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Sample records for prevention targets examples

  1. Enhancing the Net Benefits of Disseminating Efficacious Prevention Programs: A Note on Target Efficiency with Illustrative Examples

    PubMed Central

    Johnston, Stephen; Karakus, Mustafa C.; Ialongo, Nicholas S.; Slade, Eric P.; Stuart, Elizabeth A.

    2016-01-01

    We consider the implementation, in a non-research setting, of a new prevention program that has previously been evaluated in a randomized trial. When the target population for the implementation is heterogeneous, the overall net benefits of the implementation may differ substantially from those reported in the economic evaluation of the randomized trial, and from those that would be realized if the program were implemented within a selected subgroup of the target population. This note illustrates a simple and practical approach to targeting that can combine risk-factor results from the literature with the overall cost-benefit results from the program’s randomized trial to maximize the expected net benefit of implementing the program in a heterogeneous population. PMID:18343990

  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. Novel molecular targets for prevention of obesity and osteoporosis.

    PubMed

    Rayalam, Srujana; Yang, Jeong-Yeh; Della-Fera, Mary Anne; Baile, Clifton A

    2011-12-01

    Evidence from both epidemiological studies and basic research suggests that obesity and osteoporosis are interrelated. Though there is an increase in the prevalence of these disorders, a limited number of treatments are available, one of the reasons being the complexity of the pathways involved and difficulty in identifying a single molecular target. Due to adverse effects of pharmaceuticals, intake of herbal drugs by patients without a physician's recommendation is increasing globally. Lack of success with targeted monotherapy has encouraged scientists to determine whether combinations of phytochemicals that interfere with numerous cell-signaling pathways can be a more effective approach to treat complex diseases. For example, evidence is emerging that specific combinations of phytochemicals are far more effective than single compounds in decreasing adipogenesis and promoting bone formation. Since multiple pathways are dysfunctional in obesity and osteoporosis, an ideal approach for preventing and treating these diseases may be to use a combination of phytochemicals to address several targets simultaneously. PMID:21429725

  5. 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

  6. Targeting Polyamines and Inflammation for Cancer Prevention

    PubMed Central

    Babbar, Naveen; Gerner, Eugene W.

    2013-01-01

    Increased polyamine synthesis and inflammation have long been associated with intraepithelial neoplasia, which are risk factors for cancer development in humans. Targeting polyamine metabolism (by use of polyamine synthesis inhibitors or polyamine catabolism activators) and inflammation (by use of nonsteroidal anti-inflammatory drugs) has been studied for many cancers, including colon, prostate, and skin. Genetic epidemiology results indicate that a genetic variant associated with the expression of a polyamine biosynthetic gene is associated with risk of colon and prostate cancers. A clinical trial of difluoromethylornithine (DFMO), a selective inhibitor of polyamine synthesis, showed that the 1 year treatment duration reduced prostate volume and serum prostate-specific antigen doubling time in men with a family history of prostate cancer. A second, clinical trial of DFMO in combination with sulindac, a NSAID in patients with prior colon polyps found that the 3-year treatment was associated with a 70% reduction of all, and over a 90% reduction of advanced and/or multiple metachronous colon adenomas. In this chapter, we discuss that similar combination prevention strategies of targeting polyamines and inflammation can be effective in reducing risk factors associated with the development of human cancers. PMID:21253788

  7. 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

  8. 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

  9. 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.

  10. Hypoglycemia unawareness prevention: Targeting glucagon production.

    PubMed

    Samson, Willis K; Stein, Lauren M; Elrick, Mollisa; Salvatori, Alison; Kolar, Grant; Corbett, John A; Yosten, Gina L C

    2016-08-01

    Insulin-dependent individuals with diabetes are at risk for a severe hypoglycemic event that may predispose them to several repeat episodes during which the normal counter regulatory mechanisms that protect against hypoglycemia fail to be activated. This state of hypoglycemia unawareness is characterized by a failure of glucagon release, preventing mobilization of endogenous glucose stores from the liver. We describe the discovery of a novel hormone, produced in pancreatic delta cells, which stimulates glucagon production and release, particularly under low glucose conditions. We hypothesize that this hormone, called neuronostatin, may be effective as a co-therapy with insulin to prevent repeated, potentially fatal episodes of recurrent hypoglycemia. PMID:27080082

  11. Potential Targets for Colorectal Cancer Prevention

    PubMed Central

    Temraz, Sally; Mukherji, Deborah; Shamseddine, Ali

    2013-01-01

    The step-wise development of colorectal neoplasia from adenoma to carcinoma suggests that specific interventions could delay or prevent the development of invasive cancer. Several key factors involved in colorectal cancer pathogenesis have already been identified including cyclooxygenase 2 (COX-2), nuclear factor kappa B (NF-κB), survivin and insulin-like growth factor-I (IGF-I). Clinical trials of COX-2 inhibitors have provided the “proof of principle” that inhibition of this enzyme can prevent the formation of colonic adenomas and potentially carcinomas, however concerns regarding the potential toxicity of these drugs have limited their use as a chemopreventative strategy. Curcumin, resveratrol and quercetin are chemopreventive agents that are able to suppress multiple signaling pathways involved in carcinogenesis and hence are attractive candidates for further research. PMID:23975167

  12. 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

  13. 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

  14. 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

  15. 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

  16. Signal Transduction Molecules as Targets for Cancer Prevention

    PubMed Central

    Bode, Ann M.; Dong, Zigang

    2010-01-01

    Environmental and life-style aspects are major contributors to human carcinogenesis and, therefore, many human cancers may be preventable. Cancer is the end result of defects in cellular signaling processes that play a key role in the control of cell growth, survival, division, and differentiation. Therefore, identifying molecular and cellular targets critical in cancer development and prevention is an area of intensive research, driving the development of highly specific small-molecule inhibitors. A major idea today is that cancer may be prevented or treated by targeting the products of specific cancer-related genes, frequently encoding signaling proteins or transcription factors. Participants in these joint conferences discussed their latest findings in the identification of promising molecular targets and the development of agents directed against these targets with the goal of effectively transitioning these into the clinical setting. PMID:19244209

  17. 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

  18. 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

  19. 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

  20. 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...

  1. Primary Prevention from the Epidemiology Perspective: Three Examples from the Practice

    PubMed Central

    2010-01-01

    Background Primary prevention programmes are of increasing importance to reduce the impact of chronic diseases on the individual, institutional and societal level. However, most initiatives that develop and implement primary prevention programmes are not evaluated with scientific rigor. On the basis of three different projects we discuss necessary steps on the road to evidence-based primary prevention. Discussion We first discuss how to identify suitable target groups exploiting sophisticated statistical methods. This is illustrated using data from a health survey conducted in a federal state of Germany. A literature review is the more typical approach to identify target groups that is demonstrated using a European project on the prevention of childhood obesity. In the next step, modifiable risk factors and realistic targets of the intervention have to be specified. These determine the outcome measures that in turn are used for effect evaluation. Both, the target groups and the outcome measures, lay the ground for the study design and the definition of comparison groups as can be seen in our European project. This project also illustrates the development and implementation of a prevention programme. These may require active involvement of participants which can be achieved by participatory approaches taking into account the socio-cultural and living environment. Evaluation is of utmost importance for any intervention to assess structure, process and outcome according to rigid scientific criteria. Different approaches used for this are discussed and illustrated by a methodological project developed within a health promotion programme in a deprived area. Eventually the challenge of transferring an evidence-based intervention into practice and to achieve its sustainability is addressed. Summary This article describes a general roadmap to primary prevention comprising (1) the identification of target groups and settings, (2) the identification of modifiable risk

  2. 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

  3. Jump start: a targeted substance abuse prevention program.

    PubMed

    Harrington, N G; Donohew, L

    1997-10-01

    A substance abuse prevention and life skills program for economically disadvantaged, high sensation seeking African American teens was developed and tested in Cincinnati, Ohio. Formative research was conducted to determine program content and format. Over two implementations, 289 individuals in the target population were recruited as participants for the field test of the program. For the first implementation, participants were randomly selected from the city's summer youth employment program. For the second, a media campaign was designed to recruit participants. Process evaluation indicated that participants evaluated the program extremely positively. Outcome evaluation indicated that significant pretest differences between high and low sensation seekers were neutralized for liquor and marijuana in both years of the program and for attitude toward drugs in the first year of the program. These results suggest that sensation seeking is a useful message design and audience-targeting variable for substance abuse prevention program design. Implications and recommendations for future research are discussed. PMID:9307894

  4. 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

  5. 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

  6. 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

  7. Familial Breast Cancer – Targeted Therapy in Secondary and Tertiary Prevention

    PubMed Central

    Kast, Karin; Rhiem, Kerstin

    2015-01-01

    Summary The introduction of an increasing number of individualized molecular targeted therapies into clinical routine mirrors their importance in modern cancer prevention and treatment. Well-known examples for targeted agents are the monoclonal antibody trastuzumab and the selective estrogen receptor modulator tamoxifen. The identification of an unaltered gene in tumor tissue in colon cancer (KRAS) is a predictor for the patient's response to targeted therapy with a monoclonal antibody (cetuximab). Targeted therapy for hereditary breast and ovarian cancer has become a reality with the approval of olaparib for platin-sensitive late relapsed BRCA-associated ovarian cancer in December 2014. This manuscript reviews the status quo of poly-ADP-ribose polymerase inhibitors (PARPi) in the therapy of breast and ovarian cancer as well as the struggle for carboplatin as a potential standard of care for triple-negative and, in particular, BRCA-associated breast cancer. Details of the mechanism of action with information on tumor development are provided, and an outlook for further relevant research is given. The efficacy of agents against molecular targets together with the identification of an increasing number of cancer-associated genes will open the floodgates to a new era of treatment decision-making based on molecular tumor profiles. Current clinical trials involving patients with BRCA-associated cancer explore the efficacy of the molecular targeted therapeutics platinum and PARPi. PMID:25960722

  8. 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

  9. Bioactive Food Components, Inflammatory Targets, and Cancer Prevention

    PubMed Central

    Kim, Young S.; Young, Matthew R.; Bobe, Gerd; Colburn, Nancy H.; Milner, John A.

    2012-01-01

    Various dietary components may modify chronic inflammatory processes at the stage of cytokine production, amplification of nuclear factor-κB–mediated inflammatory gene expression, and the release of anti-inflammatory cytokine, transforming growth factor-β. This review provides a synopsis of the strengths and weaknesses of the evidence that specific bioactive food components influence inflammation-related targets linked to cancer. A target repeatedly surfacing as a site of action for several dietary components is transforming growth factor β. Whereas the use of dietary intervention strategies offers intriguing possibilities for maintaining normal cell function by modifying a process that is essential for cancer development and progression, more information is needed to characterize the minimum quantity of the bioactive food components required to bring about a change in inflammation-mediated cancer, the ideal time for intervention, and the importance of genetics in determining the response. Unquestionably, the societal benefits of using foods and their components to prevent chronic inflammation and associated complications, including cancer, are enormous. PMID:19258539

  10. 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.

  11. 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

  12. 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. PMID:25600295

  13. 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

  14. 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

  15. 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

  16. Patchy progress on obesity prevention: emerging examples, entrenched barriers, and new thinking.

    PubMed

    Roberto, Christina A; Swinburn, Boyd; Hawkes, Corinna; Huang, Terry T-K; Costa, Sergio A; Ashe, Marice; Zwicker, Lindsey; Cawley, John H; Brownell, Kelly D

    2015-06-13

    Despite isolated areas of improvement, no country to date has reversed its obesity epidemic. Governments, together with a broad range of stakeholders, need to act urgently to decrease the prevalence of obesity. In this Series paper, we review several regulatory and non-regulatory actions taken around the world to address obesity and discuss some of the reasons for the scarce and fitful progress. Additionally, we preview the papers in this Lancet Series, which each identify high-priority actions on key obesity issues and challenge some of the entrenched dichotomies that dominate the thinking about obesity and its solutions. Although obesity is acknowledged as a complex issue, many debates about its causes and solutions are centred around overly simple dichotomies that present seemingly competing perspectives. Examples of such dichotomies explored in this Series include personal versus collective responsibilities for actions, supply versus demand-type explanations for consumption of unhealthy food, government regulation versus industry self-regulation, top-down versus bottom-up drivers for change, treatment versus prevention priorities, and a focus on undernutrition versus overnutrition. We also explore the dichotomy of individual versus environmental drivers of obesity and conclude that people bear some personal responsibility for their health, but environmental factors can readily support or undermine the ability of people to act in their own self-interest. We propose a reframing of obesity that emphasises the reciprocal nature of the interaction between the environment and the individual. Today's food environments exploit people's biological, psychological, social, and economic vulnerabilities, making it easier for them to eat unhealthy foods. This reinforces preferences and demands for foods of poor nutritional quality, furthering the unhealthy food environments. Regulatory actions from governments and increased efforts from industry and civil society will be

  17. 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…

  18. INDEXES THAT ENHANCE STRATEGIC POLLUTION PREVENTION TARGETING AND REPORTING

    EPA Science Inventory

    Demonstrates innovative approaches to producing Green and Clean Indexes for Sectors and States using available Toxic Release Inventory (TRI) and Manufacturing Gross Product Data. The current national Pollution Prevention Measure used by US EPA is TRI Waste Managed (less recycl...

  19. 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. PMID:23292574

  20. 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

  1. 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

  2. Hospital Readmissions: Necessary Evil or Preventable Target For Quality Improvement

    PubMed Central

    Brown, Erin G.; Burgess, Debra; Li, Chin-Shang; Canter, Robert J.; Bold, Richard J.

    2014-01-01

    OBJECTIVES To evaluate readmission rates and associated factors in order to identify potentially preventable readmissions. SUMMARY BACKGROUND DATA The decision to penalize hospitals for readmissions is compelling healthcare systems to develop processes to minimize readmissions. Research to identify preventable readmissions is critical to achieve these goals. METHODS We performed a retrospective review of University HealthSystem Consortium database for cancer patients hospitalized from 1/2010–9/2013. Outcome measures were 7-, 14-, and 30-day readmission rates and readmission diagnoses. Hospital and disease characteristics were evaluated to evaluate relationships with readmission. RESULTS 2,517,886 patients were hospitalized for cancer treatment. Readmission rates at 7, 14, and 30 days were 2.2%, 3.7%, and 5.6%. Despite concern that premature hospital discharge may be associated with increased readmissions, a shorter initial length of stay predicted lower readmission rates. Furthermore, high volume centers and designated cancer centers had higher readmission rates. Evaluating institutional data (N=2517 patients) demonstrated that factors associated with higher readmission rates include: discharge from a medical service, site of malignancy, emergent primary admission. When examining readmission within 7 days for surgical services, the most common readmission diagnoses were infectious causes (46.3%), nausea/vomiting/dehydration (26.8%), and pain (6.1%). CONCLUSIONS A minority of patients following hospitalization for cancer-related therapy are readmitted with potentially preventable conditions such as nausea, vomiting, dehydration and pain. However, most factors associated with readmission cannot be modified. Additionally, high volume centers and designated cancer centers have higher readmission rates, which may indicate that readmission rates may not be an appropriate marker for quality improvement. PMID:25203874

  3. 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

  4. Targeting transcription factor STAT3 for cancer prevention and therapy.

    PubMed

    Chai, Edna Zhi Pei; Shanmugam, Muthu K; Arfuso, Frank; Dharmarajan, Arunasalam; Wang, Chao; Kumar, Alan Prem; Samy, Ramar Perumal; Lim, Lina H K; Wang, Lingzhi; Goh, Boon Cher; Ahn, Kwang Seok; Hui, Kam Man; Sethi, Gautam

    2016-06-01

    Signal Transducers and Activators of Transcription (STATs) comprise an important class of transcription factors that have been implicated in a wide variety of essential cellular functions related to proliferation, survival, and angiogenesis. Among various STAT members, STAT3 is frequently overexpressed in tumor cells as well as tissue samples, and regulates the expression of numerous oncogenic genes controlling the growth and metastasis of tumor cells. The current review briefly discusses the importance of STAT3 as a potential target for cancer therapy and also provides novel insights into various classes of existing pharmacological inhibitors of this transcription factor that can be potentially developed as anti-cancer drugs. PMID:26478441

  5. Targeting memory processes with drugs to prevent or cure PTSD

    PubMed Central

    Cain, Christopher K.; Maynard, George D.; Kehne, John H.

    2015-01-01

    Introduction Post-traumatic stress disorder (PTSD) is a chronic debilitating psychiatric disorder resulting from exposure to a severe traumatic stressor and an area of great unmet medical need. Advances in pharmacological treatments beyond the currently approved SSRIs are needed. Areas covered Background on PTSD, as well as the neurobiology of stress responding and fear conditioning, is provided. Clinical and preclinical data for investigational agents with diverse pharmacological mechanisms are summarized. Expert opinion Advances in the understanding of stress biology and mechanisms of fear conditioning plasticity provide a rationale for treatment approaches that may reduce hyperarousal and dysfunctional aversive memories in PTSD. One challenge is to determine if these components are independent or reflect a common underlying neurobiological alteration. Numerous agents reviewed have potential for reducing PTSD core symptoms or targeted symptoms in chronic PTSD. Promising early data support drug approaches that seek to disrupt dysfunctional aversive memories by interfering with consolidation soon after trauma exposure, or in chronic PTSD, by blocking reconsolidation and/or enhancing extinction. Challenges remain for achieving selectivity when attempting to alter aversive memories. Targeting the underlying traumatic memory with a combination of pharmacological therapies applied with appropriate chronicity, and in combination with psychotherapy, is expected to substantially improve PTSD treatment. PMID:22834476

  6. The "Lugna Gatan" Project--An Example of Enterprise in Crime Prevention Work

    ERIC Educational Resources Information Center

    Roth, Niklas

    2004-01-01

    Over the course of the last decade, Stockholm has witnessed the emergence of a number of voluntary organizations that are active in the field of crime prevention. This article describes the "Lugna Gatan" project, which was initiated in Stockholm in 1994. The idea was to create an organization comprised of young adults aged between 20 and 30 whose…

  7. 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.

  8. 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

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

    PubMed

    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

  10. Target delamination by spallation and ejecta dragging: An example from the Ries crater's periphery

    NASA Astrophysics Data System (ADS)

    Kenkmann, Thomas; Ivanov, Boris A.

    2006-11-01

    Subhorizontal shear planes (detachments) are observed in bedded limestones in the periphery of the Ries impact crater, Germany. These detachments occur at 0.8-1.8 crater radii distance from the crater center beneath deposits of the continuous ejecta blanket. Striations on detachment planes and offsets of markers indicate top-outward shearing with radial slip vectors. Detachments were found at depths between a few meters and more than 50 m beneath the target surface. The displacements along these faults range from meters to decameters and decrease with increasing depth and distance from the crater center. With increasing crater distance, detachment horizons tend to climb to shallower levels. Cross-cutting relationships to faults associated with the crater collapse indicate that detachment faulting started prior to the collapse but continued during crater modification. Numerical modeling of the cratering process shows that near-surface deformation outside the transient crater is induced by two separate mechanisms: (i) weak spallation by interference of shock and release waves near the target surface and (ii) subsequent dragging by the deposition of the ejecta curtain. Spallation causes an upward and outward directed motion of target material that increases in magnitude toward the target surface. It leads to decoupling of the uppermost target layers in the early cratering stage without totally disintegrating the rock. The subsequent arrival of the oblique impact shower of the ejecta curtain at the target surface delivers a horizontal momentum to the uppermost target area and results in a second horizontal displacement increment by dragging. With increasing depth this effect vanishes rapidly. Spallation decoupling and subsequent ejecta dragging of near-surface rocks is probably a general cratering mechanism around craters in layered targets with weak interbeds.

  11. Organizing for Quality Improvement in Health Care: An Example From Childhood Obesity Prevention.

    PubMed

    Shaikh, Ulfat; Romano, Patrick; Paterniti, Debora A

    2015-01-01

    Children in rural areas face higher rates of obesity than children in urban areas, and their clinicians face challenges with preventing and managing obesity and translation of evidence into practice. We evaluated how the quality improvement (QI) intervention, Healthy Eating Active Living TeleHealth Community of Practice (HEALTH COP), at 7 rural California clinics addressed these challenges. Focus group interviews with QI team members assessed their experiences and factors related to adoption of key changes. Key challenges were clinician and staff buy-in, changing ingrained clinical practices, and motivating patient and families. Facilitators were top-down organizational requirements for QI, linkages to local QI resources, involvement of clinical champions, alignment with existing practices, incorporating a learning system connecting similar clinics, and clear and consistent communication channels. Evaluations of QI interventions should include not only measurement of effectiveness but also identification of factors associated with change and interactions with organizational processes and contexts. PMID:26115059

  12. Evaluating process in child and family interventions: aggression prevention as an example.

    PubMed

    Tolan, Patrick H; Hanish, Laura D; McKay, Mary M; Dickey, Mitchell H

    2002-06-01

    This article reports on 2 studies designed to develop and validate a set of measures for use in evaluating processes of child and family interventions. In Study 1 responses from 187 families attending an outpatient clinic for child behavior problems were factor analyzed to identify scales, consistent across sources: Alliance (Satisfactory Relationship with Interventionist and Program Satisfaction), Parenting Skill Attainment, Child Cooperation During Session, Child Prosocial Behavior, and Child Aggressive Behavior. Study 2 focused on patterns of scale scores among 78 families taking part in a 22-week preventive intervention designed to affect family relationships, parenting, and child antisocial and prosocial behaviors. The factor structure identified in Study 1 was replicated. Scale construct validity was demonstrated through across-source convergence, sensitivity to intervention change, and ability to discriminate individual differences. Path analysis validated the scales' utility in explaining key aspects of the intervention process. Implications for evaluating processes in family interventions are discussed. PMID:12085734

  13. Role of Suppressor Variables in Primary Prevention Obesity Research: Examples from Two Predictive Models

    PubMed Central

    Knowlden, Adam P.

    2014-01-01

    Pediatric obesity is a pertinent public health challenge. Child physical activity and screen time behaviors enacted within the context of the family and home environment are important determinants of pediatric obesity. The purpose of this study was to operationalize five, maternal-facilitated, social cognitive theory constructs for predicting physical activity and screen time behaviors in children. A secondary purpose was to elucidate the function of suppressor variables in the design and implementation of family- and home-based interventions seeking to prevent pediatric obesity. Instrumentation included face and content validity of the measurement tool by a panel of experts, test-retest reliability of the theoretical constructs, and predictive validity of the constructs through structural equation modeling. Physical activity and screen time were modeled separately according to the five selected social cognitive theory constructs. Data were collected from 224 mothers with children between four and six years of age. Specification indices indicated satisfactory fit for the final physical activity and screen time models. Through a series of four procedures, the structural models identified emotional coping and expectations as suppressor variables for self-efficacy. Suppressor variables can complement program design recommendations by providing a suggested ordering to construct integration within an intervention. PMID:24634793

  14. Designs for Evaluating the Community-Level Impact of Comprehensive Prevention Programs: Examples from the CDC Centers of Excellence in Youth Violence Prevention.

    PubMed

    Farrell, Albert D; Henry, David; Bradshaw, Catherine; Reischl, Thomas

    2016-04-01

    This article discusses the opportunities and challenges of developing research designs to evaluate the impact of community-level prevention efforts. To illustrate examples of evaluation designs, we describe six projects funded by the Centers for Disease Control and Prevention to evaluate multifaceted approaches to reduce youth violence in high-risk communities. Each of these projects was designed to evaluate the community-level impact of multiple intervention strategies to address individual and contextual factors that place youth at risk for violent behavior. Communities differed across projects in their setting, size, and how their boundaries were defined. Each project is using multiple approaches to compare outcomes in one or more intervention communities to those in comparison communities. Five of the projects are using comparative interrupted time-series designs to compare outcomes in an intervention community to matched comparison communities. A sixth project is using a multiple baseline design in which the order and timing of intervention activities is randomized across three communities. All six projects are also using regression point displacement designs to compare outcomes within intervention communities to those within broader sets of similar communities. Projects are using a variety of approaches to assess outcomes including archival records, surveys, and direct observations. We discuss the strengths and weaknesses of the designs of these projects and illustrate the challenges of designing high-quality evaluations of comprehensive prevention approaches implemented at the community level. PMID:26957507

  15. 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

  16. Paving the way for therapeutic prevention of tumor metastasis with agents targeting mitochondrial superoxide

    PubMed Central

    Porporato, Paolo E; Sonveaux, Pierre

    2015-01-01

    Metastatic dissemination is associated with poor prognosis of cancer patients. While exploring glucose metabolism in metastatic progenitor cells, we recently found that several different dysfunctions that share the ability to induce mitochondrial superoxide production also promote tumor metastasis. Selective targeting of mitochondrial superoxide prevented spontaneous metastasis in mice, opening a new avenue for therapy. PMID:27308448

  17. Prevention-Related Research Targeting African American Alternative Education Program Students

    ERIC Educational Resources Information Center

    Carswell, Steven B.; Hanlon, Thomas E.; Watts, Amy M.; O'Grady, Kevin E.

    2014-01-01

    This article reports on a program of research that examined the background, planning, implementation, and evaluation of an after-school preventive intervention program within an ongoing urban alternative education program targeting African American students referred to the school because of their problematic behavior in regular schools. The…

  18. The Feminist Theory of Rape: Implications for Prevention Programming Targeted at Male College Students.

    ERIC Educational Resources Information Center

    Haggard, William K.

    1991-01-01

    Briefly describes three prevailing theories of rape: evolutionary theory, social learning theory, and feminist theory. Applies feminist theory of rape to practice rationale for prevention programming targeted specifically at traditional-aged college males. Support for the theory, based on results of previous studies, is presented, and implications…

  19. 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…

  20. Prevention of hepatocellular carcinoma: potential targets, experimental models, and clinical challenges

    PubMed Central

    Hoshida, Yujin; Fuchs, Bryan C.; Tanabe, Kenneth K.

    2013-01-01

    Chronic fibrotic liver diseases such as viral hepatitis eventually develop liver cirrhosis, which causes occurrence of hepatocellular carcinoma (HCC). Given the limited therapeutic efficacy in advanced HCC, prevention of HCC development could be an effective strategy for improving patient prognosis. However, there is still no established therapy to meet the goal. Studies have elucidated a wide variety of molecular mechanisms and signaling pathways involved in HCC development. Genetically-engineered or chemically-treated experimental models of cirrhosis and HCC have been developed and shown their potential value in investigating molecular therapeutic targets and diagnostic biomarkers for HCC prevention. In this review, we overview potential targets of prevention and currently available experimental models, and discuss strategies to translate the findings into clinical practice. PMID:22873223

  1. A Community Forum to Assess the Needs and Preferences for Domestic Violence Prevention Targeting Hispanics

    PubMed Central

    Gonzalez-Guarda, Rosa Maria; Diaz, Elizabeth Grace Lipman; Cummings, Amanda M.

    2012-01-01

    Hispanics are disproportionately affected by the occurrence and consequences of domestic violence when compared to their non-Hispanic counterparts. The Partnership for Domestic Violence used a community-based participatory research approach to assess the needs and preferences for preventing domestic violence (DV) among Hispanics in Miami-Dade County. Researchers conducted a community forum in which data collected from focus groups were presented to approximately 100 community members to gather their feedback regarding the development of DV prevention programs tailored for Hispanics. Participants were in high agreement that a program targeting youth is the highest priority and that specific cultural variables should be incorporated to make the program most effective. Recommendations for DV prevention targeting Hispanics and the use of community forums as a method of research are provided. PMID:23268109

  2. [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

  3. 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

  4. Early life programming as a target for prevention of child and adolescent mental disorders

    PubMed Central

    2014-01-01

    This paper concerns future policy development and programs of research for the prevention of mental disorders based on research emerging from fetal and early life programming. The current review offers an overview of findings on pregnancy exposures such as maternal mental health, lifestyle factors, and potential teratogenic and neurotoxic exposures on child outcomes. Outcomes of interest are common child and adolescent mental disorders including hyperactive, behavioral and emotional disorders. This literature suggests that the preconception and perinatal periods offer important opportunities for the prevention of deleterious fetal exposures. As such, the perinatal period is a critical period where future mental health prevention efforts should be focused and prevention models developed. Interventions grounded in evidence-based recommendations for the perinatal period could take the form of public health, universal and more targeted interventions. If successful, such interventions are likely to have lifelong effects on (mental) health. PMID:24559477

  5. 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

    2015-01-01

    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

  6. 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

  7. 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

  8. Analysing Time to Event Data in Dementia Prevention Trials: The Example of the GuidAge Study of EGb761.

    PubMed

    Scherrer, B; Andrieu, S; Ousset, P J; Berrut, G; Dartigues, J F; Dubois, B; Pasquier, F; Piette, F; Robert, P; Touchon, J; Garnier, P; Mathiex-Fortunet, H; Vellas, B

    2015-12-01

    Time-to-event analysis is frequently used in medical research to investigate potential disease-modifying treatments in neurodegenerative diseases. Potential treatment effects are generally evaluated using the logrank test, which has optimal power and sensitivity when the treatment effect (hazard ratio) is constant over time. However, there is generally no prior information as to how the hazard ratio for the event of interest actually evolves. In these cases, the logrank test is not necessarily the most appropriate to use. When the hazard ratio is expected to decrease or increase over time, alternative statistical tests such as the Fleming-Harrington test, provide a better sensitivity. An example of this comes from a large, five-year randomised, placebo-controlled prevention trial (GuidAge) in 2854 community-based subjects making spontaneous memory complaints to their family physicians, which evaluated whether treatment with EGb761 can modify the risk of developing AD. The primary outcome measure was the time to conversion from memory complaint to Alzheimer's type dementia. Although there was no significant difference in the hazard function of conversion between the two treatment groups according to the preplanned logrank test, a significant treatment-by-time interaction for the incidence of AD was observed in a protocol-specified subgroup analysis, suggesting that the hazard ratio is not constant over time. For this reason, additional post hoc analyses were performed using the Fleming-Harrington test to evaluate whether there was a signal of a late effect of EGb761. Applying the Fleming-Harrington test, the hazard function for conversion to dementia in the placebo group was significantly different from that in the EGb761 treatment group (p = 0.0054), suggesting a late effect of EGb761. Since this was a post hoc analysis, no definitive conclusions can be drawn as to the effectiveness of the treatment. This post hoc analysis illustrates the interest of performing

  9. 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

  10. 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

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

    PubMed

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

    2016-08-01

    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

  12. 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

  13. 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

  14. HSV Usurps Eukaryotic Initiation Factor 3 Subunit M for Viral Protein Translation: Novel Prevention Target

    PubMed Central

    Cheshenko, Natalia; Trepanier, Janie B.; Segarra, Theodore J.; Fuller, A. Oveta; Herold, Betsy C.

    2010-01-01

    Prevention of genital herpes is a global health priority. B5, a recently identified ubiquitous human protein, was proposed as a candidate HSV entry receptor. The current studies explored its role in HSV infection. Viral plaque formation was reduced by ∼90% in human cells transfected with small interfering RNA targeting B5 or nectin-1, an established entry receptor. However, the mechanisms were distinct. Silencing of nectin-1 prevented intracellular delivery of viral capsids, nuclear transport of a viral tegument protein, and release of calcium stores required for entry. In contrast, B5 silencing had no effect on these markers of entry, but inhibited viral protein translation. Specifically, viral immediate early genes, ICP0 and ICP4, were transcribed, polyadenylated and transported from the nucleus to the cytoplasm, but the viral transcripts did not associate with ribosomes or polysomes in B5-silenced cells. In contrast, immediate early gene viral transcripts were detected in polysome fractions isolated from control cells. These findings are consistent with sequencing studies demonstrating that B5 is eukaryotic initiation factor 3 subunit m (eIF3m). Although B5 silencing altered the polysome profile of cells, silencing had little effect on cellular RNA or protein expression and was not cytotoxic, suggesting that this subunit is not essential for host cellular protein synthesis. Together these results demonstrate that B5 plays a major role in the initiation of HSV protein translation and could provide a novel target for strategies to prevent primary and recurrent herpetic disease. PMID:20676407

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

    PubMed

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

    2015-11-01

    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

  16. [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

  17. Cyclooxygenase inhibition targets neurons to prevent early behavioural decline in Alzheimer's disease model mice.

    PubMed

    Woodling, Nathaniel S; Colas, Damien; Wang, Qian; Minhas, Paras; Panchal, Maharshi; Liang, Xibin; Mhatre, Siddhita D; Brown, Holden; Ko, Novie; Zagol-Ikapitte, Irene; van der Hart, Marieke; Khroyan, Taline V; Chuluun, Bayarsaikhan; Priyam, Prachi G; Milne, Ginger L; Rassoulpour, Arash; Boutaud, Olivier; Manning-Boğ, Amy B; Heller, H Craig; Andreasson, Katrin I

    2016-07-01

    Identifying preventive targets for Alzheimer's disease is a central challenge of modern medicine. Non-steroidal anti-inflammatory drugs, which inhibit the cyclooxygenase enzymes COX-1 and COX-2, reduce the risk of developing Alzheimer's disease in normal ageing populations. This preventive effect coincides with an extended preclinical phase that spans years to decades before onset of cognitive decline. In the brain, COX-2 is induced in neurons in response to excitatory synaptic activity and in glial cells in response to inflammation. To identify mechanisms underlying prevention of cognitive decline by anti-inflammatory drugs, we first identified an early object memory deficit in APPSwe-PS1ΔE9 mice that preceded previously identified spatial memory deficits in this model. We modelled prevention of this memory deficit with ibuprofen, and found that ibuprofen prevented memory impairment without producing any measurable changes in amyloid-β accumulation or glial inflammation. Instead, ibuprofen modulated hippocampal gene expression in pathways involved in neuronal plasticity and increased levels of norepinephrine and dopamine. The gene most highly downregulated by ibuprofen was neuronal tryptophan 2,3-dioxygenase (Tdo2), which encodes an enzyme that metabolizes tryptophan to kynurenine. TDO2 expression was increased by neuronal COX-2 activity, and overexpression of hippocampal TDO2 produced behavioural deficits. Moreover, pharmacological TDO2 inhibition prevented behavioural deficits in APPSwe-PS1ΔE9 mice. Taken together, these data demonstrate broad effects of cyclooxygenase inhibition on multiple neuronal pathways that counteract the neurotoxic effects of early accumulating amyloid-β oligomers. PMID:27190010

  18. 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

  19. [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

  20. Cancer prevention as biomodulation: targeting the initiating stimulus and secondary adaptations.

    PubMed

    Furth, Priscilla A

    2012-10-01

    In a medical sense, biomodulation could be considered a biochemical or cellular response to a disease or therapeutic stimulus. In cancer pathophysiology, the initial oncogenic stimulus leads to cellular and biochemical changes that allow cells, tissue, and organism to accommodate and accept the oncogenic insult. In epithelial cell cancer development, the process of carcinogenesis is frequently characterized by sequential cellular and biochemical adaptations as cells transition through hyperplasia, dysplasia, atypical dysplasia, carcinoma in situ, and invasive cancer. In some cases, the adaptations may persist after the initial oncogenic stimulus is gone in a type of "hit-and-run" oncogenesis. These pathophysiological changes may interfere with cancer prevention therapies targeted solely to the initial oncogenic insult, perhaps contributing to resistance development. Characterization of these accommodating adaptations could provide insight for the development of cancer preventive regimens that might more effectively biomodulate preneoplastic cells toward a more normal state. PMID:23050958

  1. 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

  2. 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

  3. 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

  4. Molecular targets of dietary agents for prevention and therapy of cancer.

    PubMed

    Aggarwal, Bharat B; Shishodia, Shishir

    2006-05-14

    While fruits and vegetables are recommended for prevention of cancer and other diseases, their active ingredients (at the molecular level) and their mechanisms of action less well understood. Extensive research during the last half century has identified various molecular targets that can potentially be used not only for the prevention of cancer but also for treatment. However, lack of success with targeted monotherapy resulting from bypass mechanisms has forced researchers to employ either combination therapy or agents that interfere with multiple cell-signaling pathways. In this review, we present evidence that numerous agents identified from fruits and vegetables can interfere with several cell-signaling pathways. The agents include curcumin (turmeric), resveratrol (red grapes, peanuts and berries), genistein (soybean), diallyl sulfide (allium), S-allyl cysteine (allium), allicin (garlic), lycopene (tomato), capsaicin (red chilli), diosgenin (fenugreek), 6-gingerol (ginger), ellagic acid (pomegranate), ursolic acid (apple, pears, prunes), silymarin (milk thistle), anethol (anise, camphor, and fennel), catechins (green tea), eugenol (cloves), indole-3-carbinol (cruciferous vegetables), limonene (citrus fruits), beta carotene (carrots), and dietary fiber. For instance, the cell-signaling pathways inhibited by curcumin alone include NF-kappaB, AP-1, STAT3, Akt, Bcl-2, Bcl-X(L), caspases, PARP, IKK, EGFR, HER2, JNK, MAPK, COX2, and 5-LOX. The active principle identified in fruit and vegetables and the molecular targets modulated may be the basis for how these dietary agents not only prevent but also treat cancer and other diseases. This work reaffirms what Hippocrates said 25 centuries ago, let food be thy medicine and medicine be thy food. PMID:16563357

  5. 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

  6. 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…

  7. Targeting the TGF-β1 Pathway to Prevent Normal Tissue Injury After Cancer Therapy

    PubMed Central

    2010-01-01

    With >10,000,000 cancer survivors in the U.S. alone, the late effects of cancer treatment are a significant public health issue. Over the past 15 years, much work has been done that has led to an improvement in our understanding of the molecular mechanisms underlying the development of normal tissue injury after cancer therapy. In many cases, these injuries are characterized at the histologic level by loss of parenchymal cells, excessive fibrosis, and tissue atrophy. Among the many cytokines involved in this process, transforming growth factor (TGF)-β1 is thought to play a pivotal role. TGF-β1 has a multitude of functions, including both promoting the formation and inhibiting the breakdown of connective tissue. It also inhibits epithelial cell proliferation. TGF-β1 is overexpressed at sites of injury after radiation and chemotherapy. Thus, TGF-β1 represents a logical target for molecular therapies designed to prevent or reduce normal tissue injury after cancer therapy. Herein, the evidence supporting the critical role of TGF-ß1 in the development of normal tissue injury after cancer therapy is reviewed and the results of recent research aimed at preventing normal tissue injury by targeting the TGF-ß1 pathway are presented. PMID:20413640

  8. Differential Challenges in Coalition Building among HIV Prevention Coalitions Targeting Specific Youth Populations

    PubMed Central

    Robles-Schrader, Grisel M.; Harper, Gary W.; Purnell, Marjorie; Monarrez, Veronica; Ellen, Jonathan M.

    2012-01-01

    Coalitions provide the potential for merging the power, influence, and resources of fragmented individuals and institutions into one collective group that can more effectively focus its efforts on a specific community health issue. Connect to Protect® coalitions devote resources to address the HIV epidemic at a structural level. This research examines differential challenges in coalition processes that may facilitate/hinder coalition building to achieve HIV prevention through structural change. Qualitative interviews conducted with community partners participating across 10 coalitions were analyzed to compare responses of those individuals working on HIV prevention coalitions targeting adolescent and young adult gay and bisexual men versus those targeting adolescent and young adult heterosexual women. Community partner responses revealed differences across several key areas including: a) acceptability and goals in discussing sexual issues with adolescents, b) goals of sexual health promotion activities, and c) competition among collaborating agencies. Themes highlighted in this research can complement existing community intervention literature by helping community mobilizers, interventionists, and researchers understand how cultural norms affect youth-specific coalition work. PMID:24188354

  9. Mitochondria-targeted antioxidant prevents cardiac dysfunction induced by tafazzin gene knockdown in cardiac myocytes.

    PubMed

    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

  10. 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,…

  11. 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

  12. 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

  13. 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

  14. 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

  15. 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

  16. 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

  17. 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

  18. Readability of skin cancer prevention brochures targeting parents of young children.

    PubMed

    Slaten, D; Parrott, R; Steiner, C

    1999-06-01

    Long-term exposure to UV radiation and severe sunburns increase one's risk of experiencing malignant melanoma later in life, so parents need to be informed about how to protect children from overexposure to the sun. We attempted to determine readability of skin cancer brochures targeted toward parents of young children. SMOG and FOG readability formulas were applied to 8 brochures published by the American Cancer Society, Skin Cancer Foundation, American Academy of Dermatology, and the Anti-Cancer Council. Readability levels of the brochures ranged between the 8th and 12th grade levels. To reduce the incidence of skin cancer, sun-safe knowledge and behavior should start in childhood. Pediatricians need access to brochures written at readability levels for the average parent. Skin cancer brochures written at the eighth or ninth grade comprehension levels may allow pediatricians to educate more parents about the importance of skin cancer prevention in childhood. PMID:10365934

  19. 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

  20. 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

  1. Nonmuscle myosin IIB as a therapeutic target for the prevention of relapse to methamphetamine use.

    PubMed

    Young, E J; Blouin, A M; Briggs, S B; Sillivan, S E; Lin, L; Cameron, M D; Rumbaugh, G; Miller, C A

    2016-05-01

    Memories associated with drug use increase vulnerability to relapse in substance use disorder (SUD), and there are no pharmacotherapies for the prevention of relapse. Previously, we reported a promising finding that storage of memories associated with methamphetamine (METH), but not memories for fear or food reward, is vulnerable to disruption by actin depolymerization in the basolateral amygdala complex (BLC). However, actin is not a viable therapeutic target because of its numerous functions throughout the body. Here we report the discovery of a viable therapeutic target, nonmuscle myosin IIB (NMIIB), a molecular motor that supports memory by directly driving synaptic actin polymerization. A single intra-BLC treatment with Blebbistatin (Blebb), a small-molecule inhibitor of class II myosin isoforms, including NMIIB, produced a long-lasting disruption of context-induced drug seeking (at least 30 days). Further, postconsolidation genetic knockdown of Myh10, the heavy chain of the most highly expressed NMII in the BLC, was sufficient to produce METH-associated memory loss. Blebb was found to be highly brain penetrant. A single systemic injection of the compound selectively disrupted the storage of METH-associated memory and reversed the accompanying increase in BLC spine density. This effect was specific to METH-associated memory, as it had no effect on an auditory fear memory. The effect was also independent of retrieval, as METH-associated memory was disrupted 24 h after a single systemic injection of Blebb delivered in the home cage. Together, these results argue for the further development of small-molecule inhibitors of NMII as potential therapeutics for the prevention of SUD relapse triggered by drug associations. PMID:26239291

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

    PubMed

    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

  3. 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

  4. Methylphenidate and μ opioid receptor interactions: A pharmacological target for prevention of stimulant abuse

    PubMed Central

    Zhu, Jinmin; Spencer, Thomas J.; Kachroo, Anil; Liu-Chen, Lee-Yuan; Biederman, Joseph; Bhide, Pradeep G.

    2011-01-01

    Methylphenidate (MPH) is one of the most commonly used and highly effective treatments for attention deficit hyperactivity disorder (ADHD) in children and adults. As the therapeutic use of MPH has increased, so has its abuse and illicit street-use. Yet, the mechanisms associated with development of MPH-associated abuse and dependence are not well understood making it difficult to develop methods to help its mitigation. As a result, many ADHD patients especially children and youth, that could benefit from MPH treatment do not receive it and risk life-long disabilities associated with untreated ADHD. Therefore, understanding the mechanisms associated with development of MPH addiction and designing methods to prevent it assume high public health significance. Using a mouse model we show that supra-therapeutic doses of MPH produce rewarding effects (surrogate measure for addiction in humans) in a conditioned place preference paradigm and upregulate μ opioid receptor (MOPR) activity in the striatum and nucleus accumbens, brain regions associated with reward circuitry. Co-administration of naltrexone, a non-selective opioid receptor antagonist, prevents MPH-induced MOPR activation and the rewarding effects. The MPH-induced MOPR activation and rewarding effect require activation of the dopamine D1 but not the D2 receptor. These findings identify the MOPR as a potential target for attenuating rewarding effects of MPH and suggest that a formulation that combines naltrexone with MPH could be a useful pharmaceutical approach to alleviate abuse potential of MPH and other stimulants. PMID:21545805

  5. Identifying target groups for the prevention of depression among caregivers of dementia patients

    PubMed Central

    Joling, Karlijn J.; Smit, Filip; van Marwijk, Harm W. J.; van der Horst, Henriëtte E.; Scheltens, Philip; Schulz, Richard; van Hout, Hein P. J.

    2014-01-01

    Background Depression in informal caregivers of persons with dementia is a major, costly and growing problem. However, it is not yet clear which caregivers are at increased risk of developing depression. With this knowledge preventive strategies could focus on these groups to maximize health gain and minimize effort. Methods The onset of clinically relevant depression was measured with the Center for Epidemiologic Studies - Depression Scale in 725 caregivers who were not depressed at baseline and who were providing care for a relative with dementia. Caregivers were followed over 18 months. The indices calculated to identify the most important risk indicators were: odds ratio, attributable fraction, exposure rate and number needing to be treated. Results The following significant indicators of depression onset were identified: increased initial depressive symptoms, poor self-rated health status and white or Hispanic race/ethnicity. The incidence of depression would decrease by 72.3% (attributive fraction) if these risk indicators together are targeted by a completely effective intervention. Race/ethnicity was not a significant predictor if caregivers of patients who died or were institutionalized were left out of the analyses. Conclusion Detection of only a few characteristics makes it possible to identify high-risk groups in an efficient way. Focusing on these easy-to-assess characteristics might contribute to a cost-effective prevention of depression in caregivers. PMID:21880175

  6. The uterine myocyte as a target for prevention of preterm birth

    PubMed Central

    Mitchell, B.F.; Aguilar, H.N.; Mosher, A.; Wood, S.; Slater, D.M.

    2013-01-01

    Preterm birth (PTB) remains the most common cause of neonatal morbidity and mortality as well as long-term disability. Current strategies to prevent or arrest spontaneous preterm labor (SPTL) have limited success. For almost three decades, there have been no novel pharmacological agents used clinically to address this important obstetrical complication. In this review, we focus on the uterine myocyte as a target for prevention of spontaneous PTB. After presenting an overview of intracellular signaling pathways that are important in regulation of smooth muscle contractility, we discuss previous and current pharmacological approaches to manage SPTL. We also present recent evidence from our own laboratories suggesting a potentially novel and uterine-specific approach to maintain or impose uterine relaxation. Finally, we briefly discuss extrinsic systems that might affect uterine activity and reinforce the concept that SPTL represents a syndrome that is the end result of a variety of pathophysiologic etiologies leading to PTB. We conclude by emphasizing the need for much more research to provide sufficient understanding of the mechanisms of SPTL and to make inroads towards reducing the incidence and adverse consequences of this common and serious syndrome. PMID:24753931

  7. 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

  8. 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

  9. Targeting FSTL1 prevents tumor bone metastasis and consequent immune dysfunction.

    PubMed

    Kudo-Saito, Chie; Fuwa, Takafumi; Murakami, Kouichi; Kawakami, Yutaka

    2013-10-15

    Bone metastasis greatly deteriorates the quality of life in patients with cancer. Although mechanisms have been widely investigated, the relationship between cancer bone metastasis and antitumor immunity in the host has been much less studied. Here, we report a novel mechanism of bone metastasis mediated by FSTL1, a follistatin-like glycoprotein secreted by Snail(+) tumor cells, which metastasize frequently to bone. We found that FSTL1 plays a dual role in bone metastasis-in one way by mediating tumor cell invasion and bone tropism but also in a second way by expanding a population of pluripotent mesenchymal stem-like CD45(-)ALCAM(+) cells derived from bone marrow. CD45(-)ALCAM(+) cells induced bone metastasis de novo, but they also generated CD8(low) T cells with weak CTL activity in the periphery, which also promoted bone metastasis in an indirect manner. RNA interference-mediated attenuation of FSTL1 in tumor cells prevented bone metastasis along with the parallel increase in ALCAM(+) cells and CD8(low) T cells. These effects were accompanied by heightened antitumor immune responses in vitro and in vivo. In clinical specimens of advanced breast cancer, ALCAM(+) cells increased with FSTL1 positivity in tumor tissues, but not in adjacent normal tissues, consistent with a causal connection between these molecules. Our findings define FSTL1 as an attractive candidate therapeutic target to prevent or treat bone metastasis, which remains a major challenge in patients with cancer. PMID:23966294

  10. Molecular Mechanisms of Diabetic Retinopathy, General Preventive Strategies, and Novel Therapeutic Targets

    PubMed Central

    Safi, Sher Zaman; Kumar, Selva; Ismail, Ikram Shah Bin

    2014-01-01

    The growing number of people with diabetes worldwide suggests that diabetic retinopathy (DR) and diabetic macular edema (DME) will continue to be sight threatening factors. The pathogenesis of diabetic retinopathy is a widespread cause of visual impairment in the world and a range of hyperglycemia-linked pathways have been implicated in the initiation and progression of this condition. Despite understanding the polyol pathway flux, activation of protein kinase C (KPC) isoforms, increased hexosamine pathway flux, and increased advanced glycation end-product (AGE) formation, pathogenic mechanisms underlying diabetes induced vision loss are not fully understood. The purpose of this paper is to review molecular mechanisms that regulate cell survival and apoptosis of retinal cells and discuss new and exciting therapeutic targets with comparison to the old and inefficient preventive strategies. This review highlights the recent advancements in understanding hyperglycemia-induced biochemical and molecular alterations, systemic metabolic factors, and aberrant activation of signaling cascades that ultimately lead to activation of a number of transcription factors causing functional and structural damage to retinal cells. It also reviews the established interventions and emerging molecular targets to avert diabetic retinopathy and its associated risk factors. PMID:25105142

  11. Host-targeting agents for prevention and treatment of chronic hepatitis C - perspectives and challenges.

    PubMed

    Zeisel, Mirjam B; Lupberger, Joachim; Fofana, Isabel; Baumert, Thomas F

    2013-02-01

    Hepatitis C virus (HCV) infection is a major cause of chronic liver disease and hepatocellular carcinoma worldwide. Furthermore, HCV-induced liver disease is a major indication of liver transplantation. In the past years, direct-acting antivirals (DAAs) targeting HCV enzymes have been developed. DAAs increase the virologic response to anti-HCV therapy but may lead to selection of drug-resistant variants and treatment failure. To date, strategies to prevent HCV infection are still lacking and antiviral therapy in immunocompromised patients, patients with advanced liver disease and HIV/HCV-co-infection remains limited. Alternative or complementary approaches addressing the limitations of current antiviral therapies are to boost the host's innate immunity or interfere with host factors required for pathogenesis. Host-targeting agents (HTAs) provide an interesting perspective for novel antiviral strategies against viral hepatitis since they have (i) a high genetic barrier to resistance, (ii) a pan-genotypic antiviral activity, and (iii) complementary mechanisms of action to DAAs and might therefore act in a synergistic manner with current standard of care or DAAs in clinical development. This review highlights HTAs against HCV infection that have potential as novel antivirals and are in preclinical or clinical development. PMID:23041307

  12. Bone targeted therapy for preventing skeletal-related events in metastatic breast cancer.

    PubMed

    Irelli, Azzurra; Cocciolone, Valentina; Cannita, Katia; Zugaro, Luigi; Di Staso, Mario; Lanfiuti Baldi, Paola; Paradisi, Stefania; Sidoni, Tina; Ricevuto, Enrico; Ficorella, Corrado

    2016-06-01

    Cancer cells can alter physiological mechanisms within bone resulting in high bone turnover, and consequently in skeletal-related events (SREs), causing severe morbidity in affected patients. The goals of bone targeted therapy, as bisphosphonates and denosumab, are the reduction of incidence and the delay in occurrence of the SREs, to improve quality of life and pain control. The toxicity profile is similar between bisphosphonates and denosumab, even if pyrexia, bone pain, arthralgia, renal failure and hypercalcemia are more common with bisphosphonates, while hypocalcemia and toothache are more frequently reported with denosumab. Osteonecrosis of the jaw (ONJ) occurred infrequently without statistically significant difference. The present review aims to provide an assessment on bone targeted therapies for preventing the occurrence of SREs in bone metastatic breast cancer patients, critically analyzing the evidence available so far on their effectiveness, in light of the different mechanisms of action. Thus, we try to provide tools for the most fitting treatment of bone metastatic breast cancer patients. We also provide an overview on the usefulness of bone turnover markers in clinical practice and new molecules currently under study for the treatment of bone metastatic disease. PMID:27091227

  13. Molecular mechanisms of diabetic retinopathy, general preventive strategies, and novel therapeutic targets.

    PubMed

    Safi, Sher Zaman; Qvist, Rajes; Kumar, Selva; Batumalaie, Kalaivani; Ismail, Ikram Shah Bin

    2014-01-01

    The growing number of people with diabetes worldwide suggests that diabetic retinopathy (DR) and diabetic macular edema (DME) will continue to be sight threatening factors. The pathogenesis of diabetic retinopathy is a widespread cause of visual impairment in the world and a range of hyperglycemia-linked pathways have been implicated in the initiation and progression of this condition. Despite understanding the polyol pathway flux, activation of protein kinase C (KPC) isoforms, increased hexosamine pathway flux, and increased advanced glycation end-product (AGE) formation, pathogenic mechanisms underlying diabetes induced vision loss are not fully understood. The purpose of this paper is to review molecular mechanisms that regulate cell survival and apoptosis of retinal cells and discuss new and exciting therapeutic targets with comparison to the old and inefficient preventive strategies. This review highlights the recent advancements in understanding hyperglycemia-induced biochemical and molecular alterations, systemic metabolic factors, and aberrant activation of signaling cascades that ultimately lead to activation of a number of transcription factors causing functional and structural damage to retinal cells. It also reviews the established interventions and emerging molecular targets to avert diabetic retinopathy and its associated risk factors. PMID:25105142

  14. 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

  15. Peptides Targeting the Desmoglein 3 Adhesive Interface Prevent Autoantibody-induced Acantholysis in Pemphigus*

    PubMed Central

    Heupel, Wolfgang-Moritz; Müller, Thomas; Efthymiadis, Athina; Schmidt, Enno; Drenckhahn, Detlev; Waschke, Jens

    2009-01-01

    Pemphigus vulgaris (PV) autoantibodies directly inhibit desmoglein (Dsg) 3-mediated transinteraction. Because cellular signaling also seems to be required for PV pathogenesis, it is important to characterize the role of direct inhibition in pemphigus acantholysis to allow establishment of new therapeutic approaches. Therefore, we modeled the Dsg1 and Dsg3 sequences into resolved cadherin structures and predicted peptides targeting the adhesive interface of both Dsg3 and Dsg1. In atomic force microscopy single molecule experiments, the self-designed cyclic single peptide specifically blocked homophilic Dsg3 and Dsg1 transinteraction, whereas a tandem peptide (TP) consisting of two combined single peptides did not. TP did not directly block binding of pemphigus IgG to their target Dsg antigens but prevented PV-IgG-induced inhibition of Dsg3 transinteraction in cell-free (atomic force microscopy) and cell-based (laser tweezer) experiments, indicating stabilization of Dsg3 bonds. Similarly, PV-IgG-mediated acantholysis and disruption of Dsg3 localization in HaCaT keratinocytes was partially blocked by TP. This is the first evidence that direct inhibition of Dsg3 binding is important for PV pathogenesis and that peptidomimetics stabilizing Dsg transinteraction may provide a novel approach for PV treatment. PMID:19164289

  16. SUMO-targeted ubiquitin ligase RNF4 plays a critical role in preventing chromosome loss.

    PubMed

    Hirota, Kouji; Tsuda, Masataka; Murai, Junko; Takagi, Tokiyo; Keka, Islam Shamima; Narita, Takeo; Fujita, Mari; Sasanuma, Hiroyuki; Kobayashi, Junya; Takeda, Shunichi

    2014-10-01

    RING finger protein 4 (RNF4) represents a subclass of ubiquitin ligases that target proteins modified by the small ubiquitin-like modifier (SUMO) for ubiquitin-mediated degradation. We disrupted the RNF4 gene in chicken DT40 cells and found that the resulting RNF4(-/-) cells gradually lost proliferation capability. Strikingly, this compromised proliferation was associated with an unprecedented cellular effect: the gradual decrease in the number of intact chromosomes. In the 6 weeks after gene targeting, there was a 25% reduction in the DNA content of the RNF4(-/-) cells. Regarding trisomic chromosome 2, 60% of the RNF4(-/-) cells lost one homologue, suggesting that DNA loss was mediated by whole chromosome loss. To determine the cause of this chromosome loss, we examined cell-cycle checkpoint pathways. RNF4(-/-) cells showed a partial defect in the spindle assembly checkpoint, premature dissociation of sister chromatids, and a marked increase in the number of lagging chromosomes at anaphase. Thus, combined defects in SAC and sister chromatid cohesion may result in increased lagging chromosomes, leading to chromosome loss without accompanying chromosome gain in RNF4(-/-) cells. We therefore propose that RNF4 plays a novel role in preventing the loss of intact chromosomes and ensures the maintenance of chromosome integrity. PMID:25205350

  17. 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

  18. 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 ...

  19. 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

  20. International organizations and NGOs: an example of international collaboration to improve women's health by preventing unsafe abortion.

    PubMed

    Zaidi, Shahida; Hassan, Ezzeldin Osman; Hodorogea, Stelian; Leke, Robert J I; Távara, Luis; de Gil, Marina Padilla

    2010-07-01

    International collaboration with organizations and agencies is a basic requirement for the success of the FIGO Initiative for the Prevention of Unsafe Abortion and its Consequences. Many activities being carried out by the organizations form a part of the plans of action of all countries participating in the Initiative. It was, therefore, not difficult to obtain their collaboration in implementing the plans of action. The many ways in which they have collaborated and continue to do so are described in this article. This collaboration has saved time, avoided duplication of effort, and has also satisfied the Accra Agenda of Action by reducing fragmentation of funding. It has already contributed toward preventing unsafe abortion and reducing abortion-related maternal deaths and morbidities, and is expected to contribute even more significantly in the coming months and years. PMID:20451202

  1. Targeted deletion of p53 in the proximal tubule prevents ischemic renal injury.

    PubMed

    Ying, Yuan; Kim, Jinu; Westphal, Sherry N; Long, Kelly E; Padanilam, Babu J

    2014-12-01

    The contribution of p53 to kidney dysfunction, inflammation, and tubular cell death, hallmark features of ischemic renal injury (IRI), remains undefined. Here, we studied the role of proximal tubule cell (PTC)-specific p53 activation on the short- and long-term consequences of renal ischemia/reperfusion injury in mice. After IRI, mice with PTC-specific deletion of p53 (p53 knockout [KO]) had diminished whole-kidney expression levels of p53 and its target genes, improved renal function, which was shown by decreased plasma levels of creatinine and BUN, and attenuated renal histologic damage, oxidative stress, and infiltration of neutrophils and macrophages compared with wild-type mice. Notably, necrotic cell death was attenuated in p53 KO ischemic kidneys as well as oxidant-injured p53-deficient primary PTCs and pifithrin-α-treated PTC lines. Reduced oxidative stress and diminished expression of PARP1 and Bax in p53 KO ischemic kidneys may account for the decreased necrosis. Apoptosis and expression of proapoptotic p53 targets, including Bid and Siva, were also significantly reduced, and cell cycle arrest at the G2/M phase was attenuated in p53 KO ischemic kidneys. Furthermore, IRI-induced activation of TGF-β and the long-term development of inflammation and interstitial fibrosis were significantly reduced in p53 KO mice. In conclusion, specific deletion of p53 in the PTC protects kidneys from functional and histologic deterioration after IRI by decreasing necrosis, apoptosis, and inflammation and modulates the long-term sequelae of IRI by preventing interstitial fibrogenesis. PMID:24854277

  2. Targeting NK-1 Receptors to Prevent and Treat Pancreatic Cancer: A New Therapeutic Approach

    PubMed Central

    Muñoz, Miguel; Coveñas, Rafael

    2015-01-01

    Pancreatic cancer (PC) is the fourth leading cause of cancer related-deaths in both men and women, and the 1- and 5-year relative survival rates are 25% and 6%, respectively. It is known that smoking, alcoholism and psychological stress are risk factors that can promote PC and increase PC progression. To date, the prevention of PC is crucial because there is no curative treatment. After binding to the neurokinin-1 (NK-1) receptor (a receptor coupled to the stimulatory G-protein Gαs that activates adenylate cyclase), the peptide substance P (SP)—at high concentrations—is involved in many pathophysiological functions, such as depression, smoking, alcoholism, chronic inflammation and cancer. It is known that PC cells and samples express NK-1 receptors; that the NK-1 receptor is overexpressed in PC cells in comparison with non-tumor cells, and that nanomolar concentrations of SP induce PC cell proliferation. By contrast, NK-1 receptor antagonists exert antidepressive, anxiolytic and anti-inflammatory effects and anti-alcohol addiction. These antagonists also exert an antitumor action since in vitro they inhibit PC cell proliferation (PC cells death by apoptosis), and in a xenograft PC mouse model they exert both antitumor and anti-angiogenic actions. NK-1 receptor antagonists could be used for the treatment of PC and hence the NK-1 receptor could be a new promising therapeutic target in PC. PMID:26154566

  3. 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

  4. 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

  5. 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

  6. 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

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

    PubMed

    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

  8. 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

  9. 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

  10. 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 ( ...

  11. 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

  12. 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

  13. Variations in magnetic properties of target basalts with the direction of asteroid impact: Example from Lonar crater, India

    NASA Astrophysics Data System (ADS)

    Arif, Md.; Basavaiah, N.; Misra, S.; Deenadayalan, K.

    2012-08-01

    The Lonar crater in Maharashtra state, India, has been completely excavated on the Deccan Traps basalt (approximately 65 Ma) at approximately 570 ± 47 ka by an oblique impact of a possible chondritic asteroid that struck the preimpact target from the east at an angle of approximately 30-45o to the horizon where the total duration of the shock event was approximately 1 s. It is shown by our early work that the distribution of ejecta and deformation of target rocks around the crater rim are symmetrical to the east-west plane of impact (Misra et al. 2010). The present study shows that some of the rock magnetic properties of these shocked target basalts, e.g., low-field anisotropy of magnetic susceptibility (AMS), natural remanent magnetization (NRM)/bulk susceptibility (χ), and high-coercivity and high-temperature (HC_HT) magnetization component, are also almost symmetrically oriented with reference to the plane of impact. Studies on the relative displacements of K3 (minimum) AMS axes of shocked basalts from around the crater rim and from the adjacent target rocks to the approximately 2-3 km west of the crater center suggest that the impact stress could have branched out into the major southwestward and northwestward components in the downrange direction immediately after the impact. The biaxial distribution of AMS axes in stereographic plots for the unshocked basalts transforms mostly into triaxial distribution for the shocked basalts, although transitional type distribution also exists. The degree of anisotropy (P') of AMS ellipsoids of the shocked basalts decreases by approximately 2% when compared with those of the unshocked target (approximately 1.03). The NRM/χ (Am-1) values of the shocked basalts on the rim of the Lonar crater do not show much change in the uprange or downrange direction on and close to the east-west plane of impact, and the values are only approximately 1.5 times higher on average over the unshocked basalts around the crater. However, the

  14. 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

  15. 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

  16. Using formative research to lay the foundation for community level HIV prevention efforts: an example from the AIDS Community Demonstration Projects.

    PubMed Central

    Higgins, D L; O'Reilly, K; Tashima, N; Crain, C; Beeker, C; Goldbaum, G; Elifson, C S; Galavotti, C; Guenther-Grey, C

    1996-01-01

    The AIDS Community Demonstration Projects provided community-level HIV prevention interventions to historically hard-to-reach groups at high risk for HIV infection. The projects operated under a common research protocol which encompassed formative research, intervention delivery, process evaluation, and outcome evaluation. A formative research process specifically focusing on intervention development was devised to assist project staff in identifying, prioritizing, accessing, and understanding the intervention target groups. This process was central to the creation of interventions that were acceptable and unique to the target populations. Intended to be rapid, the process took 6 months to complete. Drawn from the disciplines of anthropology, community psychology, sociology, and public health, the formative research process followed distinct steps which included (a) defining the populations at high-risk for HIV; (b) gathering information about these populations through interviews with persons who were outside of, but who had contact with, the target groups (such as staff from the health department and alcohol and drug treatment facilities, as well as persons who interacted in an informal manner with the target groups, such as clerks in neighborhood grocery stores and bartenders); (c) interviewing people with access to the target populations (gatekeepers), and conducting observations in areas where these high-risk groups were reported to gather (from previous interviews); (d) interviewing members of these groups at high risk for HIV infection or transmission; and (e) systematically integrating information throughout the process. Semistructured interview schedules were used for all data collection in this process. This standardized systematic method yielded valuable information about the focal groups in each demonstration project site. The method, if adopted by others, would assist community intervention specialists in developing interventions that are culturally

  17. Innate immunity against HIV: a priority target for HIV prevention research

    PubMed Central

    2010-01-01

    This review summarizes recent advances and current gaps in understanding of innate immunity to human immunodeficiency virus (HIV) infection, and identifies key scientific priorities to enable application of this knowledge to the development of novel prevention strategies (vaccines and microbicides). It builds on productive discussion and new data arising out of a workshop on innate immunity against HIV held at the European Commission in Brussels, together with recent observations from the literature. Increasing evidence suggests that innate responses are key determinants of the outcome of HIV infection, influencing critical events in the earliest stages of infection including the efficiency of mucosal HIV transmission, establishment of initial foci of infection and local virus replication/spread as well as virus dissemination, the ensuing acute burst of viral replication, and the persisting viral load established. They also impact on the subsequent level of ongoing viral replication and rate of disease progression. Modulation of innate immunity thus has the potential to constitute a powerful effector strategy to complement traditional approaches to HIV prophylaxis and therapy. Importantly, there is increasing evidence to suggest that many arms of the innate response play both protective and pathogenic roles in HIV infection. Consequently, understanding the contributions made by components of the host innate response to HIV acquisition/spread versus control is a critical pre-requisite for the employment of innate immunity in vaccine or microbicide design, so that appropriate responses can be targeted for up- or down-modulation. There is also an important need to understand the mechanisms via which innate responses are triggered and mediate their activity, and to define the structure-function relationships of individual innate factors, so that they can be selectively exploited or inhibited. Finally, strategies for achieving modulation of innate functions need to be

  18. 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

  19. 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

  20. 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

  1. 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. PMID:26970137

  2. 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

  3. [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

  4. 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

  5. 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

  6. A target enrichment method for gathering phylogenetic information from hundreds of loci: An example from the Compositae1

    PubMed Central

    Mandel, Jennifer R.; Dikow, Rebecca B.; Funk, Vicki A.; Masalia, Rishi R.; Staton, S. Evan; Kozik, Alex; Michelmore, Richard W.; Rieseberg, Loren H.; Burke, John M.

    2014-01-01

    • Premise of the study: The Compositae (Asteraceae) are a large and diverse family of plants, and the most comprehensive phylogeny to date is a meta-tree based on 10 chloroplast loci that has several major unresolved nodes. We describe the development of an approach that enables the rapid sequencing of large numbers of orthologous nuclear loci to facilitate efficient phylogenomic analyses. • Methods and Results: We designed a set of sequence capture probes that target conserved orthologous sequences in the Compositae. We also developed a bioinformatic and phylogenetic workflow for processing and analyzing the resulting data. Application of our approach to 15 species from across the Compositae resulted in the production of phylogenetically informative sequence data from 763 loci and the successful reconstruction of known phylogenetic relationships across the family. • Conclusions: These methods should be of great use to members of the broader Compositae community, and the general approach should also be of use to researchers studying other families. PMID:25202605

  7. Targeting attention on local vulnerabilities using an integrated index approach: the example of the climate vulnerability index.

    PubMed

    Sullivan, C; Meigh, J

    2005-01-01

    It is known that climate impacts can have significant effects on the environment, societies and economies. For human populations, climate change impacts can be devastating, giving rise to economic disruption and mass migration as agricultural systems fail, either through drought or floods. Such events impact significantly, not only where they happen, but also in the neighbouring areas. Vulnerability to the impacts of climate change needs to be assessed, so that adaptation strategies can be developed and populations can be protected. In this paper, we address the issue of vulnerability assessment through the use of an indicator approach, the climate vulnerability index (CVI). We show how this can overcome some of the difficulties of incommensurability associated with the combination of different types of data, and how the approach can be applied at a variety of scales. Through the development of nested index values, more reliable and robust coverage of large areas can be achieved, and we provide an indication of how this could be done. While further work is required to improve the methodology through wider application and component refinement, it seems likely that this approach will have useful application in the assessment of climate vulnerability. Through its application at sub-national and community scales, the CVI can help to identify those human populations most at risk from climate change impacts, and as a result, resources can be targeted towards those most in need. PMID:15918360

  8. In vivo prevention of arterial restenosis with paclitaxel-encapsulated targeted lipid-polymeric nanoparticles.

    PubMed

    Chan, Juliana M; Rhee, June-Wha; Drum, Chester L; Bronson, Roderick T; Golomb, Gershon; Langer, Robert; Farokhzad, Omid C

    2011-11-29

    Following recent successes with percutaneous coronary intervention (PCI) for treating coronary artery disease (CAD), many challenges remain. In particular, mechanical injury from the procedure results in extensive endothelial denudation, exposing the underlying collagen IV-rich basal lamina, which promotes both intravascular thrombosis and smooth muscle proliferation. Previously, we reported the engineering of collagen IV-targeting nanoparticles (NPs) and demonstrated their preferential localization to sites of arterial injury. Here, we develop a systemically administered, targeted NP system to deliver an antiproliferative agent to injured vasculature. Approximately 60-nm lipid-polymeric NPs were surface functionalized with collagen IV-targeting peptides and loaded with paclitaxel. In safety studies, the targeted NPs showed no signs of toxicity and a ≥3.5-fold improved maximum tolerated dose versus paclitaxel. In efficacy studies using a rat carotid injury model, paclitaxel (0.3 mg/kg or 1 mg/kg) was i.v. administered postprocedure on days 0 and 5. The targeted NP group resulted in lower neointima-to-media (N/M) scores at 2 wk versus control groups of saline, paclitaxel, or nontargeted NPs. Compared with sham-injury groups, an ∼50% reduction in arterial stenosis was observed with targeted NP treatment. The combination of improved tolerability, sustained release, and vascular targeting could potentially provide a safe and efficacious option in the management of CAD. PMID:22087004

  9. 4D Geomodeling: a Tool for Targeting New Potential Mineralization - Example of the Kupferschiefer in the Lubin Region, Poland

    NASA Astrophysics Data System (ADS)

    Mejia-Herrera, Pablo; Royer, Jean-Jacques; Fraboulet, Jean-Gabriel; Zielinska, Agata

    2013-04-01

    Understanding the history of sedimentary basins is of paramount importance for reconstituting oil and gas migration, but also in mineral exploration for identifying brine pathways. Advanced modeling technology such as 3&4D geomodeling can be fruitfully used to explore with new eyes old matured mining field. The Polish Kupferschiefers, a sediment-hosted polymetallic (Cu, Ag, Au, PGE) deposit, is one of the most important sources for copper and silver in the world. Within the framework of the ProMine European project, the Lubin region (south west of Poland), was selected for modeling in 3&4D the geological formations in order to better understand the distribution of the Cu-Ag mineralization, and possibly to define new potential targets. A regional scale 4D reconstitution of the North European basin was undertaken to better understand the burial, deformation and natural hydro-fracturing history of the Lubin Kupferschiefer. It comprises the creation of a 3D model of the present geological formation including more than 200 wells coming from the mining exploitation of the Kupferschiefer, cross sections from seismic exploration and geological maps. This 3D model has been then restored and decompacted using the Kine3D-2 Gocad plug-in. The PetroMode 1D was then used to reconstitute the temperatures, pressures, fluid overpressure, and oil and gas maturation during the burying history of the Southern-Western Poland basin. Conditions for hydraulic fracturing were identified within the base of the Zechstein shales, during an inversion phase at the Late Cretaceous-Early Paleocene time. This up-lifting yields the conditions for hydrothermal recirculation of mineralizing brines explaining the location of Cu (Cu-Fe) sulfides ores in the area. The low permeable Zechstein series (including evaporite, clays and marls) seem to have played an important role as an impermeable cover confining the hydrothermal fluids in the pre-Triassic series. The 4D restoring-decompacting modeling allows

  10. Targeting inflammatory pathways by flavonoids for prevention and treatment of cancer.

    PubMed

    Prasad, Sahdeo; Phromnoi, Kannokarn; Yadav, Vivek R; Chaturvedi, Madan M; Aggarwal, Bharat B

    2010-08-01

    Observational studies have suggested that lifestyle risk factors such as tobacco, alcohol, high-fat diet, radiation, and infections can cause cancer and that a diet consisting of fruits and vegetables can prevent cancer. Evidence from our laboratory and others suggests that agents either causing or preventing cancer are linked through the regulation of inflammatory pathways. Genes regulated by the transcription factor NF- kappaB have been shown to mediate inflammation, cellular transformation, tumor cell survival, proliferation, invasion, angiogenesis, and metastasis. Whereas various lifestyle risk factors have been found to activate NF- kappaB and NF- kappaB-regulated gene products, flavonoids derived from fruits and vegetables have been found to suppress this pathway. The present review describes various flavones, flavanones, flavonols, isoflavones, anthocyanins, and chalcones derived from fruits, vegetables, legumes, spices, and nuts that can suppress the proinflammatory cell signaling pathways and thus can prevent and even treat the cancer. PMID:20635307

  11. From research to policy: Targeting the primary prevention of childhood lead poisoning.

    PubMed Central

    Rabito, Felicia A.; White, LuAnn E.; Shorter, Charles

    2004-01-01

    Public policy can be an effective method of promoting public health and preventing disease in a population. The proposing and passing of a municipal ordinance regulating power-sanding of leaded paint in New Orleans is a policy-level intervention that implements a primary prevention measure to address a community-wide risk. The process of achieving policy change involves defining the problem and the proposed intervention, integrating the resources of the individuals and groups with a stake in the situation, and disseminating information to the general public and to legislators. The implementation of the ordinance regulating power-sanding in New Orleans is a community-level lead poisoning prevention strategy. PMID:15158106

  12. Targeting ornithine decarboxylase in Myc-induced lymphomagenesis prevents tumor formation.

    PubMed

    Nilsson, Jonas A; Keller, Ulrich B; Baudino, Troy A; Yang, Chunying; Norton, Sara; Old, Jennifer A; Nilsson, Lisa M; Neale, Geoffrey; Kramer, Debora L; Porter, Carl W; Cleveland, John L

    2005-05-01

    Checkpoints that control Myc-mediated proliferation and apoptosis are bypassed during tumorigenesis. Genes encoding polyamine biosynthetic enzymes are overexpressed in B cells from E mu-Myc transgenic mice. Here, we report that disabling one of these Myc targets, Ornithine decarboxylase (Odc), abolishes Myc-induced suppression of the Cdk inhibitors p21(Cip1) and p27(Kip1), thereby impairing Myc's proliferative, but not apoptotic, response. Moreover, lymphoma development was markedly delayed in E mu-Myc;Odc(+/-) transgenic mice and in E mu-Myc mice treated with the Odc inhibitor difluoromethylornithine (DFMO). Strikingly, tumors ultimately arising in E mu-Myc;Odc(+/-) transgenics lacked deletions of Arf, suggesting that targeting Odc forces other routes of transformation. Therefore, Odc is a critical Myc transcription target that regulates checkpoints that guard against tumorigenesis and is an effective target for cancer chemoprevention. PMID:15894264

  13. 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…

  14. Prevention Programmes Targeting Emotional and Social Development in Preschoolers: Current Status and Future Directions

    ERIC Educational Resources Information Center

    Stefan, Catrinel A.; Miclea, Mircea

    2010-01-01

    Early intervention has become a widely recognised practice because preschool years offer the best timing for preventing early onset conduct problems. Moreover, some factors have been consistently identified as putting children at risk for developing mental health problems, as well as school readiness problems. Such risk factors are poor…

  15. 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...

  16. 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…

  17. 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

  18. 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…

  19. 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…

  20. Targeted delivery of CCR2 antagonist to activated pulmonary endothelium prevents metastasis.

    PubMed

    Roblek, Marko; Calin, Manuela; Schlesinger, Martin; Stan, Daniela; Zeisig, Reiner; Simionescu, Maya; Bendas, Gerd; Borsig, Lubor

    2015-12-28

    Enhanced levels of the inflammatory chemokine CCL2 are known to correlate with increased tumorigenesis and metastases, and thereby poor prognosis for cancer patients. The CCL2-CCR2 chemokine axis was shown to facilitate the metastatic initiation through the recruitment of inflammatory monocytes and the activation of endothelial cells at metastatic sites. Both steps are required for efficient cancer cell trans-endothelial migration and seeding in the targeted tissue. The translation of preclinical evidence proved to be challenging due to systemic effects of chemokine inhibition and limited target specificity. Here we tested an approach of a targeted delivery of the CCR2 antagonist Teijin Compound 1 to metastatic sites. VCAM-1 binding peptide tagged liposomes carrying the CCR2 antagonist enabled a specific delivery to cancer cell-activated endothelium. The subsequent binding of target-sensitive liposomes triggered the release of the Teijin Compound 1 and thereby local inhibition of CCR2 in the lungs. Blocking of CCR2 resulted in reduced induction of the lungs vascular permeability, and thereby reduced tumor cell extravasation. However, the recruitment of inflammatory monocytes to the pre-metastatic lungs remained unaltered. Endothelial VCAM-1 targeted delivery of the CCR2 antagonist resulted in inhibition of pulmonary metastases both in a murine (MC-38GFP cells) and a human xenograft (patient-derived cells) model. Thus, timely- and spatially-defined inhibition of CCR2 signaling represents a potential therapeutic approach for treatment of metastasis without affecting homeostatic functions. PMID:26522070

  1. The RNA Binding Protein IMP2 Preserves Glioblastoma Stem Cells by Preventing let-7 Target Gene Silencing.

    PubMed

    Degrauwe, Nils; Schlumpf, Tommy B; Janiszewska, Michalina; Martin, Patricia; Cauderay, Alexandra; Provero, Paolo; Riggi, Nicolo; Suvà, Mario-L; Paro, Renato; Stamenkovic, Ivan

    2016-05-24

    Cancer stem cells (CSCs) can drive tumor growth, and their maintenance may rely on post-transcriptional regulation of gene expression, including that mediated by microRNAs (miRNAs). The let-7 miRNA family has been shown to induce differentiation by silencing stem cell programs. Let-7-mediated target gene suppression is prevented by LIN28A/B, which reduce let-7 biogenesis in normal embryonic and some cancer stem cells and ensure maintenance of stemness. Here, we find that glioblastoma stem cells (GSCs) lack LIN28 and express both let-7 and their target genes, suggesting LIN28-independent protection from let-7 silencing. Using photoactivatable-ribonucleoside-enhanced crosslinking and immunoprecipitation (PAR-CLIP), we show that insulin-like growth factor 2 mRNA-binding protein 2 (IMP2) binds to let-7 miRNA recognition elements (MREs) and prevents let-7 target gene silencing. Our observations define the RNA-binding repertoire of IMP2 and identify a mechanism whereby it supports GSC and neural stem cell specification. PMID:27184842

  2. Preventing diet-induced obesity in mice by adipose tissue transformation and angiogenesis using targeted nanoparticles.

    PubMed

    Xue, Yuan; Xu, Xiaoyang; Zhang, Xue-Qing; Farokhzad, Omid C; Langer, Robert

    2016-05-17

    The incidence of obesity, which is recognized by the American Medical Association as a disease, has nearly doubled since 1980, and obesity-related comorbidities have become a major threat to human health. Given that adipose tissue expansion and transformation require active growth of new blood vasculature, angiogenesis offers a potential target for the treatment of obesity-associated disorders. Here we construct two peptide-functionalized nanoparticle (NP) platforms to deliver either Peroxisome Proliferator-Activated Receptor gamma (PPARgamma) activator rosiglitazone (Rosi) or prostaglandin E2 analog (16,16-dimethyl PGE2) to adipose tissue vasculature. These NPs were engineered through self-assembly of a biodegradable triblock polymer composed of end-to-end linkages between poly(lactic-coglycolic acid)-b-poly(ethylene glycol) (PLGA-b-PEG) and an endothelial-targeted peptide. In this system, released Rosi promotes both transformation of white adipose tissue (WAT) into brown-like adipose tissue and angiogenesis, which facilitates the homing of targeted NPs to adipose angiogenic vessels, thereby amplifying their delivery. We show that i.v. administration of these NPs can target WAT vasculature, stimulate the angiogenesis that is required for the transformation of adipose tissue, and transform WAT into brown-like adipose tissue, by the up-regulation of angiogenesis and brown adipose tissue markers. In a diet-induced obese mouse model, these angiogenesis-targeted NPs have inhibited body weight gain and modulated several serological markers including cholesterol, triglyceride, and insulin, compared with the control group. These findings suggest that angiogenesis-targeting moieties with angiogenic stimulator-loaded NPs could be incorporated into effective therapeutic regimens for clinical treatment of obesity and other metabolic diseases. PMID:27140638

  3. Targeting the inflammation in HCV-associated hepatocellular carcinoma: a role in the prevention and treatment

    PubMed Central

    2010-01-01

    Epidemiological, preclinical and clinical studies demonstrated that chronic inflammation induced by hepatitis C virus (HCV) is crucial in hepatocellular carcinogenesis. The interaction between hepatocytes and microenvironment regards virus, inflammatory and immunocompetent cells, chemo- and cyto-kines, reactive oxygen species (ROS) and nitric oxide (NO), generating cell transformation. We suggest hepatocarcinoma (HCC) as a model in which the targeting of microenvironment determine neoplastic transformation. The present review focuses on: the role of inflammation in carcinogenesis, the clinical impact of HCC and the inadequacy of the actual therapy, the chemoprevention targeting the microenvironment. PMID:21047421

  4. 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

  5. Targeting Complement Pathways During Cold Ischemia and Reperfusion Prevents Delayed Graft Function.

    PubMed

    Yu, Z X; Qi, S; Lasaro, M A; Bouchard, K; Dow, C; Moore, K; Wu, Z; Barama, A; Xu, J; Johnson, K; Marozsan, A J; Wang, Y

    2016-09-01

    The complement system plays a critical role in ischemia-reperfusion injury (IRI)-mediated delayed graft function (DGF). To better understand the roles of complement activation pathways in IRI in kidney transplantation, donor kidneys were treated ex vivo with terminal complement pathway (TP) inhibitor, anti-rat C5 mAb 18A10, or complement alternative pathway (AP) inhibitor TT30 for 28 h at 4°C pretransplantation in a syngeneic kidney transplantation rat model. All 18A10- and 67% of TT30-pretreated grafts, but only 16.7% of isotype control-pretreated grafts, survived beyond day 21 (p < 0.01). Inhibitor treatment in the final 45 min of 28-h cold ischemia (CI) similarly improved graft survival. Systemic posttransplant treatment with 18A10 resulted in 60% increased graft survival beyond day 21 (p < 0.01), while no TT30-treated rat survived > 6 days. Our results demonstrate that AP plays a prominent role during CI and that blocking either the AP or, more effectively the TP prevents ischemic injury and subsequent DGF. Multiple complement pathways may be activated and contribute to reperfusion injury; blocking the TP, but not the AP, posttransplant is effective in preventing reperfusion injury and increasing graft survival. These results demonstrate the feasibility of using complement inhibitors for prevention of DGF in humans. PMID:27003920

  6. Feasibility study of an obesity "Prevention Plus" intervention targeting children and parenting practices: Helping HAND

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The purpose of this study was to test for feasibility and obesity intervention, targeting 5-8 year old children with BMI 85-99%tile in community primary care clinics. Randomized controlled trial with child and parenting data obtained pre and post intervention. Based on social cognitive and parenting...

  7. 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")…

  8. 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

  9. 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

  10. 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

  11. 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. |

  12. Opposing effects of androgen deprivation and targeted therapy on prostate cancer prevention

    PubMed Central

    Jia, Shidong; Gao, Xueliang; Lee, Sang Hyun; Maira, Sauveur-Michel; Wu, Xiaoqiu; Stack, Edward C.; Signoretti, Sabina; Loda, Massimo; Zhao, Jean J; Roberts, Thomas M.

    2012-01-01

    Prostate cancer is an ideal target for chemoprevention. To date, chemoprevention clinical trials with 5α-reductase inhibitors (5-ARI) have yielded encouraging yet ultimately confounding results. Using a pre-clinical mouse model of high-grade prostatic intraepithelial neoplasia (HG-PIN) induced by PTEN loss, we observed unprecedented deteriorating effects of androgen deprivation, where surgical castration or MDV3100 treatment accelerated disease progression of the otherwise stable HG-PIN to invasive castration-resistant prostate cancer (CRPC). As an alternative, targeting the PI3K signaling pathway via either genetic ablation of PI3K components or pharmacological inhibition of PI3K pathway reversed the PTEN loss-induced HG-PIN phenotype. Finally, concurrent inhibition of PI3K and MAPK pathways was effective in blocking the growth of PTEN-null CRPC. Together, these data have revealed the potential adverse effects of anti-androgen chemoprevention in certain genetic contexts (such as PTEN loss) while demonstrating the promise of targeted therapy in the clinical management of this complex and prevalent disease. PMID:23258246

  13. Using process data to understand outcomes in sexual health promotion: an example from a review of school-based programmes to prevent sexually transmitted infections.

    PubMed

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

    2014-08-01

    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 outcome evaluations, 9 of which included a process evaluation. There were few statistically significant effects in terms of changes in sexual behaviour outcomes, but statistically significant effects were more common for knowledge and self-efficacy. Synthesis of the findings of the process evaluations identified a range of factors that might explain outcomes, and these were organized into two overarching categories: the implementation of interventions, and student engagement and intervention acceptability. Factors which supported implementation and engagement and acceptability included good quality teacher training, involvement and motivation of key school stakeholders and relevance and appeal to young people. Factors which had a negative impact included teachers' failure to comprehend the theoretical basis for behaviour change, school logistical problems and omission of topics that young people considered important. It is recommended that process indicators such as these be assessed in future evaluations of school-based sexual health behavioural interventions, as part of a logic model. PMID:24488650

  14. Empirical development of brief smoking prevention videotapes which target African-American adolescents.

    PubMed

    Sussman, S; Parker, V C; Lopes, C; Crippens, D L; Elder, P; Scholl, D

    1995-07-01

    Two studies are described which provide evaluations for two brief videotapes developed as supplemental materials in the prevention of tobacco use among African-American adolescents. One videotape (the "soap opera") provides a more general audience-oriented presentation of prevention material and it was filmed primarily at a shopping mall, whereas the other videotape (the "rap") provides a "hip-hop generation" presentation, and it was filmed primarily at an outdoor hangout. The first study compared the two videotapes against each other. The second study compared the two videotapes combined in the same presentation, controlling for order of presentation, against a discussion group control. The results of the two studies indicated few differences in receptivity to the two videotapes among primarily African-American and Latino young adolescents. The rap videotape was rated as more accurate in its depiction of the African-American lifestyle, although both videotapes were equally liked. When shown together, the videotapes were not found to be superior in decreasing behavioral intention to smoke compared to a discussion group control. No change in trial of smoking was observed within or across conditions measured over a pre-post summer interval. These data suggest that "culturally sensitive" videotapes have no more of a short-term effect on youth than do other types of brief interventions which involve minority implementers. PMID:7591353

  15. Cyclooxygenases: mediators of UV-induced skin cancer and potential targets for prevention.

    PubMed

    Elmets, Craig A; Ledet, Johnathan J; Athar, Mohammad

    2014-10-01

    Non-melanoma skin cancers (NMSCs) are among the most common human malignancies. Current methods for their prevention include avoidance of natural and artificial sources of UV radiation and using photoprotective clothing and sunscreens. However, these methods have proven to be inadequate in stemming the rise in skin cancer incidence over the past several years. There is accumulating evidence that cyclooxygenase-2 (COX-2), an enzyme involved in prostaglandin synthesis, may be involved in the pathogenesis of NMSC. In preclinical studies, animals genetically deficient in the COX-2 enzyme or that have been treated with pharmacological inhibitors of COX-2 develop significantly fewer tumors when subjected to a UV-induced skin carcinogenesis protocol compared with control mice. Several epidemiological studies in humans support the concept that this enzyme is intimately involved in UV-induced skin cancer development, and UV radiation is known to augment COX-2 expression in human skin. Recent studies suggest that drugs that block COX-2 expression may prevent the development of NMSCs. Thus, pharmacologic agents that inhibit the enzyme COX-2 may be effective chemopreventive agents for NMSCs. PMID:24804836

  16. 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. PMID:19424164

  17. 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. PMID:24377653

  18. Pharmacological Targeting of the Atherogenic Dyslipidemia Complex: The Next Frontier in CVD Prevention Beyond Lowering LDL Cholesterol.

    PubMed

    Xiao, Changting; Dash, Satya; Morgantini, Cecilia; Hegele, Robert A; Lewis, Gary F

    2016-07-01

    Notwithstanding the effectiveness of lowering LDL cholesterol, residual CVD risk remains in high-risk populations, including patients with diabetes, likely contributed to by non-LDL lipid abnormalities. In this Perspectives in Diabetes article, we emphasize that changing demographics and lifestyles over the past few decades have resulted in an epidemic of the "atherogenic dyslipidemia complex," the main features of which include hypertriglyceridemia, low HDL cholesterol levels, qualitative changes in LDL particles, accumulation of remnant lipoproteins, and postprandial hyperlipidemia. We briefly review the underlying pathophysiology of this form of dyslipidemia, in particular its association with insulin resistance, obesity, and type 2 diabetes, and the marked atherogenicity of this condition. We explain the failure of existing classes of therapeutic agents such as fibrates, niacin, and cholesteryl ester transfer protein inhibitors that are known to modify components of the atherogenic dyslipidemia complex. Finally, we discuss targeted repurposing of existing therapies and review promising new therapeutic strategies to modify the atherogenic dyslipidemia complex. We postulate that targeting the central abnormality of the atherogenic dyslipidemia complex, the elevation of triglyceride-rich lipoprotein particles, represents a new frontier in CVD prevention and is likely to prove the most effective strategy in correcting most aspects of the atherogenic dyslipidemia complex, thereby preventing CVD events. PMID:27329952

  19. 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…

  20. Targeting JAK/STAT Signaling to Prevent Rejection After Kidney Transplantation: A Reappraisal.

    PubMed

    Baan, Carla C; Kannegieter, Nynke M; Felipe, Claudia Rosso; Tedesco Silva, Helio

    2016-09-01

    The profound involvement of cytokines in allograft rejection makes the molecules that control their actions, members of the Jak-Stat pathway, ideal targets for pharmacological intervention. Numerous studies have demonstrated that Jak3 is widely involved in the activation cascade and function of most immune cells. Tofacitinib, an oral Janus kinase inhibitor that targets Jak1/Jak3 dependent Stat activation, has been assessed as a substitute for calcineurin inhibitor therapy after low-to-moderate risk kidney transplantation in 3 randomized trials. Results using fixed-dose regimens showed a low incidence of rejection and better renal function with less interstitial fibrosis/tubular atrophy versus calcineurin inhibitor therapy. However, the safety profile of tofacitinib was poor, including increased incidences of cytomegalovirus disease, herpes zoster, BK virus, and nephropathy, which led to the discontinuation of its development for transplantation. High tofacitinib concentrations were independently associated with serious infection. Dosing according to exposure levels, coupled with pharmacodynamic monitoring based on phosphorylation of Stat5, could improve safety compared to the early fixed-dose regimens. Future studies could assess individualized dosing based on pharmacokinetic and pharmacodynamic monitoring. Additionally, because the increase of viral infections under tofacitinib may have been influenced by overlapping toxicity with concomitant mycophenolic acid, exploration of alternative adjunctive therapies (eg, a mammalian target of rapamycin inhibitor or belatacept) may demonstrate a better efficacy/safety profile. We believe that Jak inhibitors are a good and useful addition to the immunosuppressive armentarium for kidney transplant patients, and that new studies with personalized drug dosing, improved immune monitoring, and better patient selection should be performed. PMID:27163538

  1. The cell cycle: A critical therapeutic target to prevent vascular proliferative disease

    PubMed Central

    Charron, Thierry; Nili, Nafiseh; Strauss, Bradley H

    2006-01-01

    Percutaneous coronary intervention is the preferred revascularization approach for most patients with coronary artery disease. However, this strategy is limited by renarrowing of the vessel by neointimal hyperplasia within the stent lumen (in-stent restenosis). Vascular smooth muscle cell proliferation is a major component in this healing process. This process is mediated by multiple cytokines and growth factors, which share a common pathway in inducing cell proliferation: the cell cycle. The cell cycle is highly regulated by numerous mechanisms ensuring orderly and coordinated cell division. The present review discusses current concepts related to regulation of the cell cycle and new therapeutic options that target aspects of the cell cycle. PMID:16498512

  2. Thymosin Beta 4 Prevents Oxidative Stress by Targeting Antioxidant and Anti-Apoptotic Genes in Cardiac Fibroblasts

    PubMed Central

    Kumar, Sandeep; Gupta, Sudhiranjan

    2011-01-01

    Rationale Thymosin beta-4 (Tβ4) is a ubiquitous protein with diverse functions relating to cell proliferation and differentiation that promotes wound healing and modulates inflammatory responses. The effecter molecules targeted by Tβ4 for cardiac protection remains unknown. The purpose of this study is to determine the molecules targeted by Tβ4 that mediate cardio-protection under oxidative stress. Methods Rat neonatal fibroblasts cells were exposed to hydrogen peroxide (H2O2) in presence and absence of Tβ4 and expression of antioxidant, apoptotic and pro-fibrotic genes was evaluated by quantitative real-time PCR and western blotting. Reactive oxygen species (ROS) levels were estimated by DCF-DA using fluorescent microscopy and fluorimetry. Selected antioxidant and antiapoptotic genes were silenced by siRNA transfections in cardiac fibroblasts and the effect of Tβ4 on H2O2-induced profibrotic events was evaluated. Results Pre-treatment with Tβ4 resulted in reduction of the intracellular ROS levels induced by H2O2 in the cardiac fibroblasts. This was associated with an increased expression of antioxidant enzymes Cu/Zn superoxide dismutase (SOD) and catalase and reduction of Bax/Bcl2 ratio. Tβ4 treatment reduced the expression of pro-fibrotic genes [connective tissue growth factor (CTGF), collagen type-1 (Col-I) and collagen type-3 (Col-III)] in the cardiac fibroblasts. Silencing of Cu/Zn-SOD and catalase gene triggered apoptotic cell death in the cardiac fibroblasts, which was prevented by treatment with Tβ4. Conclusion This is the first report that exhibits the targeted molecules modulated by Tβ4 under oxidative stress utilizing the cardiac fibroblasts. Tβ4 treatment prevented the profibrotic gene expression in the in vitro settings. Our findings indicate that Tβ4 selectively targets and upregulates catalase, Cu/Zn-SOD and Bcl2, thereby, preventing H2O2-induced profibrotic changes in the myocardium. Further studies are warranted to elucidate the

  3. Neuroscience of alcohol for addiction medicine: Neurobiological targets for prevention and intervention in adolescents.

    PubMed

    Cservenka, Anita; Nagel, Bonnie J

    2016-01-01

    Structural and functional neuroimaging studies indicate that heavy alcohol use during adolescence may be neurotoxic to the brain. This chapter reviews the neuroimaging findings in cross-sectional and longitudinal studies of adolescent heavy alcohol users. These youth exhibit reductions in prefrontal, hippocampal, and cerebellar brain volume, decreased frontoparietal, and increased frontolimbic white matter integrity, as well as alterations in blood oxygen level-dependent response during working memory, inhibitory control, verbal encoding, decision making, and reward processing-some of which appear to differ between males and females. Although some exist, additional longitudinal studies will significantly advance addiction medicine by aiding prevention scientists and treatment providers to develop neurobiologically informed ways of strengthening neural networks prior to and after the onset of heavy alcohol use, thereby promoting healthy cognitive functioning across the adolescent period. PMID:26806778

  4. 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

  5. Targeting of Fn14 Prevents Cancer-Induced Cachexia and Prolongs Survival.

    PubMed

    Johnston, Amelia J; Murphy, Kate T; Jenkinson, Laura; Laine, David; Emmrich, Kerstin; Faou, Pierre; Weston, Ross; Jayatilleke, Krishnath M; Schloegel, Jessie; Talbo, Gert; Casey, Joanne L; Levina, Vita; Wong, W Wei-Lynn; Dillon, Helen; Sahay, Tushar; Hoogenraad, Joan; Anderton, Holly; Hall, Cathrine; Schneider, Pascal; Tanzer, Maria; Foley, Michael; Scott, Andrew M; Gregorevic, Paul; Liu, Spring Yingchun; Burkly, Linda C; Lynch, Gordon S; Silke, John; Hoogenraad, Nicholas J

    2015-09-10

    The cytokine TWEAK and its cognate receptor Fn14 are members of the TNF/TNFR superfamily and are upregulated in tumors. We found that Fn14, when expressed in tumors, causes cachexia and that antibodies against Fn14 dramatically extended lifespan by inhibiting tumor-induced weight loss although having only moderate inhibitory effects on tumor growth. Anti-Fn14 antibodies prevented tumor-induced inflammation and loss of fat and muscle mass. Fn14 signaling in the tumor, rather than host, is responsible for inducing this cachexia because tumors in Fn14- and TWEAK-deficient hosts developed cachexia that was comparable to that of wild-type mice. These results extend the role of Fn14 in wound repair and muscle development to involvement in the etiology of cachexia and indicate that Fn14 antibodies may be a promising approach to treat cachexia, thereby extending lifespan and improving quality of life for cancer patients. PMID:26359988

  6. 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

  7. The Keap1-Nrf2-ARE Pathway As a Potential Preventive and Therapeutic Target: An Update.

    PubMed

    Lu, Meng-Chen; Ji, Jian-Ai; Jiang, Zheng-Yu; You, Qi-Dong

    2016-09-01

    The Keap1-Nrf2-ARE ((Kelch-like ECH-Associating protein 1) nuclear factor erythroid 2 related factor 2-antioxidant response element) pathway is one of the most important defense mechanisms against oxidative and/or electrophilic stresses, and it is closely associated with inflammatory diseases, including cancer, neurodegenerative diseases, cardiovascular diseases, and aging. In recent years, progress has been made in strategies aimed at modulating the Keap1-Nrf2-ARE pathway. The Nrf2 activator DMF (Dimethylfumarates) has been approved by the FDA as a new first-line oral drug to treat patients with relapsing forms of multiple sclerosis, while a phase 3 study of another promising candidate, CDDO-Me, was terminated for safety reasons. Directly inhibiting Keap1-Nrf2 protein-protein interactions as a novel Nrf2-modulating strategy has many advantages over using electrophilic Nrf2 activators. The development of Keap1-Nrf2 protein-protein interaction inhibitors has become a topic of intense research, and potent inhibitors of this target have been identified. In addition, inhibiting Nrf2 activity has attracted an increasing amount of attention because it may provide an alternative cancer therapy. This review summarizes the molecular mechanisms and biological functions of the Keap1-Nrf2-ARE system. The main focus of this review is on recent progress in studies of agents that target the Keap1-Nrf2-ARE pathway and the therapeutic applications of such agents. PMID:27192495

  8. Taxi Drivers: A Target Population for the Prevention of Transmissible Disease?

    PubMed

    Limper, Heather M; Burns, Jennifer L; Alexander, Kenneth A

    2016-04-01

    We set out to assess the feasibility and uptake of an on-site influenza vaccination campaign targeting taxi drivers in airport taxicab lots in Chicago, Illinois. Influenza vaccine was provided by the Chicago Department of Public Health as this event aligned with ongoing efforts to provide influenza vaccinations throughout the city. Clinicians and clinic support staff were volunteers recruited from the University of Chicago Medicine and incorporated nursing staff, physicians, physician residents, and administrative support. Together, this allowed for a cost-effective approach to provide free influenza vaccines to the primarily uninsured taxi driver population. During these events, 545 taxi drivers received influenza vaccine in 2012 while 354 drivers were immunized in 2013. Nearly all drivers reported uninsured or under-insured status. The ability to use volunteers and healthcare organization's desires to meet the needs of the community, in collaboration with often under-staffed but highly dedicated local health departments have the potential to offer valuable public health services to underserved members of the community. Educational initiatives targeting vaccine hesitancy and misinformation may be necessary to improve immunization coverage among this population. PMID:26472436

  9. shRNA targeting α-synuclein prevents neurodegeneration in a Parkinson’s disease model

    PubMed Central

    Zharikov, Alevtina D.; Cannon, Jason R.; Tapias, Victor; Bai, Qing; Horowitz, Max P.; Shah, Vipul; El Ayadi, Amina; Hastings, Teresa G.; Greenamyre, J. Timothy; Burton, Edward A.

    2015-01-01

    Multiple convergent lines of evidence implicate both α-synuclein (encoded by SCNA) and mitochondrial dysfunction in the pathogenesis of sporadic Parkinson’s disease (PD). Occupational exposure to the mitochondrial complex I inhibitor rotenone increases PD risk; rotenone-exposed rats show systemic mitochondrial defects but develop specific neuropathology, including α-synuclein aggregation and degeneration of substantia nigra dopaminergic neurons. Here, we inhibited expression of endogenous α-synuclein in the adult rat substantia nigra by adeno-associated virus–mediated delivery of a short hairpin RNA (shRNA) targeting the endogenous rat Snca transcript. Knockdown of α-synuclein by ~35% did not affect motor function or cause degeneration of nigral dopaminergic neurons in control rats. However, in rotenone-exposed rats, progressive motor deficits were substantially attenuated contralateral to α-synuclein knockdown. Correspondingly, rotenone-induced degeneration of nigral dopaminergic neurons, their dendrites, and their striatal terminals was decreased ipsilateral to α-synuclein knockdown. These data show that α-synuclein knockdown is neuroprotective in the rotenone model of PD and indicate that endogenous α-synuclein contributes to the specific vulnerability of dopaminergic neurons to systemic mitochondrial inhibition. Our findings are consistent with a model in which genetic variants influencing α-synuclein expression modulate cellular susceptibility to environmental exposures in PD patients. shRNA targeting the SNCA transcript should be further evaluated as a possible neuroprotective therapy in PD. PMID:26075822

  10. shRNA targeting α-synuclein prevents neurodegeneration in a Parkinson's disease model.

    PubMed

    Zharikov, Alevtina D; Cannon, Jason R; Tapias, Victor; Bai, Qing; Horowitz, Max P; Shah, Vipul; El Ayadi, Amina; Hastings, Teresa G; Greenamyre, J Timothy; Burton, Edward A

    2015-07-01

    Multiple convergent lines of evidence implicate both α-synuclein (encoded by SCNA) and mitochondrial dysfunction in the pathogenesis of sporadic Parkinson's disease (PD). Occupational exposure to the mitochondrial complex I inhibitor rotenone increases PD risk; rotenone-exposed rats show systemic mitochondrial defects but develop specific neuropathology, including α-synuclein aggregation and degeneration of substantia nigra dopaminergic neurons. Here, we inhibited expression of endogenous α-synuclein in the adult rat substantia nigra by adeno-associated virus-mediated delivery of a short hairpin RNA (shRNA) targeting the endogenous rat Snca transcript. Knockdown of α-synuclein by ~35% did not affect motor function or cause degeneration of nigral dopaminergic neurons in control rats. However, in rotenone-exposed rats, progressive motor deficits were substantially attenuated contralateral to α-synuclein knockdown. Correspondingly, rotenone-induced degeneration of nigral dopaminergic neurons, their dendrites, and their striatal terminals was decreased ipsilateral to α-synuclein knockdown. These data show that α-synuclein knockdown is neuroprotective in the rotenone model of PD and indicate that endogenous α-synuclein contributes to the specific vulnerability of dopaminergic neurons to systemic mitochondrial inhibition. Our findings are consistent with a model in which genetic variants influencing α-synuclein expression modulate cellular susceptibility to environmental exposures in PD patients. shRNA targeting the SNCA transcript should be further evaluated as a possible neuroprotective therapy in PD. PMID:26075822

  11. 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

  12. 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

  13. 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. PMID:26886455

  14. 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

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

    PubMed Central

    Simmen, Frank A.; Simmen, Rosalia C.M.

    2011-01-01

    The dramatic rise in worldwide prevalence of obesity has necessitated the search for more efficacious anti-obesity 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 (IGF) 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. PMID:21701386

  17. Cognitive frailty, a novel target for the prevention of elderly dependency.

    PubMed

    Ruan, Qingwei; Yu, Zhuowei; Chen, Ma; Bao, Zhijun; Li, Jin; He, Wei

    2015-03-01

    Frailty is a complex and heterogeneous clinical syndrome. Cognitive frailty has been considered as a subtype of frailty. In this study, we refine the definition of cognitive frailty based on existing reports about frailty and the latest progress in cognition research. We obtain evidence from the literature regarding the role of pre-physical frailty in pathological aging. We propose that cognitive impairment of cognitive frailty results from physical or pre-physical frailty and comprises two subtypes: the reversible and the potentially reversible. Reversible cognitive impairment is indicated by subjective cognitive decline (SCD) and/or positive fluid and imaging biomarkers of amyloid-β accumulation and neurodegeneration. Potentially reversible cognitive impairment is MCI (CDR=0.5). Based on the severity of cognitive impairment, it is possible to determine the primary and secondary preventative measures for cognitive frailty. We further determine whether SCD is a component of pre-clinical AD or the early stage of other neurodegenerative diseases, which is required for guiding personal clinical intervention. PMID:25555677

  18. 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

  19. Examining Targets for HIV Prevention: Intravaginal Practices in Urban Lusaka, Zambia

    PubMed Central

    Chisembele, Maureen; Mumbi, Miriam; Malupande, Emeria; Jones, Deborah

    2014-01-01

    Abstract 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

  20. Feasibility and willingness of using e-technologies for HIV prevention and research targeting Chinese MSM.

    PubMed

    Nehl, Eric J; He, Na; Wang, Xiaodong; Lin, Lavinia; Wong, Frank Y; Yu, Fan

    2013-01-01

    This pilot study examines the feasibility and willingness for three types of e-technologies for HIV prevention and research among a sample of men who have sex with men (MSM) in Chengdu, China. A total of 605 self-identified MSM (200 HIV seropositive, 405 HIV-) were recruited through a community-based HIV/AIDS service organization and completed a cross-sectional survey. The majority used cell phones for voice and text (99 and 95%), 53% used email, and 83% used Tencent QQ (an instant messaging technology); 54% indicated they would participate in future research studies; and 77% provided contact information for at least one e-technology. In multivariate analyses, those who were not official city residents, those better educated, and those who were HIV seropositive were more likely to provide contact information. This research indicates that MSM in China would be likely to engage in e-technology research and studies should explore these innovative communication methods. PMID:23061806

  1. 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

  2. Nonalcoholic Fatty Liver: A Possible New Target for Type 2 Diabetes Prevention and Treatment

    PubMed Central

    Fruci, Barbara; Giuliano, Stefania; Mazza, Angela; Malaguarnera, Roberta; Belfiore, Antonino

    2013-01-01

    Non-alcoholic fatty liver disease (NAFLD) is the most common liver disorder worldwide. Several lines of evidence have indicated a pathogenic role of insulin resistance, and a strong association with type 2 diabetes (T2MD) and metabolic syndrome. Importantly, NAFLD appears to enhance the risk for T2MD, as well as worsen glycemic control and cardiovascular disease in diabetic patients. In turn, T2MD may promote NAFLD progression. The opportunity to take into account NAFLD in T2MD prevention and care has stimulated several clinical studies in which antidiabetic drugs, such as metformin, thiazolidinediones, GLP-1 analogues and DPP-4 inhibitors have been evaluated in NAFLD patients. In this review, we provide an overview of preclinical and clinical evidences on the possible efficacy of antidiabetic drugs in NAFLD treatment. Overall, available data suggest that metformin has beneficial effects on body weight reduction and metabolic parameters, with uncertain effects on liver histology, while pioglitazone may improve liver histology. Few data, mostly preclinical, are available on DPP4 inhibitors and GLP-1 analogues. The heterogeneity of these studies and the small number of patients do not allow for firm conclusions about treatment guidelines, and further randomized, controlled studies are needed. PMID:24264040

  3. HDL and LDL as therapeutic targets for cardiovascular disease prevention: the possible role of niacin.

    PubMed

    Olsson, A G

    2010-10-01

    Recently two studies on the effect of addition of extended-release niacin to statin treatment on measures of carotid atherosclerosis were estimated in the ARBITER 6-HALTS study (Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol 6-HDL and LDL Treatment Strategies) study and the Oxford Niacin Study were published. Adding niacin to statin treatment significantly diminished carotid atherosclerosis as measured by ultrasound carotid intima-media thickness or magnetic resonance imaging. An inhibitor of niacin induced flushing, laropiprant has been developed and demonstrated to considerably improve the tolerability of niacin therapy without impeding on its effect on lipoproteins. Still however clear evidence for the clinical benefit of long-term niacin treatment on cardiovascular morbidity and mortality is lacking. The development situation for ezetimibe is similar to that of niacin. Long-term interventional studies with hard endpoints of both therapies are ongoing. Also both drugs, when proven efficient and safe, are eagerly needed in the prevention of cardiovascular disease. PMID:20739153

  4. 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

  5. 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

  6. Targeting the IL17 pathway for the prevention of graft-versus-host disease.

    PubMed

    van der Waart, Anniek B; van der Velden, Walter J F M; Blijlevens, Nicole M; Dolstra, Harry

    2014-06-01

    Graft-versus-host disease (GVHD) is still a major complication of allogeneic stem cell transplantation (allo-SCT). The pathophysiology of GVHD is a multistep process initiated by tissue damage and proinflammatory cytokine cascades induced by the pretransplantation conditioning therapy. This eventually results in Th1-driven tissue damage. However, increasing evidence indicates the involvement of IL17-producing T cells in GVHD pathogenesis. Both CD4(+) and CD8(+) IL17-producing T cells are suspected of initiating the Th1 response and aggravating tissue inflammation, resulting in full-blown GVHD. In this review, we discuss the involvement of IL17-producing T cells in GVHD and the factors involved in their expansion, differentiation, and activation. Different dendritic cell (DC) subsets, such as plasmacytoid DCs and DC NK lectin group receptor 1(+) myeloid DCs have the capability to stimulate Th/Tc17 responses through the release of cytokines. Pivotal cytokines include IL1β, IL6, IL23, and TGFβ, which are known to drive differentiation and expansion of IL17-producing T cells, and these cytokines are highly elevated in patients after allo-SCT. Potent activators of these DC subsets are motifs that are released upon tissue damage and microbial exposure during allo-SCT. These motifs aggravate the Th/Tc17 response via the activation of various pathogen recognition receptors, thereby initiating and perpetuating GVHD. A more comprehensive understanding of the factors and DC subsets driving the IL17 pathway will result in developing and testing novel therapeutic approaches for the prevention of GVHD. PMID:24565991

  7. Targeting the CaMKII/ERK Interaction in the Heart Prevents Cardiac Hypertrophy

    PubMed Central

    Cipolletta, Ersilia; Rusciano, Maria Rosaria; Maione, Angela Serena; Santulli, Gaetano; Sorriento, Daniela; Del Giudice, Carmine; Ciccarelli, Michele; Franco, Antonietta; Crola, Catherine; Campiglia, Pietro; Sala, Marina; Gomez-Monterrey, Isabel; De Luca, Nicola; Trimarco, Bruno; Iaccarino, Guido; Illario, Maddalena

    2015-01-01

    Aims Activation of Ca2+/Calmodulin protein kinase II (CaMKII) is an important step in signaling of cardiac hypertrophy. The molecular mechanisms by which CaMKII integrates with other pathways in the heart are incompletely understood. We hypothesize that CaMKII association with extracellular regulated kinase (ERK), promotes cardiac hypertrophy through ERK nuclear localization. Methods and Results In H9C2 cardiomyoblasts, the selective CaMKII peptide inhibitor AntCaNtide, its penetratin conjugated minimal inhibitory sequence analog tat-CN17β, and the MEK/ERK inhibitor UO126 all reduce phenylephrine (PE)-mediated ERK and CaMKII activation and their interaction. Moreover, AntCaNtide or tat-CN17β pretreatment prevented PE induced CaMKII and ERK nuclear accumulation in H9C2s and reduced the hypertrophy responses. To determine the role of CaMKII in cardiac hypertrophy in vivo, spontaneously hypertensive rats were subjected to intramyocardial injections of AntCaNtide or tat-CN17β. Left ventricular hypertrophy was evaluated weekly for 3 weeks by cardiac ultrasounds. We observed that the treatment with CaMKII inhibitors induced similar but significant reduction of cardiac size, left ventricular mass, and thickness of cardiac wall. The treatment with CaMKII inhibitors caused a significant reduction of CaMKII and ERK phosphorylation levels and their nuclear localization in the heart. Conclusion These results indicate that CaMKII and ERK interact to promote activation in hypertrophy; the inhibition of CaMKII-ERK interaction offers a novel therapeutic approach to limit cardiac hypertrophy. PMID:26110816

  8. 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

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

    PubMed

    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 0.2mg/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 2mg/kg with no effect at the lowest dose of 0.2mg/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. PMID:22266348

  10. 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. PMID:26813615

  11. Targeted homozygous deletion of M-band titin in cardiomyocytes prevents sarcomere formation.

    PubMed

    Musa, Hanny; Meek, Stephen; Gautel, Mathias; Peddie, Dianna; Smith, Andrew J H; Peckham, Michelle

    2006-10-15

    Titin, a multifunctional protein that stretches from the Z-disk to the M-band in heart and skeletal muscle, contains a kinase domain, phosphorylation sites and multiple binding sites for structural and signalling proteins in the M-band. To determine whether this region is crucial for normal sarcomere development, we created mouse embryonic stem cell (ES) lines in which either one or both alleles contained a targeted deletion of the entire M-band-coding region, leaving Z-disk-binding and myosin-filament-binding sites intact. ES cells were differentiated into cardiomyocytes, and myofibrillogenesis investigated by immunofluorescence microscopy. Surprisingly, deletion of one allele did not markedly affect differentiation into cardiomyocytes, suggesting that a single intact copy of the titin gene is sufficient for normal myofibrillogenesis. By contrast, deletion of both alleles resulted in a failure of differentiation beyond an early stage of myofibrillogenesis. Sarcomeric myosin remained in non-striated structures, Z-disk proteins, such as alpha-actinin, were mainly found in primitive dot-like structures on actin stress fibres, M-band-associated proteins (myomesin, obscurin, Nbr1, p62 and MURF2) remained punctate. These results show that integration of the M-band region of titin is required for myosin filament assembly, M-band formation and maturation of the Z-disk. PMID:17038546

  12. Molecular Targeting of ERKs/RSK2 Signaling Axis in Cancer Prevention

    PubMed Central

    Yoo, Sun-Mi; Cho, Sung Jun; Cho, Yong-Yeon

    2015-01-01

    RSK2 is a downstream signaling protein of ERK1 and ERK2 and plays a key role in physiological homeostasis. For this reason, RSK2 is a highly conserved protein among the p90RSK family members. In its location in the signaling pathway, RSK2 is a kinase just upstream of transcription and epigenetic factors, and a few kinases involved in cell cycle regulation and protein synthesis. Moreover, activation of RSK2 by growth factors is directly involved in cell proliferation, anchorage-independent cell transformation and cancer development. Direct evidences regarding the etiological roles of RSK2 in cancer development in humans have been published by our research group illustrating that elevated total- and phospho-RSK2 protein levels mediated by ERK1 and ERK2 are higher in skin cancer tissues compared to normal skin tissues. Notably, it has been shown that RSK2 ectopic expression in JB6 Cl41 cells induces cell proliferation and anchorage- independent cell transformation. Importantly, knockdown of RSK2 suppresses Ras-mediated foci formation and anchorage-independent colony growth of cancer cells. Kaempferol is a one of the natural compounds showing selectivity in inhibiting RSK2 activity in epidermal growth factor-induced G1/S cell cycle transition and cell transformation. Thus, ERKs/RSK2 signaling axis is an important target signaling molecule in chemoprevention. PMID:26473154

  13. Histone Lysine-Specific Methyltransferases and Demethylases in Carcinogenesis: New Targets for Cancer Therapy and Prevention

    PubMed Central

    Tian, Xuejiao; Zhang, Saiyang; Liu, Hong-Min; Zhang, Yan-Bing; Blair, Christopher A; Mercola, Dan; Sassone-Corsi, Paolo; Zi, Xiaolin

    2013-01-01

    Aberrant histone lysine methylation that is controlled by histone lysine methyltransferases (KMTs) and demethylases (KDMs) plays significant roles in carcinogenesis. Infections by tumor viruses or parasites and exposures to chemical carcinogens can modify the process of histone lysine methylation. Many KMTs and KDMs contribute to malignant transformation by regulating the expression of human telomerase reverse transcriptase (hTERT), forming a fused gene, interacting with proto-oncogenes or being up-regulated in cancer cells. In addition, histone lysine methylation participates in tumor suppressor gene inactivation during the early stages of carcinogenesis by regulating DNA methylation and/or by other DNA methylation independent mechanisms. Furthermore, recent genetic discoveries of many mutations in KMTs and KDMs in various types of cancers highlight their numerous roles in carcinogenesis and provide rare opportunities for selective and tumor-specific targeting of these enzymes. The study on global histone lysine methylation levels may also offer specific biomarkers for cancer detection, diagnosis and prognosis, as well as for genotoxic and non-genotoxic carcinogenic exposures and risk assessment. This review summarizes the role of histone lysine methylation in the process of cellular transformation and carcinogenesis, genetic alterations of KMTs and KDMs in different cancers and recent progress in discovery of small molecule inhibitors of these enzymes. PMID:23713993

  14. Targeting macrophage activation for the prevention and treatment of S. aureus biofilm infections†

    PubMed Central

    Hanke, Mark L.; Heim, Cortney E.; Angle, Amanda; Sanderson, Sam D.; Kielian, Tammy

    2013-01-01

    Biofilm infections often lead to significant morbidity due to their chronicity and recalcitrance to antibiotics. We have demonstrated that methicillin-resistant Staphylococcus aureus (MRSA) biofilms can evade macrophage antibacterial effector mechanisms by skewing macrophages towards an alternatively activated M2 phenotype. To overcome this immune evasion, we have utilized two complementary approaches. In the first, a proinflammatory milieu was elicited by local administration of classically-activated M1 macrophages and second, by treatment with the C5a receptor (CD88) agonist EP67, which invokes macrophage proinflammatory activity. Early administration of M1-activated macrophages or EP67 significantly attenuated biofilm formation in a mouse model of MRSA catheter-associated infection. Several proinflammatory mediators were significantly elevated in biofilm infected tissues from macrophage- and EP67-treated animals, revealing effective reprogramming of the biofilm environment to a proinflammatory milieu. A requirement for macrophage proinflammatory activity was demonstrated by the fact that transfer of MyD88-deficient macrophages had minimal impact on biofilm growth. Likewise, neutrophil administration had no effect on biofilm formation. Treatment of established biofilm infections with M1-activated macrophages also significantly reduced catheter-associated biofilm burdens compared to antibiotic treatment. Collectively, these results demonstrate that targeting macrophage proinflammatory activity can overcome the local immune inhibitory environment created during biofilm infections and represents a novel therapeutic strategy. PMID:23365077

  15. Curcumin―The Paradigm of a Multi-Target Natural Compound with Applications in Cancer Prevention and Treatment

    PubMed Central

    Teiten, Marie-Hélène; Eifes, Serge; Dicato, Mario; Diederich, Marc

    2010-01-01

    As cancer is a multifactor disease, it may require treatment with compounds able to target multiple intracellular components. We summarize here how curcumin is able to modulate many components of intracellular signaling pathways implicated in inflammation, cell proliferation and invasion and to induce genetic modulations eventually leading to tumor cell death. Clinical applications of this natural compound were initially limited by its low solubility and bioavailability in both plasma and tissues but combination with adjuvant and delivery vehicles was reported to largely improve bio-availability of curcumin. Moreover, curcumin was reported to act in synergism with several natural compounds or synthetic agents commonly used in chemotherapy. Based on this, curcumin could thus be considered as a good candidate for cancer prevention and treatment when used alone or in combination with other conventional treatments. PMID:22069551

  16. 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

  17. The Actin Cytoskeleton as a Therapeutic Target for the Prevention of Relapse to Methamphetamine Use.

    PubMed

    Young, Erica J; Briggs, Sherri B; Miller, Courtney A

    2015-01-01

    A high rate of relapse is a defining characteristic of substance use disorder for which few treatments are available. Exposure to environmental cues associated with previous drug use can elicit relapse by causing the involuntary retrieval of deeply engrained associative memories that trigger a strong motivation to seek out drugs. Our lab is focused on identifying and disrupting mechanisms that support these powerful consolidated memories, with the goal of developing therapeutics. A particularly promising mechanism is regulation of synaptic dynamics by actin polymerization within dendritic spines. Emerging evidence indicates that memory is supported by structural and functional plasticity dendritic spines, for which actin polymerization is critical, and that prior drug use increases both spine and actin dynamics. Indeed we have found that inhibiting amygdala (AMY) actin polymerization immediately or twenty-four hours prior to testing disrupted methamphetamine (METH)-associated memories, but not food reward or fear memories. Furthermore, METH training increased AMY spine density which was reversed by actin depolymerization treatment. Actin dynamics were also shifted to a more dynamic state by METH training. While promising, actin polymerization inhibitors are not a viable therapeutic, as a multitude of peripheral process (e.g. cardiac function) rely on dynamic actin. For this reason, we have shifted our focus upstream of actin polymerization to nonmuscle myosin II. We and others have demonstrated that myosin IIb imparts a mechanical force that triggers spine actin polymerization in response to synaptic stimulation. Similar to an actin depolymerizing compound, pre-test inhibition of myosin II ATPase activity in the AMY produced a rapid and lasting disruption of drug-seeking behavior. While many questions remain, these findings indicate that myosin II represents a potential therapeutic avenue to target the actin cytoskeleton and disrupt the powerful, extinction

  18. 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'. PMID:26164344

  19. 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.

  20. 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

  1. 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

  2. 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

  3. 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. PMID:26747862

  4. 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

  5. Review of the Target-Specific Oral Anticoagulants in Development for the Treatment and Prevention of Venous Thromboembolism.

    PubMed

    Devabhakthuni, Sandeep; Yoon, Connie H; Pincus, Kathleen J

    2016-08-01

    Anticoagulation therapy is often indicated for the treatment and prevention of venous thromboembolism (VTE). Despite advances in anticoagulant management with parenteral anticoagulants and vitamin K antagonists, limitations to their use still exists, leading to investigation of alternative anticoagulants such as factor Xa inhibitors and direct thrombin inhibitors. To date, 3 target-specific oral anticoagulants (TSOACs) are Food and Drug Administration approved; several other agents are currently in development to optimize VTE management and minimize bleeding risks. The objective of this systematic review article is to provide clinicians an overview of the clinical evidence on the investigational TSOACs for the treatment and prevention of VTE. Of the agents in development, edoxaban holds the most promise due to robust data supporting its clinical benefit with a similar bleeding risk to currently approved agents. Clinicians should understand the TSOACs under investigation, since differences in pharmacokinetics and pharmacodynamics may influence clinical decision making and agent selection for management of VTE. Currently, no direct comparisons between TSOACs have been conducted. Agents under investigation have yet to overcome the major limitations of the currently existing TSOACs. Further studies are necessary to clarify which TSOAC agent is best for management of VTE in clinical practice. PMID:25634013

  6. 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

    2016-01-01

    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

  7. 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

  8. Molecular targets and mechanisms of cancer prevention and treatment by withaferin a, a naturally occurring steroidal lactone.

    PubMed

    Vyas, Avani R; Singh, Shivendra V

    2014-01-01

    The plants used in Ayurvedic medicine, which has been practiced in India for thousands of years for the treatment of a variety of disorders, are rich in chemicals potentially useful for prevention and treatment of cancer. Withania somnifera (commonly known as Ashwagandha in Ayurvedic medicine) is one such medicinal plant whose anticancer value was realized over four decades ago after isolation of a crystalline steroidal compound (withaferin A) from the leaves of this shrub. The root and leaf extracts of W. somnifera are shown to confer protection against chemically-induced cancers in experimental rodents, and retard tumor xenograft growth in athymic mice. Anticancer effect of W. somnifera is generally attributable to steroidal lactones collectively referred to as withanolides. Withaferin A (WA) appears most active against cancer among structurally divergent withanolides isolated from the root or leaf of W. somnifera. Cancer-protective role for WA has now been established using chemically-induced and oncogene-driven rodent cancer models. This review summarizes the key in vivo preclinical studies demonstrating anticancer effects of WA. Molecular targets and mechanisms likely contributing to the anticancer effects of WA are also discussed. Finally, challenges in clinical development of WA for the prevention and treatment of cancer are highlighted. PMID:24046237

  9. 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

  10. 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

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

    PubMed

    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

    2016-06-28

    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

  12. Mitochondria-targeted Ogg1 and Aconitase-2 Prevent Oxidant-induced Mitochondrial DNA Damage in Alveolar Epithelial Cells*

    PubMed Central

    Kim, Seok-Jo; Cheresh, Paul; Williams, David; Cheng, Yuan; Ridge, Karen; Schumacker, Paul T.; Weitzman, Sigmund; Bohr, Vilhelm A.; Kamp, David W.

    2014-01-01

    Mitochondria-targeted human 8-oxoguanine DNA glycosylase (mt-hOgg1) and aconitase-2 (Aco-2) each reduce oxidant-induced alveolar epithelial cell (AEC) apoptosis, but it is unclear whether protection occurs by preventing AEC mitochondrial DNA (mtDNA) damage. Using quantitative PCR-based measurements of mitochondrial and nuclear DNA damage, mtDNA damage was preferentially noted in AEC after exposure to oxidative stress (e.g. amosite asbestos (5–25 μg/cm2) or H2O2 (100–250 μm)) for 24 h. Overexpression of wild-type mt-hOgg1 or mt-long α/β 317–323 hOgg1 mutant incapable of DNA repair (mt-hOgg1-Mut) each blocked A549 cell oxidant-induced mtDNA damage, mitochondrial p53 translocation, and intrinsic apoptosis as assessed by DNA fragmentation and cleaved caspase-9. In contrast, compared with controls, knockdown of Ogg1 (using Ogg1 shRNA in A549 cells or primary alveolar type 2 cells from ogg1−/− mice) augmented mtDNA lesions and intrinsic apoptosis at base line, and these effects were increased further after exposure to oxidative stress. Notably, overexpression of Aco-2 reduced oxidant-induced mtDNA lesions, mitochondrial p53 translocation, and apoptosis, whereas siRNA for Aco-2 (siAco-2) enhanced mtDNA damage, mitochondrial p53 translocation, and apoptosis. Finally, siAco-2 attenuated the protective effects of mt-hOgg1-Mut but not wild-type mt-hOgg1 against oxidant-induced mtDNA damage and apoptosis. Collectively, these data demonstrate a novel role for mt-hOgg1 and Aco-2 in preserving AEC mtDNA integrity, thereby preventing oxidant-induced mitochondrial dysfunction, p53 mitochondrial translocation, and intrinsic apoptosis. Furthermore, mt-hOgg1 chaperoning of Aco-2 in preventing oxidant-mediated mtDNA damage and apoptosis may afford an innovative target for the molecular events underlying oxidant-induced toxicity. PMID:24429287

  13. Identification of putative immunologic targets for colon cancer prevention based on conserved gene upregulation from preinvasive to malignant lesions.

    PubMed

    Broussard, Elizabeth K; Kim, Rachel; Wiley, Jesse C; Marquez, Juan Pablo; Annis, James E; Pritchard, David; Disis, Mary L

    2013-07-01

    The length of time required for preinvasive adenoma to progress to carcinoma, the immunogenicity of colorectal cancer (CRC), and the identification of high-risk populations make development and testing of a prophylactic vaccine for the prevention of CRC possible. We hypothesized that genes upregulated in adenoma relative to normal tissue, which maintained increased expression in CRC, would encode proteins suitable as putative targets for immunoprevention. We evaluated existing adenoma and CRC microarray datasets and identified 160 genes that were ≥2-fold upregulated in both adenoma and CRC relative to normal colon tissue. We further identified 23 genes that showed protein overexpression in colon adenoma and CRC based on literature review. Silencing the most highly upregulated genes, CDH3, CLDN1, KRT23, and MMP7, in adenoma and CRC cell lines resulted in a significant decrease in viability (P < 0.0001) and proliferation (P < 0.0001) as compared to controls and an increase in cellular apoptosis (P < 0.05 for CDH3, KRT23). Results were duplicated across cell lines representing microsatellite instability, CpG island methylator, and chromosomal instability phenotypes, suggesting immunologic elimination of cells expressing these proteins could impact the progression of all CRC phenotypes. To determine whether these proteins were immunogens, we interrogated sera from early stage CRC patients and controls and found significantly elevated CDH3 (P = 0.006), KRT23 (P = 0.0007), and MMP7 (P < 0.0001) serum immunoglobulin G in cases as compared to controls. These data show a high throughput approach to the identification of biologically relevant putative immunologic targets for CRC and identified three candidates suitable for vaccine development. PMID:23682078

  14. 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.

  15. NF-kappaB, a mediator for lung carcinogenesis and a target for lung cancer prevention and therapy

    PubMed Central

    Chen, Wenshu; Li, Zi; Bai, Lang; Lin, Yong

    2011-01-01

    Lung cancer ranks as the first malignant tumor killer worldwide. Despite the knowledge that carcinogens from tobacco smoke and the environment constitute the main causes of lung cancer, the mechanisms for lung carcinogenesis are still elusive. Cancer development and progression depend on the balance between cell survival and death signals. Common cell survival signaling pathways are activated by carcinogens as well as by inflammatory cytokines, which contribute substantially to cancer development. As a major cell survival signal, nuclear factor-kappaB (NF-kappaB) is involved in multiple steps in carcinogenesis and in cancer cell’s resistance to chemo- and radiotherapy. Recent studies with animal models and cell culture systems have established the links between NF-kappaB and lung carcinogenesis, highlighting the significance of targeting the NF-kappaB signaling pathway for lung cancer treatment and chemoprevention. In this review, we summarize progresses in understanding the NF-kappaB pathway in lung cancer development as well as in modulating NF-kappaB for lung cancer prevention and therapy. PMID:21196225

  16. Targeting mitochondrial alterations to prevent type 2 diabetes--evidence from studies of dietary redox-active compounds.

    PubMed

    Cheng, Zhiyong; Schmelz, Eva M; Liu, Dongmin; Hulver, Matthew W

    2014-08-01

    As a growing epidemic, type 2 diabetes mellitus (T2DM) has significantly affected the individual's quality of life and economy of the society. Understanding the mechanisms of the disease and discovery of new therapeutic options has become more urgent than ever before. Mitochondrial alterations (e.g. functional alterations, and impaired biogenesis and dynamics) are strongly associated with the development of T2DM. Accumulation of reactive oxygen species or intermediates of incomplete fatty acid oxidation due to mitochondrial deficiency activates stress kinases and dampens insulin signaling. Redox-active compounds such as resveratrol, pyrroloquinoline quinone, and hydroxytyrosol can potently counteract reactive oxygen species, and improve mitochondrial function and biogenesis. Therefore, targeting the mitochondrial alterations with these redox-active compounds may lead to new therapeutic or preventive options for T2DM. In this article, we review the molecular mechanisms of mitochondrial alterations in T2DM, and the action of redox-active compounds to reverse mitochondrial changes and oxidative stress in T2DM. In addition, the current challenges and future directions are discussed and prospected. PMID:24668725

  17. 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

  18. Targeted prevention of excess weight gain and eating disorders in high-risk adolescent girls: a randomized controlled trial12345

    PubMed Central

    Shomaker, Lauren B; Wilfley, Denise E; Young, Jami F; Sbrocco, Tracy; Stephens, Mark; Ranzenhofer, Lisa M; Elliott, Camden; Brady, Sheila; Radin, Rachel M; Vannucci, Anna; Bryant, Edny J; Osborn, Robyn; Berger, Sarah S; Olsen, Cara; Kozlosky, Merel; Reynolds, James C; Yanovski, Jack A

    2014-01-01

    Background: The high prevalence and incidence of obesity and eating disorders in US adolescent girls are serious health problems. Because of the shared risk factors for obesity and eating disorders, a targeted prevention of both conditions is a priority. Objective: We determined whether an adapted interpersonal psychotherapy prevention program is more efficacious for reducing excess weight gain and worsening disordered eating than health education in adolescent girls at high risk of obesity and eating disorders. Design: A parallel-group, randomized controlled trial was conducted between September 2008 and January 2013 in a university-based laboratory and a federal research hospital. The study included 113 adolescent (12–17-y-old) girls deemed at high risk of adult obesity and eating disorders because of a body mass index (BMI) between the 75th and 97th percentiles and reports of episodes of a loss of control over their eating. Girls were randomly assigned to participate in an adapted interpersonal psychotherapy or a health-education group program for 12 weekly 90-min group sessions. Follow-up assessments occurred immediately after group programs and at 6 and 12 mo. Results: Participation in both conditions was associated with decreases in expected BMI gain, age-adjusted BMI metrics, the percentage of fat by using dual-energy X-ray absorptiometry, symptoms of depression and anxiety, and the frequency of loss-of-control eating over 12 mo of follow-up (Ps < 0.001) with no group difference. In follow-up analyses, interpersonal psychotherapy was more efficacious than health education at reducing objective binge eating at the 12-mo follow-up (P < 0.05). Conclusions: The intervention with adolescent girls with loss-of-control eating is associated with lower age-adjusted BMI and percentage of adiposity as well as improved mood symptoms over 1 y. Interpersonal psychotherapy further reduced objective binge eating. Additional research is needed to elucidate the mechanisms

  19. 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

  20. 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…

  1. Success of long-term preventive maintenance on telescope subsystems using the example of the VLT adapter-rotators at the ESO Paranal Observatory

    NASA Astrophysics Data System (ADS)

    Salgado, F.; Haddad, J.; Hudepohl, G.; Medina, R.

    2012-09-01

    More than 11 years have passed, since the first of the four Unit Telescopes of the VLT on Cerro Paranal has entered into operations. To keep four such complex telecopes at a high level of availability with only around 3 percent of technical down time does not only depend on a good and robust design and manufacturing process, but long term also on a sound preventive maintenance plan and program. In this paper the Instrument Adapter-Rotators, twelve of which are installed at the observatory, have been chosen to show how a preventive maintenance plan has been developed, implemented and executed and what the results are. In the first part the most common problems are shown and some larger interventions are described and listed. It explains the tests that have been developed to follow the status of the systems by measuring key parameters such as position error, motor current, torque and encoders status in order to detect at an early stage any degradation in performance parameters. Depending on the test results preventive actions can be planned well ahead of serious failures, making optimum use of scheduled technical time periods and consequently reducing loss of observing time. Finally some statistic charts show how problems have been reduced as a result of the preventive maintenance plan

  2. Targeting the α7 nicotinic acetylcholine receptor to prevent progressive dementia and improve cognition in adults with Down's syndrome.

    PubMed

    Deutsch, Stephen I; Burket, Jessica A; Benson, Andrew D

    2014-10-01

    As persons with Down's syndrome (DS) age into the third decade and beyond, they develop Alzheimer's disease (AD)-like histopathological changes in brain and may manifest progressive worsening of adaptive functions. Increasingly, persons with DS have near-normal to normal life spans; thus, it has become a therapeutic imperative to preserve adaptive functions and ability to live as independently as possible in the least restrictive environment throughout adulthood. Data suggest that these histopathological changes and worsening adaptive functions result, at least in part, from the binding of the amyloidogenic Aβ1-42 peptide to α7 nicotinic acetylcholine receptors (α7nAChRs) on the surface of neurons, which can lead to the internalization of the tightly-bound complex and cell lysis. Pharmacotherapeutic targeting of the α7nAChR may inhibit the creation of the Aβ1-42-α7nAChR complex, which has been observed both intraneuronally and as a component of the amyloid plaque seen in AD. Additionally, selective α7nAChR agonists may improve memory and cognition independently of their potential ability to attenuate the cytotoxicity of Aβ1-42 and retard the deposition of amyloid plaques in adults with DS. However, there are conflicting data supporting an antagonist strategy to improve cognition in the presence of elevated levels of Aβ amyloidogenic peptides, as well as to prevent emergence of pyramidal neuron hyperexcitability. A major challenge to the implementation of clinical trials of targeted α7nAChR interventions in adults with DS will be the ability to detect medication-induced changes in cognition in the context of intellectual disability. The Review will consider some of the current evidence supporting both the role of the Aβ1-42-α7nAChR complex in the pathogenesis of the AD-like histopathology in adult persons with DS, and pharmacotherapeutic interventions with α7nAChR agonists. PMID:24865150

  3. The interleukin-6 receptor as a target for prevention of coronary heart disease: a mendelian randomisation analysis

    PubMed Central

    2012-01-01

    Summary Background A high circulating concentration of interleukin 6 is associated with increased risk of coronary heart disease. Blockade of the interleukin-6 receptor (IL6R) with a monoclonal antibody (tocilizumab) licensed for treatment of rheumatoid arthritis reduces systemic and articular inflammation. However, whether IL6R blockade also reduces risk of coronary heart disease is unknown. Methods Applying the mendelian randomisation principle, we used single nucleotide polymorphisms (SNPs) in the gene IL6R to evaluate the likely efficacy and safety of IL6R inhibition for primary prevention of coronary heart disease. We compared genetic findings with the effects of tocilizumab reported in randomised trials in patients with rheumatoid arthritis. Findings In 40 studies including up to 133 449 individuals, an IL6R SNP (rs7529229) marking a non-synonymous IL6R variant (rs8192284; p.Asp358Ala) was associated with increased circulating log interleukin-6 concentration (increase per allele 9·45%, 95% CI 8·34–10·57) as well as reduced C-reactive protein (decrease per allele 8·35%, 95% CI 7·31–9·38) and fibrinogen concentrations (decrease per allele 0·85%, 95% CI 0·60–1·10). This pattern of effects was consistent with IL6R blockade from infusions of tocilizumab (4–8 mg/kg every 4 weeks) in patients with rheumatoid arthritis studied in randomised trials. In 25 458 coronary heart disease cases and 100 740 controls, the IL6R rs7529229 SNP was associated with a decreased odds of coronary heart disease events (per allele odds ratio 0·95, 95% CI 0·93–0·97, p=1·53×10−5). Interpretation On the basis of genetic evidence in human beings, IL6R signalling seems to have a causal role in development of coronary heart disease. IL6R blockade could provide a novel therapeutic approach to prevention of coronary heart disease that warrants testing in suitably powered randomised trials. Genetic studies in populations could be used more widely to help to

  4. A mitochondrial-targeted coenzyme q analog prevents weight gain and ameliorates hepatic dysfunction in high-fat-fed mice.

    PubMed

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

    2014-12-01

    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

  5. 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

  6. 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

  7. 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

  8. 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

  9. High molecular weight fibroblast growth factor-2 in the human heart is a potential target for prevention of cardiac remodeling.

    PubMed

    Santiago, Jon-Jon; McNaughton, Leslie J; Koleini, Navid; Ma, Xin; Bestvater, Brian; Nickel, Barbara E; Fandrich, Robert R; Wigle, Jeffrey T; Freed, Darren H; Arora, Rakesh C; Kardami, Elissavet

    2014-01-01

    Fibroblast growth factor 2 (FGF-2) is a multifunctional protein synthesized as high (Hi-) and low (Lo-) molecular weight isoforms. Studies using rodent models showed that Hi- and Lo-FGF-2 exert distinct biological activities: after myocardial infarction, rat Lo-FGF-2, but not Hi-FGF-2, promoted sustained cardioprotection and angiogenesis, while Hi-FGF-2, but not Lo-FGF-2, promoted myocardial hypertrophy and reduced contractile function. Because there is no information regarding Hi-FGF-2 in human myocardium, we undertook to investigate expression, regulation, secretion and potential tissue remodeling-associated activities of human cardiac (atrial) Hi-FGF-2. Human patient-derived atrial tissue extracts, as well as pericardial fluid, contained Hi-FGF-2 isoforms, comprising, respectively, 53%(±20 SD) and 68% (±25 SD) of total FGF-2, assessed by western blotting. Human atrial tissue-derived primary myofibroblasts (hMFs) expressed and secreted predominantly Hi-FGF-2, at about 80% of total. Angiotensin II (Ang II) up-regulated Hi-FGF-2 in hMFs, via activation of both type 1 and type 2 Ang II receptors; the ERK pathway; and matrix metalloprotease-2. Treatment of hMFs with neutralizing antibodies selective for human Hi-FGF-2 (neu-AbHi-FGF-2) reduced accumulation of proteins associated with fibroblast-to-myofibroblast conversion and fibrosis, including α-smooth muscle actin, extra-domain A fibronectin, and procollagen. Stimulation of hMFs with recombinant human Hi-FGF-2 was significantly more potent than Lo-FGF-2 in upregulating inflammation-associated proteins such as pro-interleukin-1β and plasminogen-activator-inhibitor-1. Culture media conditioned by hMFs promoted cardiomyocyte hypertrophy, an effect that was prevented by neu-AbHi-FGF-2 in vitro. In conclusion, we have documented that Hi-FGF-2 represents a substantial fraction of FGF-2 in human cardiac (atrial) tissue and in pericardial fluid, and have shown that human Hi-FGF-2, unlike Lo-FGF-2, promotes deleterious

  10. mTORC1/2 targeted by n-3 polyunsaturated fatty acids in the prevention of mammary tumorigenesis and tumor progression.

    PubMed

    Chen, Z; Zhang, Y; Jia, C; Wang, Y; Lai, P; Zhou, X; Wang, Y; Song, Q; Lin, Jun; Ren, Z; Gao, Q; Zhao, Z; Zheng, H; Wan, Z; Gao, T; Zhao, A; Dai, Y; Bai, X

    2014-09-11

    Although epidemiological and preclinical studies have shown the preventative effects of n-3 polyunsaturated fatty acids (PUFAs) on breast cancer, inconsistencies still remain in the data and the underlying mechanisms remain unclear. In this study, we identified mammalian target of rapamycin (mTOR) signaling, which plays an essential role in cell proliferation and breast tumorigenesis, as a target of n-3 PUFAs. In breast cancer cell lines, n-3 PUFAs rapidly and efficiently suppress both mTOR complex 1 (mTORC1) and mTORC2 and their downstream signaling, and subsequently inhibit cell proliferation and angiogenesis while promoting apoptosis. Further study indicates that stabilization of the mTOR-raptor complex by n-3 PUFAs may contribute to their inhibitory effect on mTORC1. Importantly, four complementary and well-controlled animal models were utilized to identify the role and molecular target of n-3 PUFAs in the prevention of breast carcinogenesis and progression, namely: (1) chemically induced mammary tumor rats with a high dietary intake of n-3 PUFAs; (2) nude mice implanted with mammary tumor cell lines stably expressing fat-1, a desaturase that catalyzes the conversion of n-6 to n-3 PUFAs and produces n-3 PUFAs endogenously; (3) fat-1 transgenic severe combined immune deficiency mice implanted with breast tumor cells; and (4) the fat-1 transgenic mouse mammary tumor virus-polyoma virus middle T oncogene double-hybrid mice, a model of aggressive breast cancer. In summary, dietary and endogenous n-3 PUFAs abrogate the activity of mTORC1/2 pathways in vitro and in vivo and prevent breast carcinogenesis, tumor growth and metastasis. Taken together, our findings convincingly clarify the causal relationship between n-3 PUFAs and breast cancer prevention and establish mTORC1/2 as a target of n-3 PUFAs. PMID:24096482

  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. Individualization of a Manualized Pressure Ulcer Prevention Program: Targeting Risky Life Circumstances Through a Community-Based Intervention for People with Spinal Cord Injury

    PubMed Central

    Vaishampayan, Ashwini; Clark, Florence; Carlson, Mike; Blanche, Erna Imperatore

    2012-01-01

    Purpose To sensitize practitioners working with individuals with spinal cord injury to the complex life circumstances that are implicated in the development of pressure ulcers, and to document the ways that interventions can be adapted to target individual needs. Methods Content analysis of weekly fidelity/ quality control meetings that were undertaken as part of a lifestyle intervention for pressure ulcer prevention in community-dwelling adults with spinal cord injury. Results Four types of lifestyle-relevant challenges to ulcer prevention were identified: risk-elevating life circumstances, communication difficulties, equipment problems, and individual personality issues. Intervention flexibility was achieved by changing the order of treatment modules, altering the intervention content or delivery approach, or going beyond the stipulated content. Conclusion Attention to recurrent types of individual needs, along with explicit strategies for tailoring manualized interventions, has potential to enhance pressure ulcer prevention efforts for adults with spinal cord injury. Target audience This continuing education article is intended for practitioners interested in learning about a comprehensive, context-sensitive, community-based pressure ulcer prevention program for people with spinal cord injury. Objectives After reading this article, the reader should be able to: Describe some of the contextual factors that increase pressure ulcer risk in people with spinal cord injury living in the community.Distinguish between tailored and individualized intervention approaches.Identify the issues that must be taken into account to design context-sensitive, community-based pressure ulcer prevention programs for people with spinal cord injury.Describe approaches that can be used to individualize manualized interventions. PMID:21586911

  13. [Relapse prevention in drug addicts].

    PubMed

    Rácz, József

    2013-12-01

    The literature review deals with methods of relapse prevention. Relapse prevention is the key in the treatment of clients with drug addictions according to the transtheoretical model of change. If relapse prevention is more effective then not only the relapse would be prevented, but the client would leave the circulus vitiosus of relapses. Among psychotherapies cognitive behavioural methods are proven effective. Shorter forms of cognitive therapies are also available: for example, cognitive bias modification. Pharmacotherapy partly decreases craving of the clients or ceases the effects of psychoactive substances. Specific pharmacotherapeutic methods prevent relapses in a non-abstinent treatment design. Here the goal is not the abstinence in a short time, but the reduction of harms associated with drug use. In this way, a new target group of drug users can be involved in treatment. PMID:24380964

  14. Magnetically Targeted Delivery of Therapeutic Agents to Injured Blood Vessels for Prevention of In-Stent Stenosis

    PubMed Central

    Fishbein, Ilia; Adamo, Richard F.; Forbes, Scott P.; Folchman-Wagner, Zoë; Alferiev, Ivan S.

    2012-01-01

    Magnetic guidance is a physical targeting strategy with the potential to improve the safety and efficacy of a variety of therapeutic agents — including small-molecule pharmaceuticals, proteins, gene vectors, and cells — by enabling their site-specific delivery. The application of magnetic targeting for in-stent restenosis can address the need for safer and more efficient treatment strategies. However, its translation to humans may not be possible without revising the traditional magnetic targeting scheme, which is limited by its inability to selectively guide therapeutic agents to deep localized targets. An alternative two-source strategy can be realized through the use of uniform, deep-penetrating magnetic fields in conjunction with vascular stents included as part of the magnetic setup and the platform for targeted delivery to injured arteries. Studies showing the feasibility of this novel targeting strategy in in-stent restenosis models and considerations in the design of carrier formulations for magnetically guided antirestenotic therapy are discussed in this review. PMID:22891107

  15. 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…

  16. Ultrasound-targeted transfection of tissue-type plasminogen activator gene carried by albumin nanoparticles to dog myocardium to prevent thrombosis after heart mechanical valve replacement

    PubMed Central

    Ji, Jun; Ji, Shang-Yi; Yang, Jian-An; He, Xia; Yang, Xiao-Han; Ling, Wen-Ping; Chen, Xiao-Ling

    2012-01-01

    Background There are more than 300,000 prosthetic heart valve replacements each year worldwide. These patients are faced with a higher risk of thromboembolic events after heart valve surgery and long-term or even life-long anticoagulative and antiplatelet therapies are necessary. Some severe complications such as hemorrhaging or rebound thrombosis can occur when the therapy ceases. Tissue-type plasminogen activator (t-PA) is a thrombolytic agent. One of the best strategies is gene therapy, which offers a local high expression of t-PA over a prolonged time period to avoid both systemic hemorrhaging and local rebound thrombosis. There are some issues with t-PA that need to be addressed: currently, there is no up-to-date report on how the t-PA gene targets the heart in vivo and the gene vector for t-PA needs to be determined. Aims To fabricate an albumin nano-t-PA gene ultrasound-targeted agent and investigate its targeting effect on prevention of thrombosis after heart mechanic valve replacement under therapeutic ultrasound. Methods A dog model of mechanical tricuspid valve replacement was constructed. A highly expressive t-PA gene plasmid was constructed and packaged by nanoparticles prepared with bovine serum albumin. This nanopackaged t-PA gene plasmid was further cross-linked to ultrasonic microbubbles prepared with sucrose and bovine serum albumin to form the ultrasonic-targeted agent for t-PA gene transfection. The agent was given intravenously followed by a therapeutic ultrasound treatment (1 MHz, 1.5 w/cm2, 10 minutes) of the heart soon after valve replacement had been performed. The expression of t-PA in myocardium was detected with multiclonal antibodies to t-PA by the indirect immunohistochemical method. Venous blood t-PA and D-dimer contents were tested before and 1, 2, 4, and 8 weeks after the operation. Results The high expression of t-PA could be seen in myocardium with increases in blood t-PA and D-dimer contents and thrombosis was prevented 8 weeks

  17. 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

  18. Combining targeted drugs to overcome and prevent resistance of solid cancers with some stem-like cell features

    PubMed Central

    Koivunen, Peppi; Koivunen, Jussi P.

    2014-01-01

    Treatment resistance significantly inhibits the efficiency of targeted cancer therapies in drug-sensitive genotypes. In the current work, we studied mechanisms for rapidly occurring, adaptive resistance in targeted therapy-sensitive lung, breast, and melanoma cancer cell lines. The results show that in ALK translocated lung cancer lines H3122 and H2228, cells with cancer stem-like cell features characterized by high expression of cancer stem cell markers and/or in vivo tumorigenesis can mediate adaptive resistance to oncogene ablative therapy. When pharmacological ablation of ALK oncogene was accompanied with PI3K inhibitor or salinomycin therapy, cancer stem-like cell features were reversed which was accompanied with decreased colony formation. Furthermore, co-targeting was able to block the formation of acquired resistance in H3122 line. The results suggest that cells with cancer stem-like cell features can mediate adaptive resistance to targeted therapies. Since these cells follow the stochastic model, concurrent therapy with an oncogene ablating agent and a stem-like cell-targeting drug is needed for maximal therapeutic efficiency. PMID:25238228

  19. 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

  20. 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

  1. High concentrations of drug in target tissues following local controlled release are utilized for both drug distribution and biologic effect: an example with epicardial inotropic drug delivery.

    PubMed

    Maslov, Mikhail Y; Edelman, Elazer R; Wei, Abraham E; Pezone, Matthew J; Lovich, Mark A

    2013-10-28

    Local drug delivery preferentially loads target tissues with a concentration gradient from the surface or point of release that tapers down to more distant sites. Drug that diffuses down this gradient must be in unbound form, but such drug can only elicit a biologic effect through receptor interactions. Drug excess loads tissues, increasing gradients and driving penetration, but with limited added biological response. We examined the hypothesis that local application reduces dramatically systemic circulating drug levels but leads to significantly higher tissue drug concentration than might be needed with systemic infusion in a rat model of local epicardial inotropic therapy. Epinephrine was infused systemically or released locally to the anterior wall of the heart using a novel polymeric platform that provides steady, sustained release over a range of precise doses. Epinephrine tissue concentration, upregulation of cAMP, and global left ventricular response were measured at equivalent doses and at doses equally effective in raising indices of contractility. The contractile stimulation by epinephrine was linked to drug tissue levels and commensurate cAMP upregulation for IV systemic infusion, but not with local epicardial delivery. Though cAMP was a powerful predictor of contractility with local application, tissue epinephrine levels were high and variable--only a small fraction of the deposited epinephrine was utilized in second messenger signaling and biologic effect. The remainder of deposited drug was likely used in diffusive transport and distribution. Systemic side effects were far more profound with IV infusion which, though it increased contractility, also induced tachycardia and loss of systemic vascular resistance, which were not seen with local application. Local epicardial inotropic delivery illustrates then a paradigm of how target tissues differentially handle and utilize drug compared to systemic infusion. PMID:23872515

  2. Hombres Sanos: exposure and response to a social marketing HIV prevention campaign targeting heterosexually identified Latino men who have sex with men and women.

    PubMed

    Martínez-Donate, Ana P; Zellner, Jennifer A; Fernández-Cerdeño, Araceli; Sañudo, Fernando; Hovell, Melbourne F; Sipan, Carol L; Engelberg, Moshe; Ji, Ming

    2009-10-01

    This study examined the reach and impact of a social marketing intervention to reduce HIV risk among heterosexually identified (HI) Latino men who have sex with men and women (MSMW). Repeated cross-sectional intercept surveys were conducted in selected community venues during and after the campaign with 1,137 HI Latino men. Of them, 6% were classified as HI Latino MSMW. On average, 85.9% of the heterosexual respondents and 86.8% of the HI MSMW subsample reported exposure to the campaign. Responses to the campaign included having made an appointment for a male health exam that included HIV testing and using condoms. Campaign exposure was significantly associated with HIV testing behavior and intentions and with knowledge of where to get tested. The campaign reached its underserved target audience and stimulated preventive behaviors. Social marketing represents a promising approach for HIV prevention among HI Latinos, in general, and HI Latino MSMW, in particular. PMID:19824840

  3. 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

  4. 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. PMID:26749012

  5. 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. PMID:23829690

  6. 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

  7. Osteoporosis: Cloris Leachman Leads by Example

    MedlinePlus

    ... please turn Javascript on. Feature: Osteoporosis Cloris Leachman Leads By Example Past Issues / Winter 2011 Table of ... age discrimination! Read More "Osteoporosis" Articles Cloris Leachman Leads By Example / Preventing and Treating Brittle Bones and ...

  8. 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

  9. Mitochondria-targeted antioxidants do not prevent tumour necrosis factor-induced necrosis of L929 cells.

    PubMed

    Jarvis, Reagan M; Göttert, Jana; Murphy, Michael P; Ledgerwood, Elizabeth C

    2007-09-01

    Mitochondrial production of reactive oxygen species (ROS) is widely reported as a central effector during TNF-induced necrosis. The effect of a family of mitochondria-targeted antioxidants on TNF-induced necrosis of L929 cells was studied. While the commonly used lipid-soluble antioxidant BHA effectively protected cells from TNF-induced necrosis, the mitochondria-targeted antioxidants MitoQ(3), MitoQ(5), MitoQ(10) and MitoPBN had no effect on TNF-induced necrosis. Since BHA also acts as an uncoupler of mitochondrial membrane potential, two additional uncouplers were tested. FCCP and CCCP both provided dose-dependent inhibition of TNF-induced necrosis. In conclusion, the generation of mitochondrial ROS may not be necessary for TNF-induced necrosis. Instead, these results suggest alternative mitochondrial functions, such as a respiration-dependent process, are critical for necrotic death. PMID:17729122

  10. 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

  11. Prevention of liver fibrosis by triple helix-forming oligodeoxyribonucleotides targeted to the promoter region of type I collagen gene.

    PubMed

    Koilan, Subramaniyan; Hamilton, David; Baburyan, Narina; Padala, Mythili K; Weber, Karl T; Guntaka, Ramareddy V

    2010-10-01

    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. 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

  13. Enabling implementation of the Global Vaccine Action Plan: developing investment cases to achieve targets for measles and rubella prevention.

    PubMed

    Thompson, Kimberly M; Strebel, Peter M; Dabbagh, Alya; Cherian, Thomas; Cochi, Stephen L

    2013-04-18

    Global prevention and control of infectious diseases requires significant investment of financial and human resources and well-functioning leadership and management structures. The reality of competing demands for limited resources leads to trade-offs and questions about the relative value of specific investments. Developing investment cases can help to provide stakeholders with information about the benefits, costs, and risks associated with available options, including examination of social, political, governance, and ethical issues. We describe the process of developing investment cases for globally coordinated management of action plans for measles and rubella as tools for enabling the implementation of the Global Vaccine Action Plan (GVAP). We focus on considerations related to the timing of efforts to achieve measles and rubella goals independently and within the context of ongoing polio eradication efforts, other immunization priorities, and other efforts to control communicable diseases or child survival initiatives. Our analysis suggests that the interactions between the availability and sustainability of financial support, sufficient supplies of vaccines, capacity of vaccine delivery systems, and commitments at all levels will impact the feasibility and timing of achieving national, regional, and global goals. The timing of investments and achievements will determine the net financial and health benefits obtained. The methodology, framing, and assumptions used to characterize net benefits and uncertainties in the investment cases will impact estimates and perceptions about the value of prevention achieved overall by the GVAP. We suggest that appropriately valuing the benefits of investments of measles and rubella prevention will require the use of integrated dynamic disease, economic, risk, and decision analytic models in combination with consideration of qualitative factors, and that synthesizing information in the form of investment cases may help

  14. 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

  15. Determinants for Achieving the LDL-C Target of Lipid Control for Secondary Prevention of Cardiovascular Events in Taiwan

    PubMed Central

    Ho, Li-Ting; Yin, Wei-Hsian; Chuang, Shao-Yuan; Tseng, Wei-Kung; Wu, Yen-Wen; Hsieh, I-Chang; Lin, Tsung-Hsien; Li, Yi-Heng; Huang, Lien-Chi; Wang, Kuo-Yang; Ueng, Kwo-Chang; Fang, Ching-Chang; Pan, Wen-Harn; Yeh, Hung-I; Wu, Chau-Chung; Chen, Jaw-Wen

    2015-01-01

    Background Epidemiological and clinical studies have clearly established the link between low-density lipoprotein cholesterol (LDL-C) and atherosclerosis-related cardiovascular consequences. Although it has been a common practice for physicians to prescribe lipid-lowering therapy for patients with dyslipidemia, the achievement rate is still not satisfied in Taiwan. Therefore, the determinants for achieving the LDL-C target needed to be clarified for better healthcare of the patients with dyslipidemia. Method This registry-type prospective observational study enrolled the patients with cardiovascular diseases (coronary artery disease (CAD) and cerebrovascular disease (CVD)) from 18 medical centers across Taiwan, and clinically followed them for five years. At every clinical visit, vital signs, clinical endpoints, adverse events, concurrent medications and laboratory specimens were obtained as thoroughly as possible. The lipid profile (total cholesterol, high-density lipoprotein cholesterol, LDL-C, triglyceride), liver enzymes, and creatinine phosphokinase were evaluated at baseline, and every year thereafter. The cross sectional observational data was analyzed for this report. Result Among the 3,486 registered patients, 54% had their LDL-C < 100 mg/dL. By univariate analysis, the patients achieving the LDL-C target were associated with older age, more male sex, taller height, lower blood pressure, more under lipid-lowering therapy, more smoking cessation, more history of CAD, DM, physical activity, but less history of CVD. The multivariate analysis showed statin therapy was the most significant independent determinant for achieving the treatment target, followed by age, history of CAD, diabetes, blood pressure, and sex. However, most patients were on regimens of very-low to low equipotent doses of statins. Conclusion Although the lipid treatment guideline adherence is improving in recent years, only 54% of the patients with cardiovascular diseases have achieved

  16. Alcohol-related injury among Greek-letter college students: Defining a target population for secondary prevention

    PubMed Central

    O’Brien, Mary Claire; McNamara, Robert S; McCoy, Thomas P; Sutfin, Erin L; Wolfson, Mark; Rhodes, Scott D

    2013-01-01

    Members of Greek-letter societies are the heaviest drinkers on college campuses, and experience more alcohol-related problems than their peers. This study reports the results of a web-based survey administered to stratified random samples of college students from ten North Carolina universities. Greek-letter status was a significant independent risk factor for increased injury (both experienced and caused to others), even after adjusting for drinking behaviors. Prevention, screening, and intervention strategies are discussed in the context of these results. PMID:22689586

  17. HIV risk behaviours among injecting drug users in Northeast India following scale-up of a targeted HIV prevention programme

    PubMed Central

    2011-01-01

    Background In the Northeast Indian states of Manipur and Nagaland there has been an ongoing HIV epidemic among injecting drug users (IDUs) since the mid-1990s. Project ORCHID is an Avahan-funded HIV prevention project that has been working in selected districts of Manipur and Nagaland since 2004. It supports local partner non-government organisations (NGOs) to deliver a range of harm reduction interventions, and currently reaches approximately 14,500 IDUs across the two states. To assess changes in HIV risk behaviours two Behavioural Tracking Surveys (BTS) were undertaken among IDUs in 2007 and 2009. Methods The BTS used respondent driven sampling (RDS) to recruit adult male IDUs (18 years of age and above) from Ukhrul and Chandel districts in Manipur, and Kiphire and Zunheboto districts in Nagaland. This paper reports on analysis of socio-demographics, drug use and injecting practices, sexual behaviour and condom use, knowledge of HIV, and exposure to interventions. Descriptive data were analysed using RDSAT, and odds ratios were calculated in SPSS. Results The proportion of IDUs reporting NOT sharing needles / syringes at last injection increased substantially in Ukhrul (59.6% to 91.2%) and Zunheboto (45.5% to 73.8%), remained high in Chandel (97.0% to 98.9%), and remained largely unchanged in Kiphire (63.3% to 68.8%). The use of condoms with regular partners was low in all districts at both time points. In Ukhrul, Kiphire and Zunheboto the proportion of IDUs using condoms during sexual intercourse with a casual partner increased substantially to approximately 70-85%, whilst in Chandel the increase was only marginal (57.4% to 63.6%). Exposure to NGO HIV prevention interventions was significantly associated (p<0.05) with lower odds of sharing needles during the previous month (Nagaland, OR=0.63; Manipur, OR 0.35). Conclusion Despite district-level differences, the results from this BTS study indicate that exposure to HIV prevention services, predominately

  18. Tumour suppressor HLJ1: A potential diagnostic, preventive and therapeutic target in non-small cell lung cancer

    PubMed Central

    Tsai, Meng-Feng; Wang, Chi-Chung; Chen, Jeremy JW

    2014-01-01

    Lung cancer is the leading cause of cancer-related mortality throughout the world. Non-small cell lung cancer (NSCLC) accounts for 85% of all diagnosed lung cancers. Despite considerable progress in the diagnosis and treatment of the disease, the overall 5-year survival rate of NSCLC patients remains lower than 15%. The most common causes of death in lung cancer patients are treatment failure and metastasis. Therefore, developing novel strategies that target both tumour growth and metastasis is an important and urgent mission for the next generation of anticancer therapy research. Heat shock proteins (HSPs), which are involved in the fundamental defence mechanism for maintaining cellular viability, are markedly activated during environmental or pathogenic stress. HSPs facilitate rapid cell division, metastasis, and the evasion of apoptosis in cancer development. These proteins are essential players in the development of cancer and are prime therapeutic targets. In this review, we focus on the current understanding of the molecular mechanisms responsible for HLJ1’s role in lung cancer carcinogenesis and progression. HLJ1, a member of the human HSP 40 family, has been characterised as a tumour suppressor. Research studies have also reported that HLJ1 shows promising dual anticancer effects, inhibiting both tumour growth and metastasis in NSCLC. The accumulated evidence suggests that HLJ1 is a potential biomarker and treatment target for NSCLC. PMID:25493224

  19. 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

  20. 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

  1. Relationship of inferior gluteal nerves and vessels: target for application of stimulation devices for the prevention of pressure ulcers in spinal cord injury.

    PubMed

    Skalak, Anthony F; McGee, Michael F; Wu, Gary; Bogie, Kath

    2008-02-01

    A study was carried out to determine whether the location of the inferior gluteal nerve could be reliably predicted using external anatomy or vascular imaging. This study was motivated by our group's development of an electrical stimulation system to provide direct gluteal stimulation in paralyzed individuals, in particular those with spinal cord injury (SCI). Pressure ulcers are a common complication for many individuals with reduced mobility. Numerous approaches have been employed to treat and prevent pressure ulcers; however no procedure or nursing care regimen has been successful in eradicating them completely. Our group seeks to prevent skin breakdown in susceptible patients by direct electrical stimulation of the paralyzed gluteal muscle, leading to improved circulation and increased muscle mass (hypertrophy) in the treated area. Currently, percutaneous electrodes are placed through an extensive probing process to select the motor point of the target muscle. We examined 15 cadaver gluteal regions to identify the relationship between the internal anatomy of the inferior gluteal artery and nerve as well as the relationship to external anatomic landmarks. The cadavers displayed variability with regard to the morphology of the branches of both nerve and artery. Furthermore, there did not appear to be any relationship between the relative positions of the nerve and artery. However, the potential target area of the proximal origin of the inferior gluteal nerve could reliably be predicted from the external bony anatomy of the lower pelvis. PMID:18049789

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

    PubMed

    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

  3. 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

  4. 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

  5. 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.

  6. A Novel Pentapeptide Targeting Integrin β3-Subunit Inhibits Platelet Aggregation and Its Application in Rat for Thrombosis Prevention

    PubMed Central

    Qu, Qingrong; Liu, Yamin; Yan, Xuejiao; Fan, Xiaobo; Liu, Naifeng; Wu, Guoqiu

    2016-01-01

    Background: Antiplatelet therapy plays a pivotal role in the prevention and treatment of thrombotic diseases. We reported the screening of P1C as a novel integrin-binding peptide from the C-terminal of connective tissue growth factor. Primary study indicated that P1C has potential against platelet aggregation. Objectives: We aimed to find the shortest active unit from the P1C fragments and explore its in vivo and in vitro activities. Methods: A series of truncated P1C fragments was prepared and screened for antiplatelet activity. The most active fragment was evaluated using coagulation assays. Flow cytometry and confocal microscopy were used to determine the interaction between the peptide and the integrin. The in vivo potential was further explored using two types of rat models. Results: From a series of truncated P1C forms, a so-called P1Cm peptide of 5-amino acids, namely, IRTPK was screened out as the shortest active unit with superior activity. Coagulation experiments and an in vivo toxicity assay demonstrated that P1Cm is safe in vivo and inhibits ADP- and TH-induced human platelet aggregation in vitro in a concentration-dependent manner. Furthermore, it has limited effect on the coagulation parameters. Flow cytometry and confocal microscopy experiments consistently indicated that the peptide specifically binds the β3-subunit of integrin on platelets. Further experiments using rat models of artery-vein shunt and carotid arterial thrombosis illustrated that P1Cm can effectively prevent thrombosis formation. Conclusion: P1Cm may be a new, promising antithrombotic alternative to currently available antiplatelet treatments. PMID:27014063

  7. 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

  8. 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

  9. 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

  10. 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

  11. Oxidative damage to specific proteins in replicative and chronological-aged Saccharomyces cerevisiae: common targets and prevention by calorie restriction.

    PubMed

    Reverter-Branchat, Gemma; Cabiscol, Elisa; Tamarit, Jordi; Ros, Joaquim

    2004-07-23

    Oxidative modifications of cellular components have been described as one of the main contributions to aged phenotype. In Saccharomyces cerevisiae, two distinct life spans can be considered, replicative and chronological. The relationship between both aging models is still not clear despite suggestions that these phenomena may be related. In this work, we show that replicative and chronological-aged yeast cells are affected by an oxidative stress situation demonstrated by increased protein carbonylation when compared with young cells. The data on the identification of these oxidatively modified proteins gives clues to better understand cellular dysfunction that occurs during aging. Strikingly, although in both aging models metabolic differences are important, major targets are almost the same. Common targets include stress resistance proteins (Hsp60 and Hsp70) and enzymes involved in glucose metabolism such as enolase, glyceraldehydes-3-P dehydrogenase, fructose-1,6-biphosphate aldolase, pyruvate decarboxylase, and alcohol dehydrogenase. In both aging models, calorie restriction results in decreased damage to these proteins. In addition, chronological-aged cells grown under glucose restriction displayed lowered levels of lipid peroxidation product lipofuscin. Intracellular iron concentration is kept almost unchanged, whereas in non-restricted cells, the values increase up 4-5 times. The pro-oxidant effects of such increased iron concentration would account for the damage observed. Also, calorie-restricted cells show undamaged catalase, which clearly appears carbonylated in cells grown at a high glucose concentration. These results may explain lengthening of the viability of chronological-aged cells and could have an important role in replicative life span extension by calorie restriction. PMID:15166233

  12. 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

  13. Targeting chemotherapy-induced PTX3 in tumor stroma to prevent the progression of drug-resistant cancers

    PubMed Central

    Chi, Jhih-Ying; Hsiao, Yu-Wei; Li, Chien-Feng; Lo, Yu-Chih; Lin, Zu-Yau; Hong, Jhen-Yi; Liu, Yang-Ming; Han, Xiu; Wang, Shao-Ming; Chen, Ben-Kuen; Tsai, Kelvin K.; Wang, Ju-Ming

    2015-01-01

    The tumor microenvironment has been suggested to participate in tumorigenesis, but the nature of the communication between cancer cells and the microenvironment, especially in response to anticancer drugs, remains obscure. We determined that activation of the CCAAT/enhancer binding protein delta (CEBPD) response to Cisplatin and 5-Fluorouracil in cancer-associated macrophages and fibroblasts contributed to the metastasis, invasion, acquired chemoresistance and stemness of cancer cells by in vitro and in vivo assays. Specifically, reporter and in vivo DNA binding assays were used to determine that Pentraxin 3 (PTX3) is a CEBPD responsive gene and serves a protumor role upon anticancer drug treatment. Finally, a PTX3 peptide inhibitor RI37 was developed and assessed the antitumor effects by in vivo assays. RI37 could function as a promising inhibitor for preventing cancer progression and the metastasis, invasion and progression of drug-resistant cancers. The identification of PTX3 provided a new insight in the interaction between host and tumor and the RI37 peptide showed a great opportunity to largely reduce the risk of invasion and metastasis of cancer and drug-resistant cancers. PMID:26124179

  14. Targeting inflammatory pathways for prevention and therapy of cancer: short-term friend, long-term foe.

    PubMed

    Aggarwal, Bharat B; Vijayalekshmi, R V; Sung, Bokyung

    2009-01-15

    Chronic infections, obesity, alcohol, tobacco, radiation, environmental pollutants, and high-calorie diet have been recognized as major risk factors for the most common types of cancer. All these risk factors are linked to cancer through inflammation. Although acute inflammation that persists for short-term mediates host defense against infections, chronic inflammation that lasts for long term can predispose the host to various chronic illnesses, including cancer. Linkage between cancer and inflammation is indicated by numerous lines of evidence; first, transcription factors nuclear factor-kappaB (NF-kappaB) and signal transducers and activators of transcription 3 (STAT3), two major pathways for inflammation, are activated by most cancer risk factors; second, an inflammatory condition precedes most cancers; third, NF-kappaB and STAT3 are constitutively active in most cancers; fourth, hypoxia and acidic conditions found in solid tumors activate NF-kappaB; fifth, chemotherapeutic agents and gamma-irradiation activate NF-kappaB and lead to chemoresistance and radioresistance; sixth, most gene products linked to inflammation, survival, proliferation, invasion, angiogenesis, and metastasis are regulated by NF-kappaB and STAT3; seventh, suppression of NF-kappaB and STAT3 inhibits the proliferation and invasion of tumors; and eighth, most chemopreventive agents mediate their effects through inhibition of NF-kappaB and STAT3 activation pathways. Thus, suppression of these proinflammatory pathways may provide opportunities for both prevention and treatment of cancer. PMID:19147746

  15. Healthy Weight Regulation and Eating Disorder Prevention in High School Students: A Universal and Targeted Web-Based Intervention

    PubMed Central

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

    2014-01-01

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

  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. PMID:26376177

  17. 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

  18. 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.

  19. 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

  20. 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

  1. 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. PMID:17991198

  2. 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

  3. Target population for clinical trials

    PubMed Central

    Studenski, S

    2016-01-01

    The target population for clinical trials aimed at sarcopenia depends on the goals of treatment and the expected natural history of sarcopenia. Based on a natural history where loss of muscle mass and/or quality leads to loss of strength, and eventually to reduced mobility and functional dependence, treatment goals can be defined for both preventive and therapeutic interventions. For example, a target population with low muscle mass and poor strength could be treated to prevent the onset of mobility disability, or a target population with low muscle mass and poor strength with mobility disability could be treated therapeutically to improve mobility. Eligibility for a trial should also be based on careful consideration of factors that affect 1) the ability to respond to treatment, 2) the safety of treatment, 3) expected prevalence and 4) feasibility. PMID:19657558

  4. The Ca2+-Activated K+ Channel KCa3.1 as a Potential New Target for the Prevention of Allograft Vasculopathy

    PubMed Central

    Chen, Yi-Je; Lam, Jenny; Gregory, Clare R.; Schrepfer, Sonja; Wulff, Heike

    2013-01-01

    Allograft vasculopathy (AV) remains one of the major challenges to the long-term functioning of solid organ transplants. Although its exact pathogenesis remains unclear, AV is characterized by both fibromuscular proliferation and infiltration of CD4+ memory T cells. We here tested whether two experimental immunosuppressants targeting K+ channels might be useful for preventing AV. PAP-1 inhibits the voltage-gated Kv1.3 channel, which is overexpressed on CCR7− memory T cells and we therefore hypothesize that it should suppress the memory T cell component of AV. Based on its previous efficacy in restenosis and kidney fibrosis we expected that the KCa3.1 blocker TRAM-34 would primarily affect smooth muscle and fibroblast proliferation and thus reduce intimal hyperplasia. Using immunohistochemistry we demonstrated the presence of Kv1.3 on infiltrating T cells and of KCa3.1 on lymphocytes as well as on proliferating neointimal smooth muscle cells in human vasculopathy samples and in a rat aorta transplant model developing chronic AV. Treatment of PVG rats receiving orthotopically transplanted aortas from ACI rats with TRAM-34 dose-dependently reduced aortic luminal occlusion, intimal hyperplasia, mononuclear cell infiltration and collagen deposition 120 days after transplantation. The Kv1.3 blocker PAP-1 in contrast did not reduce intima hyperplasia despite drastically reducing plasma IFN-γ levels and inhibiting lymphocyte infiltration. Our findings suggest that KCa3.1 channels play an important role in the pathogenesis of chronic AV and constitute an attractive target for the prevention of arteriopathy. PMID:24312257

  5. 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

  6. 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

  7. 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

  8. 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

  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. Should health insurers target prevention of cardiovascular disease?: a cost-effectiveness analysis of an individualised programme in Germany based on routine data

    PubMed Central

    2014-01-01

    Background Cardiovascular diseases are the main cause of death worldwide, making their prevention a major health care challenge. In 2006, a German statutory health insurance company presented a novel individualised prevention programme (KardioPro), which focused on coronary heart disease (CHD) screening, risk factor assessment, early detection and secondary prevention. This study evaluates KardioPro in CHD risk subgroups, and analyses the cost-effectiveness of different individualised prevention strategies. Methods The CHD risk subgroups were assembled based on routine data from the statutory health insurance company, making use of a quasi-beta regression model for risk prediction. The control group was selected via propensity score matching based on logistic regression and an approximate nearest neighbour approach. The main outcome was cost-effectiveness. Effectiveness was measured as event-free time, and events were defined as myocardial infarction, stroke and death. Incremental cost-effectiveness ratios comparing participants with non-participants were calculated for each subgroup. To assess the uncertainty of results, a bootstrapping approach was applied. Results The cost-effectiveness of KardioPro in the group at high risk of CHD was €20,901 per event-free year; in the medium-risk group, €52,323 per event-free year; in the low-risk group, €186,074 per event-free year; and in the group with known CHD, €26,456 per event-free year. KardioPro was associated with a significant health gain but also a significant cost increase. However, statistical significance could not be shown for all subgroups. Conclusion The cost-effectiveness of KardioPro differs substantially according to the group being targeted. Depending on the willingness-to-pay, it may be reasonable to only offer KardioPro to patients at high risk of further cardiovascular events. This high-risk group could be identified from routine statutory health insurance data. However, the long

  11. 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

  12. 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

  13. 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. PMID:25681087

  14. 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

  15. microRNA-29b prevents liver fibrosis by attenuating hepatic stellate cell activation and inducing apoptosis through targeting PI3K/AKT pathway

    PubMed Central

    Wang, Jia; Chu, Eagle S.H.; Chen, Hai-Yong; Man, Kwan; Go, Minnie Y.Y.; Huang, Xiao Ru; Lan, Hui Yao; Sung, Joseph J.Y.; Yu, Jun

    2015-01-01

    microRNA-29b (miR-29b) is known to be associated with TGF-β-mediated fibrosis, but the mechanistic action of miR-29b in liver fibrosis remains unclear and is warranted for investigation. We found that miR-29b was significantly downregulated in human and mice fibrotic liver tissues and in primary activated HSCs. miR-29b downregulation was directly mediated by Smad3 through binding to the promoter of miR-29b in hepatic stellate cell (HSC) line LX1, whilst miR-29b could in turn suppress Smad3 expression. miR-29b transduction in the liver of mice prevented CCl4 induced-fibrogenesis, concomitant with decreased expression of α-SMA, collagen I and TIMP-1. Ectopic expression of miR-29b in activated HSCs (LX-1, HSC-T6) inhibited cell viability and colony formation, and caused cell cycle arrest in G1 phase by downregulating cyclin D1 and p21cip1. Further, miR-29b induced apoptosis in HSCs mediated by caspase-9 and PARP. miR-29b inhibited its downstream effectors of PIK3R1 and AKT3 through direct targeting their 3′UTR regions. Moreover, knockdown of PIK3R1 or AKT3 suppressed α-SMA and collagen I and induced apoptosis in both HSCs and in mice. In conclusion, miR-29b prevents liver fibrogenesis by inhibiting HSC activation and inducing HSC apoptosis through inhibiting PI3K/AKT pathway. These results provide novel mechanistic insights for the anti-fibrotic effect of miR-29b. PMID:25356754

  16. 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

  17. Treatment and prevention of chemotherapy-induced alopecia with PTH-CBD, a collagen-targeted parathyroid hormone analog, in a non-depilated mouse model.

    PubMed

    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. This study compared 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

  18. 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

  19. 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

  20. CDK1 Inhibition Targets the p53-NOXA-MCL1 Axis, Selectively Kills Embryonic Stem Cells, and Prevents Teratoma Formation

    PubMed Central

    Huskey, Noelle E.; Guo, Tingxia; Evason, Kimberley J.; Momcilovic, Olga; Pardo, David; Creasman, Katelyn J.; Judson, Robert L.; Blelloch, Robert; Oakes, Scott A.; Hebrok, Matthias; Goga, Andrei

    2015-01-01

    Summary Embryonic stem cells (ESCs) have adopted an accelerated cell-cycle program with shortened gap phases and precocious expression of cell-cycle regulatory proteins, including cyclins and cyclin-dependent kinases (CDKs). We examined the effect of CDK inhibition on the pathways regulating proliferation and survival of ESCs. We found that inhibiting cyclin-dependent kinase 1 (CDK1) leads to activation of the DNA damage response, nuclear p53 stabilization, activation of a subset of p53 target genes including NOXA, and negative regulation of the anti-apoptotic protein MCL1 in human and mouse ESCs, but not differentiated cells. We demonstrate that MCL1 is highly expressed in ESCs and loss of MCL1 leads to ESC death. Finally, we show that clinically relevant CDK1 inhibitors prevent formation of ESC-derived tumors and induce necrosis in established ESC-derived tumors. Our data demonstrate that ES cells are uniquely sensitive to CDK1 inhibition via a p53/NOXA/MCL1 pathway. PMID:25733019

  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. Violence and HIV/AIDS prevention among female out-of-school youths in southwestern Nigeria: lessons learnt from interventions targeted at hawkers and apprentices.

    PubMed

    Fawole, O I; Ajuwon, A J; Osungbade, K O

    2004-12-01

    Between 1997 and 2003, four studies on hawkers and apprentices in motor parks and work shops in south west, Nigeria were carried out to evaluate the effectiveness of interventions aimed at preventing HIV infection and gender based violence (GBV). The studies were in 3 phases namely baseline survey, intervention and end line survey. Interventions consisting of:--development and distribution of education materials and training programmes for the police, judiciary, instructors, drivers, traders and apprentices/hawkers, including micro-credit facilities were implemented in some of the studies. The major lessons learnt were that: Young girls working in the informal sector of the Nigerian economy face dual risks of HIV infection and GBV and yet they are seldom targets of intervention; Many had been victims of GBV and did not seek redress either because they accept it is their lot, are afraid of being stigmatized or are put off the prolonged legal system; Perpetrators tend to deny their involvement in violence; Despite the challenges involved, interventions implemented among female apprentices and hawkers, especially those that involve multiple stakeholders, made a difference in protecting this group from dual risks of GBV and HIV/AIDS infection. We recommend more intervention programmes for this population, and regulation of activities in the informal sector of the Nigerian economy. PMID:15977443

  3. MicroRNA-27a Induces Mesangial Cell Injury by Targeting of PPARγ, and its In Vivo Knockdown Prevents Progression of Diabetic Nephropathy.

    PubMed

    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

  4. 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

  5. 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

  6. Targeting the IRE1α/XBP1 and ATF6 Arms of the Unfolded Protein Response Enhances VEGF Blockade to Prevent Retinal and Choroidal Neovascularization

    PubMed Central

    Liu, Li; Qi, Xiaoping; Chen, Zhijuan; Shaw, Lynn; Cai, Jun; Smith, Layton H.; Grant, Maria B.; Boulton, Michael E.

    2014-01-01

    Although anti-vascular endothelial growth factor (VEGF) treatments reduce pathological neovascularization in the eye and in tumors, the regression is often not sustainable or is incomplete. We investigated whether vascular endothelial cells circumvent anti-VEGF therapies by activating the unfolded protein response (UPR) to override the classic extracellular VEGF pathway. Exposure of endothelial cells to VEGF, high glucose, or H2O2 up-regulated the X-box binding protein-1/inositol-requiring protein-1 (IRE1) α and activating transcription factor 6 (ATF6) arms of the UPR compared with untreated cells. This was associated with increased expression in α-basic crystallin (CRYAB), which has previously bound VEGF. siRNA knockdown or pharmacological blockade of IRE1α, ATF6, or CRYAB increased intracellular VEGF degradation and decreased full-length intracellular VEGF. Inhibition of IRE1α, ATF6, or CRYAB resulted in an approximately 40% reduction of in vitro angiogenesis, which was further reduced in combination with a neutralizing antibody against extracellular VEGF. Blockade of IRE1α or ATF6 in the oxygen-induced retinopathy or choroidal neovascularization mouse models caused an approximately 35% reduction in angiogenesis. However, combination therapy of VEGF neutralizing antibody with UPR inhibitors or siRNAs reduced retinal/choroidal neovascularization by a further 25% to 40%, and this inhibition was significantly greater than either treatment alone. In conclusion, activation of the UPR sustains angiogenesis by preventing degradation of intracellular VEGF. The IRE1α/ATF6 arms of the UPR offer a potential therapeutic target in the treatment of pathological angiogenesis. PMID:23395094

  7. Comparison of injection drug users accessing syringes from pharmacies, syringe exchange programs, and other syringe sources to inform targeted HIV prevention and intervention strategies

    PubMed Central

    Rudolph, Abby E.; Crawford, Natalie D.; Ompad, Danielle C.; Benjamin, Ebele O.; Stern, Rachel J.; Fuller, Crystal M.

    2011-01-01

    Objective In New York, syringe exchange programs (SEPs) and pharmacies provide syringe access for IDUs but may be unable to meet the needs of all IDUs. This analysis aims to describe IDUs who access syringes through different outlets to help inform the prevention needs of IDUs who under-utilize safe syringe sources in a city where syringe availability is high relative to other U.S. cities. Design Cross-sectional study Setting New York City (2005–2007) Participants 285 IDUs recruited using street-intercept sampling Intervention(s) Not Applicable Main outcome measure(s) IDUs using SEPs, pharmacies, or other outlets as a primary syringe source were compared by sociodemographic characteristics, injection practices and medical service utilization. Results Chi-square tests and polytomous logistic regression were used to compare IDUs with different self-reported primary syringe sources used 6 months prior to study entry. Compared with IDUs using other syringe sources, those using primarily SEPs were less likely to be Black (AOR:0.26 95%CI:0.11–0.57), more likely to inject daily (AOR:3.32; 95%CI:1.58–6.98), and more likely to inject with a new syringe (AOR:2.68; 95%CI:1.30–5.54). Compared with IDUs using other syringe sources, those using primarily pharmacies were less likely to be Black (AOR:0.39; 95%CI0.17–0.90). Conclusion These data suggest that pharmacies and SEPs may be reaching different populations of IDUs and highlight a sub-population of highly marginalized IDUs (Black and infrequent injectors) who are under-utilizing safe syringe sources in New York City. Targeted interventions are needed to reduce racial disparities and increase utilization of safe syringe outlets. PMID:20199954

  8. 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

  9. 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

  10. 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

  11. 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

  12. Mechanistic role of cytochrome P450 (CYP)1B1 in oxygen-mediated toxicity in pulmonary cells: A novel target for prevention of hyperoxic lung injury.

    PubMed

    Dinu, Daniela; Chu, Chun; Veith, Alex; Lingappan, Krithika; Couroucli, Xanthi; Jefcoate, Colin R; Sheibani, Nader; Moorthy, Bhagavatula

    2016-08-01

    toxicity. Thus, CYP1B1 could be a novel target for preventative and/or therapeutic interventions against BPD in infants and ALI/ARDS in adults. PMID:27235555

  13. Preventing stroke

    MedlinePlus

    Stroke - prevention; CVA - prevention; cerebral vascular accident - prevention; TIA - prevention, transient ischemic attack - prevention ... Clinical Cardiology; Council on Functional Genomics and ... Council on Hypertension. Guidelines for the primary prevention ...

  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 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

  15. Different systolic blood pressure targets for people with history of stroke or transient ischaemic attack: PAST-BP (Prevention After Stroke—Blood Pressure) randomised controlled trial

    PubMed Central

    McManus, Richard J; Roalfe, Andrea; Fletcher, Kate; Taylor, Clare J; Martin, Una; Virdee, Satnam; Greenfield, Sheila; Hobbs, F D Richard

    2016-01-01

    Objective To assess whether using intensive blood pressure targets leads to lower blood pressure in a community population of people with prevalent cerebrovascular disease. Design Open label randomised controlled trial. Setting 99 general practices in England, with participants recruited in 2009-11. Participants People with a history of stroke or transient ischaemic attack whose systolic blood pressure was 125 mm Hg or above. Interventions Intensive systolic blood pressure target (<130 mm Hg or 10 mm Hg reduction from baseline if this was <140 mm Hg) or standard target (<140 mm Hg). Apart from the different target, patients in both arms were actively managed in the same way with regular reviews by the primary care team. Main outcome measure Change in systolic blood pressure between baseline and 12 months. Results 529 patients (mean age 72) were enrolled, 266 to the intensive target arm and 263 to the standard target arm, of whom 379 were included in the primary analysis (182 (68%) intensive arm; 197 (75%) standard arm). 84 patients withdrew from the study during the follow-up period (52 intensive arm; 32 standard arm). Mean systolic blood pressure dropped by 16.1 mm Hg to 127.4 mm Hg in the intensive target arm and by 12.8 mm Hg to 129.4 mm Hg in the standard arm (difference between groups 2.9 (95% confidence interval 0.2 to 5.7) mm Hg; P=0.03). Conclusions Aiming for target below 130 mm Hg rather than 140 mm Hg for systolic blood pressure in people with cerebrovascular disease in primary care led to a small additional reduction in blood pressure. Active management of systolic blood pressure in this population using a <140 mm Hg target led to a clinically important reduction in blood pressure. Trial registration Current Controlled Trials ISRCTN29062286. PMID:26919870

  16. 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'…

  17. Longitudinal Retention of Families in the Assessment of a Prevention Program Targeting Adolescent Alcohol and Tobacco Use: The Utility of an Ecological Systems Framework

    ERIC Educational Resources Information Center

    Jones, Deborah J.; Foster, Sarah E.; Olson, Ardis L.; Forehand, Rex L.; Gaffney, Cecelia A.; Zens, Michael S.; Bau, J. J.

    2007-01-01

    This study examined the association between ecological context (extrafamilial, familial, child factors) at baseline and longitudinal retention of families in the 36-month assessment of an adolescent alcohol and tobacco use prevention program that was conducted within a pediatric primary care setting. A total of 1,780 families were enrolled at…

  18. [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. PMID:26593803

  19. What is the evidence base for diagnosing hypertension and for subsequent blood pressure treatment targets in the prevention of cardiovascular disease?

    PubMed

    Schwartz, Claire L; McManus, Richard J

    2015-01-01

    Diagnosing and treating hypertension plays an important role in minimising the risk of cardiovascular disease and stroke. Early and accurate diagnosis of hypertension, as well as regular monitoring, is essential to meet treatment targets. In this article, current recommendations for the screening and diagnosis of hypertension are reviewed. The evidence for treatment targets specified in contemporary guidelines is evaluated and recommendations from the USA, Canada, Europe and the UK are compared. Finally, consideration is given as to how diagnosis and management of hypertension might develop in the future. PMID:26456709

  20. A novel mitochondrially-targeted apocynin derivative prevents hyposmia and loss of motor function in the leucine-rich repeat kinase 2 (LRRK2(R1441G)) transgenic mouse model of Parkinson's disease.

    PubMed

    Dranka, Brian P; Gifford, Alison; McAllister, Donna; Zielonka, Jacek; Joseph, Joy; O'Hara, Crystal L; Stucky, Cheryl L; Kanthasamy, Anumantha G; Kalyanaraman, Balaraman

    2014-11-01

    Recently, we demonstrated that dimeric apocynin prevented loss of motor function in the leucine-rich repeat kinase 2 (LRRK2(R1441G)) transgenic (tg) mouse (treated with 200mg/kg, three times per week) [B.P. Dranka et al., Neurosci. Lett. 549 (2013) 57-62]. Here we extend those studies by treating LRRK2(R1441G) mice with an orally-available, mitochondrially-targeted apocynin derivative. We hypothesized that the increased mitochondrial permeability of Mito-apocynin, due to the triphenylphosphonium moiety, would allow improvement of Parkinson's disease (PD) symptoms at lower doses than those required for diapocynin. Tests of motor coordination (pole test, Rotor-Rod) revealed a significant deficit in coordinated motor function in LRRK2(R1441G) mice by 15 months of age. Decreased performance on the pole test and Rotor-Rod in the LRRK2(R1441G) mice was prevented with Mito-apocynin treatment (3mg/kg, three times per week). Decreased olfactory function is an early indication of PD in human patients. LRRK2(R1441G) tg mice displayed deficits in sense of smell in both the hidden treat test, and a radial arm maze test. Interestingly, treatment with Mito-apocynin prevented this hyposmia, and animals retained normal ability to identify either a scented treat or a food pellet as well as wild type littermates. Together, these data demonstrate that the mitochondria-targeted apocynin analog is effective in preventing early PD-like symptoms in the LRRK2(R1441G) mouse model. PMID:25263790

  1. Generating Rules and Examples.

    ERIC Educational Resources Information Center

    Grabinger, R. Scott; Jonassen, David H.

    1989-01-01

    This seventh in a series of articles discussing expert system construction focuses on two ways to create a structure that determines a decision: (1) rule-based, or deductive, implementation; and (2) example-based, or inductive, implementation. Probability factors and confidence levels are discussed, and an example is given for selecting an…

  2. 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…

  3. 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

  4. 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

  5. Monte Carlo Example Programs

    Energy Science and Technology Software Center (ESTSC)

    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.

  6. 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

  7. Adherence to Self-Monitoring via Interactive Voice Response Technology in an eHealth Intervention Targeting Weight Gain Prevention Among Black Women: Randomized Controlled Trial

    PubMed Central

    2014-01-01

    Background eHealth interventions are effective for weight control and have the potential for broad reach. Little is known about the use of interactive voice response (IVR) technology for self-monitoring in weight control interventions, particularly among populations disproportionately affected by obesity. Objective This analysis sought to examine patterns and predictors of IVR self-monitoring adherence and the association between adherence and weight change among low-income black women enrolled in a weight gain prevention intervention. Methods The Shape Program was a randomized controlled trial comparing a 12-month eHealth behavioral weight gain prevention intervention to usual care among overweight and obese black women in the primary care setting. Intervention participants (n=91) used IVR technology to self-monitor behavior change goals (eg, no sugary drinks, 10,000 steps per day) via weekly IVR calls. Weight data were collected in clinic at baseline, 6, and 12 months. Self-monitoring data was stored in a study database and adherence was operationalized as the percent of weeks with a successful IVR call. Results Over 12 months, the average IVR completion rate was 71.6% (SD 28.1) and 52% (47/91) had an IVR completion rate ≥80%. At 12 months, IVR call completion was significantly correlated with weight loss (r =−.22; P=.04) and participants with an IVR completion rate ≥80% had significantly greater weight loss compared to those with an IVR completion rate <80% (−1.97 kg, SE 0.67 vs 0.48 kg, SE 0.69; P=.01). Similar outcomes were found for change in body mass index (BMI; mean difference −0.94 kg, 95% CI −1.64 to −0.24; P=.009). Older, more educated participants were more likely to achieve high IVR call completion. Participants reported positive attitudes toward IVR self-monitoring. Conclusions Adherence to IVR self-monitoring was high among socioeconomically disadvantaged black women enrolled in a weight gain prevention intervention. Higher adherence

  8. Utilizing the peptidyl-prolyl cis-trans isomerase pin1 as a probe of its phosphorylated target proteins. Examples of binding to nuclear proteins in a human kidney cell line and to tau in Alzheimer's diseased brain.

    PubMed

    Thorpe, J R; Morley, S J; Rulten, S L

    2001-01-01

    The human parvulin Pin1 is a member of the peptidyl-prolyl cis-trans isomerase group of proteins, which modulate the assembly, folding, activity, and transport of essential cellular proteins. Pin1 is a mitotic regulator interacting with a range of proteins that are phosphorylated before cell division. In addition, an involvement of Pin1 in the tau-related neurodegenerative brain disorders has recently been shown. In this context, Pin1 becomes depleted from the nucleus in Alzheimer's disease (AD) neurons when it is redirected to the large amounts of hyperphosphorylated tau associated with the neurofibrillary tangles. This depletion from the nucleus may ultimately contribute to neuron cell death. Recently we have devised a novel methodology in which exogenous Pin1 is used as a TEM probe for its target proteins. Here we extend this methodology to provide further evidence that Pin1 binds at enhanced levels to mitotic nuclear proteins and to hyperphosphorylated tau in AD brain. We suggest that exogenous Pin1 labeling can be used to elucidate the phosphorylation status of its target proteins in general and could specifically provide important insights into the development of tau-related neurodegenerative brain disorders. PMID:11118482

  9. Preventing Obesity through Schools

    PubMed Central

    Nihiser, Allison; Merlo, Caitlin; Lee, Sarah

    2015-01-01

    PRÉCIS This paper describes highlights from the Weight of the Nation™ 2012 Schools Track. Included is a summary of 16 presentations. Presenters shared key actions for obesity prevention through schools. The information provided at the Weight of the Nation™ can help school health practitioners access tools, apply evidence-based strategies, and model real-world examples to successfully start obesity prevention initiatives in their jurisdiction. PMID:24446995

  10. 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.

  11. Multifaceted preventive effects of single agent quercetin on a human prostate adenocarcinoma cell line (PC-3): implications for nutritional transcriptomics and multi-target therapy.

    PubMed

    Noori-Daloii, Mohammad R; Momeny, Majid; Yousefi, Mehdi; Shirazi, Forough Golsaz; Yaseri, Mehdi; Motamed, Nasrin; Kazemialiakbar, Nazanin; Hashemi, Saeed

    2011-12-01

    The aim of the present study is to evaluate the effects of quercetin, a dietary flavonoid, on human prostate adenocarcinoma PC-3 cells. Lactate dehydrogenase (LDH) release, microculture tetrazolium test (MTT assay) and real-time PCR array were employed to evaluate the effects of quercetin on cell cytotoxicity, cell proliferation and expression of various genes in PC-3 cell line. Quercetin inhibited cell proliferation and modulated the expression of genes involved in DNA repair, matrix degradation and tumor invasion, angiogenesis, apoptosis, cell cycle, metabolism and glycolysis. No cytotoxicity of quercetin on PC-3 cells was observed. Taken together, as shown by the issues of the current study, the manifold inhibitory effects of quercetin on PC-3 cells may introduce quercetin as an efficacious anticancer agent in order to be used in the future nutritional transcriptomic investigations and multi-target therapy to overcome the therapeutic impediments against prostate cancer. PMID:20596804

  12. m-Trifluoromethyl-diphenyl diselenide, a multi-target selenium compound, prevented mechanical allodynia and depressive-like behavior in a mouse comorbid pain and depression model.

    PubMed

    Brüning, César Augusto; Martini, Franciele; Soares, Suelen Mendonça; Sampaio, Tuane Bazanella; Gai, Bibiana Mozzaquatro; Duarte, Marta M M F; Nogueira, Cristina Wayne

    2015-12-01

    Chronic pain and depression are two complex states that often coexist in the clinical setting and traditional antidepressants and analgesics have shown limited clinical efficacy. There is an intricate communication between the immune system and the central nervous system and inflammation has been considered a common mediator of pain-depression comorbidity. This study evaluated the effect of m-trifluoromethyl diphenyl diselenide [(m-CF3-PhSe)2], an organoselenium compound that has been reported to have both antinociceptive and antidepressant-like actions, in the comorbidity of chronic pain and depression induced by partial sciatic nerve ligation (PSNL) in an inflammatory approach. Mice were submitted to PSNL during 4weeks and treated with (m-CF3-PhSe)2 acutely (0.1-10mg/kg, i.g.) or subchronically (0.1mg/kg, i.g., once a day during the 3rd and 4th weeks). Both treatments prevented PSNL-increased pain sensitivity and depressive-like behavior observed in Von-Frey hair (VFH) and forced swimming (FST) tests, respectively. These effects could be mainly associated with an anti-inflammatory action of (m-CF3-PhSe)2 which reduced the levels of pro-inflammatory cytokines, NF-κB and COX-2, and p38 MAPK activation that were increased by PSNL. (m-CF3-PhSe)2 also increased the BDNF levels and reduced glutamate release and 5-HT uptake altered by PSNL. Although acute and subchronic treatments with (m-CF3-PhSe)2 prevented these alterations induced by PSNL, the best results were found when (m-CF3-PhSe)2 was subchronically administered to mice. Considering the potential common mechanisms involved in the comorbidity of inflammation-induced depression and chronic pain, the results found in this study indicate that (m-CF3-PhSe)2 could become an interesting molecule to treat long-lasting pathological pain associated with depression. PMID:26025319

  13. 2-phenylethynesulfonamide Prevents Induction of Pro-inflammatory Factors and Attenuates LPS-induced Liver Injury by Targeting NHE1-Hsp70 Complex in Mice

    PubMed Central

    Huang, Chao; Wang, Jia; Chen, Zhuo; Wang, Yuzhe; Zhang, Wei

    2013-01-01

    The endotoxin-mediated production of pro-inflammatory cytokines plays an important role in the pathogenesis of liver disorders. Heat shock protein (Hsp70) overexpression has established functions in lipopolysaccharide (LPS)-mediated inflammatory response. However, little is known about the role of Hsp70 activity in LPS signaling. We hypothesized that inhibition of Hsp70 substrate binding activity can ameliorate LPS-induced liver injury by decreasing induction of pro-inflammatory factors. In this study, C57/BL6 mice were injected intraperitoneally with LPS and 2-phenylethynesulfonamide (PES), an inhibitor of Hsp70 substrate binding activity. We found that i. PES prevented LPS-induced increase in serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activity, infiltration of inflammatory cells, and liver cell apoptosis; ii. PES reduced inducible nitric oxide synthase (iNOS) protein expression as well as serum nitric oxide (NO), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) content in LPS-stimulated mice; iii. PES reduced the mRNA level of iNOS, TNF-α, and IL-6 in LPS-stimulated liver. iiii. PES attenuated the degradation of inhibitor of κB-α (IκB-α) as well as the phosphorylation and nuclear translocation of nuclear factor-κB (NF-κB) in LPS-stimulated liver. Similar changes in the protein expression of inflammatory markers, IκB-α degradation, and NF-κB phosphorylation and nuclear translocation were observed in RAW 264.7 cells. Further mechanistic studies revealed that PES remarkably reduced the elevation of [Ca2+]i and intracellular pH value (pHi) in LPS-stimulated RAW 264.7 cells. Furthermore, PES significantly reduced the increase in Na+/H+ exchanger 1 (NHE1) association to Hsp70 in LPS-stimulated macrophages and liver, suggesting that NHE1-Hsp70 interaction is required for the involvement of NHE1 in the inflammation response. In conclusion, inhibition of Hsp70 substrate binding activity in vivo reduces the induction of

  14. 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

  15. The Roles of Epithelial-to-Mesenchymal Transition (EMT) and Mesenchymal-to-Epithelial Transition (MET) in Breast Cancer Bone Metastasis: Potential Targets for Prevention and Treatment

    PubMed Central

    Demirkan, Binnaz

    2013-01-01

    Many studies have revealed molecular connections between breast and bone. Genes, important in the control of bone remodeling, such as receptor activator of nuclear kappa (RANK), receptor activator of nuclear kappa ligand (RANKL), vitamin D, bone sialoprotein (BSP), osteopontin (OPN), and calcitonin, are expressed in breast cancer and lactating breast. Epithelial-mesenchymal transition (EMT) and mesenchymal-epithelial transition (MET) effectors play critical roles during embryonic development, postnatal growth, and epithelial homeostasis, but also are involved in a number of pathological conditions, including wound repair, fibrosis, inflammation, as well as cancer progression and bone metastasis. Transforming growth factor β (TGFβ), insulin-like growth factor I & II (IGF I & II), platelet-derived growth factor (PDGF), parathyroid hormone-related protein (PTH(rP)), vascular endothelial growth factor (VEGF), epithelial growth factors II/I (ErbB/EGF), interleukin 6 (IL-6), IL-8, IL-11, IL-1, integrin αvβ3, matrix metalloproteinases (MMPs), catepsin K, hypoxia, notch, Wnt, bone morphogenetic proteins (BMP), and hedgehog signaling pathways are important EMT and MET effectors identified in the bone microenviroment facilitating bone metastasis formation. Recently, Runx2, an essential transcription factor in the regulation of mesenchymal cell differentiation into the osteoblast lineage and proper bone development, is also well-recognized for its expression in breast cancer cells promoting osteolytic bone metastasis. Understanding the precise mechanisms of EMT and MET in the pathogenesis of breast cancer bone metastasis can inform the direction of therapeutic intervention and possibly prevention. PMID:26237148

  16. 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

  17. 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. PMID:23885310

  18. 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.

  19. 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

  20. EGCG prevents PCB-126-induced endothelial cell inflammation via epigenetic modifications of NF-κB target genes in human endothelial cells.

    PubMed

    Liu, Dandan; Perkins, Jordan T; Hennig, Bernhard

    2016-02-01

    Anti-inflammatory polyphenols, such as epigallocatechin-3-gallate (EGCG), have been shown to protect against the toxicity of environmental pollutants. It is well known that bioactive food compounds such as polyphenols may exert their protection by modulating inflammatory pathways regulated through nuclear factor-kappa B (NF-κB) signaling. EGCG has been reported to inhibit NF-κB activation. We hypothesize that EGCG can protect against polychlorinated biphenyl (PCB)-induced endothelial inflammation in part through epigenetic regulation of NF-κB-regulated inflammatory genes. In order to test this hypothesis, human endothelial cells (EA.hy926) were exposed to physiologically relevant levels of coplanar PCB 126 and/or 15 or 30 μM of EGCG, followed by quantification of NF-κB subunit p65, histone acetyltransferase p300 and histone deacetylases (HDACs) accumulation through chromatin immunoprecipitation assay in the promoter region of inflammatory genes. In addition, the enrichment of the acetylated H3 was also quantified. PCB 126 exposure increased the expression of vascular inflammatory mediators, including interleukin (IL)-6, C-reactive protein, intercellular adhesion molecule-1, vascular cell adhesion molecule-1 and IL-1α/β, which were prevented by pretreatment with EGCG. This inhibitory effect by EGCG correlated with abolished nuclear import of p65, decreased chromatin binding of p65 and p300, as well as increased chromatin binding of HDAC 1/2. Furthermore, EGCG induced hypoacetylation of H3, which accounts for deactivation of downstream genes. These data suggest that EGCG-induced epigenetic modifications can decrease PCB-induced vascular toxicity. PMID:26878794

  1. 5MeCDDO Blocks Metabolic Activation but not Progression of Breast, Intestine, and Tongue Cancers. Is Antioxidant Response Element a Prevention Target?

    PubMed

    Lubet, Ronald A; Townsend, Reid; Clapper, Margie L; Juliana, M Margaret; Steele, Vernon E; McCormick, David L; Grubbs, Clinton J

    2016-07-01

    The preventive efficacy of the triterpenoid 5MeCDDO was tested in two models of mammary cancer, the Min model of intestinal cancer, and a chemically induced model of head and neck cancer. In one model of mammary cancer, female Sprague-Dawley rats were administered MNU at 50 days of age, and 5MeCDDO (27 ppm) was administered in the diet beginning 5 days later for the duration of the study; 5MeCDDO was ineffective. In contrast, in a model examining initiation of mammary cancers by the procarcinogen dimethyl-benzanthracene, 5, 6-benzoflavone (500 ppm, an Ah receptor agonist) or 5MeCDDO (27 or 2.7 ppm) decreased tumor multiplicity by 90%, 80%, and 50%, respectively. This anti-initiating effect which is presumably mediated by altered metabolic activation parallels our observation that 5MeCDDO induced proteins of various antioxidant response element (ARE)-related phase II drug-metabolizing enzymes [e.g., GST Pi, AKR 7A3 (aflatoxicol), epoxide hydrolase, and quinone reductase] in the liver. 5MeCDDO tested in the 4-nitroquinoline-l-oxide (4-NQO) head and neck cancer model failed to decrease tumor incidence or invasiveness. In the Min mouse model of intestinal cancer, a high dose of 5MeCDDO (80 ppm) was weakly effective in reducing adenoma multiplicity [∼30% (P < 0.05)]; however, a lower dose was totally ineffective. These findings question whether measuring increased levels of certain ARE-related genes (e.g., quinone reductase, GST Pi), indicating decreased carcinogen activation are sufficient to imply general chemopreventive efficacy of a given agent or mixture. Cancer Prev Res; 9(7); 616-23. ©2016 AACR. PMID:27150634

  2. Targeting T Cell Bioenergetics by Modulating P-Glycoprotein Selectively Depletes Alloreactive T Cells To Prevent Graft-versus-Host Disease.

    PubMed

    McIver, Zachariah A; Grayson, Jason M; Coe, Benjamin N; Hill, Jacqueline E; Schamerhorn, Gregory A; Ohulchanskyy, Tymish Y; Linder, Michelle K; Davies, Kellie S; Weiner, Roy S; Detty, Michael R

    2016-09-01

    T lymphocytes play a central role in many human immunologic disorders, including autoimmune and alloimmune diseases. In hematopoietic stem cell transplantation, acute graft-versus-host-disease (GVHD) is caused by an attack on the recipient's tissues from donor allogeneic T cells. Selectively depleting GVHD-causing cells prior to transplant may prevent GVHD. In this study, we evaluated 24 chalcogenorhodamine photosensitizers for their ability to selectively deplete reactive T lymphocytes and identified the photosensitizer 2-Se-Cl, which accumulates in stimulated T cells in proportion to oxidative phosphorylation. The photosensitizer is also a potent stimulator of P-glycoprotein (P-gp). Enhanced P-gp activity promotes the efficient removal of photosensitizer not sequestered in mitochondria and protects resting lymphocytes that are essential for antipathogen and antitumor responses. To evaluate the selective depletion of alloimmune responses, donor C57BL/6 splenocytes were cocultured for 5 d with irradiated BALB/c splenocytes and then photodepleted (PD). PD-treated splenocytes were infused into lethally irradiated BALB/c (same-party) or C3H/HeJ (third-party) mice. Same-party mice that received PD-treated splenocytes at the time of transplant lived 100 d without evidence of GVHD. In contrast, all mice that received untreated primed splenocytes and third-party mice that received PD-treated splenocytes died of lethal GVHD. To evaluate the preservation of antiviral immune responses, acute lymphocytic choriomeningitis virus infection was used. After photodepletion, expansion of Ag-specific naive CD8(+) T cells and viral clearance remained fully intact. The high selectivity of this novel photosensitizer may have broad applications and provide alternative treatment options for patients with T lymphocyte-mediated diseases. PMID:27456485

  3. 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

  4. 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

  5. Integrated implementation of programs targeting neglected tropical diseases through preventive chemotherapy: identifying best practices to roll out programs at national scale.

    PubMed

    Hanson, Christy; Weaver, Angela; Zoerhoff, Kathryn L; Kabore, Achille; Linehan, Mary; Doherty, Amy; Engels, Dirk; Savioli, Lorenzo; Ottesen, Eric A

    2012-03-01

    In 2006 the U.S. Agency for International Development (USAID) established the Neglected Tropical Disease (NTD) Control Program to support national governments in developing successful, cost-efficient NTD programs that integrate disease-specific programs into coordinated national initiatives, in accord with the World Health Organization recommendations. A 3-stage "roll-out package" has been developed for effectively integrating and scaling up such programs to full-national scale. Stage-1 lays the groundwork-identifying NTD leadership within the Ministry of Health, conducting a national Situation Analysis, formulating a multiyear Plan of Action, and undertaking a funding gap analysis. Stage-2 focuses on scaling up the integrated NTD program-convening national stakeholder meetings, developing annual work plans, carrying out disease mapping, and establishing monitoring and evaluation activities. Stage-3 aims at ensuring effective management-identifying clear roles and responsibilities for partners, and creating a central coordinating mechanism. Assessment and reassessment of these complex NTD programs that target literally billions of people are essential to establish "best practice" strategies for long-term public health success. PMID:22403327

  6. Rho-kinase inhibitor targeting the liver prevents ischemia/reperfusion injury in the steatotic liver without major systemic adversity in rats.

    PubMed

    Kuroda, Shintaro; Tashiro, Hirotaka; Kimura, Yasuhiro; Hirata, Kaori; Tsutada, Misaki; Mikuriya, Yoshihiro; Kobayashi, Tsuyoshi; Amano, Hironobu; Tanaka, Yuka; Ohdan, Hideki

    2015-01-01

    Rho-kinase (ROCK) inhibitors improve liver blood flow after ischemia/reperfusion (IR) injury, especially in the setting of steatosis, by decreasing the resistance of intrahepatic microcirculation through hepatic stellate cell (HSC) relaxation. However, the systemic administration of ROCK inhibitors causes severe hypotension; therefore, liver-specific ROCK inhibition is required. Here, we tested vitamin A (VA)-coupled liposomes carrying the ROCK inhibitor Y-27632 for targeted HSCs in steatotic rats. Rat livers with steatosis induced by a choline-deficient diet were subjected to IR injury. The delivery site and effect of the ROCK inhibitor were investigated. After liposomal Y-27632 injection, the survival rate after IR, the liver blood flow, the portal perfused pressure, and the hemodynamics were investigated. Immunohistochemical studies showed VA-coupled liposome accumulation in livers. Liposomal Y-27632 was 100-fold more effective in inhibiting HSC activation than free Y-27632. Liposomal Y-27632 improved the survival rate after IR injury, the liver blood flow, and the portal perfusion pressure without severe hypotension. In contrast, untargeted Y-27632 elicited severe systemic hypotension. We conclude that VA-coupled liposomes carrying the ROCK inhibitor yield enhanced drug accumulation in the liver and thus mitigate IR injury in the steatotic liver and reduce major systemic adversity. PMID:25307969

  7. SCF-FBXO31 E3 Ligase Targets DNA Replication Factor Cdt1 for Proteolysis in the G2 Phase of Cell Cycle to Prevent Re-replication*

    PubMed Central

    Johansson, Pegah; Jeffery, Jessie; Al-Ejeh, Fares; Schulz, Renèe B.; Callen, David F.; Kumar, Raman; Khanna, Kum Kum

    2014-01-01

    FBXO31 was originally identified as a putative tumor suppressor gene in breast, ovarian, hepatocellular, and prostate cancers. By screening a set of cell cycle-regulated proteins as potential FBXO31 interaction partners, we have now identified Cdt1 as a novel substrate. Cdt1 DNA replication licensing factor is part of the pre-replication complex and essential for the maintenance of genomic integrity. We show that FBXO31 specifically interacts with Cdt1 and regulates its abundance by ubiquitylation leading to subsequent degradation. We also show that Cdt1 regulation by FBXO31 is limited to the G2 phase of the cell cycle and is independent of the pathways previously described for Cdt1 proteolysis in S and G2 phase. FBXO31 targeting of Cdt1 is mediated through the N terminus of Cdt1, a region previously shown to be responsible for its cell cycle regulation. Finally, we show that Cdt1 stabilization due to FBXO31 depletion results in re-replication. Our data present an additional pathway that contributes to the FBXO31 function as a tumor suppressor. PMID:24828503

  8. A Novel Multivalent, Single-Domain Antibody Targeting TcdA and TcdB Prevents Fulminant Clostridium difficile Infection in Mice

    PubMed Central

    Yang, Zhiyong; Schmidt, Diane; Liu, Weilong; Li, Shan; Shi, Lianfa; Sheng, Jinliang; Chen, Kevin; Yu, Hua; Tremblay, Jacqueline M.; Chen, Xinhua; Piepenbrink, Kurt H.; Sundberg, Eric J.; Kelly, Ciaran P.; Bai, Guang; Shoemaker, Charles B.; Feng, Hanping

    2014-01-01

    The incidence of Clostridium difficile infection (CDI) and associated mortality have increased rapidly worldwide in recent years. Therefore, it is critical to develop new therapies for CDI. In this study, we generated a novel, potently neutralizing, tetravalent, and bispecific antibody composed of 2 heavy-chain-only VH (VHH) binding domains against both TcdA and TcdB (designated “ABA”) that reverses fulminant CDI in mice infected with an epidemic 027 strain after a single injection of the antibody. We demonstrated that ABA bound to both toxins simultaneously and displayed a significantly enhanced neutralizing activity both in vitro and in vivo. Additionally, ABA was able to broadly neutralize toxins from clinical C. difficile isolates that express both TcdA and TcdB but failed to neutralize the toxin from TcdA−TcdB+ C. difficile strains. This study thus provides a rationale for the development of multivalent VHHs that target both toxins and are broadly neutralizing for treating severe CDI. PMID:24683195

  9. Teaching Responsibility through Example

    ERIC Educational Resources Information Center

    Notar, Toni A.

    2008-01-01

    As Literacy Outreach Coordinator for Opportunity to Read (OTR), the Watsonville (CA) Public Library literacy program, this author has recognized the concept of responsibility through example. Adult learners incorporate concepts easily when these concepts are specifically demonstrated for them by someone similar to them. Sounds simple, but putting…

  10. Cyclostationarity by examples

    NASA Astrophysics Data System (ADS)

    Antoni, Jérôme

    2009-05-01

    This paper is a tutorial on cyclostationarity oriented towards mechanical applications. The approach is voluntarily intuitive and accessible to neophytes. It thrives on 20 examples devoted to illustrating key concepts on actual mechanical signals and demonstrating how cyclostationarity can be taken advantage of in machine diagnostics, identification of mechanical systems and separation of mechanical sources.

  11. 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

  12. 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

  13. Antidiabetic Drug Metformin Prevents Progression of Pancreatic Cancer by Targeting in Part Cancer Stem Cells and mTOR Signaling12

    PubMed Central

    Mohammed, Altaf; Janakiram, Naveena B; Brewer, Misty; Ritchie, Rebekah L; Marya, Anuj; Lightfoot, Stan; Steele, Vernon E; Rao, Chinthalapally V

    2013-01-01

    Epidemiologic studies have shown that diabetes mellitus is associated positively with increased risk of pancreatic ductal adenocarcinoma (PDAC), and recent meta-analysis studies showed that metformin, reduces the risk of pancreatic cancer (PC). We tested the effects of metformin on pancreatic intraepithelial neoplasia (PanIN) and their progression to PDAC in p48Cre/+.LSL-KrasG12D/+ transgenic mice. Mice fed control diet showed 80% and 62% incidence of PDAC in males and females, respectively. Male mice showed 20% and 26%, and female mice showed 7% and 0% PDAC incidence with 1000- and 2000-ppm metformin treatments, respectively. Both doses of metformin decreased pancreatic tumor weights by 34% to 49% (P < 0.03–0.001). The drug treatment caused suppression of PanIN 3 (carcinoma in situ) lesions by 28% to 39% (P < .002) and significant inhibition of carcinoma spread in the pancreas. The pancreatic tissue and/or serum of mice fed metformin showed a significant inhibition of mammalian target of rapamycin (mTOR), extracellular signal-regulated kinases (ERK), phosphorylated extracellular signal-regulated kinases (pErk), and insulin-like growth factor 1 (IGF-1) with an increase in phosphorylated 5′ adenosine monophosphate kinase (pAMPK), tuberous sclerosis complex 1 (TSC1, TSC2), C-protein and an autophagy related protein 2 (ATG2). The cancer stem cell (CSC) markers were significantly decreased (P < 0.04–0.0002) in the pancreatic tissue. These results suggest that biologic effects of metformin are mediated through decreased CSC markers cluster of differentiation 44 (CD44 and CD133), aldehyde dehydrogenase isoform 1 (ALDH1), and epithelial cell adhesion molecule (EPCAM) and modulation of the mTOR signaling pathway. Our preclinical data indicate that metformin has significant potential for use in clinical trials for PC chemoprevention. PMID:24466367

  14. 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

  15. 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

  16. Strategies for Dropout Prevention.

    ERIC Educational Resources Information Center

    Far West Lab. for Educational Research and Development, San Francisco, CA.

    This report provides descriptions of strategies for dropout prevention at the secondary level and presents examples of programs that successfully utilize these strategies. The information is based on data from a review of nearly 200 programs at secondary schools across the four-state Western region that includes Arizona, California, Nevada, and…

  17. 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

  18. Effect of Azone upon the in vivo antiviral efficacy of cidofovir or acyclovir topical formulations in treatment/prevention of cutaneous HSV-1 infections and its correlation with skin target site free drug concentration in hairless mice.

    PubMed

    Afouna, Mohsen I; Fincher, Timothy K; Zaghloul, Abdel-Azim A; Reddy, Indra K

    2003-03-01

    The purpose of this study is to examine the influence of Azone upon the skin target site free drug concentration (C(*)) and its correlation with the in vivo antiviral efficacies of cidofovir (HPMPC) and acyclovir (ACV) against HSV-1 infections. Formulations of HPMPC and ACV with or without Azone were used. The in vitro skin flux experiments were performed and the C(*) values were calculated. For the in vivo efficacy studies, hairless mice cutaneously infected with HSV-1 were used and three different treatment protocols were carried out. The protocols were chosen based upon when therapy is initiated and terminated in such a way to assess the efficacy of the test drug to cure and/or prevent HSV-1 infections. A finite dose of the formulation was topically applied twice a day for the predetermined time course for each protocol and the lesions were scored on the fifth day. For ACV formulation with Azone, the C(*) values and hence the in vivo efficacy were much higher than those for that without Azone. In protocol #1, however, early treatment did not increase the in vivo efficacy of ACV when compared with the standard treatment protocol #3. In protocol #2 where the treatment was terminated on the day of virus inoculation, the efficacies for both ACV formulations were completely absent. Although the estimated C(*) values for HPMPC formulations with and without Azone were comparable, formulation with Azone was much more effective than that without Azone in all treatment protocols. HPMPC formulations with Azone at similar flux values were much more effective in "treating and preventing" HSV-1 infections than those without Azone. For ACV formulations, in contrast, addition of Azone has failed to show any effect on the preventive in vivo antiviral efficacy and the enhancement of ACV in vivo antiviral efficacy was merely the skin permeation enhancement effect of Azone. PMID:12593946

  19. Systematic reviews. Some examples.

    PubMed Central

    Knipschild, P.

    1994-01-01

    Reviewing the literature is a scientific inquiry that needs a clear design to preclude bias. It is a real enterprise if one aims at completeness of the literature on a certain subject. Going through refereed English language journals is not enough. On line databases are helpful, but mainly as a starting point. This article gives examples of systematic reviews on vitamin C and the common cold, pyridoxine against the premenstrual syndrome, homeopathy, and physiotherapy. Images p720-a PMID:7950526

  20. Systematic reviews. Some examples.

    PubMed

    Knipschild, P

    1994-09-17

    Reviewing the literature is a scientific inquiry that needs a clear design to preclude bias. It is a real enterprise if one aims at completeness of the literature on a certain subject. Going through refereed English language journals is not enough. On line databases are helpful, but mainly as a starting point. This article gives examples of systematic reviews on vitamin C and the common cold, pyridoxine against the premenstrual syndrome, homeopathy, and physiotherapy. PMID:7950526

  1. 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.

  2. 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

  3. Multiple outcome measures and mixed methods for evaluating the effectiveness of theory-based behaviour-change interventions: a case study targeting health professionals' adoption of a national suicide prevention guideline.

    PubMed

    Hanbury, A; Wallace, L M; Clark, M

    2011-05-01

    Interest in behaviour-change interventions targeting health professionals' adoption of clinical guidelines is growing. Recommendations have been made for interventions to have a theoretical base, explore the local context and to use mixed and multiple methods of evaluation to establish intervention effectiveness. This article presents a case study of a behaviour-change intervention delivered to community mental health professionals in one Primary Care Trust, aimed at raising adherence to a national suicide prevention guideline. A discussion of how the theory-base was selected, the local context explored, and how the intervention was developed and delivered is provided. Time series analysis, mediational analysis and qualitative process evaluation were used to evaluate and explore intervention effectiveness. The time series analysis revealed that the intervention was not effective at increasing adherence to the guideline. The mediational analysis indicates that the intervention failed to successfully target the key barrier to adoption of the guidance, and the qualitative process evaluation identified certain intervention components that were well received by the health professionals, and also identified weaknesses in the delivery of the intervention. It is recommended that future research should seek to further develop the evidence-base for linking specific intervention strategies to specific behavioural barriers, explore the potential of theories that take into account broader social and organisational factors that influence health professionals' practice and focus on the process of data synthesis for identifying key factors to target with tailored interventions. Multiple and mixed evaluation techniques are recommended not only to explore whether an intervention is effective or not but also why it is effective or not. PMID:21491337

  4. Communication Skills for Preventive Interventions.

    ERIC Educational Resources Information Center

    Dube, Catherine E.; O'Donnell, Joseph F.; Novack, Dennis H.

    2000-01-01

    Defines and examines a communication model for enhancing the provision and adoption of preventive practices in the primary care setting and discusses teaching that model in the medical school context. Methods for integrating communication skills for prevention into the medical school curriculum are discussed, using examples from Dartmouth (New…

  5. 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…

  6. Preventing Diabetes: Early Versus Late Preventive Interventions.

    PubMed

    Tuomilehto, Jaakko; Schwarz, Peter E H

    2016-08-01

    There are a number of arguments in support of early measures for the prevention of type 2 diabetes (T2D), as well as for concepts and strategies at later intervention stages. Diabetes prevention is achievable when implemented in a sustainable manner. Sustainability within a T2D prevention program is more important than the actual point in time or disease process at which prevention activities may start. The quality of intervention, as well as its intensity, should vary with the degree of the identified T2D risk. Nevertheless, preventive interventions should start as early as possible in order to allow a wide variety of relatively low- and moderate-intensity programs. The later the disease risk is identified, the more intensive the intervention should be. Public health interventions for diabetes prevention represent an optimal model for early intervention. Late interventions will be targeted at people who already have significant pathophysiological derangements that can be considered steps leading to the development of T2D. These derangements may be difficult to reverse, but the worsening of dysglycemia may be halted, and thus the clinical onset of T2D can be delayed. PMID:27440823

  7. 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

  8. Prevention of STDs -- the challenge of changing behaviors.

    PubMed

    Halpern, J; Finger, W R

    1992-04-01

    STD prevention efforts in Latin America, particularly in the Dominican Republic, have begun to stress the need for behavioral changes. Traditionally, the professional public health community has focused on secondary prevention of STDs -- detection and treatment of the disease in order to prevent complications from developing. But in light of the AIDS epidemic, greater attention has been paid to primary prevention. Hoping to prevent the disease from occurring, primary prevention efforts target high risk groups (prostitutes and their clients and young people) with health education and promotion of behavioral change. Such changes include using condoms, seeking medical care for STDs, and decreasing the number of sex partners. An example of primary prevention programs is the Avancemos Project in the Dominican Republic. Launched in 1989 by the country's Ministry of Health and Family Health International's AIDSTECH Division, the project targets sex workers with several intervention measures. Initially, the Avancemos Project trained 16 sex workers to serve as peer educators to distribute condoms and educational materials. These 16 volunteers have in turn trained more than 300 other peer educators. Among the educational materials distributed by the peer educators are 2 comic books entitled "Martiza's Advice" and "The Triumphs of Maritza." A handsome, well dressed, and street-wise sex worker, the title character in these comic books instructs on a range of issues, including how to negotiate with clients how to use a condom. As those involved with the project attest, the comic books have become extremely popular among the target group, tapping into the women's buried feelings of self-worth. PMID:12343656

  9. 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 ...

  10. 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 ...

  11. 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

  12. 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.

  13. 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…

  14. 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.

  15. 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

  16. 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.

  17. Pseudo-three-dimensional simulation on stability of thin shell target implosion

    SciTech Connect

    Taguchi, T.; Mima, K.

    1995-07-01

    Pseudo-three-dimensional simulation method has been developed to analyze implosion stability of thin shell target in inertial confinement fusion. Nonlinear motion of a thin spherical surface driven by the pressure simulates the implosion of a shell target filled with fuel gas. The simulation shows that acceleration and deceleration of the shell give rise to the Rayleigh--Taylor instability and the instability prevents the target from being compressed uniformly. The results of the simulation show how the maximum volume compression ratio and breakup time of the target depend upon the initial perturbation amplitude. The new simulation scheme has also been applied to another shape of closed surfaces. The implosion phenomenon of the surface of torus is shown as an example. The toroidal target implosion is found to be more stable against the Rayleigh--Taylor instability than that of spherical targets. {copyright} {ital 1995} {ital American} {ital Institute} {ital of} {ital Physics}.

  18. 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…

  19. 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 ...

  20. 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

  1. Solid Polarized Targets and Applications

    SciTech Connect

    Crabb, D. G.

    2008-02-06

    Examples are given of dynamically polarized targets in use today and how the subsystems have changed to meet the needs of todays experiments. Particular emphasis is placed on target materials such as ammonia and lithium deuteride. Recent polarization studies of irradiated materials such as butanol, deuterated butanol, polyethylene, and deuterated polyethylene are presented. The operation of two non-DNP target systems as well as applications of traditional DNP targets are briefly discussed.

  2. 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. PMID:2231055

  3. 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.

  4. 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…

  5. Preventing Falls

    MedlinePlus

    ... from osteoporosis. Lower-body strength exercises and balance exercises can help you prevent falls and avoid the disability that may result from falling. Here are some fall prevention tips from Go4Life : l Have your eyes and hearing tested often. Always wear your glasses when you ...

  6. 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.

  7. A mass vaccination campaign targeting adults and children to prevent typhoid fever in Hechi; Expanding the use of Vi polysaccharide vaccine in Southeast China: A cluster-randomized trial

    PubMed Central

    Yang, Jin; Acosta, Camilo J; Si, Guo-ai; Zeng, Jun; Li, Cui-yun; Liang, Da-bin; Ochiai, R Leon; Page, Anne-Laure; Danovaro-Holliday, M Carolina; Zhang, Jie; Zhou, Bao-de; Liao, He-zhuang; Wang, Ming-liu; Tan, Dong-mei; Tang, Zhen-zhu; Gong, Jian; Park, Jin-Kyung; Ali, Mohammad; Ivanoff, Bernard; Liang, Gui-chen; Yang, Hong-hui; Pang, Tikki; Xu, Zhi-yi; Donner, Allan; Galindo, Claudia M; Dong, Bai-qing; Clemens, John D

    2005-01-01

    Background One of the goals of this study was to learn the coverage, safety and logistics of a mass vaccination campaign against typhoid fever in children and adults using locally produced typhoid Vi polysaccharide (PS) and group A meningococcal PS vaccines in southern China. Methods The vaccination campaign targeted 118,588 persons in Hechi, Guangxi Province, aged between 5 to 60 years, in 2003. The study area was divided into 107 geographic clusters, which were randomly allocated to receive one of the single-dose parenteral vaccines. All aspects regarding vaccination logistics, feasibility and safety were documented and systematically recorded. Results of the logistics, feasibility and safety are reported. Results The campaign lasted 5 weeks and the overall vaccination coverage was 78%. On average, the 30 vaccine teams gave immunizations on 23 days. Vaccine rates were higher in those aged ≤ 15 years (90%) than in adolescents and young adults (70%). Planned mop-up activities increased the coverage by 17%. The overall vaccine wastage was 11%. The cold chain was maintained and documented. 66 individuals reported of adverse events out of all vaccinees, where fever (21%), malaise (19%) and local redness (19%) were the major symptoms; no life-threatening event occurred. Three needle-sharp events were reported. Conclusion The mass immunization proved feasible and safe, and vaccine coverage was high. Emphasis should be placed on: injection safety measures, community involvement and incorporation of mop-up strategies into any vaccination campaign. School-based and all-age Vi mass immunizations programs are potentially important public health strategies for prevention of typhoid fever in high-risk populations in southern China. PMID:15904514

  8. Targeted estrogen delivery reverses the metabolic syndrome

    PubMed Central

    Finan, Brian; Yang, Bin; Ottaway, Nickki; Stemmer, Kerstin; Müller, Timo D; Yi, Chun-Xia; Habegger, Kirk; Schriever, Sonja C; García-Cáceres, Cristina; Kabra, Dhiraj G; Hembree, Jazzminn; Holland, Jenna; Raver, Christine; Seeley, Randy J; Hans, Wolfgang; Irmler, Martin; Beckers, Johannes; de Angelis, Martin Hrabě; Tiano, Joseph P; Mauvais-Jarvis, Franck; Perez-Tilve, Diego; Pfluger, Paul; Zhang, Lianshan; Gelfanov, Vasily; DiMarchi, Richard D; Tschöp, Matthias H

    2013-01-01

    We report the development of a new combinatorial approach that allows for peptide-mediated selective tissue targeting of nuclear hormone pharmacology while eliminating adverse effects in other tissues. Specifically, we report the development of a glucagon-like peptide-1 (GLP-1)-estrogen conjugate that has superior sex-independent efficacy over either of the individual hormones alone to correct obesity, hyperglycemia and dyslipidemia in mice. The therapeutic benefits are driven by pleiotropic dual hormone action to improve energy, glucose and lipid metabolism, as shown by loss-of-function models and genetic action profiling. Notably, the peptide-based targeting strategy also prevents hallmark side effects of estrogen in male and female mice, such as reproductive endocrine toxicity and oncogenicity. Collectively, selective activation of estrogen receptors in GLP-1–targeted tissues produces unprecedented efficacy to enhance the metabolic benefits of GLP-1 agonism. This example of targeting the metabolic syndrome represents the discovery of a new class of therapeutics that enables synergistic co-agonism through peptide-based selective delivery of small molecules. Although our observations with the GLP-1–estrogen conjugate justify translational studies for diabetes and obesity, the multitude of other possible combinations of peptides and small molecules may offer equal promise for other diseases. PMID:23142820

  9. Preventing Diabetes

    MedlinePlus

    ... a reasonable body weight —Losing even a few pounds can help reduce your risk of developing type ... 2 diabetes. For example, if you weigh 200 pounds, losing only 10 pounds could make a difference. ...

  10. 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.)

  11. 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

  12. 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

  13. Preventing falls

    MedlinePlus

    ... worsened. Improving your vision will help reduce falls. Images ... for preventing falls in older people living in the community. Cochrane Database of Systematic Reviews 2009, Issue 2. Art. No.: ...

  14. Preventing Influenza

    MedlinePlus

    ... spread in respiratory droplets distributed by coughing and sneezing, they readily spread from person to person. Additionally, ... and nose with a tissue when coughing or sneezing, you may help prevent those around you from ...

  15. 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 ...

  16. Prevention of Depression in Childhood and Adolescence.

    PubMed

    Mendelson, Tamar; Tandon, S Darius

    2016-04-01

    This article discusses strategies and programs used to prevent depression in children and adolescents. It describes the rationale for depression prevention and discusses prevention approaches in schools and other settings, highlighting examples of programs that have been empirically evaluated. Prevention effects are small but significant, comparable or greater in magnitude than adolescent prevention programs for other issues, including substance use and human immunodeficiency virus. Future research should include rigorous design features, including attention control groups, allocation concealment, larger sample sizes, longer follow-up assessments, and theory-driven tests of moderation and mediation, and should test larger-scale implementation of prevention programs. PMID:26980124

  17. Neuroimaging methods for adolescent substance use disorder prevention science

    PubMed Central

    Clark, DB; Chung, T; Pajtek, S; Zhai, Z; Long, E; Hasler, B

    2013-01-01

    Magnetic resonance imaging (MRI) methods safely provide in vivo indicators of cerebral macrostructure, microstructure, and activation that can be examined in relation to substance use disorder (SUD) risks and effects. This article will provide an overview of MRI approaches, including volumetric measures, diffusion tensor imaging, functional MRI, that have been applied to studies of adolescent neuromaturation in relationship to risk phenotypes and adolescent SUD. To illustrate these applications, examples of research findings will be presented. MRI indicators have demonstrated that neurobiological maturation continues throughout adolescence. MRI research has suggested that variations in neurobiological maturation may contribute to SUD risk, and that substance use adversely influence adolescent brain development. Directly measured neurobiological variables may be viable preventive intervention targets and outcome indicators. Further research is needed to provide definitive findings on neurodevelopmental immaturity as an SUD risk and to determine the directions such observations suggest for advancing prevention science. PMID:23417665

  18. 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.)

  19. 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…

  20. 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.

  1. 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.

  2. 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.

  3. 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

  4. 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…

  5. 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.

  6. 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.

  7. Preventing Diabetes

    MedlinePlus

    ... diabetes. For example, if you weigh 200 pounds, losing only 10 pounds could make a difference. Avoid crash diets. Instead, eat less of the foods you usually have. Limit the amount of fat you eat. Increase your physical activity. Aim for ...

  8. Preventive Health Care for the Elderly

    PubMed Central

    Stults, Barry M.

    1984-01-01

    Demographic, economic and humanitarian considerations dictate that effective preventive health care be provided to the elderly. A disease-specific approach to geriatric preventive health care will not suffice; measures to enhance or maintain physical, mental and social function must also be emphasized. Unfortunately, the effectiveness of many preventive care procedures has not been adequately investigated in the elderly. Research is urgently needed to determine the efficacy of and appropriate target population for various geriatric preventive health care measures. PMID:6395498

  9. 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 ...

  10. 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…

  11. 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…

  12. 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.

  13. Compliance, assurance, and pollution prevention at Argonne National Laboratory-East (ANL-E) - process and operations

    SciTech Connect

    Kamiya, M. A.; Trychta, K.

    2000-02-10

    Argonne National Laboratory-East (ANL-E) is a multi-program laboratory operated by the University of Chicago for the U.S. Department of Energy (DOE). ANL-E has incorporated its environmental compliance functions and pollution prevention (P2) activities into its processes. Examples of this include standard project and experimental reviews, targeted process analysis, and regulatory and oversight audits. ANL-E's implementation process has allowed them to meet regulatory drivers as well as internal goals with minimal resources. This paper reviews these processes and implementation of the environmental and pollution prevention requirements which have led to an award winning P2 program.

  14. 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

  15. 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.

  16. Target capture and target ghosts

    NASA Astrophysics Data System (ADS)

    Auerbach, Steven P.

    1996-05-01

    Optimal detection methods for small targets rely on whitened matched filters, which convolve the measured data with the signal model, and whiten the result with the noise covariance. In real-world implementations of such filters, the noise covariance must be estimated from the data, and the resulting covariance estimate may be corrupted by presence of the target. The resulting loss in SNR is called 'target capture'. Target capture is often thought to be a problem only for bright targets. This presentation shows that target capture also arises for dim targets, leading to an SNR loss which is independent of target strength and depends on the averaging method used to estimate the noise covariance. This loss is due to a 'coherent beat' between the true noise and that portion of the estimated noise covariance due to the target. This beat leads to 'ghost targets', which diminish the target SNR by producing a negative target ghost at the target's position. A quantitative estimate of this effect will be given, and shown to agree with numerical results. The effect of averaging on SNR is also discussed for data scenes with synthetic injected targets, in cases where the noise covariance is estimated using 'no target' data. For these cases, it is shown that the so-called 'optimal' filter, which uses the true noise covariance, is actually worse than a 'sub-optimal' filter which estimates the noise from scene. This apparent contradiction is resolved by showing that the optimal filter is best if the same filter is used for many scenes, but is outperformed by a filter adapted to a specific scene.

  17. 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…

  18. Prevention Opportunities in Health Care Settings.

    ERIC Educational Resources Information Center

    Johnson, Suzanne Bennett; Millstein, Susan G.

    2003-01-01

    Reviews changing patterns of health and illness that have led to increased interest in the role of patient and provider behaviors, discussing the advantages of using health care settings as prevention sites. Presents examples of successful behaviorally-based prevention programs, offering evidence supporting their cost-effectiveness. Describes…

  19. Teaching Prevention in Internal Medicine Clerkships.

    ERIC Educational Resources Information Center

    Kinsinger, Linda

    2000-01-01

    Reviews the rationale for including prevention in the clinical medicine clerkship. Summarizes current guidelines, presents examples of curricula in several medical schools, and proposes a future direction that stresses integrating teaching preventive medicine into internal medicine clerkships and across the entire four-year medical curriculum. (DB)

  20. 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

  1. 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.

  2. 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. |

  3. Allergy prevention.

    PubMed

    Muche-Borowski, Cathleen; Kopp, Matthias; Reese, Imke; Sitter, Helmut; Werfel, Thomas; Schäfer, Torsten

    2010-09-01

    The further increase of allergies in industrialized countries demands evidence-based measures of primary prevention. The recommendations as published in the guideline of 2004 were updated and consented on the basis of a systematic literature search. Evidence from the period February 2003-May 2008 was searched in the electronic databases Cochrane and MEDLINE as well as in reference lists of recent reviews and by contacting experts. The retrieved citations were screened for relevance first by title and abstract and in a second step as full paper. Levels of evidence were assigned to each included study and the methodological quality of the studies was assessed as high or low. Finally the revised recommendations were formally consented (nominal group process) by representatives of relevant societies and organizations including a self-help group. Of originally 4556 hits, 217 studies (4 Cochrane Reviews, 14 meta-analyses, 19 randomized controlled trials, 135 cohort and 45 case-control studies) were included and critically appraised. Grossly unchanged remained the recommendations on avoiding environmental tobacco smoke, breast-feeding over 4 months (alternatively hypoallergenic formulas for children at risk), avoiding a mold-promoting indoor climate, vaccination according to current recommendations, and avoidance of furry pets (especially cats) in children at risk. The recommendation on reducing the house dust mite allergen exposure as a measure of primary prevention was omitted and the impact of a delayed introduction of supplementary food was reduced. New recommendations were adopted concerning fish consumption (during pregnancy / breast-feeding and as supplementary food in the first year), avoidance of overweight, and reducing the exposure to indoor and outdoor air pollutants. The revision of this guideline on a profound evidence basis led to (1) a confirmation of existing recommendations, (2) substantial revisions, and (3) new recommendations. Thereby it is possible

  4. 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…

  5. Categorization Using Chains of Examples.

    ERIC Educational Resources Information Center

    Heit, Evan

    1992-01-01

    Presents a mathematical-categorization model using multiple-step chains of reasoning (CORs) and memory for examples. In 5 experiments, 144 undergraduates memorized descriptions of fictional people, then made predictions from incomplete descriptions using 1-, 2-, or 3-step CORs. The multiple-step context model with one- and two-step inference…

  6. 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…

  7. Learning Algebra from Worked Examples

    ERIC Educational Resources Information Center

    Lange, Karin E.; Booth, Julie L.; Newton, Kristie J.

    2014-01-01

    For students to be successful in algebra, they must have a truly conceptual understanding of key algebraic features as well as the procedural skills to complete a problem. One strategy to correct students' misconceptions combines the use of worked example problems in the classroom with student self-explanation. "Self-explanation" is…

  8. 66 FR 22234 - Grants for Rape Prevention and Education

    Federal Register 2010, 2011, 2012, 2013, 2014

    2001-05-03

    ... HUMAN SERVICES Centers for Disease Control and Prevention Grants for Rape Prevention and Education.... The Rape Prevention and Education Grant Program strengthens education and training to combat violence.... CDC will award targeted grants to State Health Departments to be used for rape prevention...

  9. 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

  10. 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.

  11. Epidemiological perspectives on maltreatment prevention.

    PubMed

    Wulczyn, Fred

    2009-01-01

    Fred Wulczyn explores how data on the incidence and distribution of child maltreatment shed light on planning and implementing maltreatment prevention programs. He begins by describing and differentiating among the three primary sources of national data on maltreatment. Wulczyn then points out several important patterns in the data. The first involves child development. Based on official reports, maltreatment rates are highest during certain periods of children's lives, especially infancy and adolescence. Bringing a new baby into the home, in particular, heightens stress and increases the risk of maltreatment by parents, who tend to be younger and less experienced as parents. These data patterns should help shape strategies that target these families. A second pattern in the data involves social context and the contribution of race and poverty to maltreatment. Children of color, for example, are much more likely than white children to be reported. Research, however, suggests that when the whites and minorities who are being compared live in a similar social context, disparities in maltreatment rates narrow to some extent. What scholars must examine more closely is the means by which community processes contribute to maltreatment. Thus, the question for researchers is not whether investments in communities are an important part of the prevention strategy, but rather what type of investment is most likely to replace what is missing in a given community. Wulczyn also explores substance abuse and maltreatment recurrence. He points out that substance abuse not only increases the risk that a parent will neglect a child but also appears to affect that child's experience in the child welfare system: when substance abuse is part of an allegation history, decisions affecting the child tilt in favor of deeper involvement with the system. Patterns of recurrence mirror those already described. Base rates of recurrence are about 9 percent but are higher for infants when

  12. Veteran-specific suicide prevention.

    PubMed

    York, Janet A; Lamis, Dorian A; Pope, Charlene A; Egede, Leonard E

    2013-06-01

    Suicide rates have been increasing in some subgroups of Veteran populations, such as those who have experienced combat. Several initiatives are addressing this critical need and the Department of Veterans Affairs (VA) has been recognized for its leadership. This integrative review adopts the Research Impact Framework (RIM) to address suicide-specific prevention activities targeting Veterans. The RIM is a standardized approach for developing issue narratives using four broad areas: societal-related impacts, research-related impacts, policy-related impacts, and service-related impacts. The questions addressed in this review are: (1) What are the major initiatives in Veteran-specific suicide prevention in four areas of impact-society, research, policy, and services? (2) Are there gaps related in each impact area? and (3) What are the implications of this narrative for other strategies to address suicide prevention targeting Veterans? Systematic application of the RIM identifies exemplars, milestones, gaps, and health disparity issues. PMID:23011459

  13. 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

  14. Selection of molecular targets for drug development against trypanosomatids.

    PubMed

    Smirlis, Despina; Soares, Milena Botelho Pereira

    2014-01-01

    Trypanosomatid parasites are a group of flagellated protozoa that includes the genera Leishmania and Trypanosoma, which are the causative agents of diseases (leishmaniases, sleeping sickness and Chagas disease) that cause considerable morbidity and mortality, affecting more than 27 million people worldwide. Today no effective vaccines for the prevention of these diseases exist, whereas current chemotherapy is ineffective, mainly due to toxic side effects of current drugs and to the emergence of drug resistance and lack of cost effectiveness. For these reasons, rational drug design and the search of good candidate drug targets is of prime importance. The search for drug targets requires a multidisciplinary approach. To this end, the completion of the genome project of many trypanosomatid species gives a vast amount of new information that can be exploited for the identification of good drug candidates with a prediction of "druggability" and divergence from mammalian host proteins. In addition, an important aspect in the search for good drug targets is the "target identification" and evaluation in a biological pathway, as well as the essentiality of the gene in the mammalian stage of the parasite, which is provided by basic research and genetic and proteomic approaches. In this chapter we will discuss how these bioinformatic tools and experimental evaluations can be integrated for the selection of candidate drug targets, and give examples of metabolic and signaling pathways in the parasitic protozoa that can be exploited for rational drug design. PMID:24264240

  15. 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

  16. 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.

  17. New pharmacological treatment strategies for relapse prevention.

    PubMed

    Spanagel, Rainer; Vengeliene, Valentina

    2013-01-01

    Here we discuss treatment strategies that are based on pharmacological interventions to reduce craving and relapse in alcohol-dependent patients. We will first provide a historical overview about relapse prevention strategies. We will then review the development of disulfiram, naltrexone, acamprosate, and nalmefene and discuss their neurobiological modes of action. Then the concept of convergent genomic analysis will be introduced for the discovery of new molecular treatment targets. Finally, we will provide convincing evidence for the use of N-methyl-D-aspartate (NMDA) receptor channel blockers as substitution drugs. Important conclusions of this review are: (i) learning from other addictive substances is very helpful-e.g., substitution therapies as applied to opiate addiction for decades could also be translated to alcoholics, (ii) the glutamate theory of alcohol addiction provides a convincing framework for the use of NMDA receptor antagonists as substitution drugs for alcohol-dependent patients, (iii) a combination of behavioral and pharmacological therapies may be the optimal approach for future treatment strategies-one promising example concerns the pharmacological disruption of reconsolidation processes of alcohol cue memories, (iv) given that many neurotransmitter systems are affected by chronic alcohol consumption, numerous druggable targets have been identified; consequently, a "cocktail" of different compounds will further improve the treatment situation, (v) in silico psychopharmacology, such as drug repurposing will yield new medications, and finally, (vi) the whole organism has to be taken into consideration to provide the best therapy for our patients. In summary, there is no other field in psychiatric research that has, in recent years, yielded so many novel, druggable targets and innovative treatment strategies than for alcohol addiction. However, it will still be several years before the majority of the "treatment-seeking population" will benefit

  18. 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.

  19. 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…

  20. Preventing clonal evolutionary processes in cancer: Insights from mathematical models

    PubMed Central

    Rodriguez-Brenes, Ignacio A.; Wodarz, Dominik

    2015-01-01

    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. PMID:26195751

  1. Gender and the Primary Prevention of Suicide.

    ERIC Educational Resources Information Center

    Canetto, Silvia Sara; Lester, David

    1995-01-01

    Reviews the national and international epidemiological data on suicide mortality systematically by gender and culture and then discusses the implications these data hold for primary prevention. Suicide morality appears highest among individuals for whom such behavior is culturally sanctioned. Thus, an important target for primary prevention may be…

  2. Targets and processes for fabricating same

    SciTech Connect

    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.

  3. Targets and processes for fabricating same

    SciTech Connect

    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.

  4. 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.

  5. 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

  6. Manganese Superoxide Dismutase in Cancer Prevention

    PubMed Central

    Robbins, Delira

    2014-01-01

    Abstract Significance: Cancer is the second leading cause of death in the United States. Considering the quality of life and treatment cost, the best way to fight against cancer is to prevent or suppress cancer development. Cancer is preventable as indicated by human papilloma virus (HPV) vaccination and tamoxifen/raloxifen treatment in breast cancer prevention. The activities of superoxide dismutases (SODs) are often lowered during early cancer development, making it a rational candidate for cancer prevention. Recent Advances: SOD liposome and mimetics have been shown to be effective in cancer prevention animal models. They've also passed safety tests during early phase clinical trials. Dietary supplement-based SOD cancer prevention provides another opportunity for antioxidant-based cancer prevention. New mechanistic studies have revealed that SOD inhibits not only oncogenic activity, but also subsequent metabolic shifts during early tumorigenesis. Critical Issues: Lack of sufficient animal model studies targeting specific cancers; and lack of clinical trials and support from pharmaceutical industries also hamper efforts in further advancing SOD-based cancer prevention. Future Directions: To educate and obtain support from our society that cancer is preventable. To combine SOD-based therapeutics with other cancer preventive agents to obtain synergistic effects. To formulate a dietary supplementation-based antioxidant approach for cancer prevention. Lastly, targeting specific populations who are prone to carcinogens, which can trigger oxidative stress as the mechanism of carcinogenesis. Antioxid. Redox Signal. 20, 1628–1645. PMID:23706068

  7. 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

  8. 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…

  9. Models for effective prevention.

    PubMed

    Perry, C L; Kelder, S H

    1992-07-01

    The social influence models do provide some optimism for primary prevention efforts. Prevention programs appear most effective when 1) the target behavior of the intervention has received increasing societal disapproval (such as cigarette smoking), 2) multiple years of behavioral health education are planned, and 3) community-wide involvement or mass media complement a school-based peer-led program (45,46). Short-term programs and those involving alcohol use have had less favorable outcomes. Future research in primary prevention should address concerns of high-risk groups and high-risk countries, such as lower income populations in the United States or countries that have large adolescent homeless populations. The utilization of adolescent leaders for program dissemination might be particularly critical in these settings. A second major and global concern should focus upon alcohol use and alcohol-related problems. In many communities adolescent alcohol use is normative and even adult supported. Thus, young people are getting quite inconsistent messages on alcohol from their schools, from TV, from peers, and from parents. This inconsistency may translate into many tragic and avoidable deaths for young people. Clearly, in the area of alcohol-related problems, community-wide involvement may be necessary. A third direction for prevention research should involve issues of norms, access, and enforcement including policy interventions, such as involve the availability of cigarette vending machines or the ease of under-age buying or levels of taxation. These methods affect adolescents more acutely since their financial resources, for the most part, are more limited. These policy level methods also signify to adolescents what adults consider appropriate.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:1390786

  10. 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)

  11. 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.

  12. 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

  13. 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.

  14. Prevention of relapsing backache

    PubMed Central

    Lühmann, Dagmar; Stoll, Susanne; Burkhardt-Hammer, Tatjana; Raspe, Heiner

    2006-01-01

    back pain. So far there are no data from controlled trials that demonstrate the effectiveness of "lifting teams" in nursing care to prevent back pain or its consequences. However, results from uncontrolled pilot studies indicate a potential for effectiveness. Among "ergonomic interventions" three different approaches have to be distinguished: interventions addressing changes of the workplace setting, interventions addressing the individual's behaviour and combined interventions. Studies evaluating the effectiveness of setting interventions (modification of the physical workplace environment, changes of production processes, organisational changes) yield no dependable results. This conclusion is not based on indifferent trial results but rather on the lack of methodologically sound studies. Results from studies on ergonomic interventions addressing the individual confirm the conclusions drawn for exercise and educational measures. The most marked results are found in trials that examine the effectiveness of combined interventions in high risk groups and contain a strong participatory component. Hardly any of the trials studying the effects of ergonomic interventions satisfied methodological quality criteria that are accepted standard for clinical or public health intervention studies. There were no data allowing firm conclusions on the cost-effectiveness of interventions from any of the categories. Discussion The significance of the results of the assessment at hand is strongly limited by the comprehensiveness of the questions addressed. Reviewing the literature on the basis of (even systematic) review articles impairs the differentiated examination of the role of target groups, program contents, application and duration, effect sizes and context factors. While the methodological quality of the review articles is quite high, the quality of individual trials (even those included in the review papers) is highly variable. While most trials examining preventive

  15. Target Mass Corrections Revisited

    SciTech Connect

    W. Melnitchouk; F. Steffens

    2006-03-07

    We propose a new implementation of target mass corrections to nucleon structure functions which, unlike existing treatments, has the correct kinematic threshold behavior at finite Q{sup 2} in the x {yields} 1 limit. We illustrate the differences between the new approach and existing prescriptions by considering specific examples for the F{sub 2} and F{sub L} structure functions, and discuss the broader implications of our results, which call into question the notion of universal parton distribution at finite Q{sup 2}.

  16. Theoretical integration and the psychology of sport injury prevention.

    PubMed

    Chan, Derwin King-Chung; Hagger, Martin S

    2012-09-01

    Integrating different theories of motivation to facilitate or predict behaviour change has received an increasing amount of attention within the health, sport and exercise science literature. A recent review article in Sports Medicine, by Keats, Emery and Finch presented an integrated model using two prominent theories in social psychology, self-determination theory (SDT) and the theory of planned behaviour (TPB), aimed at explaining and enhancing athletes' adherence to sport injury prevention. While echoing their optimistic views about the utility of these two theories to explain adherence in this area and the virtues of theoretical integration, we would like to seize this opportunity to clarify several conceptual principles arising from the authors' integration of the theories. Clarifying the theoretical assumptions and explaining precisely how theoretical integration works is crucial not only for improving the comprehensiveness of the integrated framework for predicting injury prevention behaviour, but also to aid the design of effective intervention strategies targeting behavioural adherence. In this article, we use the integration of SDT and TPB as an example to demonstrate how theoretical integration can advance the understanding of injury prevention behaviour in sport. PMID:22909184

  17. 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

  18. Functional foods for dyslipidaemia and cardiovascular risk prevention.

    PubMed

    Sirtori, Cesare R; Galli, Claudio; Anderson, James W; Sirtori, Elena; Arnoldi, Anna

    2009-12-01

    A food can be regarded as 'functional' if it can demonstrate a beneficial efficacy on one or more target functions in the body in a convincing way. Beyond adequate nutritional qualities, functional foods should either improve the state of health and wellbeing and/or reduce the risk of disease. Functional foods that are marketed with claims of heart disease reduction focus primarily on the major risk factors, i.e. cholesterol, diabetes and hypertension. Some of the most innovative products are designed to be enriched with 'protective' ingredients, believed to reduce risk. They may contain, for example, soluble fibre (from oat and psyllium), useful both for lowering cholesterol and blood pressure, or fructans, effective in diabetes. Phytosterols and stanols lower LDL-cholesterol in a dose-dependent manner. Soya protein is more hypocholesterolaemic in subjects with very high initial cholesterol and recent data indicate also favourable activities in the metabolic syndrome. n-3 Fatty acids appear to exert significant hypotriacylglycerolaemic effects, possibly partly responsible for their preventive activity. Dark chocolate is gaining much attention for its multifunctional activities, useful both for the prevention of dyslipidaemia as well as hypertension. Finally, consensus opinions about tea and coffee have not emerged yet, and the benefits of vitamin E, garlic, fenugreek and policosanols in the management of dyslipidaemia and prevention of arterial disease are still controversial. PMID:20003590

  19. 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.

  20. 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.

  1. Fluoroquinolone levels in healthy dog urine following a 20-mg/kg oral dose of enrofloxacin exceed mutant prevention concentration targets against Escherichia coli isolated from canine urinary tract infections.

    PubMed

    Daniels, J B; Tracy, G; Irom, S J; Lakritz, J

    2014-04-01

    A 3-day course of oral enrofloxacin is effective for treating uncomplicated urinary tract infection (UTI) in dogs when administered 20 mg/kg Q24H. However, emergence of fluoroquinolone-resistant mutants of uropathogens is a concern. Urine concentrations of enrofloxacin and ciprofloxacin were measured in six healthy dogs following dose of enrofloxacin 20 mg/kg. Mutant prevention concentrations of Escherichia coli isolated from canine UTI were also determined against ciprofloxacin. Urine AUC(24)/MPC ratios considering ciprofloxacin concentrations ranged 3819-7767, indicating that selection of resistant E. coli mutants in dogs with uncomplicated UTIs is unlikely in the bladder given that an AUC(24)/MPC = 39 is considered to be protective against mutant selection for ciprofloxacin. However, additional studies are required to evaluate the effects of this enrofloxacin treatment protocol on bacteria that colonize anatomic sites where fluoroquinolones achieve lower concentrations compared to the urinary bladder. PMID:23859001

  2. 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

  3. 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…

  4. 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…

  5. 16 CFR 680.2 - Examples.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 16 Commercial Practices 1 2010-01-01 2010-01-01 false Examples. 680.2 Section 680.2 Commercial Practices FEDERAL TRADE COMMISSION THE FAIR CREDIT REPORTING ACT AFFILIATE MARKETING § 680.2 Examples. The examples in this part are not exclusive. Compliance with an example, to the extent applicable,...

  6. 16 CFR 680.2 - Examples.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 16 Commercial Practices 1 2013-01-01 2013-01-01 false Examples. 680.2 Section 680.2 Commercial Practices FEDERAL TRADE COMMISSION THE FAIR CREDIT REPORTING ACT AFFILIATE MARKETING § 680.2 Examples. The examples in this part are not exclusive. Compliance with an example, to the extent applicable,...

  7. 16 CFR 680.2 - Examples.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 16 Commercial Practices 1 2012-01-01 2012-01-01 false Examples. 680.2 Section 680.2 Commercial Practices FEDERAL TRADE COMMISSION THE FAIR CREDIT REPORTING ACT AFFILIATE MARKETING § 680.2 Examples. The examples in this part are not exclusive. Compliance with an example, to the extent applicable,...

  8. 16 CFR 680.2 - Examples.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 16 Commercial Practices 1 2014-01-01 2014-01-01 false Examples. 680.2 Section 680.2 Commercial Practices FEDERAL TRADE COMMISSION THE FAIR CREDIT REPORTING ACT AFFILIATE MARKETING § 680.2 Examples. The examples in this part are not exclusive. Compliance with an example, to the extent applicable,...

  9. 16 CFR 680.2 - Examples.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 16 Commercial Practices 1 2011-01-01 2011-01-01 false Examples. 680.2 Section 680.2 Commercial Practices FEDERAL TRADE COMMISSION THE FAIR CREDIT REPORTING ACT AFFILIATE MARKETING § 680.2 Examples. The examples in this part are not exclusive. Compliance with an example, to the extent applicable,...

  10. Secular Redemptions: Biopolitics by Example.

    PubMed

    Giordano, Cristiana

    2016-01-01

    In this article, I analyze the practices of a group of Catholic nuns who run shelters for 'victims of human trafficking' in Italy, and are thus involved in state-funded rehabilitation programs for former foreign prostitutes. This case shows how the state and the Church are deeply implicated in each other's projects of redemption and the creation of new forms of life. In Italy, the legal model for rehabilitating foreign prostitutes is avowedly secular yet also deeply shaped by a Catholic impetus to purify sinners. At the same time, however, the nuns themselves develop an understanding of redemption as a secular life-saving project in line with the state's project of recognition, and thus inscribe their practices within the biopolitical effort to transform lives. Ultimately, I argue, leading by example becomes a specific Catholic instantiation of biopolitics that characterizes both the state's and the Church's approach to foreigners. PMID:26258728

  11. Microenvironmental Targets in Sarcoma

    PubMed Central

    Ehnman, Monika; Larsson, Olle

    2015-01-01

    Sarcomas are rare malignant tumors affecting all age groups. They are typically classified according to their resemblance to corresponding normal tissue. Their heterogeneous features, for example, in terms of disease-driving genetic aberrations and body location, complicate both disease classification and development of novel treatment regimens. Many years of failure of improved patient outcome in clinical trials has led to the conclusion that novel targeted therapies are likely needed in combination with current multimodality regimens. Sarcomas have not, in contrast to the common carcinomas, been the subject of larger systematic studies on how tumor behavior relates to characteristics of the tumor microenvironment. There is consequently an urgent need for identifying suitable molecular targets, not only in tumor cells but also in the tumor microenvironment. This review discusses preclinical and clinical data about potential molecular targets in sarcomas. Studies on targeted therapies involving the tumor microenvironment are prioritized. A greater understanding of the biological context is expected to facilitate more successful design of future clinical trials in sarcoma. PMID:26583076

  12. 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

  13. The targets of curcumin.

    PubMed

    Zhou, Hongyu; Beevers, Christopher S; Huang, Shile

    2011-03-01

    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-kB), 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

  14. 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

  15. 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

  16. Diet and cancer prevention.

    PubMed

    Greenwald, P; Clifford, C K; Milner, J A

    2001-05-01

    Research from several sources provides strong evidence that vegetables, fruits, and whole grains, dietary fibre, certain micronutrients, some fatty acids and physical activity protect against some cancers. In contrast, other factors, such as obesity, alcohol, some fatty acids and food preparation methods may increase risks. Unravelling the multitude of plausible mechanisms for the effects of dietary factors on cancer risk will likely necessitate that nutrition research moves beyond traditional epidemiological and metabolic studies. Nutritional sciences must build on recent advances in molecular biology and genetics to move the discipline from being largely 'observational' to focusing on 'cause and effect'. Such basic research is fundamental to cancer prevention strategies that incorporate effective dietary interventions for target populations. PMID:11334719

  17. Prevention of early childhood caries.

    PubMed

    Ismail, A I

    1998-01-01

    This paper reviews the methods used for the prevention of early childhood caries (ECC). The education of mothers or caregivers to promote healthy dietary habits in infants has been the main strategy used for the prevention of ECC. This review found that education has a modest impact on the development of ECC. While education should be promoted especially in high risk communities and population groups (low-income families and native populations), it should not be the only preventive strategy of ECC. Early screening for signs of caries development, starting from the first year of life, could identify infants and toddlers who are at risk of developing ECC and assist in providing information to parents about how to promote oral health and prevent the development of tooth decay. High risk children include those with early signs of ECC, poor oral hygiene, limited exposure to fluorides, and frequent exposure to sugary snacks and drinks. These children should be targeted with a professional preventive program that includes fluoride varnish application, fluoridated dentifrices, fluoride supplements, sealants, diet counseling, and chlorhexidine. Prevention of ECC also requires addressing the social and economic factors that face many families where ECC is endemic. PMID:9671200

  18. 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

  19. Connecting youth violence prevention, positive youth development, and community mobilization.

    PubMed

    Allison, Kevin W; Edmonds, Torey; Wilson, Karen; Pope, Michell; Farrell, Albert D

    2011-09-01

    Several disconnects serve to weaken the use of evidence based programming in community settings. Communities face the need to address the challenges of multiple risk behaviors faced by adolescents in their communities, but must also work to support successful transitions to adulthood and the broader positive development of their youth. The stronger integration of positive youth development and prevention of youth risk at the community level may offer an opportunity to support the implementation and ongoing development of evidence-based practices (EBPs). This article provides an overview of the VCU Clark-Hill Institute for Positive Youth Development Institute's community mobilization effort in Richmond, Virginia and reports preliminary findings from our integrated mobilization efforts. First, we review the role of our Community Advisory Council in their collaborative work to support positive youth development and reduce risk for youth violence. Next, we present examples of institute efforts in providing technical assistance relevant to supporting the use and development of EBPs. We then discuss the adaptation of an evidence-based program to target positive youth development. We also present overviews from qualitative investigations examining barriers and supports that inform and are relevant to the implementation of EBPs. Finally, we consider ways in which community efforts inform and shape institute efforts to develop EPBs. Taken together, these activities provide examples of how community-based mobilization efforts can integrate and inform the implementation of EBPs and the role and use of prevention science as a tool in supporting effective programming to promote positive youth development and prevent youth violence. PMID:21246272

  20. 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