention's effect on the change in the number of sex trade partners from baseline to follow-up was explored with multiple linear regression. Participants were 62.0% African American, 5.0% were currently employed, and the median age was 39 years old (Inter Quartile Range [IQR]: 34-45). Women attended an average of six (IQR: 4.5-6.0) sessions. The women sold over $7,000 worth of jewellery in eleven sales. In comparing self-reported risk behaviours pre and 3-month post intervention participation, we found significant reductions in: receiving drugs or money for sex (100% versus 71.0%, p<0.0005); the median number of sex trade partners per month (9 versus 3, p=0.02); daily drug use (76.0% vs. 55.0%, p=0.003); the amount of money spent on drugs daily (US$52.57 versus US$46.71, p = 0.01); and daily crack use (27.3% versus 13.1.0%, p = 0.014). In the presence of other variables in a multivariate linear model, income from the jewelry sale was associated with a reduction in the number of sex trade partners at follow-up. The pilot indicated effectiveness of a novel, HIV prevention, economic enhancement intervention upon HIV sexual risk behaviours and drug utilization patterns. PMID:16282070

  6. SKI2 mediates degradation of RISC 5′-cleavage fragments and prevents secondary siRNA production from miRNA targets in Arabidopsis

    PubMed Central

    Branscheid, Anja; Marchais, Antonin; Schott, Gregory; Lange, Heike; Gagliardi, Dominique; Andersen, Stig Uggerhøj; Voinnet, Olivier; Brodersen, Peter

    2015-01-01

    Small regulatory RNAs are fundamental in eukaryotic and prokaryotic gene regulation. In plants, an important element of post-transcriptional control is effected by 20–24 nt microRNAs (miRNAs) and short interfering RNAs (siRNAs) bound to the ARGONAUTE1 (AGO1) protein in an RNA induced silencing complex (RISC). AGO1 may cleave target mRNAs with small RNA complementarity, but the fate of the resulting cleavage fragments remains incompletely understood. Here, we show that SKI2, SKI3 and SKI8, subunits of a cytoplasmic cofactor of the RNA exosome, are required for degradation of RISC 5′, but not 3′-cleavage fragments in Arabidopsis. In the absence of SKI2 activity, many miRNA targets produce siRNAs via the RNA-dependent RNA polymerase 6 (RDR6) pathway. These siRNAs are low-abundant, and map close to the cleavage site. In most cases, siRNAs were produced 5′ to the cleavage site, but several examples of 3′-spreading were also identified. These observations suggest that siRNAs do not simply derive from RDR6 action on stable 5′-cleavage fragments and hence that SKI2 has a direct role in limiting secondary siRNA production in addition to its function in mediating degradation of 5′-cleavage fragments. PMID:26464441

  7. Molecular targets of the antiinflammatory Harpagophytum procumbens (devil's claw): inhibition of TNFα and COX-2 gene expression by preventing activation of AP-1.

    PubMed

    Fiebich, Bernd L; Muñoz, Eduardo; Rose, Thorsten; Weiss, Gabriele; McGregor, Gerard P

    2012-06-01

    Harpagophytum procumbens (Hp) is often used in the supportive treatment of inflammatory and degenerative diseases of the skeletal system. Although the clinical efficacy in osteoarthritis has been demonstrated in clinical trials, the molecular target(s) of Hp are unclear. This study quantified the effects of the ethanol Hp extract (60% v/v ethanol, sole active ingredient of Pascoe®-Agil), on the expression and release of the major pro-inflammatory mediators in LPS-stimulated human monocytes and the intracellular signalling pathways involved in inflammation. The Hp extract dose-dependently inhibited the release of TNFα as well as that of interleukin (IL)-6, IL-1β and prostaglandin E₂ (PGE₂). The Hp prevented TNFα and IL-6 mRNA expression in human monocytes and cyclooxygenase-2 (COX-2) in RAW 264.7 cells. Furthermore, the Hp extract inhibited LPS-stimulated AP-1-mediated gene transcription activity and binding to the AP-1 response elements. The extract had no effect on the LPS-induced binding of nuclear factor-κB in RAW 264.7 cells, on LPS-induced degradation of IκBα or on LPS-induced activation of mitogen-activated protein kinases (MAPK), p38MAPK and JNK in human monocytes. The data indicate that a standardized ethanol Hp extract inhibits induction of pro-inflammatory gene expression, possibly by blocking the AP-1 pathway. This is novel evidence of a possible mechanism of action of this antiinflammatory drug. PMID:22072539

  8. NF-kappaB signaling as a putative target for omega-3 metabolites in the prevention of age-related macular degeneration (AMD).

    PubMed

    Kaarniranta, Kai; Salminen, Antero

    2009-11-01

    Age-related macular degeneration (AMD) is the major reason of blindness of the elderly all over the world. AMD is characterized by a progressive loss of central vision attributable to degenerative and neovascular changes in the macula, the highly specialized region of the retina responsible for sharp and color visual acuity. Degeneration and cell death of retinal pigment epithelial cells (RPE) cause secondarily adverse effects on neural retina leading to visual loss. Most AMD patients cannot benefit from any treatment modalities. The prevalence of AMD is rising as a consequence of the aging of the population. As the RPE cells age, they are subject to continued oxidative stress and this believed to induce inflammation and progression of AMD. Interestingly, many clinical trials have revealed that dietary intakes of omega-3 fatty acids can reduce the risk of both early and late AMD, although their molecular targets in cellular signaling in AMD pathology are not understood. Recently, it has been proposed that the omega-3 fatty acid metabolites, resolvins and protectins, function as endogenous anti-inflammatory compounds. In this review, we propose that resolvins and protectins mediate their beneficial effects by preventing NF-kappaB signaling and this that may represent a new target for regulating the inflammatory responses in AMD. PMID:19751815

  9. Targeting Atp6v1c1 Prevents Inflammation and Bone Erosion Caused by Periodontitis and Reveals Its Critical Function in Osteoimmunology

    PubMed Central

    Wang, Lin; Lu, Yun; Li, Qian; Zhu, Zheng; Shao, Jian-Zhong; Chen, Wei

    2015-01-01

    Periodontal disease (Periodontitis) is a serious disease that affects a majority of adult Americans and is associated with other systemic diseases, including diabetes, rheumatoid arthritis, and other inflammatory diseases. While great efforts have been devoted toward understanding the pathogenesis of periodontitis, there remains a pressing need for developing potent therapeutic strategies for targeting this pervasive and destructive disease. In this study, we utilized novel adeno-associated virus (AAV)-mediated Atp6v1c1 knockdown gene therapy to treat bone erosion and inflammatory caused by periodontitis in mouse model. Atp6v1c1 is a subunit of the V-ATPase complex and regulator of the assembly of the V0 and V1 domains of the V-ATPase complex. We demonstrated previously that Atp6v1c1 has an essential function in osteoclast mediated bone resorption. We hypothesized that Atp6v1c1 may be an ideal target to prevent the bone erosion and inflammation caused by periodontitis. To test the hypothesis, we employed AAV RNAi knockdown of Atp6v1c1 gene expression to prevent bone erosion and gingival inflammation simultaneously. We found that lesion-specific injection of AAV-shRNA-Atp6v1c1 into the periodontal disease lesions protected against bone erosion (>85%) and gingival inflammation caused by P. gingivalis W50 infection. AAV-mediated Atp6v1c1 knockdown dramatically reduced osteoclast numbers and inhibited the infiltration of dendritic cells and macrophages in the bacteria-induced inflammatory lesions in periodontitis. Silencing of Atp6v1c1 expression also prevented the expressions of osteoclast-related genes and pro-inflammatory cytokine genes. Our data suggests that AAV-shRNA-Atp6v1c1 treatment can significantly attenuate the bone erosion and inflammation caused by periodontitis, indicating the dual function of AAV-shRNA-Atp6v1c1 as an inhibitor of bone erosion mediated by osteoclasts, and as an inhibitor of inflammation through down-regulation of pro

  10. Impact and Cost of Scaling Up Voluntary Medical Male Circumcision for HIV Prevention in the Context of the New 90-90-90 HIV Treatment Targets

    PubMed Central

    Kripke, Katharine; Reed, Jason; Hankins, Catherine; Smiley, Gregory; Laube, Catey

    2016-01-01

    Background The report of the Joint United Nations Programme on HIV/AIDS (UNAIDS) for World AIDS Day 2014 highlighted a Fast-Track Strategy that sets ambitious treatment and prevention targets to reduce global HIV incidence to manageable levels by 2020 and end the AIDS epidemic by 2030. The 90-90-90 treatment targets for 2020 call for 90% of people living with HIV to know their HIV status, 90% of people who know their status to receive treatment, and 90% of people on HIV treatment to be virally suppressed. This paper examines how scale-up of voluntary medical male circumcision (VMMC) services in four priority countries in sub-Saharan Africa could contribute to ending the AIDS epidemic by 2030 in the context of concerted efforts to close the treatment gap, and what the impact of VMMC scale-up would be if the 90-90-90 treatment targets were not completely met. Methods Using the Goals module of the Spectrum suite of models, this analysis modified ART (antiretroviral treatment) scale-up coverage from base scenarios to reflect the 90-90-90 treatment targets in four countries (Lesotho, Malawi, South Africa, and Uganda). In addition, a second scenario was created to reflect viral suppression levels of 75% instead of 90%, and a third scenario was created in which the 90-90-90 treatment targets are reached in women, with men reaching more moderate coverage levels. Regarding male circumcision (MC) coverage, the analysis examined both a scenario in which VMMCs were assumed to stop after 2015, and one in which MC coverage was scaled up to 90% by 2020 and maintained at 90% thereafter. Results Across all four countries, scaling up VMMC is projected to provide further HIV incidence reductions in addition to those achieved by reaching the 90-90-90 treatment targets. If viral suppression levels only reach 75%, scaling up VMMC leads to HIV incidence reduction to nearly the same levels as those achieved with 90-90-90 without VMMC scale-up. If only women reach the 90-90-90 targets

  11. Prevention of tumor growth driven by PIK3CA and HPV oncogenes by targeting mTOR signaling with metformin in oral squamous carcinomas expressing OCT3.

    PubMed

    Madera, Dmitri; Vitale-Cross, Lynn; Martin, Daniel; Schneider, Abraham; Molinolo, Alfredo A; Gangane, Nitin; Carey, Thomas E; McHugh, Jonathan B; Komarck, Christine M; Walline, Heather M; William, William N; Seethala, Raja R; Ferris, Robert L; Gutkind, J Silvio

    2015-03-01

    Most squamous cell carcinomas of the head and neck (HNSCC) exhibit a persistent activation of the PI3K-mTOR signaling pathway. We have recently shown that metformin, an oral antidiabetic drug that is also used to treat lipodystrophy in HIV-infected (HIV(+)) individuals, diminishes mTOR activity and prevents the progression of chemically induced experimental HNSCC premalignant lesions. Here, we explored the preclinical activity of metformin in HNSCCs harboring PIK3CA mutations and HPV oncogenes, both representing frequent HNSCC alterations, aimed at developing effective targeted preventive strategies. The biochemical and biologic effects of metformin were evaluated in representative HNSCC cells expressing mutated PIK3CA or HPV oncogenes (HPV(+)). The oral delivery of metformin was optimized to achieve clinical relevant blood levels. Molecular determinants of metformin sensitivity were also investigated, and their expression levels were examined in a large collection of HNSCC cases. We found that metformin inhibits mTOR signaling and tumor growth in HNSCC cells expressing mutated PIK3CA and HPV oncogenes, and that these activities require the expression of organic cation transporter 3 (OCT3/SLC22A3), a metformin uptake transporter. Coexpression of OCT3 and the mTOR pathway activation marker pS6 were observed in most HNSCC cases, including those arising in HIV(+) patients. Activation of the PI3K-mTOR pathway is a widespread event in HNSCC, including HPV(-) and HPV(+) lesions arising in HIV(+) patients, all of which coexpress OCT3. These observations may provide a rationale for the clinical evaluation of metformin to halt HNSCC development from precancerous lesions, including in HIV(+) individuals at risk of developing HPV(-) associated cancers.

  12. SUMO-targeted ubiquitin ligase (STUbL) Slx5 regulates proteolysis of centromeric histone H3 variant Cse4 and prevents its mislocalization to euchromatin

    PubMed Central

    Ohkuni, Kentaro; Takahashi, Yoshimitsu; Fulp, Alyona; Lawrimore, Josh; Au, Wei-Chun; Pasupala, Nagesh; Levy-Myers, Reuben; Warren, Jack; Strunnikov, Alexander; Baker, Richard E.; Kerscher, Oliver; Bloom, Kerry; Basrai, Munira A.

    2016-01-01

    Centromeric histone H3, CENP-ACse4, is essential for faithful chromosome segregation. Stringent regulation of cellular levels of CENP-ACse4 restricts its localization to centromeres. Mislocalization of CENP-ACse4 is associated with aneuploidy in yeast and flies and tumorigenesis in human cells; thus defining pathways that regulate CENP-A levels is critical for understanding how mislocalization of CENP-A contributes to aneuploidy in human cancers. Previous work in budding yeast shows that ubiquitination of overexpressed Cse4 by Psh1, an E3 ligase, partially contributes to proteolysis of Cse4. Here we provide the first evidence that Cse4 is sumoylated by E3 ligases Siz1 and Siz2 in vivo and in vitro. Ubiquitination of Cse4 by the small ubiquitin-related modifier (SUMO)-targeted ubiquitin ligase (STUbL) Slx5 plays a critical role in proteolysis of Cse4 and prevents mislocalization of Cse4 to euchromatin under normal physiological conditions. Accumulation of sumoylated Cse4 species and increased stability of Cse4 in slx5∆ strains suggest that sumoylation precedes ubiquitin-mediated proteolysis of Cse4. Slx5-mediated Cse4 proteolysis is independent of Psh1, since slx5∆ psh1∆ strains exhibit higher levels of Cse4 stability and mislocalization than either slx5∆ or psh1∆ strains. Our results demonstrate a role for Slx5 in ubiquitin-mediated proteolysis of Cse4 to prevent its mislocalization and maintain genome stability. PMID:26960795

  13. Arabidopsis aux1rcr1 mutation alters AUXIN RESISTANT1 targeting and prevents expression of the auxin reporter DR5:GUS in the root apex.

    PubMed

    Yu, Jing; Wen, Chi-Kuang

    2013-02-01

    Multilevel interactions of the plant hormones ethylene and auxin coordinately and synergistically regulate many aspects of plant growth and development. This study isolated the AUXIN RESISTANT1 (AUX1) allele aux1(rcr1) (RCR1 for REVERSING CTR1-10 ROOT1) that suppressed the root growth inhibition conferred by the constitutive ethylene-response constitutive triple response1-10 (ctr1-10) allele. The aux1(rcr1) mutation resulted from an L126F substitution at loop 2 of the plasma membrane-associated auxin influx carrier protein AUX1. aux1(rcr1) and the T-DNA insertion mutant aux1-T were both defective in auxin transport and many aspects of the auxin response. Unexpectedly, expression of the auxin-response reporter DR5:GUS in the root apex was substantially prevented by the aux1(rcr1) but not the aux1-T mutation, even in the presence of the wild-type AUX1 allele. Following treatment with the synthetic auxin 1-naphthaleneacetic acid (NAA), DR5:GUS expression in aux1(rcr1) and aux1-T occurred mainly in the root apex and mature zone. NAA-induced DR5:GUS expression in the root apex was markedly prevented by ethylene in genotypes with aux1(rcr1) but not in aux1-T genotypes and the wild type. The effect of aux1(rcr1) on DR5:GUS expression seemed to be associated with AUX1-expressing domains. Green fluorescence protein-fused aux1(rcr1) was localized in the cytoplasm and probably not to the plasma membrane, indicating important roles of the Lys(126) residue at loop 2 in AUX1 targeting. The possible effects of aux1(rcr1) on DR5:GUS expression are discussed.

  14. Time to abandon the hygiene hypothesis: new perspectives on allergic disease, the human microbiome, infectious disease prevention and the role of targeted hygiene

    PubMed Central

    Bloomfield, Sally F; Rook, Graham AW; Scott, Elizabeth A; Shanahan, Fergus; Stanwell-Smith, Rosalind; Turner, Paul

    2016-01-01

    Aims: To review the burden of allergic and infectious diseases and the evidence for a link to microbial exposure, the human microbiome and immune system, and to assess whether we could develop lifestyles which reconnect us with exposures which could reduce the risk of allergic disease while also protecting against infectious disease. Methods: Using methodology based on the Delphi technique, six experts in infectious and allergic disease were surveyed to allow for elicitation of group judgement and consensus view on issues pertinent to the aim. Results: Key themes emerged where evidence shows that interaction with microbes that inhabit the natural environment and human microbiome plays an essential role in immune regulation. Changes in lifestyle and environmental exposure, rapid urbanisation, altered diet and antibiotic use have had profound effects on the human microbiome, leading to failure of immunotolerance and increased risk of allergic disease. Although evidence supports the concept of immune regulation driven by microbe–host interactions, the term ‘hygiene hypothesis’ is a misleading misnomer. There is no good evidence that hygiene, as the public understands, is responsible for the clinically relevant changes to microbial exposures. Conclusion: Evidence suggests a combination of strategies, including natural childbirth, breast feeding, increased social exposure through sport, other outdoor activities, less time spent indoors, diet and appropriate antibiotic use, may help restore the microbiome and perhaps reduce risks of allergic disease. Preventive efforts must focus on early life. The term ‘hygiene hypothesis’ must be abandoned. Promotion of a risk assessment approach (targeted hygiene) provides a framework for maximising protection against pathogen exposure while allowing spread of essential microbes between family members. To build on these findings, we must change public, public health and professional perceptions about the microbiome and about

  15. Prevention of tumor growth driven by PIK3CA and HPV oncogenes by targeting mTOR signaling with metformin in oral squamous carcinomas expressing OCT3

    PubMed Central

    Madera, Dmitri; Vitale-Cross, Lynn; Martin, Daniel; Schneider, Abraham; Molinolo, Alfredo A.; Gangane, Nitin; Carey, Thomas E.; McHugh, Jonathan B.; Komarck, Christine M.; Walline, Heather M.; William, William N.; Seethala, Raja R.; Ferris, Robert; Gutkind, J. Silvio

    2015-01-01

    Most head and neck squamous cell carcinomas (HNSCC) exhibit a persistent activation of the PI3K-mTOR signaling pathway. We have recently shown that metformin, an oral antidiabetic drug that is also used to treat lipodystrophy in HIV-infected (HIV+) individuals, diminishes mTOR activity and prevents the progression of chemically-induced experimental HNSCC premalignant lesions. Here, we explored the preclinical activity of metformin in HNSCCs harboring PIK3CA mutations and HPV oncogenes, both representing frequent HNSCC alterations, aimed at developing effective targeted preventive strategies. The biochemical and biological effects of metformin were evaluated in representative HNSCC cells expressing mutated PIK3CA or HPV oncogenes (HPV+). The oral delivery of metformin was optimized to achieve clinical relevant blood levels. Molecular determinants of metformin sensitivity were also investigated, and their expression levels examined in a large collection of HNSCC cases. We found that metformin inhibits mTOR signaling and tumor growth in HNSCC cells expressing mutated PIK3CA and HPV oncogenes, and that these activities require the expression of organic cation transporter 3 (OCT3/SLC22A3), a metformin uptake transporter. Co-expression of OCT3 and the mTOR pathway activation marker pS6 were observed in most HNSCC cases, including those arising in HIV+ patients. Activation of the PI3K-mTOR pathway is a widespread event in HNSCC, including HPV− and HPV+ lesions arising in HIV+ patients, all of which co-express OCT3. These observations may provide a rationale for the clinical evaluation of metformin to halt HNSCC development from precancerous lesions, including in HIV+ individuals at risk of developing HPV-associated cancers. PMID:25681087

  16. Treatment and prevention of chemotherapy-induced alopecia with PTH-CBD, a collagen-targeted parathyroid hormone analog, in a non-depilated mouse model

    PubMed Central

    Katikaneni, Ranjitha; Ponnapakkam, Tulasi; Matsushita, Osamu; Sakon, Joshua; Gensure, Robert

    2014-01-01

    Alopecia is a psychologically devastating complication of chemotherapy for which there is currently no effective therapy. PTH-CBD is a collagen-targeted parathyroid hormone analog that has shown promise as a therapy for alopecia disorders. To compare the efficacy of prophylactic versus therapeutic administration of PTH-CBD in chemotherapy-induced alopecia using a mouse model that mimics the cyclic chemotherapy dosing used clinically. C57BL/6J mice were treated with a single subcutaneous injection of PTH-CBD (320 mcg/kg) or vehicle control before or after hair loss developing from three courses of cyclophosphamide chemotherapy (50–150 mg/kg/week). Mice receiving chemotherapy alone developed hair loss and depigmentation over 6–12 months. Mice pretreated with PTH-CBD did not develop these changes and maintained a normal-appearing coat. Mice treated with PTH-CBD after development of hair loss showed a partial recovery. Observations of hair loss were confirmed quantitatively by gray scale analysis. Histological examination showed that in mice receiving chemotherapy alone, there were small, dystrophic hair follicles mostly in the catagen phase. Mice receiving PTH-CBD before chemotherapy showed a mix of normal-appearing telogen and anagen hair follicles with no evidence of dystrophy. Mice receiving PTH-CBD therapy after chemotherapy showed intermediate histological features. PTH-CBD was effective in both the prevention and the treatment of chemotherapy-induced alopecia in mice, but pretreatment appears to result in a better cosmetic outcome. PTH-CBD shows promise as an agent in the prevention of this complication of chemotherapy and improving the quality of life for cancer patients. PMID:24025564

  17. Prevention of Youthful Marijuana Use.

    PubMed

    Cermak, Timmen L; Banys, Peter

    2016-01-01

    Considerable money and effort have been expended in attempts to prevent drug use by youth, with disappointing results. Too often, prevention programs have singled out youth with simplistic messages of exaggerated risk and the same politically acceptable solution for all-abstinence. Historically, prevention efforts have been less effective by not being soundly based in science and failing also to address adult drug and alcohol use as part of the problem. The Institute of Medicine continuum of care model developed in 1994 offers a framework for a more sophisticated, three-tiered approach to prevention, defined as all services provided prior to a clinical diagnosis of a substance use disorder. By dividing prevention efforts into universal (delivered to broad populations without consideration of individual risk for developing substance use disorder), selected (targeting sub-groups of individuals identified on the basis of characteristics known to create an elevated risk for substance use disorder), and indicated (addressing individuals identified on the basis of manifest risk behaviors), prevention can be better tailored to meet different levels of need. Student Assistance Programs (SAPs) and community coalitions provide examples of how IOM's continuum of care model can be integrated into drug prevention programs for youth. PMID:26891015

  18. Targeting Inhibitor of κB Kinase β Prevents Inflammation-Induced Preterm Delivery by Inhibiting IL-6 Production from Amniotic Cells.

    PubMed

    Toda, Aska; Sawada, Kenjiro; Fujikawa, Tomoyuki; Wakabayashi, Atsuko; Nakamura, Koji; Sawada, Ikuko; Yoshimura, Akihiko; Nakatsuka, Erika; Kinose, Yasuto; Hashimoto, Kae; Mabuchi, Seiji; Tokuhira, Atsushi; Nakayama, Masahiro; Itai, Akiko; Kurachi, Hirohisa; Kimura, Tadashi

    2016-03-01

    Preterm delivery (PTD) remains a serious challenge in perinatology. Intrauterine infection and/or inflammation, followed by increased inflammatory cytokines, represented by IL-6, are involved in this pathology. Our aim was to identify IL-6-producing cells in the placenta and to analyze the potential of targeting IκB kinase β (IKKβ) signaling to suppress IL-6 production for the treatment of PTD. Immunohistochemical analyses using placentas complicated with severe chorioamnionitis revealed that IL-6 is mainly expressed in human amniotic mesenchymal stromal cells (hAMSCs). Primary hAMSCs were collected, and strong IL-6 expression was confirmed. In hAMSCs, the treatment of tumor necrosis factor-α or IL-1β drastically induced IL-6 production, followed by the phosphorylation of IKKs. A novel IKKβ inhibitor, IMD-0560, almost completely inhibited IL-6 production from hAMSCs. Using an experimental lipopolysaccharide-induced PTD mouse model, the therapeutic potential of IMD-0560 was examined. IMD-0560 was delivered vaginally 4 hours before lipopolysaccharide administration. Mice in the IMD-0560 (30 mg/kg, twice a day) group had a significantly lower rate of PTD [10 of 22 (45%)] without any apparent adverse events on the mice and their pups. In uteri collected from mice, IMD-0560 inhibited not only IL-6 production but also production of related cytokines, such as keratinocyte-derived protein chemokine/CXCL1, macrophage inflammatory protein-2/CXCL2, and monocyte chemoattractant protein-1/chemokine ligand 2. Targeting IKKβ signaling shows promising effects through the suppression of these cytokines and can be explored as a future option for the prevention of PTD. PMID:26796146

  19. Human Immunodeficiency Virus Type 1 (HIV-1) Integration: a Potential Target for Microbicides To Prevent Cell-Free or Cell-Associated HIV-1 Infection ▿

    PubMed Central

    Terrazas-Aranda, Katty; Van Herrewege, Yven; Hazuda, Daria; Lewi, Paul; Costi, Roberta; Di Santo, Roberto; Cara, Andrea; Vanham, Guido

    2008-01-01

    Conceptually, blocking human immunodeficiency virus type 1 (HIV-1) integration is the last possibility for preventing irreversible cellular infection. Using cocultures of monocyte-derived dendritic cells and CD4+ T cells, which represent primary targets in sexual transmission, we demonstrated that blocking integration with integrase strand transfer inhibitors (InSTIs), particularly L-870812, could consistently block cell-free and cell-associated HIV-1 infection. In a pretreatment setting in which the compound was present before and during infection and was afterwards gradually diluted during the culture period, the naphthyridine carboxamide L-870812 blocked infection with the cell-free and cell-associated HIV-1 Ba-L strain at concentrations of, respectively, 1,000 and 10,000 nM. The potency of L-870812 was similar to that of the nucleotide reverse transcriptase inhibitor R-9-(2-phosphonylmethoxypropyl) adenine (PMPA) but one or two orders of magnitude lower than those of the nonnucleoside reverse transcriptase inhibitors UC781 and TMC120. In contrast, the diketo acid RDS derivative InSTIs showed clear-cut but weaker antiviral activity than L-870812. Moreover, L-870812 completely blocked subtype C and CRFO2_AG primary isolates, which are prevalent in the African heterosexual epidemic. Furthermore, the addition of micromolar concentrations of L-870812 even 24 h after infection could still block both cell-free and cell-associated Ba-L, opening the prospect of postexposure prophylaxis. Finally, an evaluation of the combined activity of L-870812 with either T20, zidovudine, PMPA, UC781, or TMC120 against replication-deficient HIV-1 Ba-L (env) pseudovirus suggested synergistic activity for all combinations. Importantly, compounds selected for the study by using the coculture model were devoid of acute or delayed cytotoxic effects at HIV-blocking concentrations. Therefore, these findings provide evidence supporting consideration of HIV-1 integration as a target for

  20. Targeted Intranasal Mupirocin To Prevent Colonization and Infection by Community-Associated Methicillin-Resistant Staphylococcus aureus Strains in Soldiers: a Cluster Randomized Controlled Trial▿

    PubMed Central

    Ellis, Michael W.; Griffith, Matthew E.; Dooley, David P.; McLean, Joseph C.; Jorgensen, James H.; Patterson, Jan E.; Davis, Kepler A.; Hawley, Joshua S.; Regules, Jason A.; Rivard, Robert G.; Gray, Paula J.; Ceremuga, Julia M.; DeJoseph, Mary A.; Hospenthal, Duane R.

    2007-01-01

    Community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) is an emerging pathogen that primarily manifests as uncomplicated skin and soft tissue infections. We conducted a cluster randomized, double-blind, placebo-controlled trial to determine whether targeted intranasal mupirocin therapy in CA-MRSA-colonized soldiers could prevent infection in the treated individual and prevent new colonization and infection within their study groups. We screened 3,447 soldiers comprising 14 training classes for CA-MRSA colonization from January to December 2005. Each training class was randomized to either the mupirocin or placebo study group, and the participants identified as CA-MRSA colonized were treated with either mupirocin or placebo. All participants underwent repeat screening after 8 to 10 weeks and were monitored for 16 weeks for development of infection. Of 3,447 participants screened, 134 (3.9%) were initially colonized with CA-MRSA. Five of 65 (7.7%; 95% confidence interval [95% CI], 4.0% to 11.4%) placebo-treated participants and 7 of 66 (10.6%; 95% CI, 7.9% to 13.3%) mupirocin-treated participants developed infections; the difference in the infection rate of the placebo- and mupirocin-treated groups was −2.9% (95% CI, −7.5% to 1.7%). Of those not initially colonized with CA-MRSA, 63 of 1,459 (4.3%; 95% CI, 2.7% to 5.9%) of the placebo group and 56 of 1,607 (3.5%; 95% CI, 2.6% to 5.2%) of the mupirocin group developed infections; the difference in the infection rate of the placebo and mupirocin groups was 0.8% (95% CI, −1.0% to 2.7%). Of 3,447 participants, 3,066 (89%) were available for the second sampling and completed follow-up. New CA-MRSA colonization occurred in 24 of 1,459 (1.6%; 95% CI, 0.05% to 2.8%) of the placebo group participants and 23 of 1,607 (1.4%; 95% CI, 0.05% to 2.3%) of the mupirocin group participants; the difference in the infection rate of the placebo and mupirocin groups was 0.2% (95% CI, −1.3% to 1.7%). Despite CA

  1. MicroRNA-27a Induces Mesangial Cell Injury by Targeting of PPARγ, and its In Vivo Knockdown Prevents Progression of Diabetic Nephropathy

    PubMed Central

    Wu, Lina; Wang, Qingzhu; Guo, Feng; Ma, Xiaojun; Ji, Hongfei; Liu, Fei; Zhao, Yanyan; Qin, Guijun

    2016-01-01

    MicroRNAs play important roles in the pathogenesis of diabetic nephropathy (DN). In this study, we found that high glucose upregulated miR-27a expression in cultured glomerular mesangial cells and in the kidney glomeruli of streptozotocin (STZ)-induced diabetic rats. miR-27a knockdown prevented high glucose-induced mesangial cell proliferation and also blocked the upregulation of extracellular matrix (ECM)-associated profibrotic genes. Reduction of cell proliferation and profibrotic gene expression by a miR-27a inhibitor depended upon the expression of peroxisome proliferator-activated receptor γ (PPARγ). Further studies showed that miR-27a negatively regulated PPARγ expression by binding to the 3′-untranslated region of rat PPARγ. An antisense oligonucleotide specific to miR-27a (antagomir-27a) significantly reduced renal miR-27a expression in STZ-induced diabetic rats and significantly increased PPARγ levels. Antagomir-27a also reduced kidney ECM accumulation and proteinuria in STZ-induced diabetic rats. These findings suggest that specific reduction of renal miR-27a decreases renal fibrosis, which may be explained in part by its regulation of PPARγ, and that targeting miR-27a may represent a novel therapeutic approach for DN. PMID:27184517

  2. Protein kinase Mζ-dependent maintenance of GluA2 at the synapse: a possible target for preventing or treating age-related memory decline?

    PubMed

    Aicardi, Giorgio

    2013-08-01

    Age-related functional alterations in the perforant path projection from the entorhinal cortex to the dentate gyrus (DG) of the hippocampus play a major role in age-related memory impairments, but little is known about the molecular mechanisms responsible for these changes. In a recent interesting study, Hara and colleagues (J Neurosci 2012;32:7336-7344) tested young and aged monkeys on the visual recognition memory test "delayed nonmatching-to-sample" (DNMS). Then they performed electron microscopy immunocytochemistry in the hippocampal DG to determine the subcellular localization of the GluA2 subunit of the glutamate α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor (AMPAR) and protein kinase Mζ (PKMζ), which promotes memory storage by regulating GluA2-containing AMPAR trafficking. The results obtained suggest that age-related deficits in visual recognition memory are coupled with impairment in PKMζ-dependent maintenance of GluA2 at the synapse. Together with previous evidence of the critical role of PKMζ in memory consolidation, these data render this enzyme an attractive potential therapeutic target for preventing or treating age-related memory decline, and support the view that the pharmacological manipulation of AMPAR trafficking in the synapses may provide new insights in the search of memory enhancers for aged individuals, including those affected by Alzheimer disease.

  3. Targeting Pili in Enterococcal Pathogenesis

    PubMed Central

    Pinkston, Kenneth L.; Singh, Kavindra V.; Gao, Peng; Wilganowski, Nathaniel; Robinson, Holly; Ghosh, Sukhen; Azhdarinia, Ali; Sevick-Muraca, Eva M.; Murray, Barbara E.

    2014-01-01

    Passive protection, the administration of antibodies to prevent infection, has garnered significant interest in recent years as a potential prophylactic countermeasure to decrease the prevalence of hospital-acquired infections. Pili, polymerized protein structures covalently anchored to the peptidoglycan wall of many Gram-positive pathogens, are ideal targets for antibody intervention, given their importance in establishing infection and their accessibility to antibody interactions. In this work, we demonstrated that a monoclonal antibody to the major component of Enterococcus faecalis pili, EbpC, labels polymerized pilus structures, diminishes biofilm formation, and significantly prevents the establishment of a rat endocarditis infection. The effectiveness of this anti-EbpC monoclonal provides strong evidence in support of its potential as a preventative. In addition, after radiolabeling, this monoclonal identified the site of enterococcal infection, providing a rare example of molecularly specific imaging of an established bacterial infection and demonstrating the versatility of this agent for use in future diagnostic and therapeutic applications. PMID:24452680

  4. Targeted Prevention of Common Mental Health Disorders in University Students: Randomised Controlled Trial of a Transdiagnostic Trait-Focused Web-Based Intervention

    PubMed Central

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

    2014-01-01

    eating. Conclusions This study suggests that a transdiagnostic web-based intervention for university students targeting underlying personality risk factors may be a promising way of preventing common mental disorders with a low-intensity intervention. Trial Registration ControlledTrials.com ISRCTN14342225 PMID:24736388

  5. Preclinical trials for prevention of tumor progression of hepatocellular carcinoma by LZ-8 targeting c-Met dependent and independent pathways.

    PubMed

    Wu, Jia-Ru; Hu, Chi-Tan; You, Ren-In; Ma, Pei-Ling; Pan, Siou-Mei; Lee, Ming-Che; Wu, Wen-Sheng

    2015-01-01

    Hepatocellular carcinoma (HCC) is among the most lethal cancers. Mounting studies highlighted the essential role of the HGF/c-MET axis in driving HCC tumor progression. Therefore, c-Met is a potential therapeutic target for HCC. However, several concerns remain unresolved in c-Met targeting. First, the status of active c-Met in HCC must be screened to determine patients suitable for therapy. Second, resistance and side effects have been observed frequently when using conventional c-Met inhibitors. Thus, a preclinical system for screening the status of c-Met signaling and identifying efficient and safe anti-HCC agents is urgently required. In this study, immunohistochemical staining of phosphorylated c-Met (Tyr1234) on tissue sections indicated that HCCs with positive c-Met signaling accounted for approximately 46% in 26 cases. Second, many patient-derived HCC cell lines were established and characterized according to motility and c-Met signaling status. Moreover, LZ8, a medicinal peptide purified from the herb Lingzhi, featuring immunomodulatory and anticancer properties, was capable of suppressing cell migration and slightly reducing the survival rate of both c-Met positive and negative HCCs, HCC372, and HCC329, respectively. LZ8 also suppressed the intrahepatic metastasis of HCC329 in SCID mice. On the molecular level, LZ8 suppressed the expression of c-Met and phosphorylation of c-Met, ERK and AKT in HCC372, and suppressed the phosphorylation of JNK, ERK, and AKT in HCC329. According to receptor array screening, the major receptor tyrosine kinase activated in HCC329 was found to be the epidermal growth factor receptor (EGFR). Moreover, tyrosine-phosphorylated EGFR (the active EGFR) was greatly suppressed in HCC329 by LZ8 treatment. In addition, LZ8 blocked HGF-induced cell migration and c-Met-dependent signaling in HepG2. In summary, we designed a preclinical trial using LZ8 to prevent the tumor progression of patient-derived HCCs with c-Met-positive or

  6. Preventing Australian football injuries with a targeted neuromuscular control exercise programme: comparative injury rates from a training intervention delivered in a clustered randomised controlled trial

    PubMed Central

    Twomey, Dara M; Fortington, Lauren V; Doyle, Tim L A; Elliott, Bruce C; Akram, Muhammad; Lloyd, David G

    2016-01-01

    Background Exercise-based training programmes are commonly used to prevent sports injuries but programme effectiveness within community men's team sport is largely unknown. Objective To present the intention-to-treat analysis of injury outcomes from a clustered randomised controlled trial in community Australian football. Methods Players from 18 male, non-elite, community Australian football clubs across two states were randomly allocated to either a neuromuscular control (NMC) (intervention n=679 players) or standard-practice (control n=885 players) exercise training programme delivered as part of regular team training sessions (2× weekly for 8-week preseason and 18-week regular-season). All game-related injuries and hours of game participation were recorded. Generalised estimating equations, adjusted for clustering (club unit), were used to compute injury incidence rates (IIRs) for all injuries, lower limb injuries (LLIs) and knee injuries sustained during games. The IIRs were compared across groups with cluster-adjusted Injury Rate Ratios (IRRs). Results Overall, 773 game injuries were recorded. The lower limb was the most frequent body region injured, accounting for 50% of injuries overall, 96 (12%) of which were knee injuries. The NMC players had a reduced LLI rate compared with control players (IRR: 0.78 (95% CI 0.56 to 1.08), p=0.14.) The knee IIR was also reduced for NMC compared with control players (IRR: 0.50 (95% CI 0.24 to 1.05), p=0.07). Conclusions These intention-to-treat results indicate that positive outcomes can be achieved from targeted training programmes for reducing knee and LLI injury rates in men's community sport. While not statistically significant, reducing the knee injury rate by 50% and the LLI rate by 22% is still a clinically important outcome. Further injury reductions could be achieved with improved training attendance and participation in the programme. PMID:26399611

  7. Targeting Nitric Oxide Signaling with nNOS Inhibitors As a Novel Strategy for the Therapy and Prevention of Human Melanoma

    PubMed Central

    Yang, Zhen; Misner, Bobbye; Ji, Haitao; Poulos, Thomas L.; Silverman, Richard B.; Meyskens, Frank L.

    2013-01-01

    Abstract Aims: Our previous studies have shown that nitric oxide (NO) plays an important role in increasing the invasion and proliferation of human melanoma cells, suggesting that targeting NO signaling may facilitate therapy and prevention. Neuronal nitric oxide synthase (nNOS) is present in melanocytes, a cell type that originates from the neural crest. The aims of this study were to determine the role of nNOS in melanoma progression and the potential antitumor effects of novel synthesized nNOS inhibitors. Results: In vitro studies demonstrated abundant expression of nNOS in melanoma compared to melanocytes, which was inducible by ultraviolet radiation and was associated with increased NO generation. nNOS was also detected in melanoma biopsies that increased with disease stage. Knockdown of nNOS in melanoma cells diminished L-arginine-induced NO production; the metastatic capacity was also reduced as well as the levels of MMP-1, Bcl-2, JunD, and APE/Ref-1. Similar inhibition of NO and invasion potential was observed utilizing novel, highly selective nNOS inhibitors. In three-dimensional human skin reconstructs, the nNOS inhibitor cpd8 effectively reversed the melanoma overgrowth stimulated by NO stress. Innovation: Our work lays the foundation for development of clinical “drug-like” nNOS inhibitors as a new and promising strategy for the chemoprevention of early melanoma progression and the inhibition of secondary melanoma in high-risk individuals. Conclusion: Based on our observations, we propose that nNOS in melanoma results in constitutive overproduction of NO, which stimulates proliferation and increases invasion potential, leading to subsequent development of metastases. Antioxid. Redox Signal. 19, 433–447. PMID:23199242

  8. A multimodal approach to investigate biomarkers for psychosis in a clinical setting: the integrative neuroimaging studies in schizophrenia targeting for early intervention and prevention (IN-STEP) project.

    PubMed

    Koike, Shinsuke; Takano, Yosuke; Iwashiro, Norichika; Satomura, Yoshihiro; Suga, Motomu; Nagai, Tatsuya; Natsubori, Tatsunobu; Tada, Mariko; Nishimura, Yukika; Yamasaki, Syudo; Takizawa, Ryu; Yahata, Noriaki; Araki, Tsuyoshi; Yamasue, Hidenori; Kasai, Kiyoto

    2013-01-01

    Longitudinal clinical investigations and biological measurements have determined not only progressive brain volumetric and functional changes especially around the onset of psychosis but also the abnormality of developmental pathways based on gene-environment interaction model. However, these studies have contributed little to clinical decisions on their diagnosis and therapeutic choices because of subtle differences between patients and healthy controls. A multi-modal approach may resolve this limitation and is favorable to explore the pathophysiology of psychosis. The integrative neuroimaging studies for schizophrenia targeting early intervention and prevention (IN-STEP) is a research project aimed at exploring the pathophysiological features of the onset of psychosis and investigating possible predictive biomarkers for the clinical treatment of psychosis. Since 2008, we have adopted blood sampling, neurocognitive batteries, neurophysiological assessment, structural imaging, and functional imaging longitudinally for help-seeking ultra-high-risk (UHR) individuals and patients with first-episode psychosis (FEP). Here, we intend to introduce the IN-STEP research study protocol and present preliminary clinical findings. Thirty-seven UHR individuals and 30 patients with FEP participated in this study. Six months later, there was no difference in objective and subjective scores between the groups, which suggests that young people having symptoms and functional deficits should be cared for regardless of their history of psychosis according to their clinical stages. The rate of transition to psychosis was 7.1%, 8.0%, and 35.3% (at 6, 12, and 24months, respectively). Through this research project, we expect to clarify the pathophysiological features around the onset of psychosis and improve the prognosis of psychosis through clinical application. PMID:23219075

  9. The Road Ahead to Cure Alzheimer’s Disease: Development of Biological Markers and Neuroimaging Methods for Prevention Trials Across all Stages and Target Populations

    PubMed Central

    Cavedo, E.; Lista, S.; Khachaturian, Z.; Aisen, P.; Amouyel, P.; Herholz, K.; Jack, C.R.; Sperling, R.; Cummings, J.; Blennow, K.; O’Bryant, S.; Frisoni, G.B.; Khachaturian, A.; Kivipelto, M.; Klunk, W.; Broich, K.; Andrieu, S.; de Schotten, M. Thiebaut; Mangin, J.-F.; Lammertsma, A.A.; Johnson, K.; Teipel, S.; Drzezga, A.; Bokde, A.; Colliot, O.; Bakardjian, H.; Zetterberg, H.; Dubois, B.; Vellas, B.; Schneider, L.S.; Hampel, H.

    2015-01-01

    techniques generate automatic and reproducible measures both in regions of interest, such as the hippocampus and in an exploratory fashion, observer and hypothesis-indedendent, throughout the entire brain. Evolving modalities such as diffusion-tensor imaging (DTI) and advanced tractography as well as resting-state functional MRI provide useful additionally useful measures indicating the degree of fiber tract and neural network disintegration (structural, effective and functional connectivity) that may substantially contribute to early detection and the mapping of progression. These modalities require further standardization and validation. The use of molecular in vivo amyloid imaging agents (the fifth validated biomarker), such as the Pittsburgh Compound-B and markers of neurodegeneration, such as fluoro-2-deoxy-D-glucose (FDG) (as the sixth validated biomarker) support the detection of early AD pathological processes and associated neurodegeneration. How to use, interpret, and disclose biomarker results drives the need for optimized standardization. Multimodal AD biomarkers do not evolve in an identical manner but rather in a sequential but temporally overlapping fashion. Models of the temporal evolution of AD biomarkers can take the form of plots of biomarker severity (degree of abnormality) versus time. AD biomarkers can be combined to increase accuracy or risk. A list of genetic risk factors is increasingly included in secondary prevention trials to stratify and select individuals at genetic risk of AD. Although most of these biomarker candidates are not yet qualified and approved by regulatory authorities for their intended use in drug trials, they are nonetheless applied in ongoing clinical studies for the following functions: (i) inclusion/exclusion criteria, (ii) patient stratification, (iii) evaluation of treatment effect, (iv) drug target engagement, and (v) safety. Moreover, novel promising hypothesis-driven, as well as exploratory biochemical, genetic

  10. Targets and targeting.

    PubMed

    Will, E

    2001-08-01

    Using the vocabulary of ballistics in medicine for emphasis can result in misleading exaggeration and semantic confusion. The dual meaning of target as either aiming point (aim at) or outcome (aim to achieve) creates a muddle in the efforts to comply with quality assurance initiatives. Disentangling the two meanings allows new approaches to the clinical technology required in a modern health care environment. An example can be shown in new strategies for the management of renal anemia with iron and erythropoietin. The potential to shape outcome distributions through validated, preemptive intervention thresholds offers the predictable results required by patients and payers. Using the management of patient cohorts as a platform for outcomes creates no necessary conflict with individualized clinical care. Future guideline statements should include the likely characteristics of compliant outcome populations, as a prompt to clinical goals and as an indication of the necessary cost and effort of compliance with treatment standards. Overemphasis in language is no substitute for considered clinical methodology.

  11. Details for Manuscript Number SSM-D-06-00377R1 “Targeted Ethnography as a Critical Step to Inform Cultural Adaptations of HIV Prevention Interventions for Adults with Severe Mental Illness.”

    PubMed Central

    Gonzalez, M. Alfredo; McKinnon, Karen; Elkington, Katherine S; Pinto, Diana; Mann, Claudio Gruber; Mattos, Paulo E

    2007-01-01

    As in other countries worldwide, adults with severe mental illness (SMI) in Brazil are disproportionately infected with HIV relative to the general population. Brazilian psychiatric facilities lack tested HIV prevention interventions. To adapt existing interventions, developed only in the U.S., we conducted targeted ethnography with adults with SMI and staff from two psychiatric institutions in Brazil. We sought to characterize individual, institutional, and interpersonal factors that may affect HIV risk behavior in this population. We conducted 350 hours of ethnographic field observations in two mental health service settings in Rio de Janeiro, and 9 focus groups (n = 72) and 16 key-informant interviews with patients and staff in these settings. Data comprised field notes and audiotapes of all exchanges, which were transcribed, coded, and systematically analyzed. The ethnography characterized the institutional culture and identified: 1) patients’ risk behaviors; 2) the institutional setting; 3) intervention content; and 4) intervention format and delivery strategies. Targeted ethnography also illuminated broader contextual issues for development and implementation of HIV prevention interventions for adults with SMI in Brazil, including an institutional culture that did not systematically address patients’ sexual behavior, sexual health, or HIV sexual risk, yet strongly impacted the structure of patients’ sexual networks. Further, ethnography identified the Brazilian concept of “social responsibility” as important to prevention work with psychiatric patients. Targeted ethnography with adults with SMI and institutional staff provided information critical to the adaptation of tested U.S. HIV prevention interventions from the US for Brazilians with SMI. PMID:17475382

  12. The Road Ahead to Cure Alzheimer’s Disease: Development of Biological Markers and Neuroimaging Methods for Prevention Trials Across all Stages and Target Populations

    PubMed Central

    Cavedo, E.; Lista, S.; Khachaturian, Z.; Aisen, P.; Amouyel, P.; Herholz, K.; Jack, C.R.; Sperling, R.; Cummings, J.; Blennow, K.; O’Bryant, S.; Frisoni, G.B.; Khachaturian, A.; Kivipelto, M.; Klunk, W.; Broich, K.; Andrieu, S.; de Schotten, M. Thiebaut; Mangin, J.-F.; Lammertsma, A.A.; Johnson, K.; Teipel, S.; Drzezga, A.; Bokde, A.; Colliot, O.; Bakardjian, H.; Zetterberg, H.; Dubois, B.; Vellas, B.; Schneider, L.S.; Hampel, H.

    2015-01-01

    techniques generate automatic and reproducible measures both in regions of interest, such as the hippocampus and in an exploratory fashion, observer and hypothesis-indedendent, throughout the entire brain. Evolving modalities such as diffusion-tensor imaging (DTI) and advanced tractography as well as resting-state functional MRI provide useful additionally useful measures indicating the degree of fiber tract and neural network disintegration (structural, effective and functional connectivity) that may substantially contribute to early detection and the mapping of progression. These modalities require further standardization and validation. The use of molecular in vivo amyloid imaging agents (the fifth validated biomarker), such as the Pittsburgh Compound-B and markers of neurodegeneration, such as fluoro-2-deoxy-D-glucose (FDG) (as the sixth validated biomarker) support the detection of early AD pathological processes and associated neurodegeneration. How to use, interpret, and disclose biomarker results drives the need for optimized standardization. Multimodal AD biomarkers do not evolve in an identical manner but rather in a sequential but temporally overlapping fashion. Models of the temporal evolution of AD biomarkers can take the form of plots of biomarker severity (degree of abnormality) versus time. AD biomarkers can be combined to increase accuracy or risk. A list of genetic risk factors is increasingly included in secondary prevention trials to stratify and select individuals at genetic risk of AD. Although most of these biomarker candidates are not yet qualified and approved by regulatory authorities for their intended use in drug trials, they are nonetheless applied in ongoing clinical studies for the following functions: (i) inclusion/exclusion criteria, (ii) patient stratification, (iii) evaluation of treatment effect, (iv) drug target engagement, and (v) safety. Moreover, novel promising hypothesis-driven, as well as exploratory biochemical, genetic

  13. The effects of scale on the costs of targeted HIV prevention interventions among female and male sex workers, men who have sex with men and transgenders in India

    PubMed Central

    Guinness, L; Kumaranayake, L; Reddy, Bhaskar; Govindraj, Y; Vickerman, P; Alary, M

    2010-01-01

    Background The India AIDS Initiative (Avahan) project is involved in rapid scale-up of HIV-prevention interventions in high-risk populations. This study examines the cost variation of 107 non-governmental organisations (NGOs) implementing targeted interventions, over the start up (defined as period from project inception until services to the key population commenced) and first 2 years of intervention. Methods The Avahan interventions for female and male sex workers and their clients, in 62 districts of four southern states were costed for the financial years 2004/2005 and 2005/2006 using standard costing techniques. Data sources include financial and economic costs from the lead implementing partners (LPs) and subcontracted local implementing NGOs retrospectively and prospectively collected from a provider perspective. Ingredients and step-down allocation processes were used. Outcomes were measured using routinely collected project data. The average costs were estimated and a regression analysis carried out to explore causes of cost variation. Costs were calculated in US$ 2006. Results The total number of registered people was 134 391 at the end of 2 years, and 124 669 had used STI services during that period. The median average cost of Avahan programme for this period was $76 per person registered with the project. Sixty-one per cent of the cost variation could be explained by scale (positive association), number of NGOs per district (negative), number of LPs in the state (negative) and project maturity (positive) (p<0.0001). Conclusions During rapid scale-up in the initial phase of the Avahan programme, a significant reduction in average costs was observed. As full scale-up had not yet been achieved, the average cost at scale is yet to be realised and the extent of the impact of scale on costs yet to be captured. Scale effects are important to quantify for planning resource requirements of large-scale interventions. The average cost after 2 years is

  14. PDZ-binding kinase/T-LAK cell-originated protein kinase is a target of the fucoidan from brown alga Fucus evanescens in the prevention of EGF-induced neoplastic cell transformation and colon cancer growth.

    PubMed

    Vishchuk, Olesia S; Sun, Huimin; Wang, Zhe; Ermakova, Svetlana P; Xiao, JuanJuan; Lu, Tao; Xue, PeiPei; Zvyagintseva, Tatyana N; Xiong, Hua; Shao, Chen; Yan, Wei; Duan, Qiuhong; Zhu, Feng

    2016-04-01

    The fucoidan with high anticancer activity was isolated from brown alga Fucus evanescens. The compound effectively prevented EGF-induced neoplastic cell transformation through inhibition of TOPK/ERK1/2/MSK 1 signaling axis. In vitro studies showed that the fucoidan attenuated mitogen-activated protein kinases downstream signaling in a colon cancer cells with different expression level of TOPK, resulting in growth inhibition. The fucoidan exerts its effects by directly interacting with TOPK kinase in vitro and ex vivo and inhibits its kinase activity. In xenograft animal model, oral administration of the fucoidan suppressed HCT 116 colon tumor growth. The phosphorylation of TOPK downstream signaling molecules in tumor tissues was also inhibited by the fucoidan. Taken together, our findings support the cancer preventive efficacy of the fucoidan through its targeting of TOPK for the prevention of neoplastic cell transformation and progression of colon carcinomas in vitro and ex vivo.

  15. PDZ-binding kinase/T-LAK cell-originated protein kinase is a target of the fucoidan from brown alga Fucus evanescens in the prevention of EGF-induced neoplastic cell transformation and colon cancer growth

    PubMed Central

    Wang, Zhe; Ermakova, Svetlana P.; Xiao, JuanJuan; Lu, Tao; Xue, PeiPei; Zvyagintseva, Tatyana N.; Xiong, Hua; Shao, Chen; Yan, Wei; Duan, Qiuhong; Zhu, Feng

    2016-01-01

    The fucoidan with high anticancer activity was isolated from brown alga Fucus evanescens. The compound effectively prevented EGF-induced neoplastic cell transformation through inhibition of TOPK/ERK1/2/MSK 1 signaling axis. In vitro studies showed that the fucoidan attenuated mitogen-activated protein kinases downstream signaling in a colon cancer cells with different expression level of TOPK, resulting in growth inhibition. The fucoidan exerts its effects by directly interacting with TOPK kinase in vitro and ex vivo and inhibits its kinase activity. In xenograft animal model, oral administration of the fucoidan suppressed HCT 116 colon tumor growth. The phosphorylation of TOPK downstream signaling molecules in tumor tissues was also inhibited by the fucoidan. Taken together, our findings support the cancer preventive efficacy of the fucoidan through its targeting of TOPK for the prevention of neoplastic cell transformation and progression of colon carcinomas in vitro and ex vivo. PMID:26936995

  16. [Identifying residential areas with heat-related health risks. Sociodemographic and climate data mapping as a planning tool for targeted prevention strategies].

    PubMed

    Blättner, B; Heckenhahn, M; Georgy, S; Grewe, H A; Kupski, S

    2010-01-01

    Prognosticated heat waves in the context of climate change require appropriate strategies to prevent harmful health effects in the population. In a model project within the public health department of the Kassel region, elderly living in areas at risk of over-heating will be identified and advised. The localization of high-risk residential areas was part of the planning process. Through mapping of demographic and microclimate data and the characteristics of the material of the residential buildings, high-risk areas that require preventive measures as a top priority were identified. The prevention of heat-related mortality and morbidity by communal health authorities requires close cooperation with other administrative bodies, especially with town planning departments. Mapping demographic and microclimate data and the characteristics of the material of the residential buildings can facilitate the planning of preventive measures.

  17. Stereotype threat prevents perceptual learning.

    PubMed

    Rydell, Robert J; Shiffrin, Richard M; Boucher, Kathryn L; Van Loo, Katie; Rydell, Michael T

    2010-08-10

    Stereotype threat (ST) refers to a situation in which a member of a group fears that her or his performance will validate an existing negative performance stereotype, causing a decrease in performance. For example, reminding women of the stereotype "women are bad at math" causes them to perform more poorly on math questions from the SAT and GRE. Performance deficits can be of several types and be produced by several mechanisms. We show that ST prevents perceptual learning, defined in our task as an increasing rate of search for a target Chinese character in a display of such characters. Displays contained two or four characters and half of these contained a target. Search rate increased across a session of training for a control group of women, but not women under ST. Speeding of search is typically explained in terms of learned "popout" (automatic attraction of attention to a target). Did women under ST learn popout but fail to express it? Following training, the women were shown two colored squares and asked to choose the one with the greater color saturation. Superimposed on the squares were task-irrelevant Chinese characters. For women not trained under ST, the presence of a trained target on one square slowed responding, indicating that training had caused the learning of an attention response to targets. Women trained under ST showed no slowing, indicating that they had not learned such an attention response.

  18. College Students' Perceptions of the Importance of Sexual Assault Prevention Education: Suggestions for Targeting Recruitment for Peer-Based Education

    ERIC Educational Resources Information Center

    Jozkowski, Kristen N.; Henry, Dayna S.; Sturm, Ashley A.

    2015-01-01

    Introduction: Sexual assault continues to be a pervasive health issue among college students in the USA. Prevention education initiatives have been implemented to address this concern. However, little is known about college students' perceptions of such programming. The purpose of this study was to assess predictors of college students'…

  19. Rapamycin prevents cadmium-induced neuronal cell death via targeting both mTORC1 and mTORC2 pathways.

    PubMed

    Xu, Chong; Liu, Chunxiao; Liu, Lei; Zhang, Ruijie; Zhang, Hai; Chen, Sujuan; Luo, Yan; Chen, Long; Huang, Shile

    2015-10-01

    Cadmium (Cd), a toxic environmental contaminant, contributes to neurodegeneration. Rapamycin, a macrocyclic lactone, has shown preventive effect on Cd-induced neuronal cell death. However, the underlying mechanism is not fully understood. Here, we show that rapamycin prevented Cd-induced apoptotic cell death in neuronal cells. Coincidently, rapamycin markedly blocked Cd-induced phosphorylation of Akt, S6K1 and 4E-BP1 in the cells. Expression of a rapamycin-resistant and kinase-active mTOR (S2035T, mTOR-T), but not a rapamycin-resistant and kinase-dead mTOR (S2035T/D2357E, mTOR-TE), conferred resistance to rapamycin inhibition of Cd-induced cell death, implying that the preventive effect of rapamycin on Cd-induced neurotoxicity is mTOR kinase activity-dependent. It appeared that both mTORC1 and mTORC2 were involved in the inhibitory activity of rapamycin, as silencing raptor, rictor or raptor/rictor enhanced rapamycin's blockage of Cd-induced cell death. Furthermore, downregulation of S6K1, ectopic expression of constitutively hypophosphorylated 4E-BP1 or dominant negative Akt, or co-treatment with Akt inhibitor also potentiated the rapamycin's inhibitory effect. The findings indicate that rapamycin prevents Cd-induced neuronal cell death via suppressing both mTORC1 and mTORC2 pathways. Our results highlight that rapamycin may be exploited for the prevention of Cd-induced neurodegenerative disorders.

  20. [Child maltreatment prevention: the pediatrician's function. Part 1: Overview, evidence, risk factors, protective factors and triggers].

    PubMed

    Mouesca, Juan P

    2015-12-01

    Child maltreatment is a common and serious problem. It harms children in the short and long term, affecting their future health and their offspring. Primary, secondary, tertiary and quaternary preventing interventions target on child abuse are described. Evidence-based recommendations on child abuse prevention and examples of researches with proven efficacy are detailed. Risk factors, protective factors and triggers of child abuse and their relationships are described.

  1. 'There is no profile it is just everyone': the challenge of targeting hepatitis C education and prevention messages to the diversity of current and future injecting drug users.

    PubMed

    Ellard, Jeanne

    2007-05-01

    This paper investigates drug use, knowledge of hepatitis C, and risk minimisation amongst participants of the Sydney inner city dance party/club scene. The aim is to identify factors that contribute to the limited success of hepatitis C education and prevention efforts in Australia and to suggest ways in which they might be improved. The method used was a thematic analysis of 31 semi-structured qualitative interviews with people drawn from the Sydney inner city dance party/club scene. This is a scene where the consumption of recreational drugs is normalised, and where the practice of injecting takes place, albeit less commonly to other routes of administration. In the material presented here, drugs are seen as sources of enjoyment and experimentation, but are not seen as necessary to the functioning of daily life. Indeed, dependency on drugs is largely seen as undesirable. Most participants consider themselves to be both well informed about the drugs they use, and in control of their drug use. Whilst participants in this scene are generally well informed about drugs (and deploy harm reduction strategies to avoid such things as overdose), their knowledge of hepatitis C is limited and vague. The marginal and stigmatised status of injecting both inside and outside the scene appears to contribute to an absence of information and communication about safer injecting and hepatitis C within the scene. Often information about safe injecting is perceived to lack relevance to scene participants and to be aimed at 'other' injecting drug users (IDU). The material discussed confirms the diversity of IDU and the crossover between social, sexual and drug networks. Whilst this poses challenges for education and prevention, the exploration of these networks or scenes has the potential to inform the content of education and prevention materials as well as identifying contexts for dissemination. PMID:17689369

  2. Targeting Binge Eating for the Prevention of Excessive Weight Gain: Interpersonal Psychotherapy for Adolescents at High-Risk for Adult Obesity

    PubMed Central

    Tanofsky-Kraff, Marian; Wilfley, Denise E.; Young, Jami F.; Mufson, Laura; Yanovski, Susan Z.; Glasofer, Deborah R.; Salaita, Christine G.

    2007-01-01

    The most prevalent disordered eating pattern described in overweight youth is loss of control (LOC) eating, during which individuals experience an inability to control the type or amount of food they consume. LOC eating is associated cross-sectionally with greater adiposity in children and adolescents, and appears to predispose youth to gain weight or body fat above that expected during normal growth, thus likely contributing to obesity in susceptible individuals. No prior studies have examined whether LOC eating can be decreased by interventions in children or adolescents without full-syndrome eating disorders, or whether programs reducing LOC eating prevent inappropriate weight gain attributable to LOC eating. Interpersonal psychotherapy, a form of therapy that was designed to treat depression and has been adapted for the treatment of eating disorders, has demonstrated efficacy in reducing binge eating episodes and inducing weight stabilization among adults diagnosed with binge eating disorder. In this paper, we propose a theoretical model of excessive weight gain in adolescents at high-risk for adult obesity who engage in LOC eating and associated overeating patterns. A rationale is provided for interpersonal psychotherapy as an intervention to slow the trajectory of weight gain in at-risk youth, with the aim of preventing or ameliorating obesity in adulthood. PMID:17557971

  3. Changing Schools to Prevent Delinquency.

    ERIC Educational Resources Information Center

    Kerr, Douglas M.

    Although community psychologists and prevention specialists view schools as the ideal vehicle for delinquency programs for children, few examples of effective school-based prevention programs are available. Delinquency prevention program developers view common school practices as contributing causes of delinquency, making school change a major…

  4. β-cell-targeted blockage of PD1 and CTLA4 pathways prevents development of autoimmune diabetes and acute allogeneic islets rejection

    PubMed Central

    El Khatib, Moustafa; Sakuma, Toshie; Tonne, Jason M.; Mohamed, Magid S.; Holditch, Sara J.; Lu, Brian; Kudva, Yogish C.; Ikeda, Yasuhiro

    2015-01-01

    Protection of beta cells from autoimmune destruction potentially cures type 1 diabetes mellitus (T1D). During antigen presentation, interactions between cytotoxic T-lymphocyte antigen-4 (CTLA4) and B7 molecules, or programmed death 1 (PD1) and its ligand PDL1, negatively regulate immune responses in a non-redundant manner. Here, we employed beta cell-targeted adeno-associated virus serotype 8 (AAV8)-based vectors to over-express an artificial PDL1-CTLA4Ig polyprotein or IL10. Beta cell-targeted expression of PDL1-CTLA4Ig or IL10 preserved beta cell mass and protected NOD mice from T1D development. When NOD mice were treated with vectors at early onset of hyperglycemia, PDL1-CTLA4Ig or IL10 alone failed to normalize the early onset of hyperglycemia. When drug-induced diabetic mice received MHC-matched allo-islets, with or without pretreatment of the PDL1-CTLA4Ig-expressing vector, PDL1-CTLA4Ig-expressing islets were protected from rejection for at least 120 days. Similarly, transplantation of PDL1-CTLA4Ig-expressing MHC-matched islets into mice with established T1D resulted in protection of allo-islets from acute rejection, although islet grafts were eventually rejected. Thus, the present study demonstrates the potent immuno-suppressive effects of beta cell-targeted PDL1-CTLA4Ig overexpression against T1D development and allo-islet rejection. The gene-based simultaneous inhibition of PD1 and CTLA4 pathways provides a unique strategy for immunosuppression-free tissue/organ transplantation, especially in the setting of no established autoimmunity. PMID:25786871

  5. Cardiomyocyte-targeted siRNA delivery by prostaglandin E(2)-Fas siRNA polyplexes formulated with reducible poly(amido amine) for preventing cardiomyocyte apoptosis.

    PubMed

    Kim, Sun Hwa; Jeong, Ji Hoon; Ou, Mei; Yockman, James W; Kim, Sung Wan; Bull, David A

    2008-11-01

    A cardiomyocyte-targeted Fas siRNA delivery system was developed using prostaglandin E(2) (PGE(2))-modified siRNA polyplexes formed by a reducible poly(amido amine) to inhibit cardiomyocyte apoptosis. PGE(2), which was used as a specific ligand for cardiomyocyte targeting, was conjugated to the terminal-end of the sense siRNA (PGE(2)-siRNA). The reducible cationic copolymer, synthesized via Michael-type polyaddition of 1,6-diaminohexane and cystamine bis-acrylamide (poly(DAH/CBA)), tightly condensed the PGE(2)-siRNA conjugate to form nanosize polyplexes having a diameter of 100-150 nm. The PGE(2)-siRNA/poly(DAH/CBA) polyplexes decomplexed to release PGE(2)-siRNA in a cytosolic reducing environment due to the degradation of the reducible poly(DAH/CBA). The cellular uptake of the PGE(2)-siRNA/poly(DAH/CBA) polyplex was increased in rat cardiomyocytes (H9C2 cells) due to PGE(2) receptor-mediated endocytosis. When H9C2 cells were transfected with siRNA against Fas, a key regulator of ischemia-induced apoptosis, the PGE(2)-Fas siRNA/poly(DAH/CBA) polyplex delivery system led to a significant increase in Fas gene silencing, resulting in inhibition of cardiomyocyte apoptosis. The PGE(2)-Fas siRNA/poly(DAH/CBA) polyplex did not induce interferon-alpha in peripheral blood mononuclear cells. These results suggest that the PGE(2)-Fas siRNA/poly(DAH/CBA) polyplex formulation may be clinically applicable as a cardiomyocyte-targeted Fas siRNA delivery system to inhibit apoptosis in cardiovascular disease.

  6. Trends in hospitalised sport/leisure injuries in New South Wales, Australia--implications for the targetting of population-focussed preventive sports medicine efforts.

    PubMed

    Finch, Caroline F; Mitchell, Rebecca; Boufous, Soufiane

    2011-01-01

    Sport/leisure injuries are a population health issue in Australia. Over 2003-2004 to 2007-2008, the rate of sport/leisure injury NSW hospitalisations was 195.5/100,000 residents. Males and children/young people had consistently highest rates of hospitalisation. There was no significant decline in rates over this period and no change in the profiles of the types of sport/leisure injuries. The extent to which effective preventive programs have been developed and implemented needs to be determined as current programs do not seem to be impacting on hospitalisation rates. Medical/health promotion agencies and sports bodies need to jointly formulate and implement policies to reduce sport/leisure injuries. This is one of the most significant challenges facing sports medicine professionals today.

  7. Crime prevention through social and physical environmental change

    PubMed Central

    Nietzel, Michael T.; Himelein, Melissa J.

    1987-01-01

    One approach to crime prevention where behavior analysts can make important contributions is the modification of environmental opportunities and victim vulnerabilities that are related to higher rates of offending. Examples of environmental crime prevention are discussed in the following areas: (1) modifying physical environments in order to “harden” targets of crime, (2) training victims to be less vulnerable to victimization, (3) eliminating portrayals of certain groups of people that legitimize their victimization, and (4) organizing neighborhoods and communities to strengthen their means of social control. Two implications of environmental crime prevention—the role of individual differences and the scope of prevention—are discussed. PMID:22477962

  8. The role of estrogen receptor {beta} (ER{beta}) in malignant diseases-A new potential target for antiproliferative drugs in prevention and treatment of cancer

    SciTech Connect

    Warner, Margaret; Gustafsson, Jan-Ake

    2010-05-21

    The discovery of ER{beta} in the middle of the 1990s represents a paradigm shift in our understanding of estrogen signaling. It has turned out that estrogen action is not mediated by one receptor, ER{alpha}, but by two balancing factors, ER{alpha} and ER{beta}, which are often antagonistic to one another. Excitingly, ER{beta} has been shown to be widespread in the body and to be involved in a multitude of physiological and pathophysiological events. This has led to a strong interest of the pharmaceutical industry to target ER{beta} by drugs against various diseases. In this review, focus is on the role of ER{beta} in malignant diseases where the anti proliferative activity of ER{beta} gives hope of new therapeutic approaches.

  9. miR-9-5p suppresses pro-fibrogenic transformation of fibroblasts and prevents organ fibrosis by targeting NOX4 and TGFBR2.

    PubMed

    Fierro-Fernández, Marta; Busnadiego, Óscar; Sandoval, Pilar; Espinosa-Díez, Cristina; Blanco-Ruiz, Eva; Rodríguez, Macarena; Pian, Héctor; Ramos, Ricardo; López-Cabrera, Manuel; García-Bermejo, Maria Laura; Lamas, Santiago

    2015-10-01

    Uncontrolled extracellular matrix (ECM) production by fibroblasts in response to injury contributes to fibrotic diseases, including idiopathic pulmonary fibrosis (IPF). Reactive oxygen species (ROS) generation is involved in the pathogenesis of IPF. Transforming growth factor-β1 (TGF-β1) stimulates the production of NADPH oxidase 4 (NOX4)-dependent ROS, promoting lung fibrosis (LF). Dysregulation of microRNAs (miRNAs) has been shown to contribute to LF. To identify miRNAs involved in redox regulation relevant for IPF, we performed arrays in human lung fibroblasts exposed to ROS. miR-9-5p was selected as the best candidate and we demonstrate its inhibitory effect on TGF-β receptor type II (TGFBR2) and NOX4 expression. Increased expression of miR-9-5p abrogates TGF-β1-dependent myofibroblast phenotypic transformation. In the mouse model of bleomycin-induced LF, miR-9-5p dramatically reduces fibrogenesis and inhibition of miR-9-5p and prevents its anti-fibrotic effect both in vitro and in vivo. In lung specimens from patients with IPF, high levels of miR-9-5p are found. In omentum-derived mesothelial cells (MCs) from patients subjected to peritoneal dialysis (PD), miR-9-5p also inhibits mesothelial to myofibroblast transformation. We propose that TGF-β1 induces miR-9-5p expression as a self-limiting homeostatic response.

  10. Using the Science of Psychology to Target Perpetrators of Racism and Race-Based Discrimination For Intervention Efforts: Preventing Another Trayvon Martin Tragedy.

    PubMed

    Mays, Vickie M; Johnson, Denise; Coles, Courtney N; Gellene, Denise; Cochran, Susan D

    2013-03-22

    Psychological science offers a variety of methods to both understand and intervene when acts of potential racial or ethnic racism, bias or prejudice occur. The Trayvon Martin killing is a reminder of how vulnerable African American men and boys, especially young African American men, are to becoming victims of social inequities in our society. We examine several historical events of racial bias (the Los Angeles civil disturbance after the Rodney King verdict, the federal government's launch of a "War on Drugs" and the killing of Trayvon Martin) to illustrate the ways in which behaviors of racism and race-based discrimination can be viewed from a psychological science lens in the hopes of eliminating and preventing these behaviors. If society is to help end the genocide of African American men and boys then we must broaden our focus from simply understanding instances of victimization to a larger concern with determining how policies, laws, and societal norms serve as the foundation for maintaining implicit biases that are at the root of race-based discrimination, prejudice, bias and inequity. In our call to action, we highlight the contributions that psychologists, particularly racial and ethnic minority professionals, can make to reduce the negative impact of racial and ethnic bias through their volunteer/pro bono clinical efforts.

  11. The Potential Role of Circuit Parties in the Spread of HIV among Men Who Have Sex with Men in Asia: A Call for Targeted Prevention

    PubMed Central

    Cheung, Doug H.; Lim, Sin How; Guadamuz, Thomas E.; Koe, Stuart; Wei, Chongyi

    2014-01-01

    We postulated that the growing popularity of circuit parties may play a role in the escalating HIV prevalence among men who have sex with men (MSM) in Asia. The present study is the first to characterize the sociodemographic and HIV-related behavioral factors of circuit party attendees living in Asia. We analyzed a subset of data from the Asia Internet MSM Sex Survey conducted from January 1 to February 28, 2010. Inclusion criteria included: being biologically male, aged 18 years or above, self-reported sex with another man, and reported international travel in the past 6 months (N = 6,094). From our multivariable logistic regression model, participants’ resident country with low HIV prevalence (among MSM) (AOR: 1.59, 95% CI: 1.27–2.00) and country of destination with high HIV prevalence were independently associated with higher odds of circuit party attendance (AOR: 1.32, 95% CI: 1.14–1.53) during international travel. Statistical interaction indicated circuit party attendees were likely to have traveled from low HIV prevalence (among MSM) countries to high HIV prevalence countries (AOR: 1.40, 95% CI: 1.20–1.64). Other independent correlates included unprotected anal sex with a male casual sex partner and recreational drug use during travel. HIV and STI prevention focusing on circuit party attendees may have a pivotal role on the spread of the HIV epidemics among MSM in Asia. PMID:25104105

  12. Using the Science of Psychology to Target Perpetrators of Racism and Race-Based Discrimination For Intervention Efforts: Preventing Another Trayvon Martin Tragedy

    PubMed Central

    Mays, Vickie M.; Johnson, Denise; Coles, Courtney N.; Gellene, Denise; Cochran, Susan D.

    2013-01-01

    Psychological science offers a variety of methods to both understand and intervene when acts of potential racial or ethnic racism, bias or prejudice occur. The Trayvon Martin killing is a reminder of how vulnerable African American men and boys, especially young African American men, are to becoming victims of social inequities in our society. We examine several historical events of racial bias (the Los Angeles civil disturbance after the Rodney King verdict, the federal government’s launch of a “War on Drugs” and the killing of Trayvon Martin) to illustrate the ways in which behaviors of racism and race-based discrimination can be viewed from a psychological science lens in the hopes of eliminating and preventing these behaviors. If society is to help end the genocide of African American men and boys then we must broaden our focus from simply understanding instances of victimization to a larger concern with determining how policies, laws, and societal norms serve as the foundation for maintaining implicit biases that are at the root of race-based discrimination, prejudice, bias and inequity. In our call to action, we highlight the contributions that psychologists, particularly racial and ethnic minority professionals, can make to reduce the negative impact of racial and ethnic bias through their volunteer/pro bono clinical efforts. PMID:23885310

  13. Harnessing publicly available genetic data to prioritize lipid modifying therapeutic targets for prevention of coronary heart disease based on dysglycemic risk.

    PubMed

    Tragante, Vinicius; Asselbergs, Folkert W; Swerdlow, Daniel I; Palmer, Tom M; Moore, Jason H; de Bakker, Paul I W; Keating, Brendan J; Holmes, Michael V

    2016-05-01

    Therapeutic interventions that lower LDL-cholesterol effectively reduce the risk of coronary artery disease (CAD). However, statins, the most widely prescribed LDL-cholesterol lowering drugs, increase diabetes risk. We used genome-wide association study (GWAS) data in the public domain to investigate the relationship of LDL-C and diabetes and identify loci encoding potential drug targets for LDL-cholesterol modification without causing dysglycemia. We obtained summary-level GWAS data for LDL-C from GLGC, glycemic traits from MAGIC, diabetes from DIAGRAM and CAD from CARDIoGRAMplusC4D consortia. Mendelian randomization analyses identified a one standard deviation (SD) increase in LDL-C caused an increased risk of CAD (odds ratio [OR] 1.63 (95 % confidence interval [CI] 1.55, 1.71), which was not influenced by removing SNPs associated with diabetes. LDL-C/CAD-associated SNPs showed consistent effect directions (binomial P = 6.85 × 10(-5)). Conversely, a 1-SD increase in LDL-C was causally protective of diabetes (OR 0.86; 95 % CI 0.81, 0.91), however LDL-cholesterol/diabetes-associated SNPs did not show consistent effect directions (binomial P = 0.15). HMGCR, our positive control, associated with LDL-C, CAD and a glycemic composite (derived from GWAS meta-analysis of four glycemic traits and diabetes). In contrast, PCSK9, APOB, LPA, CETP, PLG, NPC1L1 and ALDH2 were identified as "druggable" loci that alter LDL-C and risk of CAD without displaying associations with dysglycemia. In conclusion, LDL-C increases the risk of CAD and the relationship is independent of any association of LDL-C with diabetes. Loci that encode targets of emerging LDL-C lowering drugs do not associate with dysglycemia, and this provides provisional evidence that new LDL-C lowering drugs (such as PCSK9 inhibitors) may not influence risk of diabetes. PMID:26946290

  14. Harnessing publicly available genetic data to prioritize lipid modifying therapeutic targets for prevention of coronary heart disease based on dysglycemic risk.

    PubMed

    Tragante, Vinicius; Asselbergs, Folkert W; Swerdlow, Daniel I; Palmer, Tom M; Moore, Jason H; de Bakker, Paul I W; Keating, Brendan J; Holmes, Michael V

    2016-05-01

    Therapeutic interventions that lower LDL-cholesterol effectively reduce the risk of coronary artery disease (CAD). However, statins, the most widely prescribed LDL-cholesterol lowering drugs, increase diabetes risk. We used genome-wide association study (GWAS) data in the public domain to investigate the relationship of LDL-C and diabetes and identify loci encoding potential drug targets for LDL-cholesterol modification without causing dysglycemia. We obtained summary-level GWAS data for LDL-C from GLGC, glycemic traits from MAGIC, diabetes from DIAGRAM and CAD from CARDIoGRAMplusC4D consortia. Mendelian randomization analyses identified a one standard deviation (SD) increase in LDL-C caused an increased risk of CAD (odds ratio [OR] 1.63 (95 % confidence interval [CI] 1.55, 1.71), which was not influenced by removing SNPs associated with diabetes. LDL-C/CAD-associated SNPs showed consistent effect directions (binomial P = 6.85 × 10(-5)). Conversely, a 1-SD increase in LDL-C was causally protective of diabetes (OR 0.86; 95 % CI 0.81, 0.91), however LDL-cholesterol/diabetes-associated SNPs did not show consistent effect directions (binomial P = 0.15). HMGCR, our positive control, associated with LDL-C, CAD and a glycemic composite (derived from GWAS meta-analysis of four glycemic traits and diabetes). In contrast, PCSK9, APOB, LPA, CETP, PLG, NPC1L1 and ALDH2 were identified as "druggable" loci that alter LDL-C and risk of CAD without displaying associations with dysglycemia. In conclusion, LDL-C increases the risk of CAD and the relationship is independent of any association of LDL-C with diabetes. Loci that encode targets of emerging LDL-C lowering drugs do not associate with dysglycemia, and this provides provisional evidence that new LDL-C lowering drugs (such as PCSK9 inhibitors) may not influence risk of diabetes.

  15. Human MAF1 targets and represses active RNA polymerase III genes by preventing recruitment rather than inducing long-term transcriptional arrest

    PubMed Central

    Orioli, Andrea; Praz, Viviane; Lhôte, Philippe; Hernandez, Nouria

    2016-01-01

    RNA polymerase III (Pol III) is tightly controlled in response to environmental cues, yet a genomic-scale picture of Pol III regulation and the role played by its repressor MAF1 is lacking. Here, we describe genome-wide studies in human fibroblasts that reveal a dynamic and gene-specific adaptation of Pol III recruitment to extracellular signals in an mTORC1-dependent manner. Repression of Pol III recruitment and transcription are tightly linked to MAF1, which selectively localizes at Pol III loci, even under serum-replete conditions, and increasingly targets transcribing Pol III in response to serum starvation. Combining Pol III binding profiles with EU-labeling and high-throughput sequencing of newly synthesized small RNAs, we show that Pol III occupancy closely reflects ongoing transcription. Our results exclude the long-term, unproductive arrest of Pol III on the DNA as a major regulatory mechanism and identify previously uncharacterized, differential coordination in Pol III binding and transcription under different growth conditions. PMID:26941251

  16. Loss of the transcription factor Meis1 prevents sympathetic neurons target-field innervation and increases susceptibility to sudden cardiac death.

    PubMed

    Bouilloux, Fabrice; Thireau, Jérôme; Ventéo, Stéphanie; Farah, Charlotte; Karam, Sarah; Dauvilliers, Yves; Valmier, Jean; Copeland, Neal G; Jenkins, Nancy A; Richard, Sylvain; Marmigère, Frédéric

    2016-01-01

    Although cardio-vascular incidents and sudden cardiac death (SCD) are among the leading causes of premature death in the general population, the origins remain unidentified in many cases. Genome-wide association studies have identified Meis1 as a risk factor for SCD. We report that Meis1 inactivation in the mouse neural crest leads to an altered sympatho-vagal regulation of cardiac rhythmicity in adults characterized by a chronotropic incompetence and cardiac conduction defects, thus increasing the susceptibility to SCD. We demonstrated that Meis1 is a major regulator of sympathetic target-field innervation and that Meis1 deficient sympathetic neurons die by apoptosis from early embryonic stages to perinatal stages. In addition, we showed that Meis1 regulates the transcription of key molecules necessary for the endosomal machinery. Accordingly, the traffic of Rab5(+) endosomes is severely altered in Meis1-inactivated sympathetic neurons. These results suggest that Meis1 interacts with various trophic factors signaling pathways during postmitotic neurons differentiation. PMID:26857994

  17. Loss of the transcription factor Meis1 prevents sympathetic neurons target-field innervation and increases susceptibility to sudden cardiac death

    PubMed Central

    Bouilloux, Fabrice; Thireau, Jérôme; Ventéo, Stéphanie; Farah, Charlotte; Karam, Sarah; Dauvilliers, Yves; Valmier, Jean; Copeland, Neal G; Jenkins, Nancy A; Richard, Sylvain; Marmigère, Frédéric

    2016-01-01

    Although cardio-vascular incidents and sudden cardiac death (SCD) are among the leading causes of premature death in the general population, the origins remain unidentified in many cases. Genome-wide association studies have identified Meis1 as a risk factor for SCD. We report that Meis1 inactivation in the mouse neural crest leads to an altered sympatho-vagal regulation of cardiac rhythmicity in adults characterized by a chronotropic incompetence and cardiac conduction defects, thus increasing the susceptibility to SCD. We demonstrated that Meis1 is a major regulator of sympathetic target-field innervation and that Meis1 deficient sympathetic neurons die by apoptosis from early embryonic stages to perinatal stages. In addition, we showed that Meis1 regulates the transcription of key molecules necessary for the endosomal machinery. Accordingly, the traffic of Rab5+ endosomes is severely altered in Meis1-inactivated sympathetic neurons. These results suggest that Meis1 interacts with various trophic factors signaling pathways during postmitotic neurons differentiation. DOI: http://dx.doi.org/10.7554/eLife.11627.001 PMID:26857994

  18. School Injury Prevention Resource Guide.

    ERIC Educational Resources Information Center

    Brackett, Christine

    This guide has been developed to provide resources to teachers to address injury prevention in their classrooms. Entries in this guide represent materials which the Injury Prevention Program has identified. Chapters are divided by their target grade and age level. Curricula are listed by the youngest grade which they target. For each entry,…

  19. Monte Carlo Example Programs

    2006-05-09

    The Monte Carlo example programs VARHATOM and DMCATOM are two small, simple FORTRAN programs that illustrate the use of the Monte Carlo Mathematical technique for calculating the ground state energy of the hydrogen atom.

  20. Plasma DCLK1 is a marker of hepatocellular carcinoma (HCC): Targeting DCLK1 prevents HCC tumor xenograft growth via a microRNA-dependent mechanism

    PubMed Central

    May, Randal; Qu, Dongfeng; Ali, Naushad; Fazili, Javid; Weygant, Nathaniel; Chandrakesan, Parthasarathy; Ding, Kai; Lightfoot, Stanley A.; Houchen, Courtney W.

    2015-01-01

    Tumor stem cell marker Doublecortin-like kinase1 (DCLK1) is upregulated in several solid tumors. The role of DCLK1 in hepatocellular carcinoma (HCC) is unclear. We immunostained tissues from human livers with HCC, cirrhosis controls (CC), and non-cirrhosis controls (NCC) for DCLK1. Western blot and ELISA analyses for DCLK1 were performed with stored plasma samples. We observed increased immunoreactive DCLK1 in epithelia and stroma in HCC and CCs compared with NCCs, and observed a marked increase in plasma DCLK1 from patients with HCC compared with CC and NCC. Analysis of the Cancer Genome Atlas’ HCC dataset revealed that DCLK1 is overexpressed in HCC tumors relative to adjacent normal tissues. High DCLK1-expressing cells had more epithelial-mesenchymal transition (EMT). Various tumor suppressor miRNAs were also downregulated in HCC tumors. We evaluated the effects of DCLK1 knockdown on Huh7.5-derived tumor xenograft growth. This was associated with growth arrest and a marked downregulation of cMYC, and EMT transcription factors ZEB1, ZEB2, SNAIL, and SLUG via let-7a and miR-200 miRNA-dependent mechanisms. Furthermore, upregulation of miR-143/145, a corresponding decrease in pluripotency factors OCT4, NANOG, KLF4, and LIN28, and a reduction of let-7a, miR-143/145, and miR-200-specific luciferase activity was observed. These findings suggest that the detection of elevated plasma DCLK1 may provide a cost-effective, less invasive tool for confirmation of clinical signs of cirrhosis, and a potential companion diagnostic marker for patients with cirrhosis and HCC. Our results support evaluating DCLK1 as a biomarker for detection and as a therapeutic target for eradicating HCC. PMID:26468984

  1. Identifying High-Risk Neighborhoods Using Electronic Medical Records: A Population-Based Approach for Targeting Diabetes Prevention and Treatment Interventions

    PubMed Central

    Gakidou, Emmanuela; Roth, Gregory

    2016-01-01

    Background Increasing attention is being paid to the marked disparities in diabetes prevalence and health outcomes in the United States. There is a need to identify the small-area geographic variation in diabetes risk and related outcomes, a task that current health surveillance methods, which often rely on a self-reported diagnosis of diabetes, are not detailed enough to achieve. Broad adoption of electronic health records (EHR) and routine centralized reporting of patient-level data offers a new way to examine diabetes risk and highlight hotspots for intervention. Methods and Findings We examined small-area geographic variation in hemoglobin A1c (HgbA1C) levels in three counties though a retrospective observational analysis of the complete population of diabetic patients receiving at least two ambulatory care visits for diabetes in three counties (two urban, one rural) in Minnesota in 2013, with clinical performance measures re-aggregated to patient home zip code area. Patient level performance measures included HgbA1c, blood pressure, low-density lipoprotein cholesterol and smoking. Diabetes care was provided to 63,053 patients out of a total population of 1.48 million people aged 18–74. Within each zip code area, on average 4.1% of the population received care for diabetes. There was significant and largely consistent geographic variation in the proportion of patients within their zip code area of residence attaining HgbA1C <8.0%, ranging from 59–90% of patients within each zip code area (interquartile range (IQR) 72.0%-78.1%). Attainment of performance measures for a zip code area were correlated with household income, educational attainment and insurance coverage for the same zip code area (all p < .001). Conclusions We identified small geographic areas with the least effective control of diabetes. Centrally-aggregated EHR provides a new means of identifying and targeting at-risk neighborhoods for community-based interventions. PMID:27463641

  2. Time to add a new priority target for child injury prevention? The case for an excess burden associated with sport and exercise injury: population-based study

    PubMed Central

    Finch, Caroline F; Wong Shee, Anna; Clapperton, Angela

    2014-01-01

    hospital costs, bed-day usage and YLD impacts) for sports injury compared with road traffic injury for children aged <15 years indicates an urgent need to prioritise sports injury prevention in this age group. PMID:24993758

  3. Who Should Be Targeted for the Prevention of Birth Defects? A Latent Class Analysis Based on a Large, Population-Based, Cross-Sectional Study in Shaanxi Province, Western China

    PubMed Central

    Yang, Wenfang; Li, Danyang; Yang, Xue; Liu, Danli; Zhang, Min; Yan, Hong; Zeng, Lingxia

    2016-01-01

    Background The wide range and complex combinations of factors that cause birth defects impede the development of primary prevention strategies targeted at high-risk subpopulations. Methods Latent class analysis (LCA) was conducted to identify mutually exclusive profiles of factors associated with birth defects among women between 15 and 49 years of age using data from a large, population-based, cross-sectional study conducted in Shaanxi Province, western China, between August and October, 2013. The odds ratios (ORs) and 95% confidence intervals (CIs) of associated factors and the latent profiles of indicators of birth defects and congenital heart defects were computed using a logistic regression model. Results Five discrete subpopulations of participants were identified as follows: No folic acid supplementation in the periconceptional period (reference class, 21.37%); low maternal education level + unhealthy lifestyle (class 2, 39.75%); low maternal education level + unhealthy lifestyle + disease (class 3, 23.71%); unhealthy maternal lifestyle + advanced age (class 4, 4.71%); and multi-risk factor exposure (class 5, 10.45%). Compared with the reference subgroup, the other subgroups consistently had a significantly increased risk of birth defects (ORs and 95% CIs: class 2, 1.75 and 1.21–2.54; class 3, 3.13 and 2.17–4.52; class 4, 5.02 and 3.20–7.88; and class 5, 12.25 and 8.61–17.42, respectively). For congenital heart defects, the ORs and 95% CIs were all higher, and the magnitude of OR differences ranged from 1.59 to 16.15. Conclusions A comprehensive intervention strategy targeting maternal exposure to multiple risk factors is expected to show the strongest results in preventing birth defects. PMID:27183231

  4. Zinc Transporter 8 (ZnT8) Expression Is Reduced by Ischemic Insults: A Potential Therapeutic Target to Prevent Ischemic Retinopathy

    PubMed Central

    DeNiro, Michael; Al-Mohanna, Futwan A.

    2012-01-01

    The zinc (Zn++) transporter ZnT8 plays a crucial role in zinc homeostasis. It’s been reported that an acute decrease in ZnT8 levels impairs β cell function and Zn++ homeostasis, which contribute to the pathophysiology of diabetes mellitus (DM). Although ZnT8 expression has been detected in the retinal pigment epithelium (RPE), its expression profile in the retina has yet to be determined. Furthermore, the link between diabetes and ischemic retinopathy is well documented; nevertheless, the molecular mechanism(s) of such link has yet to be defined. Our aims were to; investigate the expression profile of ZnT8 in the retina; address the influence of ischemia on such expression; and evaluate the influence of YC-1; (3-(50-hydroxymethyl-20-furyl)-1-benzyl indazole), a hypoxia inducible factor-1 (HIF-1) inhibitor, on the status of ZnT8 expression. We used real-time RT-PCR, immunohistochemistry, and Western blot in the mouse model of oxygen-induced retinopathy (OIR) and Müller cells to evaluate the effects of ischemia/hypoxia and YC-1 on ZnT8 expression. Our data indicate that ZnT8 was strongly expressed in the outer nuclear layer (ONL), outer plexiform layer (OPL), ganglion cell layer (GCL), and nerve fiber layer (NFL), whereas the photoreceptor layer (PRL), inner nuclear layer (INL) and inner plexiform layer (IPL) showed moderate ZnT8 immunoreactivity. Furthermore, we demonstrate that retinal ischemic insult induces a significant downregulation of ZnT8 at the message and protein levels, YC-1 rescues the injured retina by restoring the ZnT8 to its basal homeostatic levels in the neovascular retinas. Our data indicate that ischemic retinopathy maybe mediated by aberrant Zn++ homeostasis caused by ZnT8 downregulation, whereas YC-1 plays a neuroprotective role against ischemic insult. Therefore, targeting ZnT8 provides a therapeutic strategy to combat neovascular eye diseases. PMID:23209723

  5. The Prevention of Adolescent Depression

    PubMed Central

    Gladstone, Tracy R.G.; Beardslee, William R.; O’Connor, Erin E.

    2011-01-01

    Synopsis This article provides a conceptual framework for research on the prevention of depression in youth and reviews the recent literature on prevention efforts targeting children and adolescents. Prevention efforts should target both specific and non-specific risk factors, enhance protective factors, use a developmental approach, and target selective and/or indicated samples. In general, a review of the literature indicates that prevention programs utilizing cognitive behavioral and/or interpersonal approaches, and family-based prevention strategies, are most helpful. Overall, it appears that there is reason for hope regarding the role of interventions in preventing depressive disorders in youth. Several new directions for future research on the prevention of depression in youth were outlined. PMID:21333838

  6. Rape prevention

    MedlinePlus

    Date rape - prevention; Sexual assault - prevention ... Centers for Disease Control and Prevention. Sexual assault and abuse and STDs. In: 2015 sexually transmitted diseases treatment guidelines 2015. Updated June 4, 2015. www.cdc.gov/ ...

  7. [Prevention of psychic disorders].

    PubMed

    Siepmann, M

    2012-06-01

    Prevention aims to avoid the occurrence of psychiatric illness and disability caused by psychic disorders. The relevant interventions refer to the individual, the family context and other environmental factors. Universal and primary prevention target the entire population or a part of this (i. e. students). Secondary and selective intervention should prevent the manifestation of psychiatric disorders in vulnerable individuals (i. e. children with behavioral problems). Tertiary measures aim at preventing the worsening or recurrence of symptoms in individuals who already suffer from mental illness. Within the past 25 years protective and risk factors that reduce or increase the probability of occurrence of mental disorders have increasingly been identified. This results in improved prevention. The present article gives an overview of preventive measures against the most common mental disorders in the light of the current evidence base.

  8. Targeting the myofibroblast genetic switch: inhibitors of myocardin-related transcription factor/serum response factor-regulated gene transcription prevent fibrosis in a murine model of skin injury.

    PubMed

    Haak, Andrew J; Tsou, Pei-Suen; Amin, Mohammad A; Ruth, Jeffrey H; Campbell, Phillip; Fox, David A; Khanna, Dinesh; Larsen, Scott D; Neubig, Richard R

    2014-06-01

    Systemic sclerosis (SSc), or scleroderma, similar to many fibrotic disorders, lacks effective therapies. Current trials focus on anti-inflammatory drugs or targeted approaches aimed at one of the many receptor mechanisms initiating fibrosis. In light of evidence that a myocardin-related transcription factor (MRTF)-and serum response factor (SRF)-regulated gene transcriptional program induced by Rho GTPases is essential for myofibroblast activation, we explored the hypothesis that inhibitors of this pathway may represent novel antifibrotics. MRTF/SRF-regulated genes show spontaneously increased expression in primary dermal fibroblasts from patients with diffuse cutaneous SSc. A novel small-molecule inhibitor of MRTF/SRF-regulated transcription (CCG-203971) inhibits expression of connective tissue growth factor (CTGF), α-smooth muscle actin (α-SMA), and collagen 1 (COL1A2) in both SSc fibroblasts and in lysophosphatidic acid (LPA)-and transforming growth factor β (TGFβ)-stimulated fibroblasts. In vivo treatment with CCG-203971 also prevented bleomycin-induced skin thickening and collagen deposition. Thus, targeting the MRTF/SRF gene transcription pathway could provide an efficacious new approach to therapy for SSc and other fibrotic disorders.

  9. Targeting the Myofibroblast Genetic Switch: Inhibitors of Myocardin-Related Transcription Factor/Serum Response Factor–Regulated Gene Transcription Prevent Fibrosis in a Murine Model of Skin Injury

    PubMed Central

    Haak, Andrew J.; Tsou, Pei-Suen; Amin, Mohammad A.; Ruth, Jeffrey H.; Campbell, Phillip; Fox, David A.; Khanna, Dinesh; Larsen, Scott D.

    2014-01-01

    Systemic sclerosis (SSc), or scleroderma, similar to many fibrotic disorders, lacks effective therapies. Current trials focus on anti-inflammatory drugs or targeted approaches aimed at one of the many receptor mechanisms initiating fibrosis. In light of evidence that a myocardin-related transcription factor (MRTF)–and serum response factor (SRF)–regulated gene transcriptional program induced by Rho GTPases is essential for myofibroblast activation, we explored the hypothesis that inhibitors of this pathway may represent novel antifibrotics. MRTF/SRF-regulated genes show spontaneously increased expression in primary dermal fibroblasts from patients with diffuse cutaneous SSc. A novel small-molecule inhibitor of MRTF/SRF-regulated transcription (CCG-203971) inhibits expression of connective tissue growth factor (CTGF), α-smooth muscle actin (α-SMA), and collagen 1 (COL1A2) in both SSc fibroblasts and in lysophosphatidic acid (LPA)–and transforming growth factor β (TGFβ)–stimulated fibroblasts. In vivo treatment with CCG-203971 also prevented bleomycin-induced skin thickening and collagen deposition. Thus, targeting the MRTF/SRF gene transcription pathway could provide an efficacious new approach to therapy for SSc and other fibrotic disorders. PMID:24706986

  10. Code query by example

    NASA Astrophysics Data System (ADS)

    Vaucouleur, Sebastien

    2011-02-01

    We introduce code query by example for customisation of evolvable software products in general and of enterprise resource planning systems (ERPs) in particular. The concept is based on an initial empirical study on practices around ERP systems. We motivate our design choices based on those empirical results, and we show how the proposed solution helps with respect to the infamous upgrade problem: the conflict between the need for customisation and the need for upgrade of ERP systems. We further show how code query by example can be used as a form of lightweight static analysis, to detect automatically potential defects in large software products. Code query by example as a form of lightweight static analysis is particularly interesting in the context of ERP systems: it is often the case that programmers working in this field are not computer science specialists but more of domain experts. Hence, they require a simple language to express custom rules.

  11. A Unifying Probability Example.

    ERIC Educational Resources Information Center

    Maruszewski, Richard F., Jr.

    2002-01-01

    Presents an example from probability and statistics that ties together several topics including the mean and variance of a discrete random variable, the binomial distribution and its particular mean and variance, the sum of independent random variables, the mean and variance of the sum, and the central limit theorem. Uses Excel to illustrate these…

  12. Compliance through pollution prevention

    SciTech Connect

    McCarty, B.D.; Coyle, S.; Kachel, W.M.

    1999-07-01

    Decreased budgetary resources have caused the Air Force Materiel Command to look for a better way to target pollution prevention investments. The new paradigm, Compliance through Pollution Prevention (CTP2), is based upon the Code of Environmental Management Principles (CEMP) for federal facilities. It provides a procedure to assure that all future AFMC P2 investments result in the greatest reduction in environmental compliance burden possible. This paper describes the evolution of this new environmental management system, both past and future.

  13. tRNAs as Antibiotic Targets

    PubMed Central

    Chopra, Shaileja; Reader, John

    2014-01-01

    Transfer RNAs (tRNAs) are central players in the protein translation machinery and as such are prominent targets for a large number of natural and synthetic antibiotics. This review focuses on the role of tRNAs in bacterial antibiosis. We will discuss examples of antibiotics that target multiple stages in tRNA biology from tRNA biogenesis and modification, mature tRNAs, aminoacylation of tRNA as well as prevention of proper tRNA function by small molecules binding to the ribosome. Finally, the role of deacylated tRNAs in the bacterial “stringent response” mechanism that can lead to bacteria displaying antibiotic persistence phenotypes will be discussed. PMID:25547494

  14. Debugging into Examples

    NASA Astrophysics Data System (ADS)

    Steinert, Bastian; Perscheid, Michael; Beck, Martin; Lincke, Jens; Hirschfeld, Robert

    Enhancing and maintaining a complex software system requires detailed understanding of the underlying source code. Gaining this understanding by reading source code is difficult. Since software systems are inherently dynamic, it is complex and time consuming to imagine, for example, the effects of a method’s source code at run-time. The inspection of software systems during execution, as encouraged by debugging tools, contributes to source code comprehension. Leveraged by test cases as entry points, we want to make it easy for developers to experience selected execution paths in their code by debugging into examples. We show how links between test cases and application code can be established by means of dynamic analysis while executing regular tests.

  15. Elementary Youth: Prevention Resource Guide.

    ERIC Educational Resources Information Center

    Alcohol, Drug Abuse, and Mental Health Administration (DHHS/PHS), Rockville, MD. Office for Substance Abuse Prevention.

    This prevention resource guide (compiled from a variety of publications and data bases and representing the most currently available information) focuses on elementary youth, and is divided into four sections. The first section contains facts and figures from current research about substance abuse prevention for elementary youth. For example, one…

  16. Preventing Aim At An Undesired Target

    NASA Technical Reports Server (NTRS)

    Goodzeit, Neil E.

    1991-01-01

    Electronic system controls changes in orientation of optical instrument. Slew-control system includes avoidance-control logic, which overrides slew-control error generator when line of sight of instrument comes within cone of avoidance around line of sight to Sun. Normal slewing trajectory interrupted by avoidance-control logic, which computes actuator torques taking line of sight around cone of avoidance. Used to protect delicate photodetectors in servocontrolled infrared spectrometer or imaging instrument against damage occurring if instrument aimed at Sun or another excessively bright object.

  17. Efforts to Prevent Concussions Target Schools

    ERIC Educational Resources Information Center

    Samuels, Christina A.

    2010-01-01

    The number of sports-related concussions reported by young athletes is on the rise, prompting awareness campaigns from athletic and medical groups, as well as proposed federal legislation to set minimum standards for concussion management in public schools. Concussions are caused by a jolt to the body or a blow to the head that causes the head to…

  18. Targeted therapy using nanotechnology: focus on cancer

    PubMed Central

    Sanna, Vanna; Pala, Nicolino; Sechi, Mario

    2014-01-01

    Recent advances in nanotechnology and biotechnology have contributed to the development of engineered nanoscale materials as innovative prototypes to be used for biomedical applications and optimized therapy. Due to their unique features, including a large surface area, structural properties, and a long circulation time in blood compared with small molecules, a plethora of nanomaterials has been developed, with the potential to revolutionize the diagnosis and treatment of several diseases, in particular by improving the sensitivity and recognition ability of imaging contrast agents and by selectively directing bioactive agents to biological targets. Focusing on cancer, promising nanoprototypes have been designed to overcome the lack of specificity of conventional chemotherapeutic agents, as well as for early detection of precancerous and malignant lesions. However, several obstacles, including difficulty in achieving the optimal combination of physicochemical parameters for tumor targeting, evading particle clearance mechanisms, and controlling drug release, prevent the translation of nanomedicines into therapy. In spite of this, recent efforts have been focused on developing functionalized nanoparticles for delivery of therapeutic agents to specific molecular targets overexpressed on different cancer cells. In particular, the combination of targeted and controlled-release polymer nanotechnologies has resulted in a new programmable nanotherapeutic formulation of docetaxel, namely BIND-014, which recently entered Phase II clinical testing for patients with solid tumors. BIND-014 has been developed to overcome the limitations facing delivery of nanoparticles to many neoplasms, and represents a validated example of targeted nanosystems with the optimal biophysicochemical properties needed for successful tumor eradication. PMID:24531078

  19. Drowning Prevention

    MedlinePlus

    ... Listen Español Text Size Email Print Share Drowning Prevention: Information for Parents Page Content Article Body Drowning ... in very cold water for lengthy periods. Drowning Prevention: Know the Warning Signs These signs may signal ...

  20. Preventing Suicide

    MedlinePlus

    ... The top three methods used in suicides include firearms (49.9%), suffocation (26.7%), and poisoning (15. ... Content source: National Center for Injury Prevention and Control, Division of Violence Prevention Page maintained by: Office ...

  1. 3H-1,2-dithiole-3-thione targets nuclear factor kappaB to block expression of inducible nitric-oxide synthase, prevents hypotension, and improves survival in endotoxemic rats.

    PubMed

    Karuri, Asok R; Huang, Yong; Bodreddigari, Sridevi; Sutter, Carrie Hayes; Roebuck, Bill D; Kensler, Thomas W; Sutter, Thomas R

    2006-04-01

    Septicemia is a major cause of death associated with noncoronary intensive care. Systemic production of nitric oxide (NO) by inducible nitric-oxide synthase (iNOS) is a major cause of hypotension and poor organ perfusion seen in septic shock. Here, we show that pretreatment of F344 rats with the cancer chemoprotective agent 3H-1,2-dithiole-3-thione (D3T) blocks lipopolysaccharide (LPS)-mediated induction of hepatic iNOS and significantly reduces the associated serum levels of NO metabolites and enzyme markers of toxicity provoked by treatment with LPS. Immunohistochemical analysis shows that this protective effect is largely due to suppression of iNOS expression in hepatocytes. Importantly, pretreatment of animals with D3T blunts LPS-mediated hypotension and dramatically increases their survival. Inasmuch as iNOS expression can be regulated by nuclear factor (NF) kappaB, mechanistic studies show that D3T blocks NFkappaB nuclear translocation and DNA binding and that these effects are accompanied by changes in the levels of phospho-inhibitor of NFkappaB. In conclusion, this study identifies new drug classes and targets that may improve the prevention and treatment of septic shock, as well as chronic diseases associated with the NFkappaB and iNOS pathways.

  2. Between Individual Agency and Structure in HIV Prevention: Understanding the Middle Ground of Social Practice

    PubMed Central

    Kippax, Susan; Parker, Richard G.; Aggleton, Peter

    2013-01-01

    When HIV prevention targets risk and vulnerability, it focuses on individual agency and social structures, ignoring the centrality of community in effective HIV prevention. The neoliberal concept of risk assumes individuals are rational agents who act on information provided to them regarding HIV transmission. This individualistic framework does not recognize the communities in which people act and connect. The concept of vulnerability on the other hand acknowledges the social world, but mainly as social barriers that make it difficult for individuals to act. Neither approach to HIV prevention offers understanding of community practices or collective agency, both central to success in HIV prevention to date. Drawing on examples of the social transformation achieved by community action in Australia and Brazil, this article focuses on this middle ground and its role in effective HIV prevention. PMID:23763397

  3. CASP9 Target Classification

    PubMed Central

    Kinch, Lisa N.; Shi, Shuoyong; Cheng, Hua; Cong, Qian; Pei, Jimin; Mariani, Valerio; Schwede, Torsten; Grishin, Nick V.

    2011-01-01

    The Critical Assessment of Protein Structure Prediction round 9 (CASP9) aimed to evaluate predictions for 129 experimentally determined protein structures. To assess tertiary structure predictions, these target structures were divided into domain-based evaluation units that were then classified into two assessment categories: template based modeling (TBM) and template free modeling (FM). CASP9 targets were split into domains of structurally compact evolutionary modules. For the targets with more than one defined domain, the decision to split structures into domains for evaluation was based on server performance. Target domains were categorized based on their evolutionary relatedness to existing templates as well as their difficulty levels indicated by server performance. Those target domains with sequence-related templates and high server prediction performance were classified as TMB, while those targets without identifiable templates and low server performance were classified as FM. However, using these generalizations for classification resulted in a blurred boundary between CASP9 assessment categories. Thus, the FM category included those domains without sequence detectable templates (25 target domains) as well as some domains with difficult to detect templates whose predictions were as poor as those without templates (5 target domains). Several interesting examples are discussed, including targets with sequence related templates that exhibit unusual structural differences, targets with homologous or analogous structure templates that are not detectable by sequence, and targets with new folds. PMID:21997778

  4. Nanomaterials in preventive dentistry

    NASA Astrophysics Data System (ADS)

    Hannig, Matthias; Hannig, Christian

    2010-08-01

    The prevention of tooth decay and the treatment of lesions and cavities are ongoing challenges in dentistry. In recent years, biomimetic approaches have been used to develop nanomaterials for inclusion in a variety of oral health-care products. Examples include liquids and pastes that contain nano-apatites for biofilm management at the tooth surface, and products that contain nanomaterials for the remineralization of early submicrometre-sized enamel lesions. However, the treatment of larger visible cavities with nanomaterials is still at the research stage. Here, we review progress in the development of nanomaterials for different applications in preventive dentistry and research, including clinical trials.

  5. Examples of Ontology

    NASA Astrophysics Data System (ADS)

    Gaševic, Dragan; Djuric, Dragan; Devedžic, Vladan

    In the previous chapters we introduced the basic concepts of MOF-based languages for developing ontologies, such as the Ontology Definition Metamodel (ODM) and the Ontology UML Profile (OUP). We also discussed mappings between those languages and the OWL language. The purpose of this chapter is to illustrate the use of MOF-based languages for developing real-world ontologies. Here we discuss two different ontologies that we developed in different domains. The first example is a Petri net ontology that formalizes the representation of Petri nets, a well-known tool for modeling, simulation, and analysis of systems and processes. This Petri net ontology overcomes the syntactic constraints of the present XMLbased standard for sharing Petri net models, namely Petri Net Markup Language.

  6. HIV prevention in the Hispanic community: sex, culture, and empowerment.

    PubMed

    Marín, Barbara VanOss

    2003-07-01

    To address the serious HIV epidemic in the Hispanic community in the United States, the underlying causes of the epidemic must be addressed. Marginalization, including homophobia, poverty, and racism, as well as cultural factors such as machismo and sexual silence disempower people, making HIV prevention difficult. This article reviews evidence for the impact of marginalization and cultural factors on HIV risk and proposes a cycle of disempowerment. Three examples of empowerment interventions developed specifically for Hispanics (targeting heterosexuals, women, and gay men) are presented, and how these interventions address disempowerment is discussed. One intervention is used to illustrate principles of developing culturally appropriate interventions.

  7. Suicide and Its Prevention on College Campuses

    ERIC Educational Resources Information Center

    Keyes, Lee

    2012-01-01

    Suicide is a significant issue facing higher education institutions. Many campuses are involved in a variety of procedures, programs, and initiatives that seek to reduce or prevent suicide and the impact of suicide-related behavior. This article offers examples of campus prevention efforts, important resources on suicide prevention for college…

  8. Target Development for Radioactive Ion Beam Generation

    NASA Astrophysics Data System (ADS)

    Kronenberg, A.; Carter, H. K.; Stracener, D. W.; Bilheux, J. C.; Cizewski, J. A.; Koester, U.

    2004-10-01

    Development of ion beams of short-lived isotopes is crucial for modern nuclear structure and nuclear astrophysics. For example, ^82Ge,^130+xSn, ^92,94,95Sr beams are of interest but impurities and low intensities have prevented them from being useful. The code HSC-5 [1], with an extensive thermochemical database, predicts which chemical compounds may be transported within the target-ion source. The code also allows us to predict stability of target materials as function of temperature and pressure. So, a number of new targets have been fabricated and tested for use at the Holifield Radioactive Ion Beam Facility (HRIBF) at Oak Ridge National Laboratory, based on the ISOL technique. Recent results from off-line and on-line tests at HRIBF and CERN-ISOLDE will be presented. This research was sponsored by the NNSA under Stewardship Science Academic Alliance program through DOE Cooperative Agreement # DE-FC03-3NA00143. [1] HSC Chemistry for Windows - Chemical Reaction and Equilibrium Software with extensive Thermochemical Database, Outokumpu Research Oy, Pori, Finnland

  9. Target Development for Radioactive Ion Beam Generation

    NASA Astrophysics Data System (ADS)

    Kronenberg, A.; Carter, H. K.; Stracener, D.; Bilheux, J.; Cizewski, J. A.; Koester, U.

    2004-11-01

    Development of ion beams of short-lived isotopes is crucial for modern nuclear structure and nuclear astrophysics. For example, ^82Ge, ^130+xSn, ^92,94,95Sr beams are of interest but impurities and low intensities have prevented them from being useful. The code HSC-5 [1], with an extensive thermochemical database predicts which chemical compounds may be transported within the target-ion source. The code also allows us to predict stability of target materials as function of temperature and pressure. So, a number of new targets have been fabricated and tested for use at the Holifield Radioactive Ion Beam Facility (HRIBF) at Oak Ridge National Laboratory, based on the ISOL technique. Recent results from off-line and on-line tests at HRIBF and CERN-ISOLDE will be presented. This research was sponsored by the NNSA under Stewardship Science Academic Alliance program through DOE Cooperative Agreement # DE-FC03-3NA00143. [1] HSC Chemistry for Windows Chemical Reaction and Equilibrium Software with extensive Thermochemical Database, Outokumpu Research Oy, Pori, Finnland

  10. Example based lesion segmentation

    NASA Astrophysics Data System (ADS)

    Roy, Snehashis; He, Qing; Carass, Aaron; Jog, Amod; Cuzzocreo, Jennifer L.; Reich, Daniel S.; Prince, Jerry; Pham, Dzung

    2014-03-01

    Automatic and accurate detection of white matter lesions is a significant step toward understanding the progression of many diseases, like Alzheimer's disease or multiple sclerosis. Multi-modal MR images are often used to segment T2 white matter lesions that can represent regions of demyelination or ischemia. Some automated lesion segmentation methods describe the lesion intensities using generative models, and then classify the lesions with some combination of heuristics and cost minimization. In contrast, we propose a patch-based method, in which lesions are found using examples from an atlas containing multi-modal MR images and corresponding manual delineations of lesions. Patches from subject MR images are matched to patches from the atlas and lesion memberships are found based on patch similarity weights. We experiment on 43 subjects with MS, whose scans show various levels of lesion-load. We demonstrate significant improvement in Dice coefficient and total lesion volume compared to a state of the art model-based lesion segmentation method, indicating more accurate delineation of lesions.

  11. Example Based Lesion Segmentation

    PubMed Central

    Roy, Snehashis; He, Qing; Carass, Aaron; Jog, Amod; Cuzzocreo, Jennifer L.; Reich, Daniel S.; Prince, Jerry; Pham, Dzung

    2016-01-01

    Automatic and accurate detection of white matter lesions is a significant step toward understanding the progression of many diseases, like Alzheimer’s disease or multiple sclerosis. Multi-modal MR images are often used to segment T2 white matter lesions that can represent regions of demyelination or ischemia. Some automated lesion segmentation methods describe the lesion intensities using generative models, and then classify the lesions with some combination of heuristics and cost minimization. In contrast, we propose a patch-based method, in which lesions are found using examples from an atlas containing multi-modal MR images and corresponding manual delineations of lesions. Patches from subject MR images are matched to patches from the atlas and lesion memberships are found based on patch similarity weights. We experiment on 43 subjects with MS, whose scans show various levels of lesion-load. We demonstrate significant improvement in Dice coefficient and total lesion volume compared to a state of the art model-based lesion segmentation method, indicating more accurate delineation of lesions.

  12. Preventing Rejection

    MedlinePlus

    ... Drug Assistance Lifestyle Changes Back to Work or School Physical Changes Relationship Changes Pregnancy Precautions Fertility Labor & Delivery Breastfeeding Risks Cancer Types Risk Factors Prevention & Early Detection ...

  13. Prevention in developing countries.

    PubMed

    Black, R E

    1990-01-01

    Developing countries have implemented primary health care programs directed primarily at prevention and management of important infectious and nutritional problems of children. Successful programs have emphasized the need for individual and community involvement and have been characterized by responsible government policies for equitable implementation of efficacious and cost-effective health interventions. Unfortunately, developing countries must also face increases in the chronic disease and social problems commonly associated with industrialized countries. Prevention efforts, for example, to reduce tobacco smoking, to modify the diet, to reduce injuries, or to avert environmental contamination, are needed to contain future morbidity and rapidly increasing medical care costs. Developing countries can build on their successful approaches to program implementation and add other measures directed at preservation of health and prevention of disease in adult as well as child populations.

  14. Prevention of occupational asthma.

    PubMed

    Tarlo, Susan M; Liss, Gary M

    2010-07-01

    Prevention of occupational asthma related to a work-sensitizing agent ideally would be achieved by avoidance of exposures that cause immunologic sensitization and subsequent asthma. There are a few examples in which a sensitizing agent has been removed from a work process and others in which exposure has been significantly changed or reduced with associated reduced rates of sensitization and disease. Additional measures include containment, use of robots, ventilation measures, exposure monitoring, and use of respiratory protective devices. Secondary prevention includes medical surveillance, which may involve periodic respiratory questionnaires, spirometry, and immunologic tests aiming to detect sensitization or disease early to allow intervention and improve outcomes. Education measures for workers to understand the meaning of work-related respiratory symptoms and appropriate workplace safety measures have not been formally evaluated but may also be expected to enhance protective measures and lead to earlier diagnosis. Tertiary prevention includes medical management and workers' compensation.

  15. Mobile text messaging solutions for obesity prevention

    NASA Astrophysics Data System (ADS)

    Akopian, David; Jayaram, Varun; Aaleswara, Lakshmipathi; Esfahanian, Moosa; Mojica, Cynthia; Parra-Medina, Deborah; Kaghyan, Sahak

    2011-02-01

    Cellular telephony has become a bright example of co-evolution of human society and information technology. This trend has also been reflected in health care and health promotion projects which included cell phones in data collection and communication chain. While many successful projects have been realized, the review of phone-based data collection techniques reveals that the existing technologies do not completely address health promotion research needs. The paper presents approaches which close this gap by extending existing versatile platforms. The messaging systems are designed for a health-promotion research to prevent obesity and obesity-related health disparities among low-income Latino adolescent girls. Messaging and polling mechanisms are used to communicate and automatically process response data for the target constituency. Preliminary survey data provide an insight on phone availability and technology perception for the study group.

  16. Preventative Maintenance.

    ERIC Educational Resources Information Center

    Migliorino, James

    Boards of education must be convinced that spending money up front for preventive maintenance will, in the long run, save districts' tax dollars. A good program of preventive maintenance can minimize disruption of service; reduce repair costs, energy consumption, and overtime; improve labor productivity and system equipment reliability; handle…

  17. Preventive Medicine.

    ERIC Educational Resources Information Center

    Jozwiak, Dick

    1998-01-01

    Argues the importance of regularly inspecting thermoplastic roofs to avoid costly repairs. Preventive measures such as access restriction and the use of protective mats and pads to prevent third-party accidents are discussed as is the importance of checking for drain blockages. (GR)

  18. Targeting melanocortin receptors as potential novel therapeutics.

    PubMed

    Getting, Stephen J

    2006-07-01

    Adrenocorticotrophic hormone (ACTH(1-39)) and the melanocortins (alpha, beta and gamma-melanocyte-stimulating hormone [MSH]) are derived from a larger precursor molecule known as the pro-opiomelanocortin (POMC) protein. They exert their numerous biological effects by activating 7 transmembrane G-protein coupled receptors (GPCR), leading to adenylyl cyclase activation and subsequent cAMP accumulation within the target cell. To date, 5 melanocortin receptors (MCR) have been identified and termed MC1R to MC5R, they have been shown to have a wide and varied distribution throughout the body, being found in the central nervous system (CNS), periphery and immune cells. Melanocortins have a multitude of actions including: (i) modulating disease pathologies including arthritis, asthma, obesity; (ii) affecting functions, for example erectile dysfunction, skin tanning; and (iii) organ systems, for example cardiovascular system. Recently a mechanistic approach has been identified with alpha-MSH preventing NF-kappaB activation via the preservation and expression of IkappaBalphaprotein. This leads to a reduction of pro-inflammatory mediators including cytokines and inhibition of adhesion molecule expression, with subsequent reduction in leukocyte emigration. Development of selective ligands with an appropriate pharmacokinetic profile will enable a pharmacological evaluation of the potential beneficial effects of the melanocortins. In this review I have discussed the potential mechanistic action for the melanocortins and some of the disease pathologies shown to be modulated. This review proposes targeting the MCR with the ultimate aim of controlling many of the diseases that we face today.

  19. Detection and identification of human targets in radar data

    NASA Astrophysics Data System (ADS)

    Gürbüz, Sevgi Z.; Melvin, William L.; Williams, Douglas B.

    2007-04-01

    Radar offers unique advantages over other sensors, such as visual or seismic sensors, for human target detection. Many situations, especially military applications, prevent the placement of video cameras or implantment seismic sensors in the area being observed, because of security or other threats. However, radar can operate far away from potential targets, and functions during daytime as well as nighttime, in virtually all weather conditions. In this paper, we examine the problem of human target detection and identification using single-channel, airborne, synthetic aperture radar (SAR). Human targets are differentiated from other detected slow-moving targets by analyzing the spectrogram of each potential target. Human spectrograms are unique, and can be used not just to identify targets as human, but also to determine features about the human target being observed, such as size, gender, action, and speed. A 12-point human model, together with kinematic equations of motion for each body part, is used to calculate the expected target return and spectrogram. A MATLAB simulation environment is developed including ground clutter, human and non-human targets for the testing of spectrogram-based detection and identification algorithms. Simulations show that spectrograms have some ability to detect and identify human targets in low noise. An example gender discrimination system correctly detected 83.97% of males and 91.11% of females. The problems and limitations of spectrogram-based methods in high clutter environments are discussed. The SNR loss inherent to spectrogram-based methods is quantified. An alternate detection and identification method that will be used as a basis for future work is proposed.

  20. The power of example

    NASA Astrophysics Data System (ADS)

    Liliana Gheorghian, Mariana

    2014-05-01

    beginning of the XXI century" with the participation of several schools in the country in 2009 and 2011. The papers presented were diverse and gave examples of various teaching experiences and scientific information. Topics by the teachers: The impact of tourism on the environment, Tornadoes, Natural science and environmental education in school, Air Pollution and health, Ecological education of children from primary school, The effects of electromagnetic radiation, Formation of an ecological mentality using chemistry, Why should we protect water, Environmental education, Education for the future, SOS Nature, Science in the twenty-first century, etc. Topics by students: Nature- the palace of thermal phenomena, Life depends on heat, Water Mysteries, Global Heating, The Mysterious universe, etc. In March 2013 our school hosted an interesting exchange of ideas on environmental issues between our students and those from Bulgaria, Poland and Turkey, during a symposium of the Comenius multilateral project "Conserving Nature". In order to present the results of protecting nature in their communities, two projects "Citizen" qualified in the Program Civitas in the autumn of 2013. "The Battle" continues both in nature and in classrooms, in order to preserve the environment.

  1. Gene targeting in livestock.

    PubMed

    Thomson, A J; Marques, M M; McWhir, J

    2003-01-01

    The development of nuclear transfer from tissue culture cells in livestock made it possible in principle to produce animals with subtle, directed genetic changes by in vitro modification of nuclear donor cells. In the short period since nuclear transfer was first performed, gene targeting in livestock has become a reality. Although gene targeting has immediate potential in biotechnology, it is unclear whether there are practical agricultural applications, at present. The first livestock targeting experiments have been directed at engineering animals either to render their organs immunologically compatible for human transplantation, or for improving the commercial production of recombinant proteins in the transgenic mammary gland. All successful examples of targeting have involved target loci that are expressed in the nuclear donor cell line. Two important barriers to the further development of this technology are adapting protocols for non-expressed genes and modifying procedures to enhance the lifespan of targeted cells in vitro. This review provides data that illustrate the difficulty in targeting non-expressed genes and discusses some of the practical issues associated with providing targeted nuclear donor cells that are competent for nuclear transfer.

  2. Sputter target

    DOEpatents

    Gates, Willard G.; Hale, Gerald J.

    1980-01-01

    The disclosure relates to an improved sputter target for use in the deposition of hard coatings. An exemplary target is given wherein titanium diboride is brazed to a tantalum backing plate using a gold-palladium-nickel braze alloy.

  3. Child Sexual Abuse: Prevention or Promotion?

    ERIC Educational Resources Information Center

    Bolen, Rebecca M.

    2003-01-01

    Current child sexual abuse prevention programs assume that, by targeting potential victims, they can reduce the prevalence of child sexual abuse. This article presents findings that suggest this assumption is flawed. Suggests instead that potential offenders are more appropriate targets of prevention programs. (Contains 39 references.)

  4. Multiple shell fusion targets

    DOEpatents

    Lindl, J.D.; Bangerter, R.O.

    1975-10-31

    Multiple shell fusion targets for use with electron beam and ion beam implosion systems are described. The multiple shell targets are of the low-power type and use a separate relatively low Z, low density ablator at large radius for the outer shell, which reduces the focusing and power requirements of the implosion system while maintaining reasonable aspect ratios. The targets use a high Z, high density pusher shell placed at a much smaller radius in order to obtain an aspect ratio small enough to protect against fluid instability. Velocity multiplication between these shells further lowers the power requirements. Careful tuning of the power profile and intershell density results in a low entropy implosion which allows breakeven at low powers. For example, with ion beams as a power source, breakeven at 10-20 Terrawatts with 10 MeV alpha particles for imploding a multiple shell target can be accomplished.

  5. Systems and methods for processing irradiation targets through a nuclear reactor

    DOEpatents

    Dayal, Yogeshwar; Saito, Earl F.; Berger, John F.; Brittingham, Martin W.; Morales, Stephen K.; Hare, Jeffrey M.

    2016-05-03

    Apparatuses and methods produce radioisotopes in instrumentation tubes of operating commercial nuclear reactors. Irradiation targets may be inserted and removed from instrumentation tubes during operation and converted to radioisotopes otherwise unavailable during operation of commercial nuclear reactors. Example apparatuses may continuously insert, remove, and store irradiation targets to be converted to useable radioisotopes or other desired materials at several different origin and termination points accessible outside an access barrier such as a containment building, drywell wall, or other access restriction preventing access to instrumentation tubes during operation of the nuclear plant.

  6. Preventing falls

    MedlinePlus

    Dalbaere K, Sherrington C, Lord SR. Falls prevention interventions. In: Marchus R, Feldman D, Depmster DW, Luckey M, Cauley JA, eds. Osteoporosis . 4th ed. Philadelphia, PA: Elsevier; 2013:chap 70. Rubenstein ...

  7. Dengue Prevention

    MedlinePlus

    ... Compartir This photograph shows a mother applying mosquito repellent to her child's skin in order to prevent ... the lights are on. To protect yourself, use repellent on your skin while indoors or out. When ...

  8. MTH1 Substrate Recognition--An Example of Specific Promiscuity.

    PubMed

    Nissink, J Willem M; Bista, Michal; Breed, Jason; Carter, Nikki; Embrey, Kevin; Read, Jonathan; Winter-Holt, Jon J

    2016-01-01

    MTH1 (NUDT1) is an oncologic target involved in the prevention of DNA damage. We investigate the way MTH1 recognises its substrates and present substrate-bound structures of MTH1 for 8-oxo-dGTP and 8-oxo-rATP as examples of novel strong and weak binding substrate motifs. Investigation of a small set of purine-like fragments using 2D NMR resulted in identification of a fragment with weak potency. The protein-ligand X-Ray structure of this fragment provides insight into the role of water molecules in substrate selectivity. Wider fragment screening by NMR resulted in three new protein structures exhibiting alternative binding configurations to the key Asp-Asp recognition element of the protein. These inhibitor binding modes demonstrate that MTH1 employs an intricate yet promiscuous mechanism of substrate anchoring through its Asp-Asp pharmacophore. The structures suggest that water-mediated interactions convey selectivity towards oxidized substrates over their non-oxidised counterparts, in particular by stabilization of a water molecule in a hydrophobic environment through hydrogen bonding. These findings may be useful in the design of inhibitors of MTH1. PMID:26999531

  9. MTH1 Substrate Recognition—An Example of Specific Promiscuity

    PubMed Central

    Nissink, J. Willem M.; Bista, Michal; Breed, Jason; Carter, Nikki; Embrey, Kevin; Read, Jonathan; Winter-Holt, Jon J.

    2016-01-01

    MTH1 (NUDT1) is an oncologic target involved in the prevention of DNA damage. We investigate the way MTH1 recognises its substrates and present substrate-bound structures of MTH1 for 8-oxo-dGTP and 8-oxo-rATP as examples of novel strong and weak binding substrate motifs. Investigation of a small set of purine-like fragments using 2D NMR resulted in identification of a fragment with weak potency. The protein-ligand X-Ray structure of this fragment provides insight into the role of water molecules in substrate selectivity. Wider fragment screening by NMR resulted in three new protein structures exhibiting alternative binding configurations to the key Asp-Asp recognition element of the protein. These inhibitor binding modes demonstrate that MTH1 employs an intricate yet promiscuous mechanism of substrate anchoring through its Asp-Asp pharmacophore. The structures suggest that water-mediated interactions convey selectivity towards oxidized substrates over their non-oxidised counterparts, in particular by stabilization of a water molecule in a hydrophobic environment through hydrogen bonding. These findings may be useful in the design of inhibitors of MTH1. PMID:26999531

  10. Foam encapsulated targets

    DOEpatents

    Nuckolls, John H.; Thiessen, Albert R.; Dahlbacka, Glen H.

    1983-01-01

    Foam encapsulated laser-fusion targets wherein a quantity of thermonuclear fuel is embedded in low density, microcellular foam which serves as an electron conduction channel for symmetrical implosion of the fuel by illumination of the target by one or more laser beams. The fuel, such as DT, is contained within a hollow shell constructed of glass, for example, with the foam having a cell size of preferably no greater than 2 .mu.m, a density of 0.065 to 0.6.times.10.sup.3 kg/m.sup.3, and external diameter of less than 200 .mu.m.

  11. The prevention of psychopathology in African Americans: an epidemiologic perspective.

    PubMed

    Neighbors, H W

    1990-04-01

    Although improving the mental health status of African Americans is an important goal, it is not clear that this can be accomplished by increasing access to professional services. Many have argued that stressful social conditions are the major cause of mental disorder in blacks and thus, psychopathology can be prevented by eliminating racism, oppression and poor economic conditions. This review argues that while the notion of primary prevention with African Americans should be taken seriously, there is still a need for more and better epidemiologic research. Three bodies of knowledge relevant to black mental health are addressed: 1) the need for an epidemiologic knowledge base for prevention; 2) coping capacity and vulnerability to stress; 3) risk factor identification. Findings from a national survey of adult African Americans are presented as an example of risk factor identification for the purpose of specifying targets for preventive interventions. The paper concludes that before the prevention of psychopathology in black populations can be achieved, a number of measurement, theoretical and policy issues must be addressed. Specific directions for future research are outlined.

  12. Integrin Targeted Therapeutics

    PubMed Central

    Millard, Melissa; Odde, Srinivas; Neamati, Nouri

    2011-01-01

    Integrins are heterodimeric, transmembrane receptors that function as mechanosensors, adhesion molecules and signal transduction platforms in a multitude of biological processes. As such, integrins are central to the etiology and pathology of many disease states. Therefore, pharmacological inhibition of integrins is of great interest for the treatment and prevention of disease. In the last two decades several integrin-targeted drugs have made their way into clinical use, many others are in clinical trials and still more are showing promise as they advance through preclinical development. Herein, this review examines and evaluates the various drugs and compounds targeting integrins and the disease states in which they are implicated. PMID:21547158

  13. Preventive Care in Women's Health.

    PubMed

    Blanchard, Anita K; Goodall, Perpetua

    2016-06-01

    Specialists in general obstetrics and gynecology are key providers of primary care in women. They diagnose and provide the initial management of many medical conditions unrelated to reproductive health. Most importantly they can impact the overall health of patients through incorporating preventive approaches in the annual well-woman visit. This article defines preventive care and identifies leading causes of mortality in women. A framework for identifying key elements of the well-woman examination is summarized. Examples of prevention are provided, which focus on major health care issues that affect adult women. PMID:27212087

  14. Asthma: NHLBI Workshop on the Primary Prevention of Chronic Lung Diseases

    PubMed Central

    Hartert, Tina V.; Martinez, Fernando D.; Weiss, Scott T.; Fahy, John V.

    2014-01-01

    Asthma is a common disease with enormous public health costs, and its primary prevention is an ambitious and important goal. Understanding of how host and environmental factors interact to cause asthma is incomplete, but persistent questions about mechanisms should not stop clinical research efforts aimed at reducing the prevalence of childhood asthma. Achieving the goal of primary prevention of asthma will involve integrated and parallel sets of research activities in which mechanism-oriented studies of asthma inception proceed alongside clinical intervention studies to test biologically plausible prevention ideas. For example, continued research is needed, particularly in young children, to uncover biomarkers that identify asthma risk and provide potential targets of intervention, and to improve understanding of the role of microbial factors in asthma risk and disease initiation. In terms of clinical trials that could be initiated now or in the near future, we recommend three interventions for testing: (1) preventing asthma through prophylaxis against respiratory syncytial virus and human rhinovirus infections of the airway; (2) immune modulation, using prebiotics, probiotics, and bacterial lysates; and (3) prevention of allergen sensitization and allergic inflammation, using anti-IgE. These interventions should be tested while other, more universal prevention measures that may promote lung health are also investigated. These potential universal lung health measures include prevention of preterm delivery; reduced exposure of the fetus and young infant to environmental pollutants, including tobacco smoke; prevention of maternal and child obesity; and management of psychosocial stress. PMID:24754822

  15. Targeted therapy in head and neck cancer.

    PubMed

    Ward, Brent B

    2013-02-01

    The desire to target therapies to specific cancers while leaving the host unharmed remains an ongoing quest for scientists, surgeons, radiation oncologists, and medical oncologists. In recent years, great scientific progress has been made in targeted therapies. Although many modalities remain in preclinical validation, some advances affect patient care today. This article summarizes the concepts of targeting and explores current examples of successful targeting and emerging targeting technologies in head and neck oncology. PMID:23399398

  16. Some Examples of Trapped Surfaces

    NASA Astrophysics Data System (ADS)

    Bengtsson, Ingemar

    2013-03-01

    We present some simple pen and paper examples of trapped surfaces in order to help in visualising this key concept of the theory of gravitational collapse. We collect these examples from time-symmetric initial data, 2+1 dimensions, collapsing null shells, and the Vaidya solution.

  17. Rent Seeking: A Textbook Example

    ERIC Educational Resources Information Center

    Pecorino, Paul

    2007-01-01

    The author argues that the college textbook market provides a clear example of monopoly seeking as described by Tullock (1967, 1980). This behavior is also known as rent seeking. Because this market is important to students, this example of rent seeking will be of particular interest to them. (Contains 24 notes.)

  18. Constructing Programs from Example Computations.

    ERIC Educational Resources Information Center

    Bierman, A. W.; Krishnaswamy, R.

    This paper describes the construction and implementation of an autoprogramming system. An autoprogrammer is an interactive computer programming system which automatically constructs computer programs from example computations executed by the user. The example calculations are done in a scratch pad fashion at a computer display, and the system…

  19. Phase 0/I/II Cancer Prevention Clinical Trials Program (Consortia) | Division of Cancer Prevention

    Cancer.gov

    Five cancer research centers lead multiple collaborative networks to assess potential cancer preventive agents and to conduct early clinical development of promising preventive agents. Also called the Consortia for Early Phase Prevention Trials, the studies require extensive biomarker analysis, investigation of the biologic effects of the cancer preventive agents on their intended molecular targets and on multiple endpoints associated with carcinogenesis, and correlation with clinically relevant endpoints.  | Systematic early clinical development of promising preventive agents through five major medical research centers.

  20. Thinking About Preventing Nuclear War.

    ERIC Educational Resources Information Center

    Ground Zero, Washington, DC.

    Potential paths to nuclear war and the available means of prevention of nuclear war are discussed. Presented is a detailed description of six nuclear war scenarios, and brief examples of types of potential deterrents to nuclear war (firebreaks) which are relevant for each. To be effective, the right combination of firebreaks must be used, the…

  1. Preventing Tragedy.

    ERIC Educational Resources Information Center

    One Feather, Sandra

    2003-01-01

    The Navajo supervisor in the Office of Environmental Health in New Mexico identifies diseases and their risk factors, administers an injury prevention program, and ensures compliance with various health-related codes. She assists in the planning and direction of environmental health programs and public health education for local Navajo…

  2. Poison Prevention

    MedlinePlus

    ... Word Shop AAP Find a Pediatrician Safety & Prevention ... Content Article Body Post the Poison Help number 1-800-222-1222 on the emergency list next to every phone in your home and in your cell phone. A toddler or preschooler who vomits may ...

  3. Bullying Prevention

    ERIC Educational Resources Information Center

    Kemp, Patrice

    2016-01-01

    The focus of the milestone project is to focus on bridging the gap of bullying and classroom instruction methods. There has to be a defined expectations and level of accountability that has to be defined when supporting and implementing a plan linked to bullying prevention. All individuals involved in the student's learning have to be aware of…

  4. Magnetized Target Fusion collaboration

    NASA Astrophysics Data System (ADS)

    Intrator, Thomas

    2004-11-01

    Magnetized Target Fusion (MTF) may be a low cost path to fusion, in a regime that is intermediate between magnetic and inertial fusion energy. It requires compression of a magnetized target plasma and consequent heating to fusion relevant conditions inside a converging flux conserver. We hope to demonstrate the physics basis for MTF, with a Field Reversed Configuration (FRC) target plasma to be translated axially to a compression region. We show recent and improved FRC formation data, example deformable liner implosions, and a conceptual design for the upcoming translation experiments, and describe a multi institution collaboration. The FRC is an elongated, compact toroid equilibrium that is extreme among magnetic configurations, and relaxed to a non force free state. There is high plasma beta, small toroidal field, cross-field diamagnetic current and flows, vanishing rotational transform, magnetic shear, helicity and anomalously large resistivity. Scientific issues include MTF with and without FRC's, and fundamental plasma physics beyond MHD, relevant to geophysical and astrophysical phenomena.

  5. LIQUID TARGET

    DOEpatents

    Martin, M.D.; Salsig, W.W. Jr.

    1959-01-13

    A liquid handling apparatus is presented for a liquid material which is to be irradiated. The apparatus consists essentially of a reservoir for the liquid, a target element, a drain tank and a drain lock chamber. The target is in the form of a looped tube, the upper end of which is adapted to be disposed in a beam of atomic particles. The lower end of the target tube is in communication with the liquid in the reservoir and a means is provided to continuously circulate the liquid material to be irradiated through the target tube. Means to heat the reservoir tank is provided in the event that a metal is to be used as the target material. The apparatus is provided with suitable valves and shielding to provide maximum safety in operation.

  6. More examples of chimpanzees teaching.

    PubMed

    Scheel, Matthew H; Shaw, Heidi L; Gardner, R Allen

    2015-01-01

    Darwinism is a principle of biological continuity. This commentary argues against any claim of discontinuity between humans and other animals that must be based on absence of evidence. Instead, we offer additional examples of active teaching by chimpanzees.

  7. Magnetic Resonance Image Example Based Contrast Synthesis

    PubMed Central

    Roy, Snehashis; Carass, Aaron; Prince, Jerry L.

    2013-01-01

    The performance of image analysis algorithms applied to magnetic resonance images is strongly influenced by the pulse sequences used to acquire the images. Algorithms are typically optimized for a targeted tissue contrast obtained from a particular implementation of a pulse sequence on a specific scanner. There are many practical situations, including multi-institution trials, rapid emergency scans, and scientific use of historical data, where the images are not acquired according to an optimal protocol or the desired tissue contrast is entirely missing. This paper introduces an image restoration technique that recovers images with both the desired tissue contrast and a normalized intensity profile. This is done using patches in the acquired images and an atlas containing patches of the acquired and desired tissue contrasts. The method is an example-based approach relying on sparse reconstruction from image patches. Its performance in demonstrated using several examples, including image intensity normalization, missing tissue contrast recovery, automatic segmentation, and multimodal registration. These examples demonstrate potential practical uses and also illustrate limitations of our approach. PMID:24058022

  8. Teen Pregnancy Prevention. A Legislator's Guide.

    ERIC Educational Resources Information Center

    Guiden, Mary

    This publication presents an overview of adolescent pregnancy, including national and state statistical information; funding sources for teen pregnancy prevention programs; examples of the effects of teen pregnancy prevention on society; illustrations of teenagers' perspectives on the issue; recent developments and initiatives in the arena of teen…

  9. Underage Drinking: Information on Federal Funds Targeted at Prevention. Report to the Chairman, Subcommittee on Criminal Justice, Drug Policy, and Human Resources, House Committee on Government Reform, and to Representative John L. Mica.

    ERIC Educational Resources Information Center

    Stana, Richard M.

    This document describes a project undertaken to identify the nature and extent of Federal efforts related to the prevention of underage drinking to assist Congress in its deliberations on whether additional attention to alcohol use is needed. The report specifically aims to identify the amount of appropriated fiscal year 2000 Federal funds that…

  10. Preeclampsia prevention

    PubMed Central

    Herrera-Medina, Rodolfo; Pineda, Lucia M

    2015-01-01

    Background: Preeclampsia is the main complication of pregnancy in developing countries. Calcium starting at 14 weeks of pregnancy is indicated to prevent the disease. Recent advances in prevention of preeclampsia endorse the addition of conjugated linoleic acid. Objective: To estimate the protective effect from calcium alone, compared to calcium plus conjugated linoleic acid in nulliparous women at risk of preeclampsia. Methods: A case-control design nested in the cohort of nulliparous women attending antenatal care from 2010 to 2014. The clinical histories of 387 cases of preeclampsia were compared with 1,054 normotensive controls. The exposure was prescriptions for calcium alone, the first period, or calcium plus conjugated linoleic acid, the second period, from 12 to 16 weeks of gestational age to labor. Confounding variables were controlled, allowing only nulliparous women into the study and stratifying by age, education and ethnic group. Results: The average age was 26.4 yrs old (range= 13-45), 85% from mixed ethnic backgrounds and with high school education. There were no differences between women who received calcium carbonate and those who did not (OR= 0.96; 95% CI= 0.73-1.27). The group of adolescents (13 to 18 years old) in the calcium plus conjugated linoleic acid was protected for preeclampsia (OR= 0.00; 95% CI= 0.00-0.44) independent of the confounder variables. Conclusions: 1. Calcium supplementation during pregnancy did not have preventive effects on preeclampsia. 2. Calcium plus Conjugated Linoleic acid provided to adolescents was observed to have preventive effect on Preeclampsia. PMID:26848195

  11. Tamoxifen for breast cancer prevention

    SciTech Connect

    Jordan, V.C.

    1995-02-01

    The case for tamoxifen to be tested as a preventive for breast cancer has merit. Animal studies demonstrate that tamoxifen prevents mammary carcinogenesis and clinical studies now confirm that adjuvant tamoxifen therapy is the only systemic treatment that will prevent contralateral breast cancer. Developing clinical studies confirm the laboratory data that tamoxifen will maintain post-menopausal bone density in the lumbar spine and the neck of the femur; two important skeletal sites for the ultimate prevention of osteoporosis. However, a most important target site-specific effect of tamoxifen is the decrease in low-density lipoprotein cholesterol levels in postmenopausal women. This positive property of tamoxifen may be responsible for the recorded decreases in hospital visits for the treatment of cardiac conditions and the significant decrease in fatal myocardial infarction for women treated with 5 years of adjuvant tamoxifen. These data provide the scientific basis to undertake randomized, placebocontrolled clinical trials to test the worth of tamoxifen to prevent breast cancer.

  12. Prevention of suicidal behavior

    PubMed Central

    Hegerl, Ulrich

    2016-01-01

    More than 800 000 people die every year from suicide, and about 20 times more attempt suicide. In most countries, suicide risk is highest in older males, and risk of attempted suicide is highest in younger females. The higher lethal level of suicidal acts in males is explained by the preference for more lethal methods, as well as other factors. In the vast majority of cases, suicidal behavior occurs in the context of psychiatric disorders, depression being the most important one. Improving the treatment of depression, restricting access to lethal means, and avoiding the Werther effect (imitation suicide) are central aspects of suicide prevention programs. In several European regions, the four-level intervention concept of the European Alliance Against Depression (www.EAAD.net), simultaneously targeting depression and suicidal behavior, has been found to have preventive effects on suicidal behavior. It has already been implemented in more than 100 regions in Europe. PMID:27489458

  13. Prevention of suicidal behavior.

    PubMed

    Hegerl, Ulrich

    2016-06-01

    More than 800 000 people die every year from suicide, and about 20 times more attempt suicide. In most countries, suicide risk is highest in older males, and risk of attempted suicide is highest in younger females. The higher lethal level of suicidal acts in males is explained by the preference for more lethal methods, as well as other factors. In the vast majority of cases, suicidal behavior occurs in the context of psychiatric disorders, depression being the most important one. Improving the treatment of depression, restricting access to lethal means, and avoiding the Werther effect (imitation suicide) are central aspects of suicide prevention programs. In several European regions, the four-level intervention concept of the European Alliance Against Depression (www.EAAD.net), simultaneously targeting depression and suicidal behavior, has been found to have preventive effects on suicidal behavior. It has already been implemented in more than 100 regions in Europe.

  14. Annual Advances in Cancer Prevention Lecture | Division of Cancer Prevention

    Cancer.gov

    2016 Keynote Lecture Polyvalent Vaccines Targeting Oncogenic Driver Pathways A special keynote lecture became part of the NCI Summer Curriculum in Cancer Prevention in 2000. This lecture will be held on Thursday, July 21, 2016 at 1:30pm at Masur Auditorium, Building 10, NIH Main Campus, Bethesda, MD. This year’s keynote speaker is Dr. Mary L. (Nora) Disis, MD. |

  15. Vaccines to prevent leishmaniasis

    PubMed Central

    Kumar, Rajiv; Engwerda, Christian

    2014-01-01

    Leishmaniasis is a parasitic disease that encompasses a range of clinical manifestations affecting people in tropical and subtropical regions of the world. Epidemiological and experimental data indicate that protection from disease can be achieved in most people. In addition, we know how the host immune system must respond to infection in order to control parasite growth. However, there is still no vaccine for use in humans. Here, we review our understanding of host immunity following Leishmania infection and also discuss recent advances in the development of vaccines to prevent leishmaniasis, highlighting a new promising approach that targets the parasite hemoglobin receptor. PMID:25505961

  16. [Epidemiological examples of infectious disease spread].

    PubMed

    Schlüter, H; Kramer, M

    2001-08-01

    The globalisation of trade with animals and animal products and increase of travel transports are very important issues with respect to prevent and control animal diseases or epizootics respectively. The disease control concepts as a complex manner should be established on scientific basis and must be permanently evaluated and updated. Outbreak investigations in order to clarify the source of infection and/or the spread of animal diseases including zoonoses are important fields of activities of veterinary epidemiologists. The application of modern epidemiological methods is the precondition of a successful disease control. On selected examples of animal diseases, the use of these methods is demonstrated. It is urgently necessary to intensify the epidemiological work in applied research and practice.

  17. Targets and processes for fabricating same

    DOEpatents

    Cowan, Thomas; Malekos, Steven; Korgan, Grant; Adams, Jesse; Sentoku, Yasuhiko; Le Galloudec, Nathalie; Fuchs, Julien

    2012-07-24

    In particular embodiments, the present disclosure provides targets including a metal layer and defining a hollow inner surface. The hollow inner surface has an internal apex. The distance between at least two opposing points of the internal apex is less than about 15 .mu.m. In particular examples, the distance is less than about 1 .mu.m. Particular implementations of the targets are free standing. The targets have a number of disclosed shaped, including cones, pyramids, hemispheres, and capped structures. The present disclosure also provides arrays of such targets. Also provided are methods of forming targets, such as the disclosed targets, using lithographic techniques, such as photolithographic techniques. In particular examples, a target mold is formed from a silicon wafer and then one or more sides of the mold are coated with a target material, such as one or more metals.

  18. Targets and processes for fabricating same

    DOEpatents

    Cowna, Thomas; Malekos, Steven; Korgan, Grant; Adams, Jesse; Sentoku, Yasuhiko; LeGalloudec, Nathalie

    2014-06-10

    In particular embodiments, the present disclosure provides targets including a metal layer and defining a hollow inner surface. The hollow inner surface has an internal apex. The distance between at least two opposing points of the internal apex is less than about 15 .mu.m. In particular examples, the distance is less than about 1 .mu.m. Particular implementations of the targets are free standing. The targets have a number of disclosed shaped, including cones, pyramids, hemispheres, and capped structures. The present disclosure also provides arrays of such targets. Also provided are methods of forming targets, such as the disclosed targets, using lithographic techniques, such as photolithographic techniques. In particular examples, a target mold is formed from a silicon wafer and then one or more sides of the mold are coated with a target material, such as one or more metals.

  19. Targets and processes for fabricating same

    DOEpatents

    Adams, Jesse D; Malekos, Steven; Le Galloudec, Nathalie; Korgan, Grant; Cowan, Thomas; Sentoku, Yasuhiko

    2016-05-17

    In particular embodiments, the present disclosure provides targets including a metal layer and defining a hollow inner surface. The hollow inner surface has an internal apex. The distance between at least two opposing points of the internal apex is less than about 15 .mu.m. In particular examples, the distance is less than about 1 .mu.m. Particular implementations of the targets are free standing. The targets have a number of disclosed shaped, including cones, pyramids, hemispheres, and capped structures. The present disclosure also provides arrays of such targets. Also provided are methods of forming targets, such as the disclosed targets, using lithographic techniques, such as photolithographic techniques. In particular examples, a target mold is formed from a silicon wafer and then one or more sides of the mold are coated with a target material, such as one or more metals.

  20. Preventing HIV transmission in "priority" countries.

    PubMed

    Finger, W R

    1993-05-01

    A recent $168 million 5-year cooperative agreement funded by the US Agency for International Development combines elements of its earlier AIDSTECH and AIDSCOM projects under the AIDS Control and Prevention Project (AIDSCAP). Instead of working to effect broad-scale behavior change toward the prevention of HIV transmission, AIDSCAP strategically targets locations for condom distribution, behavior change messages, and the treatment of sexually transmitted diseases. In Lagos and the states of Cross River and Jigawa where the AIDS epidemic is firmly established, for example, AIDSCAP is intervening to increase condom demand and accessibility; alter sexual behaviors which carry a high risk for HIV transmission; and reduce the prevalence of STDs which enhance the transmission of HIV. The project began in fall of 1991 and has expanded to include Ethiopia, Kenya, Malawi, Nigeria, Rwanda, Senegal, Brazil, Haiti, Jamaica, India, and Thailand; limited assistance is also provided to 7 other African countries, 4 Latin America countries, and 1 in Asia. 4 more countries are in the final stages of negotiations to be included in the project. The USAID mission in the host country and the government must invite AIDSCAP involvement in order for the country to attain priority status. Countries are selected based on the HIV prevalence rate, population size and distribution, level of commitment to HIV prevention/control, capacity to respond to the AIDSCAP plan of action, level of other donor support, the USAID Mission's development priorities, and the Mission's commitment of substantial funds from its own budget. Once involved, AIDSCAP is mandated to implement interventions through in-country agencies. PMID:12344871

  1. Targeted assets risk analysis.

    PubMed

    Bouwsema, Barry

    2013-01-01

    Risk assessments utilising the consolidated risk assessment process as described by Public Safety Canada and the Centre for Security Science utilise the five threat categories of natural, human accidental, technological, human intentional and chemical, biological, radiological, nuclear or explosive (CBRNE). The categories of human intentional and CBRNE indicate intended actions against specific targets. It is therefore necessary to be able to identify which pieces of critical infrastructure represent the likely targets of individuals with malicious intent. Using the consolidated risk assessment process and the target capabilities list, coupled with the CARVER methodology and a security vulnerability analysis, it is possible to identify these targeted assets and their weaknesses. This process can help emergency managers to identify where resources should be allocated and funding spent. Targeted Assets Risk Analysis (TARA) presents a new opportunity to improve how risk is measured, monitored, managed and minimised through the four phases of emergency management, namely, prevention, preparation, response and recovery. To reduce risk throughout Canada, Defence Research and Development Canada is interested in researching the potential benefits of a comprehensive approach to risk assessment and management. The TARA provides a framework against which potential human intentional threats can be measured and quantified, thereby improving safety for all Canadians.

  2. Targeted assets risk analysis.

    PubMed

    Bouwsema, Barry

    2013-01-01

    Risk assessments utilising the consolidated risk assessment process as described by Public Safety Canada and the Centre for Security Science utilise the five threat categories of natural, human accidental, technological, human intentional and chemical, biological, radiological, nuclear or explosive (CBRNE). The categories of human intentional and CBRNE indicate intended actions against specific targets. It is therefore necessary to be able to identify which pieces of critical infrastructure represent the likely targets of individuals with malicious intent. Using the consolidated risk assessment process and the target capabilities list, coupled with the CARVER methodology and a security vulnerability analysis, it is possible to identify these targeted assets and their weaknesses. This process can help emergency managers to identify where resources should be allocated and funding spent. Targeted Assets Risk Analysis (TARA) presents a new opportunity to improve how risk is measured, monitored, managed and minimised through the four phases of emergency management, namely, prevention, preparation, response and recovery. To reduce risk throughout Canada, Defence Research and Development Canada is interested in researching the potential benefits of a comprehensive approach to risk assessment and management. The TARA provides a framework against which potential human intentional threats can be measured and quantified, thereby improving safety for all Canadians. PMID:23615063

  3. Fundamental Travel Demand Model Example

    NASA Technical Reports Server (NTRS)

    Hanssen, Joel

    2010-01-01

    Instances of transportation models are abundant and detailed "how to" instruction is available in the form of transportation software help documentation. The purpose of this paper is to look at the fundamental inputs required to build a transportation model by developing an example passenger travel demand model. The example model reduces the scale to a manageable size for the purpose of illustrating the data collection and analysis required before the first step of the model begins. This aspect of the model development would not reasonably be discussed in software help documentation (it is assumed the model developer comes prepared). Recommendations are derived from the example passenger travel demand model to suggest future work regarding the data collection and analysis required for a freight travel demand model.

  4. Molecular targets of luteolin in cancer

    PubMed Central

    2016-01-01

    Many food-derived phytochemical compounds and their derivatives represent a cornucopia of new anticancer compounds. Despite extensive study of luteolin, the literature has no information on the exact mechanisms or molecular targets through which it deters cancer progression. This review discusses existing data on luteolin’s anticancer activities and then offers possible explanations for and molecular targets of its cancer-preventive action. Luteolin prevents tumor development largely by inactivating several signals and transcription pathways essential for cancer cells. This review also offers insights into the molecular mechanisms and targets through which luteolin either prevents cancer or mediates cancer cell death. PMID:25714651

  5. Repurposing Drugs for Cancer Prevention.

    PubMed

    Lee, Daniel K; Szabo, Eva

    2016-01-01

    Development of agents for cancer prevention has been particularly challenging for two main reasons. One is the inherent difficulty in identifying targets for the heterogeneous group of processes that lead to invasive cancer arising at different target organ sites, while the other is the need for safe, tolerable interventions that can be given for lengthy periods of time. The rapidly increasing understanding of the molecular pathogenesis of cancer is providing new opportunities for early intervention, prior to the development of invasive disease. Furthermore, there is an ever-increasing number of approved drugs with many different mechanisms of action. The appeal of using drugs with well described mechanisms of action and safety profiles has led to renewed interest in repurposing such agents for cancer prevention. Here we review the rationale and evidence of effectiveness of three agents that are the current focus of much interest in the field of cancer prevention - aspirin, metformin, and pioglitazone. PMID:26881711

  6. Moving targets

    SciTech Connect

    Not Available

    1993-09-01

    This article discusses the conversion of the Westinghouse Corporation's defence arm, Electronic Systems Group, to marketing products for U.S. police rather than for U.S. defense. The uses of electronic defense technology in law enforcement are addressed. Examples of applications include hand held biosensors for detection of drugs and chemicals, remote computers in patrol cars, and a scaled down AWACS radar aircraft.

  7. Astrochemistry Examples in the Classroom

    ERIC Educational Resources Information Center

    Hudson, Reggie L.

    2006-01-01

    Astronomy and astronomy-related topics have sufficient appeal and depth that they can be used to motivate students, illustrate important chemical concepts, and demonstrate that chemistry and chemists are concerned with all parts of nature. In this article some recent developments in astrochemistry are suggested as examples for the teaching of…

  8. Ideals into Reality: Some Examples.

    ERIC Educational Resources Information Center

    Capuzzi, Dave; And Others

    Examples of innovations in college and adult reading reading programs in five states are described. At Maricopa Technical College (Arizona) adult students have access to a special reading program emphasizing the language experience approach, capitalizing on students' life experiences and oral language facility. Otero Junior College (Colorado)…

  9. Prevention and drug treatment.

    PubMed

    Testa, Mark F; Smith, Brenda

    2009-01-01

    Evidence linking alcohol and other drug abuse with child maltreatment, particularly neglect, is strong. But does substance abuse cause maltreatment? According to Mark Testa and Brenda Smith, such co-occurring risk factors as parental depression, social isolation, homelessness, or domestic violence may be more directly responsible than substance abuse itself for maltreatment. Interventions to prevent substance abuse-related maltreatment, say the authors, must attend to the underlying direct causes of both. Research on whether prevention programs reduce drug abuse or help parents control substance use and improve their parenting has had mixed results, at best. The evidence raises questions generally about the effectiveness of substance abuse services in preventing child maltreatment. Such services, for example, raise only marginally the rates at which parents are reunified with children who have been placed in foster care. The primary reason for the mixed findings, say Testa and Smith, is that almost all the parents face not only substance abuse problems but the co-occurring issues as well. To prevent recurring maltreatment and promote reunification, programs must ensure client progress in all problem areas. At some point in the intervention process, say Testa and Smith, attention must turn to the child's permanency needs and well-being. The best evidence to date suggests that substance-abusing parents pose no greater risk to their children than do parents of other children taken into child protective custody. It may be sensible, say the authors, to set a six-month timetable for parents to engage in treatment and allow twelve to eighteen months for them to show sufficient progress in all identified problem areas. After that, permanency plans should be expedited to place the child with a relative caregiver or in an adoptive home. Investing in parental recovery from substance abuse and dependence, the authors conclude, should not substitute for a comprehensive approach

  10. Active Learning with Irrelevant Examples

    NASA Technical Reports Server (NTRS)

    Wagstaff, Kiri; Mazzoni, Dominic

    2009-01-01

    An improved active learning method has been devised for training data classifiers. One example of a data classifier is the algorithm used by the United States Postal Service since the 1960s to recognize scans of handwritten digits for processing zip codes. Active learning algorithms enable rapid training with minimal investment of time on the part of human experts to provide training examples consisting of correctly classified (labeled) input data. They function by identifying which examples would be most profitable for a human expert to label. The goal is to maximize classifier accuracy while minimizing the number of examples the expert must label. Although there are several well-established methods for active learning, they may not operate well when irrelevant examples are present in the data set. That is, they may select an item for labeling that the expert simply cannot assign to any of the valid classes. In the context of classifying handwritten digits, the irrelevant items may include stray marks, smudges, and mis-scans. Querying the expert about these items results in wasted time or erroneous labels, if the expert is forced to assign the item to one of the valid classes. In contrast, the new algorithm provides a specific mechanism for avoiding querying the irrelevant items. This algorithm has two components: an active learner (which could be a conventional active learning algorithm) and a relevance classifier. The combination of these components yields a method, denoted Relevance Bias, that enables the active learner to avoid querying irrelevant data so as to increase its learning rate and efficiency when irrelevant items are present. The algorithm collects irrelevant data in a set of rejected examples, then trains the relevance classifier to distinguish between labeled (relevant) training examples and the rejected ones. The active learner combines its ranking of the items with the probability that they are relevant to yield a final decision about which item

  11. Tackling Targets.

    ERIC Educational Resources Information Center

    Further Education Unit, London (England).

    This document is designed to help British training and enterprise councils (TECs) and further education (FE) colleges develop and implement strategies for achieving the National Targets for Education and Training (NTET), which were developed by the Confederation of British Industry in 1992 and endorsed by the British government. The findings from…

  12. Preventing clonal evolutionary processes in cancer: Insights from mathematical models.

    PubMed

    Rodriguez-Brenes, Ignacio A; Wodarz, Dominik

    2015-07-21

    Clonal evolutionary processes can drive pathogenesis in human diseases, with cancer being a prominent example. To prevent or treat cancer, mechanisms that can potentially interfere with clonal evolutionary processes need to be understood better. Mathematical modeling is an important research tool that plays an ever-increasing role in cancer research. This paper discusses how mathematical models can be useful to gain insights into mechanisms that can prevent disease initiation, help analyze treatment responses, and aid in the design of treatment strategies to combat the emergence of drug-resistant cells. The discussion will be done in the context of specific examples. Among defense mechanisms, we explore how replicative limits and cellular senescence induced by telomere shortening can influence the emergence and evolution of tumors. Among treatment approaches, we consider the targeted treatment of chronic lymphocytic leukemia (CLL) with tyrosine kinase inhibitors. We illustrate how basic evolutionary mathematical models have the potential to make patient-specific predictions about disease and treatment outcome, and argue that evolutionary models could become important clinical tools in the field of personalized medicine.

  13. Mitochondria-targeting particles

    PubMed Central

    Wongrakpanich, Amaraporn; Geary, Sean M; Joiner, Mei-ling A; Anderson, Mark E; Salem, Aliasger K

    2015-01-01

    Mitochondria are a promising therapeutic target for the detection, prevention and treatment of various human diseases such as cancer, neurodegenerative diseases, ischemia-reperfusion injury, diabetes and obesity. To reach mitochondria, therapeutic molecules need to not only gain access to specific organs, but also to overcome multiple barriers such as the cell membrane and the outer and inner mitochondrial membranes. Cellular and mitochondrial barriers can be potentially overcome through the design of mitochondriotropic particulate carriers capable of transporting drug molecules selectively to mitochondria. These particulate carriers or vectors can be made from lipids (liposomes), biodegradable polymers, or metals, protecting the drug cargo from rapid elimination and degradation in vivo. Many formulations can be tailored to target mitochondria by the incorporation of mitochondriotropic agents onto the surface and can be manufactured to desired sizes and molecular charge. Here, we summarize recently reported strategies for delivering therapeutic molecules to mitochondria using various particle-based formulations. PMID:25490424

  14. Preventive treatments for breast cancer: recent developments.

    PubMed

    Alés-Martínez, J E; Ruiz, A; Chacón, J I; Lluch Hernández, A; Ramos, M; Córdoba, O; Aguirre, E; Barnadas, A; Jara, C; González, S; Plazaola, A; Florián, J; Andrés, R; Sánchez Rovira, P; Frau, A

    2015-04-01

    Breast cancer is a burden for western societies, and an increasing one in emerging economies, because of its high incidence and enormous psychological, social, sanitary and economic costs. However, breast cancer is a preventable disease in a significant proportion. Recent developments in the armamentarium of effective drugs for breast cancer prevention (namely exemestane and anastrozole), the new recommendation from the National Institute for Health and Care Excellence to use preventative drugs in women at high risk as well as updated Guidelines from the US Preventive Services Task Force and the American Society of Clinical Oncology should give renewed momentum to the pharmacological prevention of breast cancer. In this article we review recent major developments in the field and examine their ongoing repercussion for breast cancer prevention. As a practical example, the potential impact of preventive measures in Spain is evaluated and a course of practical actions is delineated.

  15. Foam shell cryogenic ICF target

    DOEpatents

    Darling, Dale H.

    1987-01-01

    A uniform cryogenic layer of DT fuel is maintained in a fusion target having a low density, small pore size, low Z rigid foam shell saturated with liquid DT fuel. Capillary action prevents gravitational slumping of the fuel layer. The saturated shell may be cooled to produce a solid fuel layer.

  16. Generic Example Proving Criteria for All

    ERIC Educational Resources Information Center

    Yopp, David; Ely, Rob; Johnson­-Leung, Jennifer

    2015-01-01

    We review literature that discusses generic example proving and highlight ambiguities that pervade our research community's discourse about generic example arguments. We distinguish between pedagogical advice for choosing good examples that can serve as generic examples when teaching and advice for developing generic example arguments. We provide…

  17. [Prevention and vaccination against hepatitis].

    PubMed

    de la Briére, Alice; Berenguerb, Marc; Destombesa, Christelle

    2013-11-01

    Vaccines against hepatitisA and B are today available and effective. The prevention of hepatitis is thereby based on the reduction of the risk of infection, notably among drug users. France is experimenting with a supervised drug consumption room. For professionals, information, training and physical means of protection are essential to avoid contamination. The operating theatre is an example of a treatment area which is particularly concerned. PMID:24409612

  18. Targets of curcumin

    PubMed Central

    Zhou, Hongyu; Beevers, Christopher S.; Huang, Shile

    2010-01-01

    Curcumin (diferuloylmethane), an orange-yellow component of turmeric or curry powder, is a polyphenol natural product isolated from the rhizome of the plant Curcuma longa. For centuries, curcumin has been used in some medicinal preparation or used as a food-coloring agent. In recent years, extensive in vitro and in vivo studies suggested curcumin has anticancer, antiviral, antiarthritic, anti-amyloid, antioxidant, and anti-inflammatory properties. The underlying mechanisms of these effects are diverse and appear to involve the regulation of various molecular targets, including transcription factors (such as nuclear factor-κB), growth factors (such as vascular endothelial cell growth factor), inflammatory cytokines (such as tumor necrosis factor, interleukin 1 and interleukin 6), protein kinases (such as mammalian target of rapamycin, mitogen-activated protein kinases, and Akt) and other enzymes (such as cyclooxygenase 2 and 5 lipoxygenase). Thus, due to its efficacy and regulation of multiple targets, as well as its safety for human use, curcumin has received considerable interest as a potential therapeutic agent for the prevention and/or treatment of various malignant diseases, arthritis, allergies, Alzheimer’s disease, and other inflammatory illnesses. This review summarizes various in vitro and in vivo pharmacological aspects of curcumin as well as the underlying action mechanisms. The recently identified molecular targets and signaling pathways modulated by curcumin are also discussed here. PMID:20955148

  19. Preventing dental caries in children: Indian scenario.

    PubMed

    Gupta, A; Marya, C M; Dahiya, V; Bhatia, H P; Dhingra, S

    2012-01-01

    The prevalence of dental caries in developing countries like India is increasing to an alarming level in contrast to developed countries where it has decreased because of variety of preventive measures at the community and individual level. There is no State or Centre funded programs for prevention of dental diseases in India. The present review enlists the targeted prevention of dental caries in permanent teeth of 6 to 16 years old children presenting for dental care.

  20. Preventing Burns and Scalds. Injury Prevention for Young Children from the National Safety Certification System.

    ERIC Educational Resources Information Center

    Fischer, Sheryl L.; Walker, April L.

    This booklet outlines a comprehensive fire and burn injury prevention program which includes an instructor's manual, a videotape, and a test: the video provides additional information and examples of injury prevention techniques, and the test measures the amount of knowledge acquired. Following an introduction, the prevalence and extent of burn…

  1. Target assembly

    DOEpatents

    Lewis, Richard A.

    1980-01-01

    A target for a proton beam which is capable of generating neutrons for absorption in a breeding blanket includes a plurality of solid pins formed of a neutron emissive target material disposed parallel to the path of the beam and which are arranged axially in a plurality of layers so that pins in each layer are offset with respect to pins in all other layers, enough layers being used so that each proton in the beam will strike at least one pin with means being provided to cool the pins. For a 300 mA, 1 GeV beam (300 MW), stainless steel pins, 12 inches long and 0.23 inches in diameter are arranged in triangular array in six layers with one sixth of the pins in each layer, the number of pins being such that the entire cross sectional area of the beam is covered by the pins with minimum overlap of pins.

  2. Blackhole formula and example relativity

    NASA Astrophysics Data System (ADS)

    Shin, Philip

    Black hole formula 1) Second dimension (x,y) f(x)=y Energy E=m*c2 2) Third dimension (x,y,z) really x=y=z Black hole formula Root(c2)=c=Root(E/m) As mass go the velocity of light, mass become black hole so there are energy as multiply by mass. Example relativity When E=m*c2 1) Root(c2)=c=Root(E/m) 2) 3*c*Root(c2)=3*c*Root(E/m)=3*c2 From 1) to 2) as an example, As velocity is faster, mass increased. It means when velocity is increased, sec(time) is slower, and m(distance) is increased. The number is good to study physics.

  3. Whole Class Laboratories: More Examples

    NASA Astrophysics Data System (ADS)

    Kouh, Minjoon

    2016-03-01

    Typically, introductory physics courses are taught with a combination of lectures and laboratories in which students have opportunities to discover the natural laws through hands-on activities in small groups. This article reports the use of Google Drive, a free online document-sharing tool, in physics laboratories for pooling experimental data from the whole class. This pedagogical method was reported earlier, and the present article offers a few more examples of such "whole class" laboratories.

  4. Drug Abuse Prevention for At-Risk Individuals.

    ERIC Educational Resources Information Center

    Eggert, Leona; Kumpfer, Karol L.

    The purpose of this resource manual is to provide the reader with an increased understanding of the concept of indicated prevention. The manual describes key features of indicated prevention strategies, briefly describes some examples of successful indicated prevention programs implemented in different settings, and presents a detailed description…

  5. Targeting polymer therapeutics to bone.

    PubMed

    Low, Stewart A; Kopeček, Jindřich

    2012-09-01

    An aging population in the developing world has led to an increase in musculoskeletal diseases such as osteoporosis and bone metastases. Left untreated many bone diseases cause debilitating pain and in the case of cancer, death. Many potential drugs are effective in treating diseases but result in side effects preventing their efficacy in the clinic. Bone, however, provides a unique environment of inorganic solids, which can be exploited in order to effectively target drugs to diseased tissue. By integration of bone targeting moieties to drug-carrying water-soluble polymers, the payload to diseased area can be increased while side effects decreased. The realization of clinically relevant bone targeted polymer therapeutics depends on (1) understanding bone targeting moiety interactions, (2) development of controlled drug delivery systems, as well as (3) understanding drug interactions. The latter makes it possible to develop bone targeted synergistic drug delivery systems.

  6. TARGETING POLYMER THERAPEUTICS TO BONE

    PubMed Central

    Low, Stewart; Kopeček, Jindřich

    2012-01-01

    An aging population in the developing world has led to an increase in musculoskeletal diseases such as osteoporosis and bone metastases. Left untreated many bone diseases cause debilitating pain and in the case of cancer, death. Many potential drugs are effective in treating diseases but result in side effects preventing their efficacy in the clinic. Bone, however, provides an unique environment of inorganic solids, which can be exploited in order to effectively target drugs to diseased tissue. By integration of bone targeting moieties to drug-carrying water-soluble polymers, the payload to diseased area can be increased while side effects decreased. The realization of clinically relevant bone targeted polymer therapeutics depends on (1) understanding bone targeting moiety interactions, (2) development of controlled drug delivery systems, as well as (3) understanding drug interactions. The latter makes it possible to develop bone targeted synergistic drug delivery systems. PMID:22316530

  7. Elementary examples of adiabatic invariance

    NASA Astrophysics Data System (ADS)

    Crawford, Frank S.

    1990-04-01

    Simple classical one-dimensional systems subject to adiabatic (gradual) perturbations are examined. The first examples are well known: the adiabatic invariance of the product Eτ of energy E and period τ for the simple pendulum and for the simple harmonic oscillator. Next, the adiabatic invariants of the vertical bouncer are found—a ball bouncing elastically from the floor of a rising elevator having slowly varying velocity and acceleration. These examples lead to consideration of adiabatic invariance for one-dimensional systems with potentials of the form V=axn, with a=a(t) slowly varying in time. Then, the horizontal bouncer is considered—a mass sliding on a smooth floor, bouncing back and forth between two impenetrable walls, one of which is slowly moving. This example is generalized to a particle in a bound state of a general potential with one slowly moving ``turning point.'' Finally, circular motion of a charged particle in a magnetic field slowly varying in time under three different configurations is considered: (a) a free particle in a uniform field; (b) a free particle in a nonuniform ``betatron'' field; and (c) a particle constrained to a circular orbit in a uniform field.

  8. Melanoma Prevention Using Topical PBISe

    PubMed Central

    Chung, Chin-Ying; Madhunapantula, SubbaRao V.; Desai, Dhimant; Amin, Shantu; Robertson, Gavin P.

    2012-01-01

    Malignant melanoma is the deadliest form of skin cancer, known for its drug resistance and high metastatic potential. Deregulated PI3 and MAP kinase pathways promote early melanocytic lesion development and confer drug resistance. No agent exists to target these deregulated pathways to prevent cutaneous non-invasive melanocytic cells or invasive melanomas from developing into more aggressive widely disseminated metastatic disease. In this study, a selenium containing isosteric analogue of PBIT [S,S′-1,4-phenylenebis(1,2-ethanediyl)bis-isothiourea] called PBISe [Se,Se′-1,4-phenylenebis(1,2-ethanediyl)bis-isoselenourea] is shown to moderate these two major signaling pathways to prevent cutaneous melanocytic lesion or melanoma development. Topical application of PBISe retarded melanocytic lesion development in laboratory-generated skin by 70-80% and in animal skin by ∼50%. Mechanistically, prevention of lesion development occurred due to decreased Akt3 signaling, which increased MAP kinase pathway activity to inhibitory levels. The combined effect of targeting these pathways led to decreased cell proliferation and increased apoptotic cell death thereby preventing melanoma development. Thus, topically applied PBISe treatment has potential to prevent non-invasive melanocytic lesion and invasive metastatic melanoma development in skin. PMID:21367959

  9. Recent advances in preventing mass violence.

    PubMed

    Hamburg, David A

    2010-10-01

    Since his presidency of the Carnegie Corporation of New York and co-chairmanship of the Carnegie Commission on Preventing Deadly Conflict, David Hamburg has been actively engaged in projects related to the prevention of genocide and other mass violence. In these remarks to the Association for Research in Nervous and Mental Disease, he describes the significance of preventing mass violence in the 21st century. In particular, he discusses the danger of nuclear and other highly lethal weapons, emphasizing examples of prevention drawn from the Cold War and subsequent period. He delineates practical steps that can be taken to prevent war and genocide, including restraints on weaponry, preventive diplomacy, fostering indigenous democracy, fostering equitable socioeconomic development, education for human survival, and international justice in relation to human rights. Training and support in preventive diplomacy are highlighted as crucially important, particularly in the context of the United Nations, using the novel Mediation Support Unit based out of the Department of Political Affairs as a key example. He concludes that the creation of international centers for the prevention of mass atrocities could provide a crucial resource in preventing mass violence. PMID:20955320

  10. Molecular and cellular targets.

    PubMed

    Bode, Ann M; Dong, Zigang

    2006-06-01

    Carcinogenesis is a multistage process consisting of initiation, promotion, and progression stages and each stage may be a possible target for chemopreventive agents. A significant outcome of these investigations on the elucidation of molecular and cellular mechanisms is the explication of signal transduction pathways induced by tumor promoters in cancer development. The current belief today is that cancer may be prevented or treated by targeting specific cancer genes, signaling proteins, and transcription factors. The molecular mechanisms explaining how normal cells undergo neoplastic transformation induced by tumor promoters are rapidly being clarified. Accumulating research evidence suggests that many of dietary factors, including tea compounds, may be used alone or in combination with traditional chemotherapeutic agents to prevent or treat cancer. The potential advantage of many natural or dietary compounds seems to focus on their potent anticancer activity combined with low toxicity and very few adverse side effects. This review summarizes some of our recent work regarding the effects of the various tea components on signal transduction pathways involved in neoplastic cell transformation and carcinogenesis. PMID:16688728

  11. Molecular and Cellular Targets

    PubMed Central

    Bode, Ann M.; Dong, Zigang

    2008-01-01

    Carcinogenesis is a multistage process consisting of initiation, promotion and progression stages and each stage may be a possible target for chemopreventive agents. A significant outcome of these investigations on the elucidation of molecular and cellular mechanisms is the explication of signal transduction pathways induced by tumor promoters in cancer development. The current belief today is that cancer may be prevented or treated by targeting specific cancer genes, signaling proteins and transcription factors. The molecular mechanisms explaining how normal cells undergo neoplastic transformation induced by tumor promoters are rapidly being clarified. Accumulating research evidence suggests that many of dietary factors, including tea compounds, may be used alone or in combination with traditional chemotherapeutic agents to prevent or treat cancer. The potential advantage of many natural or dietary compounds seems to focus on their potent anticancer activity combined with low toxicity and very few adverse side effects. This review summarizes some of our recent work regarding the effects of the various tea components on signal transduction pathways involved in neoplastic cell transformation and carcinogenesis. PMID:16688728

  12. Can cannabis use be prevented by targeting personality risk in schools? Twenty‐four‐month outcome of the adventure trial on cannabis use: a cluster‐randomized controlled trial

    PubMed Central

    Doucet, Christine; O'Leary‐Barrett, Maeve; Conrod, Patricia J.

    2015-01-01

    Aims To examine the effectiveness of a personality‐targeted intervention program (Adventure trial) delivered by trained teachers to high‐risk (HR) high‐school students on reducing marijuana use and frequency of use. Design A cluster‐randomized controlled trial. Setting Secondary schools in London, UK. Participants Twenty‐one secondary schools were randomized to intervention (n = 12) or control (n = 9) conditions, encompassing a total of 1038 HR students in the ninth grade [mean (standard deviation) age = 13.7 (0.33) years]. Interventions Brief personality‐targeted interventions to students with one of four HR profiles: anxiety sensitivity, hopelessness, impulsivity and sensation‐seeking. Measurements Primary outcome: marijuana use. Secondary outcome: frequency of use. Assessed using the Reckless Behaviour Questionnaire at intervals of 6 months for 2 years. Personality risk was measured with the Substance Use Risk Profile Scale. Findings Logistic regression analysis revealed significant intervention effects on cannabis use rates at the 6‐month follow‐up in the intent‐to‐treat sample [odds ratio (OR) = 0.67, P = 0.05, 95% confidence interval (CI) = 0.45–1.0] and significant reductions in frequency of use at 12‐ and 18‐month follow‐up (β = –0.14, P ≤ 0.05, 95% CI = –0.6 to –0.01; β = –0.12, P ≤ 0.05, 95% CI = –0.54 to 0.0), but this was not supported in two‐part latent growth models. Subgroup analyses (both logistic and two‐part models) reveal that the sensation‐seeking intervention delayed the onset of cannabis use among sensation seekers (OR = 0.25, β = –0.833, standard error = 0.342, P = 0.015). Conclusions Personality‐targeted interventions can be delivered effectively by trained school staff to delay marijuana use onset among a subset of high‐risk teenagers: sensation‐seekers. PMID:26011508

  13. Promoting Health and Preventing Chronic Degenerative Pathologies for Elders: The Empirical Scenario in Italy

    ERIC Educational Resources Information Center

    Lucchetti, Maria; Mazzoni, Ermanna; Principi, Andrea; Greco, Cosetta

    2007-01-01

    The article provides an overview of health prevention programs implemented by local authorities to target the needs of older people in Italy. Interventions include health promotion and primary prevention, secondary prevention, and tertiary prevention. The most important characteristics of the interventions are described in terms of type, targets,…

  14. Transdermal deferoxamine prevents pressure-induced diabetic ulcers.

    PubMed

    Duscher, Dominik; Neofytou, Evgenios; Wong, Victor W; Maan, Zeshaan N; Rennert, Robert C; Inayathullah, Mohammed; Januszyk, Michael; Rodrigues, Melanie; Malkovskiy, Andrey V; Whitmore, Arnetha J; Walmsley, Graham G; Galvez, Michael G; Whittam, Alexander J; Brownlee, Michael; Rajadas, Jayakumar; Gurtner, Geoffrey C

    2015-01-01

    There is a high mortality in patients with diabetes and severe pressure ulcers. For example, chronic pressure sores of the heels often lead to limb loss in diabetic patients. A major factor underlying this is reduced neovascularization caused by impaired activity of the transcription factor hypoxia inducible factor-1 alpha (HIF-1α). In diabetes, HIF-1α function is compromised by a high glucose-induced and reactive oxygen species-mediated modification of its coactivator p300, leading to impaired HIF-1α transactivation. We examined whether local enhancement of HIF-1α activity would improve diabetic wound healing and minimize the severity of diabetic ulcers. To improve HIF-1α activity we designed a transdermal drug delivery system (TDDS) containing the FDA-approved small molecule deferoxamine (DFO), an iron chelator that increases HIF-1α transactivation in diabetes by preventing iron-catalyzed reactive oxygen stress. Applying this TDDS to a pressure-induced ulcer model in diabetic mice, we found that transdermal delivery of DFO significantly improved wound healing. Unexpectedly, prophylactic application of this transdermal delivery system also prevented diabetic ulcer formation. DFO-treated wounds demonstrated increased collagen density, improved neovascularization, and reduction of free radical formation, leading to decreased cell death. These findings suggest that transdermal delivery of DFO provides a targeted means to both prevent ulcer formation and accelerate diabetic wound healing with the potential for rapid clinical translation.

  15. Sudden cardiac death in haemodialysis patients: preventative options.

    PubMed

    Chiu, Diana Yuan Yng; Sinha, Smeeta; Kalra, Philip A; Green, Darren

    2014-12-01

    Sudden cardiac death (SCD) is the most common cause of death in haemodialysis patients, accounting for 25% of all-cause mortality. There are many potential pathological precipitants as most patients with end-stage renal disease have structurally or functionally abnormal hearts. For example, at initiation of dialysis, 74% of patients have left ventricular hypertrophy. The pathophysiological and metabolic milieu of patients with end-stage renal disease, allied to the regular stresses of dialysis, may provide the trigger to a fatal cardiac event. Prevention of SCD can be seen as a legitimate target to improve survival in this patient group. In the general population, this is most effective by reducing the burden of ischaemic heart disease. However, the aetiology of SCD in haemodialysis patients appears to be different, with myocardial fibrosis, vascular calcification and autonomic dysfunction implicated as possible causes. Thus, the range of therapies is different to the general population. There are potential preventative measures emerging as our understanding of the underlying mechanisms progresses. This article aims to review the evidence for therapies to prevent SCD effective in the general population when applied to dialysis patients, as well as promising new treatments specific to this population group.

  16. Transdermal deferoxamine prevents pressure-induced diabetic ulcers

    PubMed Central

    Duscher, Dominik; Neofytou, Evgenios; Wong, Victor W.; Maan, Zeshaan N.; Rennert, Robert C.; Januszyk, Michael; Rodrigues, Melanie; Malkovskiy, Andrey V.; Whitmore, Arnetha J.; Galvez, Michael G.; Whittam, Alexander J.; Brownlee, Michael; Rajadas, Jayakumar; Gurtner, Geoffrey C.

    2015-01-01

    There is a high mortality in patients with diabetes and severe pressure ulcers. For example, chronic pressure sores of the heels often lead to limb loss in diabetic patients. A major factor underlying this is reduced neovascularization caused by impaired activity of the transcription factor hypoxia inducible factor-1 alpha (HIF-1α). In diabetes, HIF-1α function is compromised by a high glucose-induced and reactive oxygen species-mediated modification of its coactivator p300, leading to impaired HIF-1α transactivation. We examined whether local enhancement of HIF-1α activity would improve diabetic wound healing and minimize the severity of diabetic ulcers. To improve HIF-1α activity we designed a transdermal drug delivery system (TDDS) containing the FDA-approved small molecule deferoxamine (DFO), an iron chelator that increases HIF-1α transactivation in diabetes by preventing iron-catalyzed reactive oxygen stress. Applying this TDDS to a pressure-induced ulcer model in diabetic mice, we found that transdermal delivery of DFO significantly improved wound healing. Unexpectedly, prophylactic application of this transdermal delivery system also prevented diabetic ulcer formation. DFO-treated wounds demonstrated increased collagen density, improved neovascularization, and reduction of free radical formation, leading to decreased cell death. These findings suggest that transdermal delivery of DFO provides a targeted means to both prevent ulcer formation and accelerate diabetic wound healing with the potential for rapid clinical translation. PMID:25535360

  17. Progress towards the prevention and treatment of norovirus infections

    PubMed Central

    Arias, Armando; Emmott, Edward; Vashist, Surender; Goodfellow, Ian

    2014-01-01

    Noroviruses are now recognized as the major cause of acute gastroenteritis in the developed world, yet our ability to prevent and control infection is limited. Recent work has highlighted that, while typically an acute infection in the population, immunocompromised patients often experience long-term infections that may last many years. This cohort of patients and those regularly exposed to infectious material, for example, care workers and others, would benefit greatly from the development of a vaccine or antiviral therapy. While a licensed vaccine or antiviral has yet to be developed, work over the past 10 years in this area has intensified and trials with a vaccine candidate have proven promising. Numerous antiviral targets and small molecule inhibitors that have efficacy in cell culture have now been identified; however, further studies in this area are required in order to make these suitable for clinical use. PMID:24199805

  18. Rationale and design of a home-based trial using wearable sensors to detect asymptomatic atrial fibrillation in a targeted population: The mHealth Screening To Prevent Strokes (mSToPS) trial.

    PubMed

    Steinhubl, Steven R; Mehta, Rajesh R; Ebner, Gail S; Ballesteros, Marissa M; Waalen, Jill; Steinberg, Gregory; Van Crocker, Percy; Felicione, Elise; Carter, Chureen T; Edmonds, Shawn; Honcz, Joseph P; Miralles, Gines Diego; Talantov, Dimitri; Sarich, Troy C; Topol, Eric J

    2016-05-01

    Efficient methods for screening populations for undiagnosed atrial fibrillation (AF) are needed to reduce its associated mortality, morbidity, and costs. The use of digital technologies, including wearable sensors and large health record data sets allowing for targeted outreach toward individuals at increased risk for AF, might allow for unprecedented opportunities for effective, economical screening. The trial's primary objective is to determine, in a real-world setting, whether using wearable sensors in a risk-targeted screening population can diagnose asymptomatic AF more effectively than routine care. Additional key objectives include (1) exploring 2 rhythm-monitoring strategies-electrocardiogram-based and exploratory pulse wave-based-for detection of new AF, and (2) comparing long-term clinical and resource outcomes among groups. In all, 2,100 Aetna members will be randomized 1:1 to either immediate or delayed monitoring, in which a wearable patch will capture a single-lead electrocardiogram during the first and last 2 weeks of a 4-month period beginning immediately or 4 months after enrollment, respectively. An observational, risk factor-matched control group (n = 4,000) will be developed from members who did not receive an invitation to participate. The primary end point is the incidence of new AF in the immediate- vs delayed-monitoring arms at the end of the 4-month monitoring period. Additional efficacy and safety end points will be captured at 1 and 3 years. The results of this digital medicine trial might benefit a substantial proportion of the population by helping identify and refine screening methods for undiagnosed AF.

  19. A novel small-molecule PPI inhibitor targeting integrin αvβ3-osteopontin interface blocks bone resorption in vitro and prevents bone loss in mice.

    PubMed

    Park, Doori; Park, Chan-Won; Choi, YoungJin; Lin, Jingjing; Seo, Dong-Hyun; Kim, Han-Sung; Lee, Soo Young; Kang, In-Cheol

    2016-08-01

    Small molecule-inhibition targeting protein-protein interaction (PPI) is now recognized as an emerging and challenging area in drug design. We developed a novel interactive drug discovery methodology known as Protein Chip technology (ProteoChip) as a cutting-edge PPI assay system applicable for unique PPI-targeting therapeutics integrated with computer-aided drug design (CADD). Here, we describe a novel small molecular PPI inhibitor, IPS-02001, which the blocks integrin αvβ3-osteopontin interface a novel PPI inhibitor identified by the interactive methodology of both ProteoChip- and CADD-based PPI assay. IPS-02001 (6,7-Dichloro-2,3,5,8-tetrahydroxy-1,4-naphthoquinone) was screened from different compound libraries (InterBioScreen, Commercial libraries) using an in silico structure-based molecular docking simulation method and a protein chip-based protein-protein interaction assay system. Additionally, integrin αvβ3, an adhesion receptor expressed in osteoclasts (OCs), was implicated in the regulation of OC function via regulation of the cytoskeletal organization of OCs. IPS-02001 blocked OC maturation from murine bone marrow-derived macrophages, as well as the resorptive function of OCs. Moreover, treatment with IPS-02001 impaired downstream signaling of integrin αvβ3 linked to Pyk2, c-Src, PLCγ2, and Vav3 and disrupted the actin cytoskeleton in mature OCs. Furthermore, IPS-02001 blocked RANKL-induced bone destruction by reducing the number of OCs and protected against ovariectomy-induced bone loss in mice. Thus, IPS-02001 may represent a promising new class of anti-resorptive drugs for treatment of bone diseases associated with increased OC function. PMID:27187277

  20. Accelerator target

    DOEpatents

    Schlyer, D.J.; Ferrieri, R.A.; Koehler, C.

    1999-06-29

    A target includes a body having a depression in a front side for holding a sample for irradiation by a particle beam to produce a radioisotope. Cooling fins are disposed on a backside of the body opposite the depression. A foil is joined to the body front side to cover the depression and sample therein. A perforate grid is joined to the body atop the foil for supporting the foil and for transmitting the particle beam therethrough. A coolant is circulated over the fins to cool the body during the particle beam irradiation of the sample in the depression. 5 figs.

  1. Accelerator target

    DOEpatents

    Schlyer, David J.; Ferrieri, Richard A.; Koehler, Conrad

    1999-01-01

    A target includes a body having a depression in a front side for holding a sample for irradiation by a particle beam to produce a radioisotope. Cooling fins are disposed on a backside of the body opposite the depression. A foil is joined to the body front side to cover the depression and sample therein. A perforate grid is joined to the body atop the foil for supporting the foil and for transmitting the particle beam therethrough. A coolant is circulated over the fins to cool the body during the particle beam irradiation of the sample in the depression.

  2. An example in surface area.

    PubMed

    Goffman, C

    1969-05-01

    For length and area, a central fact is that the value of the length of a curve or the area of a surface, as given by the Lebesgue theory, is at least as great as that given by the classical formula, whenever the latter has meaning. This is now found not to be valid in higher dimensions. We give an example of a continuous mapping of the unit cube into itself for which the value given by the formula exceeds the three-dimensional Lebesgue area of the corresponding suface.

  3. EXAMPLES OF RADIATION SHIELDING MODELS

    SciTech Connect

    Willison, J

    2006-07-27

    The attached pictures are examples of shielding models used by WSMS. The models were used in shielding evaluations for Tank 50 pump replacement. They show the relative location of shielding to radiation sources for pumps and pipes. None of the calculations that were associated with these models involved UCNI. The last page contains two pictures from a shielding calculation for the saltstone area. The upper picture is a conceptual drawing. The lower picture is an image copied from the website of a supplier for the project.

  4. Projector Method: theory and examples

    SciTech Connect

    Dahl, E.D.

    1985-01-01

    The Projector Method technique for numerically analyzing lattice gauge theories was developed to take advantage of certain simplifying features of gauge theory models. Starting from a very general notion of what the Projector Method is, the techniques are applied to several model problems. After these examples have traced the development of the actual algorithm from the general principles of the Projector Method, a direct comparison between the Projector and the Euclidean Monte Carlo is made, followed by a discussion of the application to Periodic Quantum Electrodynamics in two and three spatial dimensions. Some methods for improving the efficiency of the Projector in various circumstances are outlined. 10 refs., 7 figs. (LEW)

  5. Spatial filtering through elementary examples

    NASA Astrophysics Data System (ADS)

    Gluskin, Emanuel

    2004-05-01

    The spatial filtering features of resistive grids have become important in microelectronics in the last two decades, in particular because of the current interest in the design of 'vision chips.' However, these features of the grids are unexpected for many who received a basic physics or electrical engineering education. The author's opinion is that the concept of spatial filtering is important in itself, and should be introduced and separately considered at an early educational stage. We thus discuss some simple examples, of both continuous and discrete systems in which spatial filtering may be observed, using only basic physics concepts.

  6. [Diabetes type 2--criteria concerning the recognition and prevention, as well as therapeutic targets in the light of research results and guidelines formulated by the American Diabetes Association in 2012].

    PubMed

    Kucharska, Ewa

    2013-01-01

    The article summarizes the current state of knowledge on the detection of pre-diabetic condition and type 2 diabetes, as well as therapeutic purposes. ADA guidelines published in January 2012, in line with the earlier experts' findings allow the detection of diabetes on the basis of HbA1C (> or = 6.5%) marking. Moreover, there are still applicable criteria that impose the following methods of blood glucose level monitoring: fasted, and 2 hours after a 75 gram of oral glucose intake. Screening for diabetes type 2 is indicated especially in obese patients and patients with arterial hypertension. This includes also those, in whom a prediabetic condition is found, and who would benefit most from their lifestyle modification, or from pharmacological diabetes prevention with the use of metformin. The results of clinical trials and recent meta-analyses indicate that for most patients, the therapeutic goal in the treatment of diabetes may be less precise than it was previously thought, and for HbA1C it is < 7.0%. An individualized approach is, however, advised, as patients with respect to whom a short period of time has elapsed after diabetes was diagnosed in them, young people and those with a high life expectancy and low hypoglycemia risk may benefit from a stricter controlling regime (< 6.5%).

  7. Resistance to Antibiotics Mediated by Target Alterations

    NASA Astrophysics Data System (ADS)

    Spratt, Brian G.

    1994-04-01

    The development of resistance to antibiotics by reductions in the affinities of their enzymatic targets occurs most rapidly for antibiotics that inactivate a single target and that are not analogs of substrate. In these cases of resistance (for example, resistance to rifampicin), numerous single amino acid substitutions may provide large decreases in the affinity of the target for the antibiotic, leading to clinically significant levels of resistance. Resistance due to target alterations should occur much more slowly for those antibiotics (penicillin, for example) that inactivate multiple targets irreversibly by acting as close analogs of substrate. Resistance to penicillin because of target changes has emerged, by unexpected mechanisms, only in a limited number of species. However, inactivating enzymes commonly provide resistance to antibiotics that, like penicillin, are derived from natural products, although such enzymes have not been found for synthetic antibiotics. Thus, the ideal antibiotic would be produced by rational design, rather than by the modification of a natural product.

  8. Asymptotic safety: A simple example

    NASA Astrophysics Data System (ADS)

    Braun, Jens; Gies, Holger; Scherer, Daniel D.

    2011-04-01

    We use the Gross-Neveu model in 2example for Weinberg’s asymptotic safety scenario: despite being perturbatively nonrenormalizable, the model defines an interacting quantum field theory being valid to arbitrarily high momentum scales owing to the existence of a non-Gaussian fixed point. Using the functional renormalization group, we study the uv behavior of the model in both the purely fermionic as well as a partially bosonized language. We show that asymptotic safety is realized at non-Gaussian fixed points in both formulations, the universal critical exponents of which we determine quantitatively. The partially bosonized formulation allows to make contact to the large-Nf expansion where the model is known to be renormalizable to all orders. In this limit, the fixed-point action as well as all universal critical exponents can be computed analytically. As asymptotic safety has become an important scenario for quantizing gravity, our description of a well-understood model is meant to provide for an easily accessible and controllable example of modern nonperturbative quantum field theory.

  9. Asymptotic safety: A simple example

    SciTech Connect

    Braun, Jens; Gies, Holger; Scherer, Daniel D.

    2011-04-15

    We use the Gross-Neveu model in 2example for Weinberg's asymptotic safety scenario: despite being perturbatively nonrenormalizable, the model defines an interacting quantum field theory being valid to arbitrarily high momentum scales owing to the existence of a non-Gaussian fixed point. Using the functional renormalization group, we study the uv behavior of the model in both the purely fermionic as well as a partially bosonized language. We show that asymptotic safety is realized at non-Gaussian fixed points in both formulations, the universal critical exponents of which we determine quantitatively. The partially bosonized formulation allows to make contact to the large-N{sub f} expansion where the model is known to be renormalizable to all orders. In this limit, the fixed-point action as well as all universal critical exponents can be computed analytically. As asymptotic safety has become an important scenario for quantizing gravity, our description of a well-understood model is meant to provide for an easily accessible and controllable example of modern nonperturbative quantum field theory.

  10. Translating Developmental Neuroscience to Substance Use Prevention

    PubMed Central

    Riggs, Nathaniel R.

    2015-01-01

    Several preventive interventions have demonstrated efficacy in reducing substance use. However, opportunities exist to further improve prevention approaches. The application of recent advances in developmental neuroscience can inform the design, implementation, and evaluation of substance use prevention programs. This paper first briefly describes the developmental integration of the prefrontal cortex with emotion and motivation centers of the brain, and the implications of this process for substance use vulnerability. Discussed next are specific examples of how developmental neuroscience can inform prevention timing, development, and evaluation. Contextual considerations are then suggested including a critical role for schools in substance misuse prevention. Finally, current theoretical and methodological challenges to the translation of developmental neuroscience to substance use prevention are discussed. PMID:26236576

  11. Prevention Neuroscience: A new frontier for preventive medicine.

    PubMed

    Hall, Peter A

    2016-05-01

    Prevention neuroscience may be defined as follows: an interdisciplinary field concerned with the neurobiological factors that influence susceptibility to preventable disease, disability or mortality. It includes, but is not limited to: examination of brain health as an outcome, brain activity as a predictor of health outcomes, brain structures/systems as causal determinants of health outcomes (e.g., health behaviours), and the brain as a mediator of other causal influences (e.g., social conditions) on health outcomes. This commentary describes concepts, theory and research illustrating each of these scenarios using exercise, smoking cessation, dietary behaviour, and health disparities as examples. It is argued that neuroscience may provide both concepts and methods that may be possible (even fruitful) to incorporate into preventive medicine research and health promotion practise. Although public health practitioners and cognitive neuroscientists have not traditionally crossed paths outside of the context of neurodegenerative diseases such as Alzheimer's and other dementias, it is easy to envision a future where many common disease prevention activities involve collaboration between the two disciplines, and the cache of tools available to the preventive medicine expert includes neuroimaging and neuromodulation techniques. PMID:26876625

  12. The putative Agrobacterium transcriptional activator-like virulence protein VirD5 may target T-complex to prevent the degradation of coat proteins in the plant cell nucleus.

    PubMed

    Wang, Yafei; Peng, Wei; Zhou, Xu; Huang, Fei; Shao, Lingyun; Luo, Meizhong

    2014-09-01

    Agrobacterium exports at least five virulence proteins (VirE2, VirE3, VirF, VirD2, VirD5) into host cells and hijacks some host plant factors to facilitate its transformation process. Random DNA binding selection assays (RDSAs), electrophoretic mobility shift assays (EMSAs) and yeast one-hybrid systems were used to identify protein-bound DNA elements. Bimolecular fluorescence complementation, glutathione S-transferase pull-down and yeast two-hybrid assays were used to detect protein interactions. Protoplast transformation, coprecipitation, competitive binding and cell-free degradation assays were used to analyze the relationships among proteins. We found that Agrobacterium VirD5 exhibits transcriptional activation activity in yeast, is located in the plant cell nucleus, and forms homodimers. A specific VirD5-bound DNA element designated D5RE (VirD5 response element) was identified. VirD5 interacted directly with Arabidopsis VirE2 Interacting Protein 1 (AtVIP1). However, the ternary complex of VirD5-AtVIP1-VirE2 could be detected, whereas that of VirD5-AtVIP1-VBF (AtVIP1 Binding F-box protein) could not. We demonstrated that VirD5 competes with VBF for binding to AtVIP1 and stabilizes AtVIP1 and VirE2 in the cell-free degradation system. Our results indicated that VirD5 may act as both a transcriptional activator-like effector to regulate host gene expression and a protector preventing the coat proteins of the T-complex from being quickly degraded by the host's ubiquitin proteasome system (UPS).

  13. The future of HIV prevention.

    PubMed

    Padian, Nancy S; Isbell, Michael T; Russell, Elizabeth S; Essex, M

    2012-08-01

    In the decades since the emergence of HIV, numerous approaches to prevent transmission have been tested with varying degrees of success. Because a highly effective vaccine will not be available within the next decade, it is increasingly clear that preventing new HIV infections will require successful implementation of promising behavioral and biomedical interventions in combination. These prevention packages must be sufficiently flexible to include a variety of evidence-based interventions that serve each dynamic population they target, particularly those who are most vulnerable. To optimize the impact of combination intervention packages, well-designed implementation science studies are vital. Efficacy in a clinical trial does not necessarily translate to effectiveness at the population-level, and prioritized research studies should investigate programmatic implementation and operations scale-up and new methods to monitor and evaluate these processes both for organization and cost-effectiveness. With an estimated 2.7 million people becoming newly infected with HIV in 2010, the prevention of HIV remains an urgent global health priority. Since the emergence of HIV/AIDS more than 30 years ago, the evidence base for HIV prevention has expanded and evolved. Here we explore the status of evidence-based HIV prevention, describing both the continuing challenges and the emerging opportunities to reduce HIV incidence. PMID:22772385

  14. The Structuring of Personal Example Spaces

    ERIC Educational Resources Information Center

    Sinclair, Nathalie; Watson, Anne; Zazkis, Rina; Mason, John

    2011-01-01

    This paper elaborates the notion of a personal example space as the set of mathematical objects and construction techniques that a learner has access to as examples of a concept while working on a given task. This is different from the conventional space of examples that is represented by the worked examples and exercises in textbooks. We refer to…

  15. [Prevention of chronic wound infection].

    PubMed

    Kucisec-Tepes, Nastja

    2013-10-01

    An integral follow-up of the patient starting with medical history, present status and the wound itself will lead us to decide which plan of prevention, care and treatment will be efficient. The interaction of host immune abnormalities and growth of the microbial population invading the wound have a significant impact on the clinical presentation and direction of the development of the wound. Infection of a chronic wound is a consequence of a large number and composition of microbe populations in the tissue, along with the presence of virulence factors depending on the type and representation in the biofilm as a factor of greatest importance, the synergy of various microbial communities of aerobes-anaerobes in various combinations, and the host immune response. The basic procedures in preventing the development of infection from the colonization status are reduction of the total mass of microbes along with necrotic tissue, removal or destruction of virulent factors such as the biofilm, destruction of the synergy of various microbial communities, and increasing the level and quality of the host immune response. Prevention of the chronic wound infection demands numerous strategies or procedures, which should be applied simultaneously, but must rapidly and frequently follow each other in succession. Therefore, various methods are being applied depending on the indications, such as mechanical washing and cleaning, application of antiseptics, debridement, vacuum-assisted closing of the wound, oxygenation, moist wound healing - active and passive compresses, methods of removal or destruction of the biofilm, application of specific cells, i.e. factors of growth, and removal of mechanical stress. Antibiotics are not used in the prevention of chronic wound infection. They are used only in a targeted fashion when infection has been proven and the agent identified, as well as its sensitivity to antibiotics obtained from target samples. An ideal prevention would be a method

  16. Cancer prevention and therapy through the modulation of the tumor microenvironment.

    PubMed

    Casey, Stephanie C; Amedei, Amedeo; Aquilano, Katia; Azmi, Asfar S; Benencia, Fabian; Bhakta, Dipita; Bilsland, Alan E; Boosani, Chandra S; Chen, Sophie; Ciriolo, Maria Rosa; Crawford, Sarah; Fujii, Hiromasa; Georgakilas, Alexandros G; Guha, Gunjan; Halicka, Dorota; Helferich, William G; Heneberg, Petr; Honoki, Kanya; Keith, W Nicol; Kerkar, Sid P; Mohammed, Sulma I; Niccolai, Elena; Nowsheen, Somaira; Vasantha Rupasinghe, H P; Samadi, Abbas; Singh, Neetu; Talib, Wamidh H; Venkateswaran, Vasundara; Whelan, Richard L; Yang, Xujuan; Felsher, Dean W

    2015-12-01

    Cancer arises in the context of an in vivo tumor microenvironment. This microenvironment is both a cause and consequence of tumorigenesis. Tumor and host cells co-evolve dynamically through indirect and direct cellular interactions, eliciting multiscale effects on many biological programs, including cellular proliferation, growth, and metabolism, as well as angiogenesis and hypoxia and innate and adaptive immunity. Here we highlight specific biological processes that could be exploited as targets for the prevention and therapy of cancer. Specifically, we describe how inhibition of targets such as cholesterol synthesis and metabolites, reactive oxygen species and hypoxia, macrophage activation and conversion, indoleamine 2,3-dioxygenase regulation of dendritic cells, vascular endothelial growth factor regulation of angiogenesis, fibrosis inhibition, endoglin, and Janus kinase signaling emerge as examples of important potential nexuses in the regulation of tumorigenesis and the tumor microenvironment that can be targeted. We have also identified therapeutic agents as approaches, in particular natural products such as berberine, resveratrol, onionin A, epigallocatechin gallate, genistein, curcumin, naringenin, desoxyrhapontigenin, piperine, and zerumbone, that may warrant further investigation to target the tumor microenvironment for the treatment and/or prevention of cancer.

  17. Waterfowl diseases: causes, prevention, and control

    USGS Publications Warehouse

    Friend, M.; Cross, D.H.

    1995-01-01

    Preventing and controlling disease in waterfowl is a difficult job. Few tools are available to deal with disease in highly mobile, unconfined animal populations, and few managers are trained and experienced in the prevention and control of avian diseases. Furthermore, the geographic distribution, frequency of occurrence, magnitude of losses, and causes of diseases in waterfowl, as in other life forms, change over time. Waterfowl mortality from infectious diseases, for example, has increased in the past 20 years (Friend 1992).

  18. Prevention of youth injuries.

    PubMed Central

    Laraque, D.; Barlow, B.; Durkin, M.

    1999-01-01

    There are four categories of causes responsible for the majority of injuries in youth 10-19 years of age: 1) motor vehicle traffic; 2) violence (intra-familial, extra-familial, self, pregnancy-related); 3) recreational; and 4) occupational. This article presents data from the National Center for Health Statistics mortality data and the National Pediatric Trauma Registry morbidity data. Nationwide, the pediatric injury death rate is highest among adolescents 15-19 years of age. Motor vehicle-related deaths account for 41% and firearm-related deaths account for 36% of injury deaths in this age group. For youths aged 10-14 years, motor vehicle-related deaths account for 38% and; firearm-related deaths account for 26% of injury deaths. For both age groups, occupant motor vehicle-related deaths account for the majority of deaths and underscore the need for seat belt use. Using theoretical principles based on the Haddon matrix and a knowledge of adolescent development, proposed interventions to decrease injuries and deaths related to motor vehicles and firearms include graduated licensing, occupant restraint, speed limits, conflict resolution, and gun control. Occupational injuries, particularly injury associated with agricultural production, account for an estimated 100,000 injuries per year. Preventive strategies include OSHA regulations imposing standards for protective devices and further study for guidelines for adolescent work in agriculture. Injuries related to recreation include drowning and sports injuries. Preventive strategies may include proper supervision and risk reduction with respect to use of alcohol/drugs. The data presented support the use of primary prevention to achieve the most effective, safe community interventions targeting adolescents. PMID:10599188

  19. SCF ubiquitin ligase targeted therapies

    PubMed Central

    Skaar, Jeffrey R.; Pagan, Julia K.; Pagano, Michele

    2015-01-01

    Summary The recent clinical successes of inhibitors of the proteasome for the treatment of cancer have highlighted the therapeutic potential of this protein degradation system. Proteasome inhibitors prevent the degradation of numerous proteins, so increased specificity could be achieved by inhibiting the components of the ubiquitin-proteasome system that target specific subsets of proteins for degradation. F-box proteins are the substrate-targeting subunits of SKP1-CUL1-F-box protein (SCF) ubiquitin ligase complexes. Through the degradation of a plethora of diverse substrates, SCF ubiquitin ligases control a large number of processes at the cellular and organismal levels, and their misregulation is implicated in many pathologies. SCF ligases are characterized by a high specificity for their substrates, so they represent promising drug targets. However, the potential for therapeutic manipulation of SCF complexes remains an underdeveloped area. This review will explore and discuss potential strategies to target SCF-mediated biology to treat human diseases. PMID:25394868

  20. Versatile surface engineering of porous nanomaterials with bioinspired polyphenol coatings for targeted and controlled drug delivery

    NASA Astrophysics Data System (ADS)

    Li, Juan; Wu, Shuxian; Wu, Cuichen; Qiu, Liping; Zhu, Guizhi; Cui, Cheng; Liu, Yuan; Hou, Weijia; Wang, Yanyue; Zhang, Liqin; Teng, I.-Ting; Yang, Huang-Hao; Tan, Weihong

    2016-04-01

    The development of biocompatible drug delivery systems with targeted recognition and controlled release has experienced a number of design challenges, including, for example, complicated preparation steps and premature drug release. Herein, we address these problems through an in situ self-polymerization method that synthesizes biodegradable polyphenol-coated porous nanomaterials for targeted and controlled drug delivery. As a proof of concept, we synthesized polyphenol-coated mesoporous silica nanoparticles, termed MSN@polyphenol. The polyphenol coatings not only improved colloidal stability and prevented premature drug leakage, but also provided a scaffold for immobilization of targeting moieties, such as aptamers. Both immobilization of targeting aptamers and synthesis of polyphenol coating are easily accomplished without the aid of any other organic reagents. Importantly, the polyphenol coating (EGCg) used in this study could be biodegraded by acidic pH and intracellular glutathione, resulting in the release of trapped anticancer drugs. Based on confocal fluorescence microscopy and cytotoxicity experiments, drug-loaded and polyphenol-coated MSNs were shown to possess highly efficient internalization and an apparent cytotoxic effect on target cancer, but not control, cells. Our results suggest that these highly biocompatible and biodegradable polyphenol-coated MSNs are promising vectors for controlled-release biomedical applications and cancer therapy.The development of biocompatible drug delivery systems with targeted recognition and controlled release has experienced a number of design challenges, including, for example, complicated preparation steps and premature drug release. Herein, we address these problems through an in situ self-polymerization method that synthesizes biodegradable polyphenol-coated porous nanomaterials for targeted and controlled drug delivery. As a proof of concept, we synthesized polyphenol-coated mesoporous silica nanoparticles