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Sample records for active targeting strategy

  1. Novel strategies for ultrahigh specific activity targeted nanoparticles

    SciTech Connect

    Zhou, Dong

    2012-12-13

    We have developed novel strategies optimized for preparing high specific activity radiolabeled nanoparticles, targeting nuclear imaging of low abundance biomarkers. Several compounds have been labeled with F-18 and Cu-64 for radiolabeling of SCK-nanoparticles via Copper(I) catalyzed or copper-free alkyne-azide cyclolization. Novel strategies have been developed to achieve ultrahigh specific activity with administrable amount of dose for human study using copper-free chemistry. Ligands for carbonic anhydrase 12 (CA12), a low abundance extracellular biomarker for the responsiveness of breast cancer to endocrine therapie, have been labeled with F-18 and Cu-64, and one of them has been evaluated in animal models. The results of this project will lead to major improvements in the use of nanoparticles in nuclear imaging and will significantly advance their potential for detecting low abundance biomarkers of medical importance.

  2. Artificial Chemical Reporter Targeting Strategy Using Bioorthogonal Click Reaction for Improving Active-Targeting Efficiency of Tumor.

    PubMed

    Yoon, Hong Yeol; Shin, Min Lee; Shim, Man Kyu; Lee, Sangmin; Na, Jin Hee; Koo, Heebeom; Lee, Hyukjin; Kim, Jong-Ho; Lee, Kuen Yong; Kim, Kwangmeyung; Kwon, Ick Chan

    2017-03-15

    Biological ligands such as aptamer, antibody, glucose, and peptide have been widely used to bind specific surface molecules or receptors in tumor cells or subcellular structures to improve tumor-targeting efficiency of nanoparticles. However, this active-targeting strategy has limitations for tumor targeting due to inter- and intraheterogeneity of tumors. In this study, we demonstrated an alternative active-targeting strategy using metabolic engineering and bioorthogonal click reaction to improve tumor-targeting efficiency of nanoparticles. We observed that azide-containing chemical reporters were successfully generated onto surface glycans of various tumor cells such as lung cancer (A549), brain cancer (U87), and breast cancer (BT-474, MDA-MB231, MCF-7) via metabolic engineering in vitro. In addition, we compared tumor targeting of artificial azide reporter with bicyclononyne (BCN)-conjugated glycol chitosan nanoparticles (BCN-CNPs) and integrin αvβ3 with cyclic RGD-conjugated CNPs (cRGD-CNPs) in vitro and in vivo. Fluorescence intensity of azide-reporter-targeted BCN-CNPs in tumor tissues was 1.6-fold higher and with a more uniform distribution compared to that of cRGD-CNPs. Moreover, even in the isolated heterogeneous U87 cells, BCN-CNPs could bind artificial azide reporters on tumor cells more uniformly (∼92.9%) compared to cRGD-CNPs. Therefore, the artificial azide-reporter-targeting strategy can be utilized for targeting heterogeneous tumor cells via bioorthogonal click reaction and may provide an alternative method of tumor targeting for further investigation in cancer therapy.

  3. From protective intelligence to threat assessment: Strategies critical to preventing targeted violence and the active shooter.

    PubMed

    Doherty, Matthew

    Acts of targeted violence - including active shooter incidents - are typically over within 15 minutes, often before the first law enforcement personnel can respond to the scene. More than a third of active shooter incidents in the USA, for example, last less than five minutes. While this stark fact is often used, with unimpeachable validity, as the cornerstone of employee security awareness training and the need for each employee to make a quick decision on whether to run, hide or fight, it also underscores the importance of another critical priority: prevention. This paper focuses on several of the most effective strategies and tactics - increasingly used across the USA, but applicable all over the world - in preventing an act of targeted violence or active shooter event. It starts with a brief discussion of the common roadblocks to prevention within enterprises today as well as the warning signs that can reveal an individual's path toward an act of violence. Next, it defines targeted violence and summarises patterns that research has helped uncover with respect to attackers' backgrounds, motives and target selection. This paper also outlines the crucial role played by protective intelligence and threat assessment protocols and provides several case studies to illustrate key concepts in real-world applications. Finally, this discussion points to several emerging trends in the USA and Europe, among other regions - such as radicalisation within the workforce - that are likely to continue to mature in 2016 and the years ahead.

  4. An Incremental Target-Adapted Strategy for Active Geometric Calibration of Projector-Camera Systems

    PubMed Central

    Chen, Chia-Yen; Chien, Hsiang-Jen

    2013-01-01

    The calibration of a projector-camera system is an essential step toward accurate 3-D measurement and environment-aware data projection applications, such as augmented reality. In this paper we present a two-stage easy-to-deploy strategy for robust calibration of both intrinsic and extrinsic parameters of a projector. Two key components of the system are the automatic generation of projected light patterns and the incremental calibration process. Based on the incremental strategy, the calibration process first establishes a set of initial parameters, and then it upgrades these parameters incrementally using the projection and captured images of dynamically-generated calibration patterns. The scene-driven light patterns allow the system to adapt itself to the pose of the calibration target, such that the difficulty in feature detection is greatly lowered. The strategy forms a closed-loop system that performs self-correction as more and more observations become available. Compared to the conventional method, which requires a time-consuming process for the acquisition of dense pixel correspondences, the proposed method deploys a homography-based coordinate computation, allowing the calibration time to be dramatically reduced. The experimental results indicate that an improvement of 70% in reprojection errors is achievable and 95% of the calibration time can be saved. PMID:23435056

  5. Synergistic retention strategy of RGD active targeting and radiofrequency-enhanced permeability for intensified RF & chemotherapy synergistic tumor treatment.

    PubMed

    Zhang, Kun; Li, Pei; He, Yaping; Bo, Xiaowan; Li, Xiaolong; Li, Dandan; Chen, Hangrong; Xu, Huixiong

    2016-08-01

    Despite gaining increasing attention, chelation of multiple active targeting ligands greatly increase the formation probability of protein corona, disabling active targeting. To overcome it, a synergistic retention strategy of RGD-mediated active targeting and radiofrequency (RF) electromagnetic field-enhanced permeability has been proposed here. It is validated that such a special synergistic retention strategy can promote more poly lactic-co-glycolic acid (PLGA)-based capsules encapsulating camptothecin (CPT) and solid DL-menthol (DLM) to enter and retain in tumor in vitro and in vivo upon exposure to RF irradiation, receiving an above 8 fold enhancement in HeLa retention. Moreover, the PLGA-based capsules can respond RF field to trigger the entrapped DLM to generate solid-liquid-gas (SLG) tri-phase transformation for enhancing RF ablation and CPT release. Therefore, depending on the enhanced RF ablation and released CPT and the validated synergistic retention effect, the inhibitory outcome for tumor growth has gained an over 10-fold improvement, realizing RF ablation & chemotherapy synergistic treatment against HeLa solid tumor, which indicates a significant promise in clinical RF ablation.

  6. NF-κB pathway activators as potential ageing biomarkers: targets for new therapeutic strategies

    PubMed Central

    2013-01-01

    Chronic inflammation is a major biological mechanism underpinning biological ageing process and age-related diseases. Inflammation is also the key response of host defense against pathogens and tissue injury. Current opinion sustains that during evolution the host defense and ageing process have become linked together. Thus, the large array of defense factors and mechanisms linked to the NF-κB system seem to be involved in ageing process. This concept leads us in proposing inductors of NF-κB signaling pathway as potential ageing biomarkers. On the other hand, ageing biomarkers, represented by biological indicators and selected through apposite criteria, should help to characterize biological age and, since age is a major risk factor in many degenerative diseases, could be subsequently used to identify individuals at high risk of developing age-associated diseases or disabilities. In this report, some inflammatory biomarkers will be discussed for a better understanding of the concept of biological ageing, providing ideas on eventual working hypothesis about potential targets for the development of new therapeutic strategies and improving, as consequence, the quality of life of elderly population. PMID:23786653

  7. An efficient antiviral strategy for targeting hepatitis B virus genome using transcription activator-like effector nucleases.

    PubMed

    Chen, Jieliang; Zhang, Wen; Lin, Junyu; Wang, Fan; Wu, Min; Chen, Cuncun; Zheng, Ye; Peng, Xiuhua; Li, Jianhua; Yuan, Zhenghong

    2014-02-01

    The hepatitis B virus (HBV) is a DNA virus that can cause chronic hepatitis B (CHB) in humans. Current therapies for CHB infection are limited in efficacy and do not target the pre-existing viral genomic DNA, which are present in the nucleus as a covalently closed circular DNA (cccDNA) form. The transcription activator-like (TAL) effector nucleases (TALENs) are newly developed enzymes that can cleave sequence-specific DNA targets. Here, TALENs targeting the conserved regions of the viral genomic DNA among different HBV genotypes were constructed. The expression of TALENs in Huh7 cells transfected with monomeric linear full-length HBV DNA significantly reduced the viral production of HBeAg, HBsAg, HBcAg, and pgRNA, resulted in a decreased cccDNA level and misrepaired cccDNAs without apparent cytotoxic effects. The anti-HBV effect of TALENs was further demonstrated in a hydrodynamic injection-based mouse model. In addition, an enhanced antiviral effect with combinations of TALENs and interferon-α (IFN-α) treatment was observed and expression of TALENs restored HBV suppressed IFN-stimulated response element-directed transcription. Taken together, these data indicate that TALENs can specifically target and successfully inactivate the HBV genome and are potently synergistic with IFN-α, thus providing a potential therapeutic strategy for treating CHB infection.

  8. Kras mutations increase telomerase activity and targeting telomerase is a promising therapeutic strategy for Kras-mutant NSCLC

    PubMed Central

    Shi, Bowen; Zhang, Lianmin; Qian, Dong; Li, Chenguang; Zhang, Hua; Wang, Shengguang; Zhu, Jinfang; Gao, Liuwei; Zhang, Qiang; Jia, Bin; Hao, Ligang; Wang, Changli; Zhang, Bin

    2017-01-01

    As shortened telomeres inhibit tumor formation and prolong life span in a KrasG12D mouse lung cancer model, we investigated the implications of telomerase in Kras-mutant NSCLC. We found that Kras mutations increased TERT (telomerase reverse transcriptase) mRNA expression and telomerase activity and telomere length in both immortalized bronchial epithelial cells (BEAS-2B) and lung adenocarcinoma cells (Calu-3). MEK inhibition led to reduced TERT expression and telomerase activity. Furthermore, telomerase inhibitor BIBR1532 shortened telomere length and inhibited mutant Kras-induced long-term proliferation, colony formation and migration capabilities of BEAS-2B and Calu-3 cells. Importantly, BIBR1532 sensitized oncogenic Kras expressing Calu-3 cells to chemotherapeutic agents. The Calu-3-KrasG12D xenograft mouse model confirmed that BIBR1532 enhanced the antitumor efficacy of paclitaxel in vivo. In addition, higher TERT expression was seen in Kras-mutant NSCLC than that with wild-type Kras. Our data suggest that Kras mutations increase telomerase activity and telomere length by activating the RAS/MEK pathway, which contributes to an aggressive phenotype of NSCLC. Kras mutations-induced lung tumorigenesis and chemoresistance are attenuated by telomerase inhibition. Targeting telomerase/telomere may be a promising therapeutic strategy for patients with Kras-mutant NSCLC. PMID:27329725

  9. Mapping calcium phosphate activated gene networks as a strategy for targeted osteoinduction of human progenitors in vitro and in vivo

    PubMed Central

    Eyckmans, J.; Roberts, S.J.; Bolander, J.; Schrooten, J.; Chen, C.S.; Luyten, F.P.

    2014-01-01

    Although calcium phosphate-containing biomaterials are promising scaffolds for bone regenerative strategies, the osteoinductive capacity of such materials is poorly understood. In this study, we investigated whether endogenous mechanisms of in vivo calcium phosphate-driven, ectopic bone formation could be identified and used to induce enhanced differentiation in vitro of the same progenitor population. To accomplish this, human periosteum derived cells (hPDCs) were seeded on hydroxyapatite/collagen scaffolds (calcium phosphate rich matrix or CPRM), or on decalcified scaffolds (calcium phosphate depleted matrix or CPDM), followed by subcutaneous implantation in nude mice to trigger ectopic bone formation. In this system, osteoblast differentiation occurred in CPRM scaffolds, but not in CPDM scaffolds. Gene expression was assessed by human full-genome microarray at 20 hours after seeding, and 2, 8 and 18 days after implantation. In both matrices, implantation of the cell constructs triggered a similar gene expression cascade, however, gene expression dynamics progressed faster in CPRM scaffolds than in CPDM scaffolds. The difference in gene expression dynamics was associated with differential activation of hub genes and molecular signaling pathways related to calcium signaling (CREB), inflammation (TNFα, NFkB, and IL6) and bone development (TGFβ, β-catenin, BMP, EGF, and ERK signaling). Starting from this set of pathways, a growth factor cocktail was developed that robustly enhanced osteogenesis in vitro and in vivo. Taken together, our data demonstrate that through the identification and subsequent stimulation of genes, proteins and signaling pathways associated with calcium phosphate mediated osteoinduction, a focused approach to develop targeted differentiation protocols in adult progenitor cells can be achieved. PMID:23537666

  10. Targeted Strategies for Henipavirus Therapeutics

    PubMed Central

    Bossart, Katharine N; Bingham, John; Middleton, Deborah

    2007-01-01

    Hendra and Nipah viruses are related emergent paramyxoviruses that infect and cause disease in animals and humans. Disease manifests as a generalized vasculitis affecting multiple organs, but is the most severe in the respiratory and central nervous systems. The high case fatality and person-to-person transmission associated with the most recent NiV outbreaks, and the recent re-emergence of HeV, emphasize the importance and necessity of effective therapeutics for these novel agents. In recent years henipavirus research has revealed a more complete understanding of pathogenesis and, as a consequence, viable approaches towards vaccines and therapeutics have emerged. All strategies target early steps in viral replication including receptor binding and membrane fusion. Animal models have been developed, some of which may prove more valuable than others for evaluating the efficacy of therapeutic agents and regimes. Assessments of protective host immunity and drug pharmacokinetics will be crucial to the further advancement of therapeutic compounds. PMID:19440455

  11. MALT1--a universal soldier: multiple strategies to ensure NF-κB activation and target gene expression.

    PubMed

    Afonina, Inna S; Elton, Lynn; Carpentier, Isabelle; Beyaert, Rudi

    2015-09-01

    The paracaspase MALT1 (mucosa associated lymphoid tissue lymphoma translocation gene 1) is an intracellular signaling protein that plays a key role in innate and adaptive immunity. It is essential for nuclear factor κB (NF-κB) activation and proinflammatory gene expression downstream of several cell surface receptors. MALT1 has been most studied in the context of T-cell receptor-induced NF-κB signaling, supporting T-cell activation and proliferation. In addition, MALT1 hyperactivation is associated with specific subtypes of B-cell lymphoma, where it controls tumor cell proliferation and survival. For a long time, MALT1 was believed to function solely as a scaffold protein, providing a platform for the assembly of other NF-κB signaling proteins. However, this view changed dramatically when MALT1 was found to have proteolytic activity that further fine-tunes signaling. MALT1 proteolytic activity is essential for T-cell activation and lymphomagenesis, suggesting that MALT1 is a promising therapeutic target for the treatment of autoimmune diseases and distinct lymphoma entities. However, interference with MALT1 activity may pose a dangerous threat to the normal functioning of the immune system and should be evaluated with great care. Here we discuss the current knowledge on the scaffold and protease functions of MALT1, including an overview of its substrates and the functional implications of their cleavage.

  12. Clinical and pharmacodynamic analysis of pomalidomide dosing strategies in myeloma: impact of immune activation and cereblon targets

    PubMed Central

    Sehgal, Kartik; Das, Rituparna; Zhang, Lin; Verma, Rakesh; Deng, Yanhong; Kocoglu, Mehmet; Vasquez, Juan; Koduru, Srinivas; Ren, Yan; Wang, Maria; Couto, Suzana; Breider, Mike; Hansel, Donna; Seropian, Stuart; Cooper, Dennis; Thakurta, Anjan; Yao, Xiaopan; Dhodapkar, Kavita M.

    2015-01-01

    In preclinical studies, pomalidomide mediated both direct antitumor effects and immune activation by binding cereblon. However, the impact of drug-induced immune activation and cereblon/ikaros in antitumor effects of pomalidomide in vivo is unknown. Here we evaluated the clinical and pharmacodynamic effects of continuous or intermittent dosing strategies of pomalidomide/dexamethasone in lenalidomide-refractory myeloma in a randomized trial. Intermittent dosing led to greater tumor reduction at the cost of more frequent adverse events. Both cohorts experienced similar event-free and overall survival. Both regimens led to a distinct pattern but similar degree of mid-cycle immune activation, manifested as increased expression of cytokines and lytic genes in T and natural killer (NK) cells. Pomalidomide induced poly-functional T-cell activation, with increased proportion of coinhibitory receptor BTLA+ T cells and Tim-3+ NK cells. Baseline levels of ikaros and aiolos protein in tumor cells did not correlate with response or survival. Pomalidomide led to rapid decline in Ikaros in T and NK cells in vivo, and therapy-induced activation of CD8+ T cells correlated with clinical response. These data demonstrate that pomalidomide leads to strong and rapid immunomodulatory effects involving both innate and adaptive immunity, even in heavily pretreated multiple myeloma, which correlates with clinical antitumor effects. This trial was registered at www.clinicaltrials.gov as #NCT01319422. PMID:25869284

  13. Combined active and passive immunization against nicotine: minimizing monoclonal antibody requirements using a target antibody concentration strategy.

    PubMed

    Cornish, Katherine E; Harris, Andrew C; LeSage, Mark G; Keyler, Dan E; Burroughs, Danielle; Earley, Cathy; Pentel, Paul R

    2011-11-01

    Nicotine vaccines have shown preliminary evidence of efficacy for enhancing smoking cessation rates, but the serum nicotine-specific antibody (NicAb) concentrations produced are highly variable and many subjects do not develop effective levels. As an alternative to vaccination, passive immunization with nicotine-specific monoclonal antibodies could produce more uniform serum NicAb concentrations, but its use is limited by their high cost and shorter elimination half-life. This study investigated supplementing vaccination with monoclonal antibodies in a targeted fashion to increase vaccine efficacy while minimizing the required monoclonal antibody dose. Rats were vaccinated and then given individualized supplemental doses of the nicotine-specific monoclonal antibody Nic311 to achieve a target total serum NicAb concentration known to be effective for blocking locomotor sensitization (LMS) to nicotine. Rats received vaccine, Nic311, both, or neither, followed by 0.3 mg/kg nicotine s.c. for 10 days to produce LMS. Combination immunotherapy completely blocked the development of LMS, while monotherapy with vaccine or Nic311 alone was only minimally effective. Lower brain nicotine levels were associated with reduced locomotor activity averaged over days 7-10. Despite its greater efficacy, combination immunotherapy did not reduce the variability in the resulting total serum NicAb concentrations. Variability in total serum NicAb concentrations was contributed to by both vaccine-generated antibody and by Nic311. These data show that combination immunotherapy, using a Nic311 dose that is by itself only minimally effective, can substantially enhance nicotine vaccine efficacy. However, variability in serum NicAb levels with combination immunotherapy may make translation of this approach challenging.

  14. Limiting the protein corona: A successful strategy for in vivo active targeting of anti-HER2 nanobody-functionalized nanostars.

    PubMed

    D'Hollander, Antoine; Jans, Hilde; Velde, Greetje Vande; Verstraete, Charlotte; Massa, Sam; Devoogdt, Nick; Stakenborg, Tim; Muyldermans, Serge; Lagae, Liesbet; Himmelreich, Uwe

    2017-04-01

    Gold nanoparticles hold great promise as anti-cancer theranostic agents against cancer by actively targeting the tumor cells. As this potential has been supported numerously during in vitro experiments, the effective application is hampered by our limited understanding and control of the interactions within complex in vivo biological systems. When these nanoparticles are exposed to a biological environment, their surfaces become covered with proteins and biomolecules, referred to as the protein corona, reducing the active targeting capabilities. We demonstrate a chemical strategy to overcome this issue by reducing the protein corona's thickness by blocking the active groups of the self-assembled monolayer on gold nanostars. An optimal blocking agent, 2-mercapto ethanol, has been selected based on charge and length of the carbon chain. By using a nanobody as a biological ligand of the human epidermal growth factor 2 receptor (HER2), the active targeting is demonstrated in vitro and in vivo in an experimental tumor model by using darkfield microscopy and photoacoustic imaging. In this study, we have established gold nanostars as a conceivable theranostic agent with a specificity for HER2-positive tumors.

  15. Target marketing strategies for occupational therapy entrepreneurs.

    PubMed

    Kautzmann, L N; Kautzmann, F N; Navarro, F H

    1989-01-01

    Understanding marketing techniques is one of the skills needed by successful entre renews. Target marketing is an effective method for occupational therapy entrepreneurs to use in determining when and where to enter the marketplace. The two components of target marketing, market segmentation and the development of marketing mix strategies for each identified market segment, are described. The Profife of Attitudes Toward Health Care (PATH) method of psychographic market segmentation of health care consumers is presented. Occupational therapy marketing mix strategies for each PATH consumer group are delineated and compatible groupings of market segments are suggested.

  16. A Novel Tumor-Activated Prodrug Strategy Targeting Ferrous Iron Is Effective in Multiple Preclinical Cancer Models

    PubMed Central

    2016-01-01

    Here we describe a new approach for tumor targeting in which augmented concentrations of Fe(II) in cancer cells and/or the tumor microenvironment triggers drug release from an Fe(II)-reactive prodrug conjugate. The 1,2,4-trioxolane scaffold developed to enable this approach can in principle be applied to a broad range of cancer therapeutics and is illustrated here with Fe(II)-targeted forms of a microtubule toxin and a duocarmycin-class DNA-alkylating agent. We show that the intrinsic reactivity/toxicity of the duocarmycin analog is masked in the conjugated form and this greatly reduced toxicity in mice. This in turn permitted elevated dosing levels, leading to higher systemic exposure and a significantly improved response in tumor xenograft models. Overall our results suggest that Fe(II)-dependent drug delivery via trioxolane conjugates could have significant utility in expanding the therapeutic index of a range of clinical and preclinical stage cancer chemotherapeutics. PMID:27936709

  17. Targeting Signal Transducers and Activators of Transcription-3 (Stat3) As a Novel Strategy In Sensitizing Breast Cancer To Egfr-Targeted Therapy

    DTIC Science & Technology

    2008-06-01

    transition of the epithelial to the mesenchymal -like phenotype in cultured breast cancer cells . Cancer cells of epithelial origin undergo EMT as...induce epithelial mesenchymal transition by activating expression of TWIST, an E-cadherin repressor. In breast cancer cells with high levels of EGFR...expressing cancer cells to undergo a transition from the epithelial to the spindle-like

  18. Target discrimination strategies in optics detection

    NASA Astrophysics Data System (ADS)

    Sjöqvist, Lars; Allard, Lars; Henriksson, Markus; Jonsson, Per; Pettersson, Magnus

    2013-10-01

    Detection and localisation of optical assemblies used for weapon guidance or sniper rifle scopes has attracted interest for security and military applications. Typically a laser system is used to interrogate a scene of interest and the retro-reflected radiation is detected. Different system approaches for area coverage can be realised ranging from flood illumination to step-and-stare or continuous scanning schemes. Independently of the chosen approach target discrimination is a crucial issue, particularly if a complex scene such as in an urban environment and autonomous operation is considered. In this work target discrimination strategies in optics detection are discussed. Typical parameters affecting the reflected laser radiation from the target are the wavelength, polarisation properties, temporal effects and the range resolution. Knowledge about the target characteristics is important to predict the target discrimination capability. Two different systems were used to investigate polarisation properties and range resolution information from targets including e.g. road signs, optical reflexes, rifle sights and optical references. The experimental results and implications on target discrimination will be discussed. If autonomous operation is required target discrimination becomes critical in order to reduce the number of false alarms.

  19. Biocomputational strategies for microbial drug target identification.

    PubMed

    Sakharkar, Kishore R; Sakharkar, Meena K; Chow, Vincent T K

    2008-01-01

    The complete genome sequences of about 300 bacteria (mostly pathogenic) have been determined, and many more such projects are currently in progress. The detection of bacterial genes that are non-homologous to human genes and are essential for the survival of the pathogen represent a promising means of identifying novel drug targets. We present a subtractive genomics approach for the identification of putative drug targets in microbial genomes and demonstrate its execution using Pseudomonas aeruginosa as an example. The resultant analyses are in good agreement with the results of systematic gene deletion experiments. This strategy enables rapid potential drug target identification, thereby greatly facilitating the search for new antibiotics. It should be recognized that there are limitations to this computational approach for drug target identification. Distant gene relationships may be missed since the alignment scores are likely to have low statistical significance. In conclusion, the results of such a strategy underscore the utility of large genomic databases for in silico systematic drug target identification in the post-genomic era.

  20. FGFR3 targeting strategies for achondroplasia.

    PubMed

    Laederich, Melanie B; Horton, William A

    2012-01-19

    Mutations that exaggerate signalling of the receptor tyrosine kinase fibroblast growth factor receptor 3 (FGFR3) give rise to achondroplasia, the most common form of dwarfism in humans. Here we review the clinical features, genetic aspects and molecular pathogenesis of achondroplasia and examine several therapeutic strategies designed to target the mutant receptor or its signalling pathways, including the use of kinase inhibitors, blocking antibodies, physiologic antagonists, RNAi and chaperone inhibitors. We conclude by discussing the challenges of treating growth plate disorders in children.

  1. Therapeutic strategies targeting cancer stem cells

    PubMed Central

    Ning, Xiaoyan; Shu, Jianchang; Du, Yiqi; Ben, Qiwen; Li, Zhaoshen

    2013-01-01

    Increasing studies have demonstrated a small proportion of cancer stem cells (CSCs) exist in the cancer cell population. CSCs have powerful self-renewal capacity and tumor-initiating ability and are resistant to chemotherapy and radiation. Conventional anticancer therapies kill the rapidly proliferating bulk cancer cells but spare the relatively quiescent CSCs, which cause cancer recurrence. So it is necessary to develop therapeutic strategies acting specifically on CSCs. In recent years, studies have shown that therapeutic agents such as metformin, salinomycin, DECA-14, rapamycin, oncostatin M (OSM), some natural compounds, oncolytic viruses, microRNAs, cell signaling pathway inhibitors, TNF-related apoptosis inducing ligand (TRAIL), interferon (IFN), telomerase inhibitors, all-trans retinoic acid (ATRA) and monoclonal antibodies can suppress the self-renewal of CSCs in vitro and in vivo. A combination of these agents and conventional chemotherapy drugs can significantly inhibit tumor growth, metastasis and recurrence. These strategies targeting CSCs may bring new hopes to cancer therapy. PMID:23358473

  2. Targeted proteomic strategy for clinical biomarker discovery.

    PubMed

    Schiess, Ralph; Wollscheid, Bernd; Aebersold, Ruedi

    2009-02-01

    The high complexity and large dynamic range of blood plasma proteins currently prohibit the sensitive and high-throughput profiling of disease and control plasma proteome sample sets large enough to reliably detect disease indicating differences. To circumvent these technological limitations we describe here a new two-stage strategy for the mass spectrometry (MS) assisted discovery, verification and validation of disease biomarkers. In an initial discovery phase N-linked glycoproteins with distinguishable expression patterns in primary normal and diseased tissue are detected and identified. In the second step the proteins identified in the initial phase are subjected to targeted MS analysis in plasma samples, using the highly sensitive and specific selected reaction monitoring (SRM) technology. Since glycosylated proteins, such as those secreted or shed from the cell surface are likely to reside and persist in blood, the two-stage strategy is focused on the quantification of tissue derived glycoproteins in plasma. The focus on the N-glycoproteome not only reduces the complexity of the analytes, but also targets an information-rich subproteome which is relevant for remote sensing of diseases in the plasma. The N-glycoprotein based biomarker discovery and validation workflow reviewed here allows for the robust identification of protein candidate panels that can finally be selectively monitored in the blood plasma at high sensitivity in a reliable, non-invasive and quantitative fashion.

  3. Dual targeting strategy of magnetic nanoparticle-loaded and RGD peptide-activated stimuli-sensitive polymeric micelles for delivery of paclitaxel

    NASA Astrophysics Data System (ADS)

    Lin, Meng Meng; Kang, Yoon Joong; Sohn, Youngjoo; Kim, Do Kyung

    2015-06-01

    A double targeting strategy of anti-neoplastic agent paclitaxel (PTX) was developed by incorporating magnetic nanoparticles and RGD peptide for enhanced cell cytotoxicity effect at lower dosage. A dual targeting mechanism including magnetic targeting and RGD ligand-specific targeting enhanced the overall cytotoxicity and reduced the effective dosage of PTX to achieve enhanced and sustained release of PTX in vitro. We addressed the issues of water-insolubility of oleic acid (OA)-stabilized SPIONs and low incorporation efficiency of hydrophobic PTX with SPION nanocarriers by using an amphiphilic polymer poly[( N-isopropylacrylamide-r-acrylamide)-b- l-lactic acid] (PNAL) as micelle-forming materials. A targeting moiety, GGGGRGD peptide, a RGD sequence-containing peptide with a short linker, is attached to the surface of PNAL-SPIONs via a homo-crosslinker. Confocal microscopy image analysis revealed that the cellular uptake was increased from (1.5 ± 0.5 % (PNAL) to 11.7 ± 0.8 % (RGD-PNAL-SPIONs) at 6 h incubation, once both RGD peptide and magnetic force attraction were incorporated into the carriers. Such multi-targeting nanocarriers showed promising potential in cancer-oriented diagnosis and therapy.

  4. Strategy as active waiting.

    PubMed

    Sull, Donald N

    2005-09-01

    Successful executives who cut their teeth in stable industries or in developed countries often stumble when they face more volatile markets. They falter, in part, because they assume they can gaze deep into the future and develop a long-term strategy that will confer a sustainable competitive advantage. But visibility into the future of volatile markets is sharply limited because so many different variables are in play. Factors such as technological innovation, customers' evolving needs, government policy, and changes in the capital markets interact with one another to create unexpected outcomes. Over the past six years, Donald Sull, an associate professor at London Business School, has led a research project examining some of the world's most volatile markets, from national markets like China and Brazil to industries like enterprise software, telecommunications, and airlines. One of the most striking findings from this research is the importance of taking action during comparative lulls in the storm. Huge business opportunities are relatively rare; they come along only once or twice in a decade. And, for the most part, companies can't manufacture those opportunities; changes in the external environment converge to make them happen. What managers can do is prepare for these golden opportunities by managing smart during the comparative calm of business as usual. During these periods of active waiting, leaders must probe the future and remain alert to anomalies that signal potential threats or opportunities; exercise restraint to preserve their war chests; and maintain discipline to keep the troops battle ready. When a golden opportunity or"sudden death"threat emerges, managers must have the courage to declare the main effort and concentrate resources to seize the moment.

  5. Pharmacological strategies to target oncogenic KRAS signaling in pancreatic cancer.

    PubMed

    Chuang, Hsiao-Ching; Huang, Po-Hsien; Kulp, Samuel K; Chen, Ching-Shih

    2017-03-01

    The clear importance of mutated KRAS as a therapeutic target has driven the investigation of multiple approaches to inhibit oncogenic KRAS signaling at different molecular levels. However, no KRAS-targeted therapy has reached the clinic to date, which underlies the intrinsic difficulty in developing effective, direct inhibitors of KRAS. Thus, this article provides an overview of the history and recent progress in the development of pharmacological strategies to target oncogenic KRAS with small molecule agents. Mechanistically, these KRAS-targeted agents can be classified into the following four categories. (1) Small-molecule RAS-binding ligands that prevent RAS activation by binding within or outside the nucleotide-binding motif. (2) Inhibitors of KRAS membrane anchorage. (3) Inhibitors that bind to RAS-binding domains of RAS-effector proteins. (4) Inhibitors of KRAS expression. The advantage and limitation of each type of these anti-KRAS agents are discussed.

  6. Significance of targeting polyamine metabolism as an antineoplastic strategy: unique targets for polyamine analogues.

    PubMed

    Casero, Robert A; Frydman, Benjamin; Stewart, Tracy Murray; Woster, Patrick M

    2005-01-01

    The polyamines, putrescine, spermidine, and spermine, are naturally occurring polycationic alkylamines that are absolutely required for eukaryotic cell growth. Importantly, the polyamine metabolic pathway, as well as the requirement of polyamines for cell growth, is frequently dysregulated in cancer cells, thus providing a unique set of targets for therapeutic intervention. Ornithine decarboxylase (ODC), a rate-limiting enzyme in polyamine biosynthesis, is frequently up-regulated in preneoplastic cells, and has been implicated as an oncogene in multiple tumor types. Several model systems have demonstrated that inhibition of ODC's enzymatic activity and down-regulation of its expression are rational strategies for both chemotherapy and chemoprevention. Specific inhibitors of ODC, most notably 2-difluoromethylornithine (DFMO), have been used experimentally to validate polyamine metabolism as an antineoplastic strategy. However, multiple biochemical and clinical limitations to these ODC-targeting strategies minimize their value as therapeutic tools. Included among these limitations are poor bioavailability of the inhibitor, and the compensatory up-regulation of polyamine metabolism and transport that allow tumor cells to escape the growth inhibitory effects of blockers specifically targeting ODC. As a strategy to overcome the limitations of direct enzyme inhibition, several groups have pursued the design of polyamine analogues that specifically target the dysregulated polyamine metabolism found in tumors. These analogues have been developed specifically to target the specific polyamine transporter, thus competing with circulating natural polyamines. Additionally, most of the analogues examined thus far maintain the regulatory function of the natural polyamines, but are unable to functionally substitute for them in promoting growth. Specifically, individual analogues have demonstrated the ability to down-regulate each of the biosynthetic enzymes without causing

  7. 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.

  8. Paramyxovirus evasion of innate immunity: Diverse strategies for common targets

    PubMed Central

    Audsley, Michelle D; Moseley, Gregory W

    2013-01-01

    The paramyxoviruses are a family of > 30 viruses that variously infect humans, other mammals and fish to cause diverse outcomes, ranging from asymptomatic to lethal disease, with the zoonotic paramyxoviruses Nipah and Hendra showing up to 70% case-fatality rate in humans. The capacity to evade host immunity is central to viral infection, and paramyxoviruses have evolved multiple strategies to overcome the host interferon (IFN)-mediated innate immune response through the activity of their IFN-antagonist proteins. Although paramyxovirus IFN antagonists generally target common factors of the IFN system, including melanoma differentiation associated factor 5, retinoic acid-inducible gene-I, signal transducers and activators of transcription (STAT)1 and STAT2, and IFN regulatory factor 3, the mechanisms of antagonism show remarkable diversity between different genera and even individual members of the same genus; the reasons for this diversity, however, are not currently understood. Here, we review the IFN antagonism strategies of paramyxoviruses, highlighting mechanistic differences observed between individual species and genera. We also discuss potential sources of this diversity, including biological differences in the host and/or tissue specificity of different paramyxoviruses, and potential effects of experimental approaches that have largely relied on in vitro systems. Importantly, recent studies using recombinant virus systems and animal infection models are beginning to clarify the importance of certain mechanisms of IFN antagonism to in vivo infections, providing important indications not only of their critical importance to virulence, but also of their potential targeting for new therapeutic/vaccine approaches. PMID:24175230

  9. Student Target Marketing Strategies for Universities

    ERIC Educational Resources Information Center

    Lewison, Dale M.; Hawes, Jon M.

    2007-01-01

    As colleges and universities adopt marketing orientations to an ever-increasing extent, the relative merits of mass marketing and target marketing must also be explored. Researchers identify buyer types as potential students focused on quality, value or economy. On the other axis, learner types are described as those who focus on career,…

  10. Molecular Strategies for Targeting Antioxidants to Mitochondria: Therapeutic Implications

    PubMed Central

    2015-01-01

    Abstract Mitochondrial function and specifically its implication in cellular redox/oxidative balance is fundamental in controlling the life and death of cells, and has been implicated in a wide range of human pathologies. In this context, mitochondrial therapeutics, particularly those involving mitochondria-targeted antioxidants, have attracted increasing interest as potentially effective therapies for several human diseases. For the past 10 years, great progress has been made in the development and functional testing of molecules that specifically target mitochondria, and there has been special focus on compounds with antioxidant properties. In this review, we will discuss several such strategies, including molecules conjugated with lipophilic cations (e.g., triphenylphosphonium) or rhodamine, conjugates of plant alkaloids, amino-acid- and peptide-based compounds, and liposomes. This area has several major challenges that need to be confronted. Apart from antioxidants and other redox active molecules, current research aims at developing compounds that are capable of modulating other mitochondria-controlled processes, such as apoptosis and autophagy. Multiple chemically different molecular strategies have been developed as delivery tools that offer broad opportunities for mitochondrial manipulation. Additional studies, and particularly in vivo approaches under physiologically relevant conditions, are necessary to confirm the clinical usefulness of these molecules. Antioxid. Redox Signal. 22, 686–729. PMID:25546574

  11. Economic Sanctions Targeting Yugoslavia - An Effective National Security Strategy Component

    DTIC Science & Technology

    2006-05-31

    USAWC STRATEGY RESEARCH PROJECT Economic Sanctions Targeting Yugoslavia – An Effective National Security Strategy Component by COL Charles J. Kacsur...Jr. U.S. Army Dr. Clayton K. S. Chun Project Advisor The views expressed in this academic research paper are those of the author and do not...National Security Strategy Component 5a. CONTRACT NUMBER 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) Charles Kacsur; 5d. PROJECT

  12. Macrophage Targeted Theranostics as Personalized Nanomedicine Strategies for Inflammatory Diseases

    PubMed Central

    Patel, Sravan Kumar; Janjic, Jelena M.

    2015-01-01

    Inflammatory disease management poses challenges due to the complexity of inflammation and inherent patient variability, thereby necessitating patient-specific therapeutic interventions. Theranostics, which integrate therapeutic and imaging functionalities, can be used for simultaneous imaging and treatment of inflammatory diseases. Theranostics could facilitate assessment of safety, toxicity and real-time therapeutic efficacy leading to personalized treatment strategies. Macrophages are an important cellular component of inflammatory diseases, participating in varied roles of disease exacerbation and resolution. The inherent phagocytic nature, abundance and disease homing properties of macrophages can be targeted for imaging and therapeutic purposes. This review discusses the utility of theranostics in macrophage ablation, phenotype modulation and inhibition of their inflammatory activity leading to resolution of inflammation in several diseases. PMID:25553105

  13. Mast Cell-Targeted Strategies in Cancer Therapy

    PubMed Central

    Ammendola, Michele; Sacco, Rosario; Sammarco, Giuseppe; Luposella, Maria; Patruno, Rosa; Gadaleta, Cosmo Damiano; Sarro, Giovambattista De; Ranieri, Girolamo

    2016-01-01

    Summary Mast cells (MCs) are cells that originate in the bone marrow from pluripotent CD34+ hematopoietic stem cells. Precursors of MCs migrate through the circulation to their target tissues, completing their maturation process into granulated cells under the influence of several microenvironment growth factors. The most important of these factors is the ligand for the c-Kit receptor (c-Kit-R) namely stem cell factor (SCF), secreted mainly by fibroblasts and endothelial cells (ECs). SCF also regulates development, survival and de novo proliferation of MCs. It has already been demonstrated that gain-of-function mutations of gene c-Kit encoding c-Kit-R result in the development of some tumors. Furthermore, MCs are able also to modulate both innate and adaptive immune response and to express the high-affinity IgE receptor following IgE activation. Among the other IgE-independent MC activation mechanisms, a wide variety of other surface receptors for cytokines, chemokines, immunoglobulins, and complement are also described. Interestingly, MCs can stimulate angiogenesis by releasing of several pro-angiogenic cytokines stored in their cytoplasm. Studies published in the last year suggest that angiogenesis stimulated by MCs may play an important role in tumor growth and progression. Here, we aim to focus several biological features of MCs and to summarize new anti-cancer MC-targeted strategies with potential translation in human clinical trials. PMID:27330532

  14. Deterministic optimal maneuver strategy for multi-target missions

    NASA Technical Reports Server (NTRS)

    Dwivedi, N. P.

    1975-01-01

    This paper presents an optimal strategy for making impulsive correction to a multi-target trajectory by a single maneuver. The concept of an optimal maneuver time is introduced. The choice of suitable weighting functions is explored to enable one to properly translate the subjective desire of mission success into an objective cost function whose minimization yields the optimal strategy. It is shown that a number of strategies previously formulated are derivable from one general expression. A number of other interesting properties of the optimal strategy are described. Numerical results are presented for a typical two-target mission. It is shown that the strategy formulated is optimal. For some perturbations, there exists an optimal maneuver time different from the time of initiation of the perturbation. That is, the physical properties of the trajectory can be exploited to select the optimal time of making a corrective maneuver.

  15. A novel prostate cancer therapeutic strategy using icaritin-activated arylhydrocarbon-receptor to co-target androgen receptor and its splice variants

    PubMed Central

    Sun, Feng; Indran, Inthrani R.; Zhang, Zhi Wei; Tan, M.H.Eileen; Li, Yu; Lim, Z.L.Ryan; Hua, Rui; Yang, Chong; Soon, Fen-Fen; Li, Jun; Xu, H.Eric; Cheung, Edwin; Yong, Eu-Leong

    2015-01-01

    Persistent androgen receptor (AR) signaling is the key driving force behind progression and development of castration-resistant prostate cancer (CRPC). In many patients, AR COOH-terminal truncated splice variants (ARvs) play a critical role in contributing to the resistance against androgen depletion therapy. Unfortunately, clinically used antiandrogens like bicalutamide (BIC) and enzalutamide (MDV), which target the ligand binding domain, have failed to suppress these AR variants. Here, we report for the first time that a natural prenylflavonoid, icaritin (ICT), can co-target both persistent AR and ARvs. ICT was found to inhibit transcription of key AR-regulated genes, such as KLK3 [prostate-specific antigen (PSA)] and ARvs-regulated genes, such as UBE2C and induce apoptosis in AR-positive prostate cancer (PC) cells. Mechanistically, ICT promoted the degradation of both AR and ARvs by binding to arylhydrocarbon-receptor (AhR) to mediate ubiquitin-proteasomal degradation. Therefore, ICT impaired AR transactivation in PC cells. Knockdown of AhR gene restored AR stability and partially prevented ICT-induced growth suppression. In clinically relevant murine models orthotopically implanted with androgen-sensitive and CRPC cells, ICT was able to target AR and ARvs, to inhibit AR signaling and tumor growth with no apparent toxicity. Our results provide a mechanistic framework for the development of ICT, as a novel lead compound for AR-positive PC therapeutics, especially for those bearing AR splice variants. PMID:25908644

  16. Targeting transcription factor activity as a strategy to inhibit pro-inflammatory genes involved in cystic fibrosis: decoy oligonucleotides and low-molecular weight compounds.

    PubMed

    Cabrini, G; Bezzerri, V; Mancini, I; Nicolis, E; Dechecchi, M C; Tamanini, A; Lampronti, I; Piccagli, L; Bianchi, N; Borgatti, M; Gambari, R

    2010-01-01

    The development of drugs able to inhibit the expression of pro-inflammatory genes is of great interest in the treatment of cystic fibrosis (CF). Chronic pulmonary inflammation in the lungs of patients affected by CF is characterized by massive intra-bronchial infiltrates of neutrophils. This process is initiated upon interaction of pathogens (including Pseudomonas aeruginosa) with surface bronchial cells. Consequently, they release cytokines, the most represented being the potent neutrophilic chemokine Interleukin (IL)-8 and the pro-inflammatory cytokine IL-6. The chronic inflammatory process is crucial, since it leads to progressive tissue damage and severe respiratory insufficiency. In order to reduce the adverse effects of the excessive inflammatory response, one of the approaches leading to inhibition of IL-8 and IL-6 gene expression is the transcription factor (TF) decoy approach, based on intracellular delivery of double stranded oligodeoxynucleotides (ODNs) mimicking the binding sites of TFs and causing inhibition of binding of TF-related proteins to regulatory sequences identified in the promoters of specific genes. Since the promoters of IL-8 and IL-6 contain consensus sequences for NF-κ B and Sp1, double stranded TF "decoy" ODNs targeting NF-κB and Sp1 can be used. Alternatively, screening of drugs targeting relevant TFs can be performed using drug cocktails constituted by extracts from medicinal plants inhibiting TF/DNA interactions. Finally, virtual screening might lead to identification of putative bioactive molecules to be validated using molecular and cellular approaches. By these means, low-molecular drugs targeting NF-κB and inhibiting IL-8 gene expression are available for pre-clinical testing using experimental systems recapitulating chronic pulmonary inflammation of patients affected by CF.

  17. Control strategy of hand movement depends on target redundancy

    PubMed Central

    Togo, Shunta; Yoshioka, Toshinori; Imamizu, Hiroshi

    2017-01-01

    Reaching toward a point target has been intensively studied in human motor control. However, little is known about reaching toward a redundant target, such as grasping a bar, in which the grasping point is irrelevant to the achievement of a task. We examined whether humans could solve the target-redundancy and control problems in a serial fashion or control their body without solving the target-redundancy problem. We equalized the target ranges between two reaching tasks: a point-to-point reaching task without target-redundancy and a point-to-bar reaching task with target-redundancy. In the both tasks, we measured hand viscoelasticity at movement end as parameters that reflect the adopted control strategy. As a result, the hand viscoelasticity in the point-to-bar reaching task was smaller than that in the point-to-point reaching task, even under the same kinematics. These results indicate that the hand viscoelasticity was modulated depending on the target-redundancy. Moreover, it is suggested that a human reaches toward a redundant target by effectively utilizing information of target redundancy rather than explicitly solving the target-redundancy problem. PMID:28361888

  18. The Expression of a Xylanase Targeted to ER-Protein Bodies Provides a Simple Strategy to Produce Active Insoluble Enzyme Polymers in Tobacco Plants

    PubMed Central

    Llop-Tous, Immaculada; Ortiz, Miriam; Torrent, Margarita; Ludevid, M. Dolors

    2011-01-01

    Background Xylanases deserve particular attention due to their potential application in the feed, pulp bleaching and paper industries. We have developed here an efficient system for the production of an active xylanase in tobacco plants fused to a proline-rich domain (Zera) of the maize storage protein γ-zein. Zera is a self-assembling domain able to form protein aggregates in vivo packed in newly formed endoplasmic reticulum-derived organelles known as protein bodies (PBs). Methodology/Principal Findings Tobacco leaves were transiently transformed with a binary vector containing the Zera-xylanase coding region, which was optimized for plant expression, under the control of the 35S CaMV promoter. The fusion protein was efficiently expressed and stored in dense PBs, resulting in yields of up to 9% of total protein. Zera-xylanase was post-translationally modified with high-mannose-type glycans. Xylanase fused to Zera was biologically active not only when solubilized from PBs but also in its insoluble form. The resistance of insoluble Zera-xylanase to trypsin digestion demonstrated that the correct folding of xylanase in PBs was not impaired by Zera oligomerization. The activity of insoluble Zera-xylanase was enhanced when substrate accessibility was facilitated by physical treatments such as ultrasound. Moreover, we found that the thermostability of the enzyme was improved when Zera was fused to the C-terminus of xylanase. Conclusion/Significance In the present work we have successfully produced an active insoluble aggregate of xylanase fused to Zera in plants. Zera-xylanase chimeric protein accumulates within ER-derived protein bodies as active aggregates that can easily be recovered by a simple density-based downstream process. The production of insoluble active Zera-xylanase protein in tobacco outlines the potential of Zera as a fusion partner for producing enzymes of biotechnological relevance. Zera-PBs could thus become efficient and low-cost bioreactors for

  19. High efficiency cell-specific targeting of cytokine activity

    NASA Astrophysics Data System (ADS)

    Garcin, Geneviève; Paul, Franciane; Staufenbiel, Markus; Bordat, Yann; van der Heyden, José; Wilmes, Stephan; Cartron, Guillaume; Apparailly, Florence; de Koker, Stefaan; Piehler, Jacob; Tavernier, Jan; Uzé, Gilles

    2014-01-01

    Systemic toxicity currently prevents exploiting the huge potential of many cytokines for medical applications. Here we present a novel strategy to engineer immunocytokines with very high targeting efficacies. The method lies in the use of mutants of toxic cytokines that markedly reduce their receptor-binding affinities, and that are thus rendered essentially inactive. Upon fusion to nanobodies specifically binding to marker proteins, activity of these cytokines is selectively restored for cell populations expressing this marker. This ‘activity-by-targeting’ concept was validated for type I interferons and leptin. In the case of interferon, activity can be directed to target cells in vitro and to selected cell populations in mice, with up to 1,000-fold increased specific activity. This targeting strategy holds promise to revitalize the clinical potential of many cytokines.

  20. Telomeres and telomerase: Pharmacological targets for new anticancer strategies?

    PubMed

    Pendino, F; Tarkanyi, I; Dudognon, C; Hillion, J; Lanotte, M; Aradi, J; Ségal-Bendirdjian, E

    2006-03-01

    Telomeres are located at the ends of eukaryotic chromosomes. Human telomerase, a cellular reverse transcriptase, is a ribonucleoprotein enzyme that catalyzes the synthesis and extension of telomeric DNA. It is composed of at least, a template RNA component (hTR; human Telomerase RNA) and a catalytic subunit, the telomerase reverse transcriptase (hTERT). The absence of telomerase is associated with telomere shortening and aging of somatic cells, while high telomerase activity is observed in over 85% of human cancer cells, strongly indicating its key role during tumorigenesis. Several details regarding telomere structure and telomerase regulation have already been elucidated, providing new targets for therapeutic exploitation. Further support for anti-telomerase approaches comes from recent studies indicating that telomerase is endowed of additional functions in the control of growth and survival of tumor cells that do not depend only on the ability of this enzyme to maintain telomere length. This observation suggests that inhibiting telomerase or its synthesis may have additional anti-proliferative and apoptosis inducing effect, independently of the reduction of telomere length during cell divisions. This article reviews the basic information about the biology of telomeres and telomerase and attempts to present various approaches that are currently under investigation to inhibit its expression and its activity. We summarize herein distinct anti-telomerase approaches like antisense strategies, reverse transcriptase inhibitors, and G-quadruplex interacting agents, and also review molecules targeting hTERT expression, such as retinoids and evaluate them for their therapeutic potential. "They conceive a certain theory, and everything has to fit into that theory. If one little fact will not fit it, they throw it aside. But it is always the facts that will not fit in that are significant". "Death on the Nile". Agatha Christie.

  1. Targeting SOX2 as a Therapeutic Strategy in Glioblastoma

    PubMed Central

    Garros-Regulez, Laura; Garcia, Idoia; Carrasco-Garcia, Estefania; Lantero, Aquilino; Aldaz, Paula; Moreno-Cugnon, Leire; Arrizabalaga, Olatz; Undabeitia, Jose; Torres-Bayona, Sergio; Villanua, Jorge; Ruiz, Irune; Egaña, Larraitz; Sampron, Nicolas; Matheu, Ander

    2016-01-01

    Glioblastoma is the most common and malignant brain cancer in adults. Current therapy consisting of surgery followed by radiation and temozolomide has a moderate success rate and the tumor reappears. Among the features that a cancer cell must have to survive the therapeutic treatment and reconstitute the tumor is the ability of self-renewal. Therefore, it is vital to identify the molecular mechanisms that regulate this activity. Sex-determining region Y (SRY)-box 2 (SOX2) is a transcription factor whose activity has been associated with the maintenance of the undifferentiated state of cancer stem cells in several tissues, including the brain. Several groups have detected increased SOX2 levels in biopsies of glioblastoma patients, with the highest levels associated with poor outcome. Therefore, SOX2 silencing might be a novel therapeutic approach to combat cancer and particularly brain tumors. In this review, we will summarize the current knowledge about SOX2 in glioblastoma and recapitulate several strategies that have recently been described targeting SOX2 in this malignancy. PMID:27822457

  2. Targeting melanocortin receptors as a novel strategy to control inflammation.

    PubMed

    Catania, Anna; Gatti, Stefano; Colombo, Gualtiero; Lipton, James M

    2004-03-01

    Adrenocorticotropic hormone and alpha-, beta-, and gamma-melanocyte-stimulating hormones, collectively called melanocortin peptides, exert multiple effects upon the host. These effects range from modulation of fever and inflammation to control of food intake, autonomic functions, and exocrine secretions. Recognition and cloning of five melanocortin receptors (MCRs) has greatly improved understanding of peptide-target cell interactions. Preclinical investigations indicate that activation of certain MCR subtypes, primarily MC1R and MC3R, could be a novel strategy to control inflammatory disorders. As a consequence of reduced translocation of the nuclear factor kappaB to the nucleus, MCR activation causes a collective reduction of the major molecules involved in the inflammatory process. Therefore, anti-inflammatory influences are broad and are not restricted to a specific mediator. Short half-life and lack of selectivity could be an obstacle to the use of the natural melanocortins. However, design and synthesis of new MCR ligands with selective chemical properties are already in progress. This review examines how marshaling MCR could control inflammation.

  3. Strategies that Target Leukocyte Traffic in IBD: Recent Developments

    PubMed Central

    Rivera-Nieves, Jesús

    2015-01-01

    Purpose of review We review the most recent developments regarding the targeting of molecules involved in the traffic of leukocytes for the treatment of IBD. Recent Findings We discuss the most important findings of one published phase II trial that targeted the β7 integrin (Etrolizumab), two phase II trials that targeted the α4β7 integrin ligand: Mucosal Addressin Cell Adhesion Molecule-1 (MAdCAM-1, PF-00547659), a phase II targeting the chemokine IP-10 (CXCL10) in Crohn’s and a phase II trial that targeted the sphingosine-1-phosphate receptor-1 (S1P1): ozanimod in patients with ulcerative colitis (UC). Summary Targeting molecules involved in leukocyte traffic has recently become an effective and safe strategy for the treatment of IBD. Novel approaches now not only target the integrins on the lymphocyte surface, but also its endothelial ligand: MAdCAM-1. As with vedolizumab, antibodies against MAdCAM-1 appear most effective in ulcerative colitis rather than in Crohn’s. Targeting chemokines or their receptors does not appear to have the same efficacy as those that target the most stable integrin:immunoglobulin superfamily interactions between the lymphocyte and endothelium. Preliminary results also suggest that the sphingosine-1-phosphate pathway might also be targeted therapeutically in IBD, no longer with parenterally administered antibodies but with orally administered small molecules. PMID:26398681

  4. Active Targets For Capacitive Proximity Sensors

    NASA Technical Reports Server (NTRS)

    Jenstrom, Del T.; Mcconnell, Robert L.

    1994-01-01

    Lightweight, low-power active targets devised for use with improved capacitive proximity sensors described in "Capacitive Proximity Sensor Has Longer Range" (GSC-13377), and "Capacitive Proximity Sensors With Additional Driven Shields" (GSC-13475). Active targets are short-distance electrostatic beacons; they generate known alternating electro-static fields used for alignment and/or to measure distances.

  5. Targeting Strategies for Multifunctional Nanoparticles in Cancer Imaging and Therapy

    PubMed Central

    Yu, Mi Kyung; Park, Jinho; Jon, Sangyong

    2012-01-01

    Nanomaterials offer new opportunities for cancer diagnosis and treatment. Multifunctional nanoparticles harboring various functions including targeting, imaging, therapy, and etc have been intensively studied aiming to overcome limitations associated with conventional cancer diagnosis and therapy. Of various nanoparticles, magnetic iron oxide nanoparticles with superparamagnetic property have shown potential as multifunctional nanoparticles for clinical translation because they have been used asmagnetic resonance imaging (MRI) constrast agents in clinic and their features could be easily tailored by including targeting moieties, fluorescence dyes, or therapeutic agents. This review summarizes targeting strategies for construction of multifunctional nanoparticles including magnetic nanoparticles-based theranostic systems, and the various surface engineering strategies of nanoparticles for in vivo applications. PMID:22272217

  6. Stakeholder analysis and mapping as targeted communication strategy.

    PubMed

    Shirey, Maria R

    2012-09-01

    This department highlights change management strategies that may be successful in strategically planning and executing organizational change initiatives. With the goal of presenting practical approaches helpful to nurse leaders advancing organizational change, content includes evidence-based projects, tools, and resources that mobilize and sustain organizational change initiatives. In this article, the author highlights the importance of stakeholder theory and discusses how to apply the theory to conduct a stakeholder analysis. This article also provides an explanation of how to use related stakeholder mapping techniques with targeted communication strategies.

  7. Hierarchical Targeting Strategy for Enhanced Tumor Tissue Accumulation/Retention and Cellular Internalization.

    PubMed

    Wang, Sheng; Huang, Peng; Chen, Xiaoyuan

    2016-09-01

    Targeted delivery of therapeutic agents is an important way to improve the therapeutic index and reduce side effects. To design nanoparticles for targeted delivery, both enhanced tumor tissue accumulation/retention and enhanced cellular internalization should be considered simultaneously. So far, there have been very few nanoparticles with immutable structures that can achieve this goal efficiently. Hierarchical targeting, a novel targeting strategy based on stimuli responsiveness, shows good potential to enhance both tumor tissue accumulation/retention and cellular internalization. Here, the recent design and development of hierarchical targeting nanoplatforms, based on changeable particle sizes, switchable surface charges and activatable surface ligands, will be introduced. In general, the targeting moieties in these nanoplatforms are not activated during blood circulation for efficient tumor tissue accumulation, but re-activated by certain internal or external stimuli in the tumor microenvironment for enhanced cellular internalization.

  8. Targeting environmental priorities in agriculture: Reforming program strategies

    SciTech Connect

    1995-09-01

    This report responds to a bipartisan request from the Senate Agriculture, Nutrition, and Forestry Committee. The analysis identifies priority environmental tergets across the country for quality, wildlife, and soil quality. A triparite set of programs designed to lower cost and achieve more enduring solutions illustrates possible approaches to the targets. One program strategy, the development of a new generation of technologies that retain frame profits while achieving environmental gains, has received litle emphasis but appears to hold considerable promise.

  9. Target activation by regulatory RNAs in bacteria

    PubMed Central

    Papenfort, Kai; Vanderpool, Carin K.

    2015-01-01

    Bacterial small regulatory RNAs (sRNAs) are commonly known to repress gene expression by base pairing to target mRNAs. In many cases, sRNAs base pair with and sequester mRNA ribosome-binding sites, resulting in translational repression and accelerated transcript decay. In contrast, a growing number of examples of translational activation and mRNA stabilization by sRNAs have now been documented. A given sRNA often employs a conserved region to interact with and regulate both repressed and activated targets. However, the mechanisms underlying activation differ substantially from repression. Base pairing resulting in target activation can involve sRNA interactions with the 5′ untranslated region (UTR), the coding sequence or the 3′ UTR of the target mRNAs. Frequently, the activities of protein factors such as cellular ribonucleases and the RNA chaperone Hfq are required for activation. Bacterial sRNAs, including those that function as activators, frequently control stress response pathways or virulence-associated functions required for immediate responses to changing environments. This review aims to summarize recent advances in knowledge regarding target mRNA activation by bacterial sRNAs, highlighting the molecular mechanisms and biological relevance of regulation. PMID:25934124

  10. Method validation strategies involved in non-targeted metabolomics.

    PubMed

    Naz, Shama; Vallejo, Maria; García, Antonia; Barbas, Coral

    2014-08-01

    Non-targeted metabolomics is the hypothesis generating, global unbiased analysis of all the small-molecule metabolites present within a biological system, under a given set of conditions. It includes several common steps such as selection of biological samples, sample pre-treatment, analytical conditions set-up, acquiring data, data analysis by chemometrics, database search and biological interpretation. Non-targeted metabolomics offers the potential for a holistic approach in the area of biomedical research in order to improve disease diagnosis and to understand its pathological mechanisms. Various analytical methods have been developed based on nuclear magnetic resonance spectroscopy (NMR) and mass spectrometry (MS) coupled with different separation techniques. The key points in any analytical method development are the validation of every step to get a reliable and reproducible result and non-targeted metabolomics is not beyond this criteria, although analytical challenges are completely new and different to target methods. This review paper will describe the available validation strategies that are being used and as well will recommend some steps to consider during a non-targeted metabolomics analytical method development.

  11. DRUG DEVELOPMENT. Phthalimide conjugation as a strategy for in vivo target protein degradation.

    PubMed

    Winter, Georg E; Buckley, Dennis L; Paulk, Joshiawa; Roberts, Justin M; Souza, Amanda; Dhe-Paganon, Sirano; Bradner, James E

    2015-06-19

    The development of effective pharmacological inhibitors of multidomain scaffold proteins, notably transcription factors, is a particularly challenging problem. In part, this is because many small-molecule antagonists disrupt the activity of only one domain in the target protein. We devised a chemical strategy that promotes ligand-dependent target protein degradation using as an example the transcriptional coactivator BRD4, a protein critical for cancer cell growth and survival. We appended a competitive antagonist of BET bromodomains to a phthalimide moiety to hijack the cereblon E3 ubiquitin ligase complex. The resultant compound, dBET1, induced highly selective cereblon-dependent BET protein degradation in vitro and in vivo and delayed leukemia progression in mice. A second series of probes resulted in selective degradation of the cytosolic protein FKBP12. This chemical strategy for controlling target protein stability may have implications for therapeutically targeting previously intractable proteins.

  12. Design strategies for self-assembly of discrete targets

    SciTech Connect

    Madge, Jim; Miller, Mark A.

    2015-07-28

    Both biological and artificial self-assembly processes can take place by a range of different schemes, from the successive addition of identical building blocks to hierarchical sequences of intermediates, all the way to the fully addressable limit in which each component is unique. In this paper, we introduce an idealized model of cubic particles with patterned faces that allows self-assembly strategies to be compared and tested. We consider a simple octameric target, starting with the minimal requirements for successful self-assembly and comparing the benefits and limitations of more sophisticated hierarchical and addressable schemes. Simulations are performed using a hybrid dynamical Monte Carlo protocol that allows self-assembling clusters to rearrange internally while still providing Stokes-Einstein-like diffusion of aggregates of different sizes. Our simulations explicitly capture the thermodynamic, dynamic, and steric challenges typically faced by self-assembly processes, including competition between multiple partially completed structures. Self-assembly pathways are extracted from the simulation trajectories by a fully extendable scheme for identifying structural fragments, which are then assembled into history diagrams for successfully completed target structures. For the simple target, a one-component assembly scheme is most efficient and robust overall, but hierarchical and addressable strategies can have an advantage under some conditions if high yield is a priority.

  13. Assay strategies for identification of therapeutic leads that target protein trafficking

    PubMed Central

    Conn, P. Michael; Spicer, Timothy P.; Scampavia, Louis; Janovick, Jo Ann

    2015-01-01

    Receptors, enzymes and ion channels are traditional targets of therapeutic development. A common strategy is to target these proteins with agents that either activate or suppress their activity with ligands or substrates that occupy orthosteric sites or have allosteric interactions. An alternative approach involves regulation of protein trafficking. In principle, this approach enables (i) “rescue” of misfolded and misrouted mutant proteins to restore function, (ii) “shipwrecking” of undesirable proteins by targeting them for destruction and (iii) regulation of levels of partially expressed wild-type (WT) proteins at their functional sites of action. Presented here are drug discovery strategies that identify “pharmacoperones,” small molecules that serve as molecular templates and cause otherwise-misfolded mutant proteins to fold and route correctly. PMID:26067100

  14. Feature Extraction and Selection Strategies for Automated Target Recognition

    NASA Technical Reports Server (NTRS)

    Greene, W. Nicholas; Zhang, Yuhan; Lu, Thomas T.; Chao, Tien-Hsin

    2010-01-01

    Several feature extraction and selection methods for an existing automatic target recognition (ATR) system using JPLs Grayscale Optical Correlator (GOC) and Optimal Trade-Off Maximum Average Correlation Height (OT-MACH) filter were tested using MATLAB. The ATR system is composed of three stages: a cursory region of-interest (ROI) search using the GOC and OT-MACH filter, a feature extraction and selection stage, and a final classification stage. Feature extraction and selection concerns transforming potential target data into more useful forms as well as selecting important subsets of that data which may aide in detection and classification. The strategies tested were built around two popular extraction methods: Principal Component Analysis (PCA) and Independent Component Analysis (ICA). Performance was measured based on the classification accuracy and free-response receiver operating characteristic (FROC) output of a support vector machine(SVM) and a neural net (NN) classifier.

  15. Quantitative proteomics in cardiovascular research: global and targeted strategies

    PubMed Central

    Shen, Xiaomeng; Young, Rebeccah; Canty, John M.; Qu, Jun

    2014-01-01

    Extensive technical advances in the past decade have substantially expanded quantitative proteomics in cardiovascular research. This has great promise for elucidating the mechanisms of cardiovascular diseases (CVD) and the discovery of cardiac biomarkers used for diagnosis and treatment evaluation. Global and targeted proteomics are the two major avenues of quantitative proteomics. While global approaches enable unbiased discovery of altered proteins via relative quantification at the proteome level, targeted techniques provide higher sensitivity and accuracy, and are capable of multiplexed absolute quantification in numerous clinical/biological samples. While promising, technical challenges need to be overcome to enable full utilization of these techniques in cardiovascular medicine. Here we discuss recent advances in quantitative proteomics and summarize applications in cardiovascular research with an emphasis on biomarker discovery and elucidating molecular mechanisms of disease. We propose the integration of global and targeted strategies as a high-throughput pipeline for cardiovascular proteomics. Targeted approaches enable rapid, extensive validation of biomarker candidates discovered by global proteomics. These approaches provide a promising alternative to immunoassays and other low-throughput means currently used for limited validation. PMID:24920501

  16. Diverse molecular targets for therapeutic strategies in Alzheimer's disease.

    PubMed

    Han, Sun-Ho; Mook-Jung, Inhee

    2014-07-01

    Alzheimer's disease (AD) is the most common form of dementia caused by neurodegenerative process and is tightly related to amyloid β (Aβ) and neurofibrillary tangles. The lack of early diagnostic biomarker and therapeutic remedy hinders the prevention of increasing population of AD patients every year. In spite of accumulated scientific information, numerous clinical trials for candidate drug targets have failed to be preceded into therapeutic development, therefore, AD-related sufferers including patients and caregivers, are desperate to seek the solution. Also, effective AD intervention is desperately needed to reduce AD-related societal threats to public health. In this review, we summarize various drug targets and strategies in recent preclinical studies and clinical trials for AD therapy: Allopathic treatment, immunotherapy, Aβ production/aggregation modulator, tau-targeting therapy and metabolic targeting. Some has already failed in their clinical trials and the others are still in various stages of investigations, both of which give us valuable information for future research in AD therapeutic development.

  17. Diverse Molecular Targets for Therapeutic Strategies in Alzheimer's Disease

    PubMed Central

    Han, Sun-Ho

    2014-01-01

    Alzheimer's disease (AD) is the most common form of dementia caused by neurodegenerative process and is tightly related to amyloid β (Aβ) and neurofibrillary tangles. The lack of early diagnostic biomarker and therapeutic remedy hinders the prevention of increasing population of AD patients every year. In spite of accumulated scientific information, numerous clinical trials for candidate drug targets have failed to be preceded into therapeutic development, therefore, AD-related sufferers including patients and caregivers, are desperate to seek the solution. Also, effective AD intervention is desperately needed to reduce AD-related societal threats to public health. In this review, we summarize various drug targets and strategies in recent preclinical studies and clinical trials for AD therapy: Allopathic treatment, immunotherapy, Aβ production/aggregation modulator, tau-targeting therapy and metabolic targeting. Some has already failed in their clinical trials and the others are still in various stages of investigations, both of which give us valuable information for future research in AD therapeutic development. PMID:25045220

  18. Asialoglycoprotein receptor mediated hepatocyte targeting - strategies and applications.

    PubMed

    D'Souza, Anisha A; Devarajan, Padma V

    2015-04-10

    Hepatocyte resident afflictions continue to affect the human population unabated. The asialoglycoprotein receptor (ASGPR) is primarily expressed on hepatocytes and minimally on extra-hepatic cells. This makes it specifically attractive for receptor-mediated drug delivery with minimum concerns of toxicity. ASGPR facilitates internalization by clathrin-mediated endocytosis and exhibits high affinity for carbohydrates specifically galactose, N-acetylgalactosamine and glucose. Isomeric forms of sugar, galactose density and branching, spatial geometry and galactose linkages are key factors influencing ligand-receptor binding. Popular ligands for ASGPR mediated targeting are carbohydrate polymers, arabinogalactan and pullulan. Other ligands include galactose-bearing glycoproteins, glycopeptides and galactose modified polymers and lipids. Drug-ligand conjugates provide a viable strategy; nevertheless ligand-anchored nanocarriers provide an attractive option for ASGPR targeted delivery and are widely explored. The present review details various ligands and nanocarriers exploited for ASGPR mediated delivery of drugs to hepatocytes. Nanocarrier properties affecting ASGPR mediated uptake are discussed at length. The review also highlights the clinical relevance of ASGPR mediated targeting and applications in diagnostics. ASGPR mediated hepatocyte targeting provides great promise for improved therapy of hepatic afflictions.

  19. Quantitative proteomics in cardiovascular research: global and targeted strategies.

    PubMed

    Shen, Xiaomeng; Young, Rebeccah; Canty, John M; Qu, Jun

    2014-08-01

    Extensive technical advances in the past decade have substantially expanded quantitative proteomics in cardiovascular research. This has great promise for elucidating the mechanisms of cardiovascular diseases and the discovery of cardiac biomarkers used for diagnosis and treatment evaluation. Global and targeted proteomics are the two major avenues of quantitative proteomics. While global approaches enable unbiased discovery of altered proteins via relative quantification at the proteome level, targeted techniques provide higher sensitivity and accuracy, and are capable of multiplexed absolute quantification in numerous clinical/biological samples. While promising, technical challenges need to be overcome to enable full utilization of these techniques in cardiovascular medicine. Here, we discuss recent advances in quantitative proteomics and summarize applications in cardiovascular research with an emphasis on biomarker discovery and elucidating molecular mechanisms of disease. We propose the integration of global and targeted strategies as a high-throughput pipeline for cardiovascular proteomics. Targeted approaches enable rapid, extensive validation of biomarker candidates discovered by global proteomics. These approaches provide a promising alternative to immunoassays and other low-throughput means currently used for limited validation.

  20. Active Targeted Drug Delivery for Microbes Using Nano-Carriers

    PubMed Central

    Lin, Yung-Sheng; Lee, Ming-Yuan; Yang, Chih-Hui; Huang, Keng-Shiang

    2015-01-01

    Although vaccines and antibiotics could kill or inhibit microbes, many infectious diseases remain difficult to treat because of acquired resistance and adverse side effects. Nano-carriers-based technology has made significant progress for a long time and is introducing a new paradigm in drug delivery. However, it still has some challenges like lack of specificity toward targeting the infectious site. Nano-carriers utilized targeting ligands on their surface called ‘active target’ provide the promising way to solve the problems like accelerating drug delivery to infectious areas and preventing toxicity or side-effects. In this mini review, we demonstrate the recent studies using the active targeted strategy to kill or inhibit microbes. The four common nano-carriers (e.g. liposomes, nanoparticles, dendrimers and carbon nanotubes) delivering encapsulated drugs are introduced. PMID:25877093

  1. Mass Media Strategies Targeting High Sensation Seekers: What Works and Why

    ERIC Educational Resources Information Center

    Stephenson, Michael T.

    2003-01-01

    Objectives: To examine strategies for using the mass media effectively in drug prevention campaigns targeting high sensation seekers. Methods: Both experimental lab and field studies were used to develop a comprehensive audience segmentation strategy targeting high sensation seekers. Results: A 4-pronged targeting strategy employed in an…

  2. Active Targets for Experiments with Rare Isotopes

    NASA Astrophysics Data System (ADS)

    Wiedenhoever, Ingo

    2014-09-01

    Experimental studies of un-bound nuclear states and nuclear reaction rates relevant for astrophysical processes are an important area of research with rare isotope beams. Both topics require the development of specialized experimental methods to study resonant reactions. The so-called active target approach, where the target material becomes part of the detection process, promises to combine high yields from thicker targets and low background with high resolution. This presentation will describe the implementation of the active-target technique in the ANASEN detector, which was developed by researchers from Louisiana State University and Florida State University. ANASEN was used in a number of stable and rare iosotope experiments in α- and proton scattering, as well as (α , p) and (d , p) reactions at FSU's in-flight radioactive beam facility RESOLUT. ANASEN also was used to perform the first experiment, proton scattering off a 37K beam at the ReA3 facility. Another active-target detector with a very different approach is found in the Active Target Time-Projection Chamber, which was developed by a collaboration between researchers from MSU, the University of Notre Dame, Western Michigan University, LLNL, LBNL, and St. Mary's University (Canada). First experiments with an AT-TPC prototype have been reported. The talk will summarize the results from the first experiments with these systems, describe further development and future research projects. Experimental studies of un-bound nuclear states and nuclear reaction rates relevant for astrophysical processes are an important area of research with rare isotope beams. Both topics require the development of specialized experimental methods to study resonant reactions. The so-called active target approach, where the target material becomes part of the detection process, promises to combine high yields from thicker targets and low background with high resolution. This presentation will describe the implementation of the

  3. Targeting the endocannabinoid system with cannabinoid receptor agonists: pharmacological strategies and therapeutic possibilities.

    PubMed

    Pertwee, Roger G

    2012-12-05

    Human tissues express cannabinoid CB(1) and CB(2) receptors that can be activated by endogenously released 'endocannabinoids' or exogenously administered compounds in a manner that reduces the symptoms or opposes the underlying causes of several disorders in need of effective therapy. Three medicines that activate cannabinoid CB(1)/CB(2) receptors are now in the clinic: Cesamet (nabilone), Marinol (dronabinol; Δ(9)-tetrahydrocannabinol (Δ(9)-THC)) and Sativex (Δ(9)-THC with cannabidiol). These can be prescribed for the amelioration of chemotherapy-induced nausea and vomiting (Cesamet and Marinol), stimulation of appetite (Marinol) and symptomatic relief of cancer pain and/or management of neuropathic pain and spasticity in adults with multiple sclerosis (Sativex). This review mentions several possible additional therapeutic targets for cannabinoid receptor agonists. These include other kinds of pain, epilepsy, anxiety, depression, Parkinson's and Huntington's diseases, amyotrophic lateral sclerosis, stroke, cancer, drug dependence, glaucoma, autoimmune uveitis, osteoporosis, sepsis, and hepatic, renal, intestinal and cardiovascular disorders. It also describes potential strategies for improving the efficacy and/or benefit-to-risk ratio of these agonists in the clinic. These are strategies that involve (i) targeting cannabinoid receptors located outside the blood-brain barrier, (ii) targeting cannabinoid receptors expressed by a particular tissue, (iii) targeting upregulated cannabinoid receptors, (iv) selectively targeting cannabinoid CB(2) receptors, and/or (v) adjunctive 'multi-targeting'.

  4. Particle therapy of moving targets-the strategies for tumour motion monitoring and moving targets irradiation.

    PubMed

    Kubiak, Tomasz

    2016-10-01

    Particle therapy of moving targets is still a great challenge. The motion of organs situated in the thorax and abdomen strongly affects the precision of proton and carbon ion radiotherapy. The motion is responsible for not only the dislocation of the tumour but also the alterations in the internal density along the beam path, which influence the range of particle beams. Furthermore, in case of pencil beam scanning, there is an interference between the target movement and dynamic beam delivery. This review presents the strategies for tumour motion monitoring and moving target irradiation in the context of hadron therapy. Methods enabling the direct determination of tumour position (fluoroscopic imaging of implanted radio-opaque fiducial markers, electromagnetic detection of inserted transponders and ultrasonic tumour localization systems) are presented. Attention is also drawn to the techniques which use external surrogate motion for an indirect estimation of target displacement during irradiation. The role of respiratory-correlated CT [four-dimensional CT (4DCT)] in the determination of motion pattern prior to the particle treatment is also considered. An essential part of the article is the review of the main approaches to moving target irradiation in hadron therapy: gating, rescanning (repainting), gated rescanning and tumour tracking. The advantages, drawbacks and development trends of these methods are discussed. The new accelerators, called "cyclinacs", are presented, because their application to particle therapy will allow making a breakthrough in the 4D spot scanning treatment of moving organs.

  5. CFTR targeting during activation of human neutrophils.

    PubMed

    Ng, Hang Pong; Valentine, Vincent G; Wang, Guoshun

    2016-12-01

    Cystic fibrosis transmembrane conductance regulator (CFTR), a cAMP-activated chloride channel, plays critical roles in phagocytic host defense. However, how activated neutrophils regulate CFTR channel distribution subcellularly is not well defined. To investigate, we tested multiple Abs against different CFTR domains, to examine CFTR expression in human peripheral blood neutrophils by flow cytometry. The data confirmed that resting neutrophils had pronounced CFTR expression. Activation of neutrophils with soluble or particulate agonists did not significantly increase CFTR expression level, but induced CFTR redistribution to cell surface. Such CFTR mobilization correlated with cell-surface recruitment of formyl-peptide receptor during secretory vesicle exocytosis. Intriguingly, neutrophils from patients with ΔF508-CF, despite expression of the mutant CFTR, showed little cell-surface mobilization upon stimulation. Although normal neutrophils effectively targeted CFTR to their phagosomes, ΔF508-CF neutrophils had impairment in that process, resulting in deficient hypochlorous acid production. Taken together, activated neutrophils regulate CFTR distribution by targeting this chloride channel to the subcellular sites of activation, and ΔF508-CF neutrophils fail to achieve such targeting, thus undermining their host defense function.

  6. Prospective strategies for targeting HIV-1 integrase function

    PubMed Central

    Luo, Yang; Muesing, Mark A

    2011-01-01

    Integration is a key step in the HIV-1 life cycle in which the ends of linear viral DNA are covalently joined with host chromosomal DNA. Integrase is the highly conserved and essential viral protein that performs two catalytically related reactions that ultimately lead to the insertion of the viral genome into that of the host cell. The only chemotherapeutic agents against integrase currently available for HIV-1 infected individuals are those that interrupt strand transfer, the second step of catalysis. Accordingly, this article outlines possible future strategies targeting the first catalytic step, 3′ processing, as well as other nonenzymatic, yet indispensible, functions thought to be coordinated by integrase. Importantly, the interruption of irremediable recombination between viral and host DNAs represents the last step after viral entry at which an otherwise irreversible infection can be prevented. PMID:21359091

  7. An innovative pre-targeting strategy for tumor cell specific imaging and therapy

    NASA Astrophysics Data System (ADS)

    Qin, Si-Yong; Peng, Meng-Yun; Rong, Lei; Jia, Hui-Zhen; Chen, Si; Cheng, Si-Xue; Feng, Jun; Zhang, Xian-Zheng

    2015-08-01

    A programmed pre-targeting system for tumor cell imaging and targeting therapy was established based on the ``biotin-avidin'' interaction. In this programmed functional system, transferrin-biotin can be actively captured by tumor cells with the overexpression of transferrin receptors, thus achieving the pre-targeting modality. Depending upon avidin-biotin recognition, the attachment of multivalent FITC-avidin to biotinylated tumor cells not only offered the rapid fluorescence labelling, but also endowed the pre-targeted cells with targeting sites for the specifically designed biotinylated peptide nano-drug. Owing to the successful pre-targeting, tumorous HepG2 and HeLa cells were effectively distinguished from the normal 3T3 cells via fluorescence imaging. In addition, the self-assembled peptide nano-drug resulted in enhanced cell apoptosis in the observed HepG2 cells. The tumor cell specific pre-targeting strategy is applicable for a variety of different imaging and therapeutic agents for tumor treatments.A programmed pre-targeting system for tumor cell imaging and targeting therapy was established based on the ``biotin-avidin'' interaction. In this programmed functional system, transferrin-biotin can be actively captured by tumor cells with the overexpression of transferrin receptors, thus achieving the pre-targeting modality. Depending upon avidin-biotin recognition, the attachment of multivalent FITC-avidin to biotinylated tumor cells not only offered the rapid fluorescence labelling, but also endowed the pre-targeted cells with targeting sites for the specifically designed biotinylated peptide nano-drug. Owing to the successful pre-targeting, tumorous HepG2 and HeLa cells were effectively distinguished from the normal 3T3 cells via fluorescence imaging. In addition, the self-assembled peptide nano-drug resulted in enhanced cell apoptosis in the observed HepG2 cells. The tumor cell specific pre-targeting strategy is applicable for a variety of different imaging

  8. Strategies for skeletal muscle targeting in drug discovery.

    PubMed

    Ebner, David C; Bialek, Peter; El-Kattan, Ayman F; Ambler, Catherine M; Tu, Meihua

    2015-01-01

    The targeting of drugs to skeletal muscle is an emerging area of research. Driven by the need for new therapies to treat a range of muscle-associated diseases, these strategies aim to provide improved drug exposure at the site of action in skeletal muscle with reduced concentration in other tissues where unwanted side effects could occur. By interacting with muscle-specific cell surface recognition elements, both tissue localization and selective uptake into skeletal muscle cells can be achieved. The design of molecules that are substrates for muscle uptake transporters can provide concentration in m uscle tissue. For example, drug conjugates with carnitine can provide improved muscle uptake via OCTN2 transport. Binding to muscle surface recognition elements followed by endocytosis can allow even large molecules such as antibodies to enter muscle cells. Monoclonal antibody 3E10 demonstrated selective uptake into skeletal muscle in vivo. Hybrid adeno-associated viral vectors have recently shown promise for high skeletal muscle selectivity in gene transfer applications. Delivery technology methods, including electroporation of DNA plasmids, have also been investigated for selective muscle uptake. This review discusses challenges and opportunities for skeletal muscle targeting, highlighting specific examples and areas in need of additional research.

  9. Targeting mitochondria: strategies, innovations and challenges: The future of medicine will come through mitochondria.

    PubMed

    Edeas, Marvin; Weissig, Volkmar

    2013-09-01

    Mitochondrial dysfunction has been associated with the aging process and a large variety of human disorders, such as cardiovascular and neurodegenerative diseases, cancer, migraine, infertility, kidney and liver diseases, toxicity of drugs and many more. It is well recognized that the physiological role of mitochondria widely exceeds that of solely being the biochemical power plant of our cells. Over the recent years, mitochondria have become an interesting target for drug therapy, and the research field aimed at "targeting mitochondria" is active and expanding as witnessed by this already third edition of the world congress on targeting mitochondria. It is becoming a necessity and an urge to know why and how to target mitochondria with bioactive molecules and drugs in order to treat and prevent mitochondria-based pathologies and chronic diseases. This special issue covers a variety of new strategies and innovations as well as clinical applications in mitochondrial medicine.

  10. Targeting the endocannabinoid system with cannabinoid receptor agonists: pharmacological strategies and therapeutic possibilities

    PubMed Central

    Pertwee, Roger G.

    2012-01-01

    Human tissues express cannabinoid CB1 and CB2 receptors that can be activated by endogenously released ‘endocannabinoids’ or exogenously administered compounds in a manner that reduces the symptoms or opposes the underlying causes of several disorders in need of effective therapy. Three medicines that activate cannabinoid CB1/CB2 receptors are now in the clinic: Cesamet (nabilone), Marinol (dronabinol; Δ9-tetrahydrocannabinol (Δ9-THC)) and Sativex (Δ9-THC with cannabidiol). These can be prescribed for the amelioration of chemotherapy-induced nausea and vomiting (Cesamet and Marinol), stimulation of appetite (Marinol) and symptomatic relief of cancer pain and/or management of neuropathic pain and spasticity in adults with multiple sclerosis (Sativex). This review mentions several possible additional therapeutic targets for cannabinoid receptor agonists. These include other kinds of pain, epilepsy, anxiety, depression, Parkinson's and Huntington's diseases, amyotrophic lateral sclerosis, stroke, cancer, drug dependence, glaucoma, autoimmune uveitis, osteoporosis, sepsis, and hepatic, renal, intestinal and cardiovascular disorders. It also describes potential strategies for improving the efficacy and/or benefit-to-risk ratio of these agonists in the clinic. These are strategies that involve (i) targeting cannabinoid receptors located outside the blood-brain barrier, (ii) targeting cannabinoid receptors expressed by a particular tissue, (iii) targeting upregulated cannabinoid receptors, (iv) selectively targeting cannabinoid CB2 receptors, and/or (v) adjunctive ‘multi-targeting’. PMID:23108552

  11. Novel therapeutic strategies targeting fibroblasts and fibrosis in heart disease.

    PubMed

    Gourdie, Robert G; Dimmeler, Stefanie; Kohl, Peter

    2016-09-01

    Our understanding of the functions of cardiac fibroblasts has moved beyond their roles in heart structure and extracellular matrix generation and now includes their contributions to paracrine, mechanical and electrical signalling during ontogenesis and normal cardiac activity. Fibroblasts also have central roles in pathogenic remodelling during myocardial ischaemia, hypertension and heart failure. As key contributors to scar formation, they are crucial for tissue repair after interventions including surgery and ablation. Novel experimental approaches targeting cardiac fibroblasts are promising potential therapies for heart disease. Indeed, several existing drugs act, at least partially, through effects on cardiac connective tissue. This Review outlines the origins and roles of fibroblasts in cardiac development, homeostasis and disease; illustrates the involvement of fibroblasts in current and emerging clinical interventions; and identifies future targets for research and development.

  12. Variable size small targets detection using density-based clustering combined with backtracking strategy

    NASA Astrophysics Data System (ADS)

    Zhang, Haiying; Lin, Yonggui; Xiao, Fangxiong

    2016-10-01

    The series problem of infrared small target detection in heavy clutter is a challenging work in active vision. During different imaging environments the size and gray intensity of target will keep changing which lead to unstable detection. Focus on mining more robust feature of small targets and following the sequential detection framework, we propose a novel research scheme based on density-based clustering and backtracking strategy in this paper. First, point of interest is extracted by the speeded up robust feature (SURF) detector for its better performance in digging features invariant to uniform scaling, orientation and illumination changes. Second, due to the local aggregation property of target trajectory in space, a new proposed density-based clustering method is introduced to segment the target trajectory, so that the target detection problem is transformed into the extract the target trajectory. Then, In order to keep the integral and independence of the trace as much as possible, two factors: percent and are exploited to help deciding the clustering granularity. Later, the backtracking strategy is adopted to search for the target trajectory with pruning function on the basis of the consistence and continuity of the short-time target trajectory in temporal-spatial. Extended experiments show the validity of our method. Compared with the data association methods executed on the huge candidate trajectory space, the time-consuming is reduced obviously. Additional, the feature detection is more stable for the use of SURF and the false alarm suppression rate is superior to most baseline and state-of-arts methods.

  13. Assessing an ensemble docking-based virtual screening strategy for kinase targets by considering protein flexibility.

    PubMed

    Tian, Sheng; Sun, Huiyong; Pan, Peichen; Li, Dan; Zhen, Xuechu; Li, Youyong; Hou, Tingjun

    2014-10-27

    In this study, to accommodate receptor flexibility, based on multiple receptor conformations, a novel ensemble docking protocol was developed by using the naïve Bayesian classification technique, and it was evaluated in terms of the prediction accuracy of docking-based virtual screening (VS) of three important targets in the kinase family: ALK, CDK2, and VEGFR2. First, for each target, the representative crystal structures were selected by structural clustering, and the capability of molecular docking based on each representative structure to discriminate inhibitors from non-inhibitors was examined. Then, for each target, 50 ns molecular dynamics (MD) simulations were carried out to generate an ensemble of the conformations, and multiple representative structures/snapshots were extracted from each MD trajectory by structural clustering. On average, the representative crystal structures outperform the representative structures extracted from MD simulations in terms of the capabilities to separate inhibitors from non-inhibitors. Finally, by using the naïve Bayesian classification technique, an integrated VS strategy was developed to combine the prediction results of molecular docking based on different representative conformations chosen from crystal structures and MD trajectories. It was encouraging to observe that the integrated VS strategy yields better performance than the docking-based VS based on any single rigid conformation. This novel protocol may provide an improvement over existing strategies to search for more diverse and promising active compounds for a target of interest.

  14. Targeting Gli Transcription Activation by Small Molecule Suppresses Tumor Growth

    PubMed Central

    Bosco-Clément, Geneviève; Zhang, Fang; Chen, Zhao; Zhou, Hai-Meng; Li, Hui; Mikami, Iwao; Hirata, Tomomi; Yagui-Beltran, Adam; Lui, Natalie; Do, Hanh T.; Cheng, Tiffany; Tseng, Hsin-Hui; Choi, Helen; Fang, Li-Tai; Kim, Il-Jin; Yue, Dongsheng; Wang, Changli; Zheng, Qingfeng; Fujii, Naoaki; Mann, Michael; Jablons, David M.; He, Biao

    2014-01-01

    Targeted inhibition of Hedgehog signaling at the cell membrane has been associated with anti-cancer activity in preclinical and early clinical studies. Hedgehog signaling involves activation of Gli transcription factors that can also be induced by alternative pathways. In this study we identified an interaction between Gli proteins and a transcription co-activator TAF9, and validated its functional relevance in regulating Gli transactivation. We also describe a novel, synthetic small molecule, FN1-8, that efficiently interferes with Gli/TAF9 interaction and down-regulate Gli/TAF9 dependent transcriptional activity. More importantly, FN1-8 suppresses cancer cell proliferation in vitro and inhibits tumor growth in vivo. Our results suggest that blocking Gli transactivation, a key control point of multiple oncogenic pathways, may be an effective anti-cancer strategy. PMID:23686308

  15. Rationale for mitochondria-targeting strategies in cancer bioenergetic therapies.

    PubMed

    Jose, Caroline; Rossignol, Rodrigue

    2013-01-01

    In the 1920s, Otto Warburg first hypothesized that mitochondrial impairment is a leading cause of cancer although he recognized the existence of oxidative tumors. Likewise, Weinhouse and others in the 50s found that deficient mitochondrial respiration is not an obligatory feature of cancer and Peter Vaupel suggested in the 1990s that tumor oxygenation rather than OXPHOS capacity was the limiting factor of mitochondrial energy production in cancer. Recent studies now clearly indicate that mitochondria are highly functional in mice tumors and the field of oncobioenergetic identified MYC, Oct1 and RAS as pro-OXPHOS oncogenes. In addition, cancer cells adaptation to aglycemia, metabolic symbiosis between hypoxic and non-hypoxic tumor regions as well the reverse Warburg hypothesis support the crucial role of mitochondria in the survival of a subclass of tumors. Therefore, mitochondria are now considered as potential targets for anti-cancer therapy and tentative strategies including a bioenergetic profile characterization of the tumor and the subsequent adapted bioenergetic modulation could be considered for cancer killing. This article is part of a Directed Issue entitled: Bioenergetic dysfunction, adaptation and therapy.

  16. Targeted alternative splicing of TAF4: a new strategy for cell reprogramming

    PubMed Central

    Kazantseva, Jekaterina; Sadam, Helle; Neuman, Toomas; Palm, Kaia

    2016-01-01

    Reprogramming of somatic cells has become a versatile tool for biomedical research and for regenerative medicine. In the current study, we show that manipulating alternative splicing (AS) is a highly potent strategy to produce cells for therapeutic applications. We demonstrate that silencing of hTAF4-TAFH activity of TAF4 converts human facial dermal fibroblasts to melanocyte-like (iMel) cells. iMel cells produce melanin and express microphthalmia-associated transcription factor (MITF) and its target genes at levels comparable to normal melanocytes. Reprogramming of melanoma cells by manipulation with hTAF4-TAFH activity upon TAFH RNAi enforces cell differentiation towards chondrogenic pathway, whereas ectoptic expression of TAF4 results in enhanced multipotency and neural crest-like features in melanoma cells. In both cell states, iMels and cancer cells, hTAF4-TAFH activity controls migration by supporting E- to N-cadherin switches. From our data, we conclude that targeted splicing of hTAF4-TAFH coordinates AS of other TFIID subunits, underscoring the role of TAF4 in synchronised changes of Pol II complex composition essential for efficient cellular reprogramming. Taken together, targeted AS of TAF4 provides a unique strategy for generation of iMels and recapitulating stages of melanoma progression. PMID:27499390

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

    PubMed

    Purcell, M; Magette, W L

    2011-01-01

    Urgent transformation is required in Ireland to divert biodegradable municipal waste (BMW) from landfill and prevent increases in overall waste generation. When BMW is optimally managed, it becomes a resource with value instead of an unwanted by-product requiring disposal. An analysis of survey responses from commercial and residential sectors for the Dublin region in previous research by the authors proved that attitudes towards and behaviour regarding municipal solid waste is spatially variable. This finding indicates that targeted intervention strategies designed for specific geographic areas should lead to improved diversion rates of BMW from landfill, a requirement of the Landfill Directive 1999/31/EC. In the research described in this paper, survey responses and GIS model predictions from previous research were the basis for goal setting, after which logic modelling and behavioural research were employed to develop site-specific waste management intervention strategies. The main strategies devised include (a) roll out of the Brown Bin (Organics) Collection and Community Workshops in Dún Laoghaire Rathdown, (b) initiation of a Community Composting Project in Dublin City (c) implementation of a Waste Promotion and Motivation Scheme in South Dublin (d) development and distribution of a Waste Booklet to promote waste reduction activities in Fingal (e) region wide distribution of a Waste Booklet to the commercial sector and (f) Greening Irish Pubs Initiative. Each of these strategies was devised after interviews with both the residential and commercial sectors to help make optimal waste management the norm for both sectors. Strategy (b), (e) and (f) are detailed in this paper. By integrating a human element into accepted waste management approaches, these strategies will make optimal waste behaviour easier to achieve. Ultimately this will help divert waste from landfill and improve waste management practice as a whole for the region. This method of devising

  18. Targeting Nuclear EGFR: Strategies for Improving Cetuximab Therapy in Lung Cancer

    DTIC Science & Technology

    2015-12-01

    AWARD NUMBER: W81XWH-12-1-0467 TITLE: Targeting Nuclear EGFR: Strategies for Improving Cetuximab Therapy in Lung Cancer PRINCIPAL...2012-08/31/2015 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER Targeting Nuclear EGFR: Strategies for Improving Cetuximab Therapy in Lung Cancer 5b. GRANT...features FY14 LCRP publicity materials; LC110082 - Targeting Nuclear EGFR: Strategies for Improving Cetuximab Therapy in Lung Cancer) was highlighted in

  19. Active debris removal of multiple priority targets

    NASA Astrophysics Data System (ADS)

    Braun, Vitali; Lüpken, A.; Flegel, S.; Gelhaus, J.; Möckel, M.; Kebschull, C.; Wiedemann, C.; Vörsmann, P.

    2013-05-01

    Today's space debris environment shows major concentrations of objects within distinct orbital regions for nearly all size regimes. The most critical region is found at orbital altitudes near 800 km with high declinations. Within this region many satellites are operated in so called sun-synchronous orbits (SSO). Among those, there are Earth observation, communication and weather satellites. Due to the orbital geometry in SSO, head-on encounters with relative velocities of about 15 km/s are most probable and would thus result in highly energetic collisions, which are often referred to as catastrophic collisions, leading to the complete fragmentation of the participating objects. So called feedback collisions can then be triggered by the newly generated fragments, thus leading to a further population increase in the affected orbital region. This effect is known as the Kessler syndrome.Current studies show that catastrophic collisions are not a major problem today, but will become the main process for debris generation within the SSO region in the near future, even without any further launches. In order to avoid this effect, objects with a major impact on collisional cascading have to be actively removed from the critical region after their end of life. Not having the capability to perform an end-of-life maneuver in order to transfer to a graveyard orbit or to de-orbit, many satellites and rocket bodies would have to be de-orbited within a dedicated mission. In such a mission, a service satellite would perform a de-orbit maneuver, after having docked to a specific target.In this paper, chemical and electric propulsion systems were analysed with the main focus on removing multiple targets within one single mission. The targets were chosen from a previously defined priority list in order to enhance the mission efficiency. Total mission time, ΔV and system mass were identified as key parameters to allow for an evaluation of the different concepts. It was shown that it

  20. Redox therapy in neonatal sepsis: reasons, targets, strategy, and agents.

    PubMed

    Bajčetić, Milica; Spasić, Snežana; Spasojević, Ivan

    2014-09-01

    Neonatal sepsis is one of the most fulminating conditions in neonatal intensive care units. Antipathogen and supportive care are administered routinely, but do not deliver satisfactory results. In addition, the efforts to treat neonatal sepsis with anti-inflammatory agents have generally shown to be futile. The accumulating data imply that intracellular redox changes intertwined into neonatal sepsis redox cycle represent the main cause of dysfunction of mitochondria and cells in neonatal sepsis. Our aim here is to support the new philosophy in neonatal sepsis treatment, which involves the integration of mechanisms that are responsible for cellular dysfunction and organ failure, the recognition of the most important targets, and the selection of safe agents that can stop the neonatal sepsis redox cycle by hitting the hot spots. Redox-active agents that could be beneficial for neonatal sepsis treatment according to these criteria include lactoferrin, interleukin 10, zinc and selenium supplements, ibuprofen, edaravone, and pentoxifylline.

  1. Prefrontal activity and impaired memory encoding strategies in schizophrenia.

    PubMed

    Guimond, Synthia; Hawco, Colin; Lepage, Martin

    2017-03-08

    Schizophrenia patients have significant memory difficulties that have far-reaching implications in their daily life. These impairments are partly attributed to an inability to self-initiate effective memory encoding strategies, but its core neurobiological correlates remain unknown. The current study addresses this critical gap in our knowledge of episodic memory impairments in schizophrenia. Schizophrenia patients (n = 35) and healthy controls (n = 23) underwent a Semantic Encoding Memory Task (SEMT) during an fMRI scan. Brain activity was examined for conditions where participants were a) prompted to use semantic encoding strategies, or b) not prompted but required to self-initiate such strategies. When prompted to use semantic encoding strategies, schizophrenia patients exhibited similar recognition performance and brain activity as healthy controls. However, when required to self-initiate these strategies, patients had significant reduced recognition performance and brain activity in the left dorsolateral prefrontal cortex, as well as in the left temporal gyrus, left superior parietal lobule, and cerebellum. When patients were divided based on performance on the SEMT, the subgroup with more severe deficits in self-initiation also showed greater reduction in left dorsolateral prefrontal activity. These results suggest that impaired self-initiation of elaborative encoding strategies is a driving feature of memory deficits in schizophrenia. We also identified the neural correlates of impaired self-initiation of semantic encoding strategies, in which a failure to activate the left dorsolateral prefrontal cortex plays a key role. These findings provide important new targets in the development of novel treatments aiming to improve memory and ultimately patients' outcome.

  2. Active Learning Strategies and Vocabulary Achievement

    ERIC Educational Resources Information Center

    Griffith, John R.

    2015-01-01

    Using a quantitative method of data collection, this research explored the question: Do active learning strategies used in grades 5 and 6 affect student vocabulary achievement in a positive or negative direction? In their research, Wolfe (2001), Headley, et al., (1995), Freiberg, et al., (1992), and Brunner (2009) emphasize the importance of…

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

    SciTech Connect

    Purcell, M.; Magette, W.L.

    2011-09-15

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

  4. ERYTHROPOIETIN: ELUCIDATING NEW CELLULAR TARGETS THAT BROADEN THERAPEUTIC STRATEGIES

    PubMed Central

    Maiese, Kenneth; Chong, Zhao Zhong; Li, Faqi; Shang, Yan Chen

    2008-01-01

    Given that erythropoietin (EPO) is no longer believed to have exclusive biological activity in the hematopoietic system, EPO is now considered to have applicability in a variety of nervous system disorders that can overlap with vascular disease, metabolic impairments, and immune system function. As a result, EPO may offer efficacy for a broad number of disorders that involve Alzheimer’s disease, cardiac insufficiency, stroke, trauma, and diabetic complications. During a number of clinical conditions, EPO is robust and can prevent metabolic compromise, neuronal and vascular degeneration, and inflammatory cell activation. Yet, use of EPO is not without its considerations especially in light of frequent concerns that may compromise clinical care. Recent work has elucidated a number of novel cellular pathways governed by EPO that can open new avenues to avert deleterious effects of this agent and offer previously unrecognized perspectives for therapeutic strategies. Obtaining greater insight into the role of EPO in the nervous system and elucidating its unique cellular pathways may provide greater cellular viability not only in the nervous system but also throughout the body. PMID:18396368

  5. Swarm Robots Search for Multiple Targets Based on an Improved Grouping Strategy.

    PubMed

    Tang, Qirong; Ding, Lu; Yu, Fangchao; Zhang, Yuan; Li, Yinghao; Tu, Haibo

    2017-03-14

    Swarm robots search for multiple targets in collaboration in unknown environments has been addressed in this paper. An improved grouping strategy based on constriction factors Particle Swarm Optimization is proposed. Robots are grouped under this strategy after several iterations of stochastic movements, which considers the influence range of targets and environmental information they have sensed. The group structure may change dynamically and each group focuses on searching one target. All targets are supposed to be found finally. Obstacle avoidance is considered during the search process. Simulation compared with previous method demonstrates the adaptability, accuracy and efficiency of the proposed strategy in multiple targets searching.

  6. Targeted Screening Strategies to Detect Trypanosoma cruzi Infection in Children

    PubMed Central

    Levy, Michael Z.; Kawai, Vivian; Bowman, Natalie M.; Waller, Lance A.; Cabrera, Lilia; Pinedo-Cancino, Viviana V.; Seitz, Amy E.; Steurer, Frank J.; Cornejo del Carpio, Juan G.; Cordova-Benzaquen, Eleazar; Maguire, James H.; Gilman, Robert H.; Bern, Caryn

    2007-01-01

    Background Millions of people are infected with Trypanosoma cruzi, the causative agent of Chagas disease in Latin America. Anti-trypanosomal drug therapy can cure infected individuals, but treatment efficacy is highest early in infection. Vector control campaigns disrupt transmission of T. cruzi, but without timely diagnosis, children infected prior to vector control often miss the window of opportunity for effective chemotherapy. Methods and Findings We performed a serological survey in children 2–18 years old living in a peri-urban community of Arequipa, Peru, and linked the results to entomologic, spatial and census data gathered during a vector control campaign. 23 of 433 (5.3% [95% CI 3.4–7.9]) children were confirmed seropositive for T. cruzi infection by two methods. Spatial analysis revealed that households with infected children were very tightly clustered within looser clusters of households with parasite-infected vectors. Bayesian hierarchical mixed models, which controlled for clustering of infection, showed that a child's risk of being seropositive increased by 20% per year of age and 4% per vector captured within the child's house. Receiver operator characteristic (ROC) plots of best-fit models suggest that more than 83% of infected children could be identified while testing only 22% of eligible children. Conclusions We found evidence of spatially-focal vector-borne T. cruzi transmission in peri-urban Arequipa. Ongoing vector control campaigns, in addition to preventing further parasite transmission, facilitate the collection of data essential to identifying children at high risk of T. cruzi infection. Targeted screening strategies could make integration of diagnosis and treatment of children into Chagas disease control programs feasible in lower-resource settings. PMID:18160979

  7. Investigation of the strategies for targeting of the afterglow nanoparticles to tumor cells.

    PubMed

    Rashidi, Leila Hossein; Homayoni, Homa; Zou, Xiaoju; Liu, Li; Chen, Wei

    2016-03-01

    Afterglow nanoparticles have been widely investigated as new agents for cancer imaging and as a light source for photodynamic activation for cancer treatment. For both applications, the targeting of the afterglow nanoparticles to tumor cells is an important and challenging issue. Here we report the strategies for targeting Sr3MgSi2O8:Eu(2+),Dy(3+) afterglow nanoparticles to tumor cells by conjugating with variety of targeting molecules such as folic acid, RGD peptide, and R-11 peptide. For folic acid targeting, experimental observations were conducted on PC-3 cells (folate receptor negative), MCF-7 (folate receptor positive), and KB cells (folate receptor positive) to compare the cellular uptake and confirm targeted delivery. For the cyclic RGDfK peptide, experiments were carried out on the integrin αvβ3 positive MDA-MB-231 breast cancer cell line and the integrin αvβ3 negative MCF-7 breast cancer cell lines in order to compare the cellular uptakes. As for R11-SH peptide, cellular uptake of the afterglow nanoparticles was observed on LNCaP and PC3 prostate cancer cell lines. All the observations showed that the cellular uptakes of the nanoparticles were enhanced by conjugation to variety of targeting molecules which are specific for breast and prostate cancer cells.

  8. Activation and Molecular Targets of Peroxisome Proliferator-Activated Receptor-γ Ligands in Lung Cancer

    PubMed Central

    Nemenoff, Raphael A.; Weiser-Evans, Mary; Winn, Robert A.

    2008-01-01

    Lung cancer is the leading cause of cancer death, and five-year survival remains poor, raising the urgency for new treatment strategies. Activation of PPARγ represents a potential target for both the treatment and prevention of lung cancer. Numerous studies have examined the effect of thiazolidinediones such as rosiglitazone and pioglitazone on lung cancer cells in vitro and in xenograft models. These studies indicate that activation of PPARγ inhibits cancer cell proliferation as well as invasiveness and metastasis. While activation of PPARγ can occur by direct binding of pharmacological ligands to the molecule, emerging data indicate that PPARγ activation can occur through engagement of other signal transduction pathways, including Wnt signaling and prostaglandin production. Data, both from preclinical models and retrospective clinical studies, indicate that activation of PPARγ may represent an attractive chemopreventive strategy. This article reviews the existing biological and mechanistic experiments focusing on the role of PPARγ in lung cancer, focusing specifically on nonsmall cell lung cancer. PMID:18509496

  9. Yugoslavia. "Migration" -- programme activities targeting men.

    PubMed

    Dzeletovic, A; Matovic-miljanovic, S

    1999-01-01

    In Yugoslavia, companies send their workers to different parts of the world, including countries with a high incidence of AIDS. It has been noted that it is characteristic for migrants to accommodate themselves to foreign conditions, which subsequently lead to health problems, especially with regards to reproductive and sexual health. Often, in the case of partner separation, men may seek sexual relations with an unknown partner and/or neglect to use proper protection. According to research carried out in Yugoslavia, there are critical gaps in workers' knowledge on sexual and reproductive health. Based on research results, an educational program for migrants, designed to train and strengthen individuals¿ capabilities and modify their risky behavior, was created. Program activities include production of brochures targeting those people travelling to countries with a high incidence of HIV/AIDS. In addition, a process for creating more cooperation between the state and other organizations at regional and local levels was initiated.

  10. Investigation of strategies for drug delivery by combination targeting of nanocarriers to multiple epitopes or receptors

    NASA Astrophysics Data System (ADS)

    Papademetriou, Iason Titos

    Development of drug delivery systems (ie. nanocarriers) with controllable composition, architecture, and functionalities is heavily investigated in the field of drug delivery in order to improve clinical interventions. Designing drug nanocarriers which possess targeting properties is critical to enable them to reach the intended site of intervention in the body. To achieve this goal, the surface of drug nanocarriers can be modified with targeting moieties (antibodies, peptides, etc.) addressed to cell surface molecules expressed on the diseased tissues and cells. If these molecules are receptors capable of internalizing bound ligands via endocytosis, targeting can then enable drug transport into cells or across cellular barriers in the body. Yet, addressing nanocarriers to single targets presents limited control over cellular interactions and biodistribution. Since most cell-surface markers are not exclusively expressed in a precise site in vivo, high affinity of targeted nanocarriers may lead to non-desired accumulation in regions of the body associated with low expression. Modification of nanocarriers to achieve combined-targeting (binding to more than one cell-surface receptor) may help modulate binding to cells and also endocytosis, since cell receptors possess distinct functions and features affecting these parameters, such as their expression, location on the plasmalemma, activation in disease, mechanism of endocytosis, etc. Further, targeting nanocarriers to multiple epitopes of the same receptor, a strategy which has never been tested, may also modulate these parameters since they are highly epitope specific. In this dissertation, we investigate the effect of targeting model polymer nanocarriers to: (1) multiple receptors of similar function (intercellular-, platelet-endothelial-, and/or vascular-cell adhesion molecules), (2) multiple receptors of different function (intercellular adhesion molecule 1 and transferrin receptor), or (3) multiple epitopes of

  11. The place of physical activity in the WHO Global Strategy on Diet and Physical Activity

    PubMed Central

    Bauman, Adrian; Craig, Cora L

    2005-01-01

    In an effort to reduce the global burden of non-communicable disease, the World Health Organization released a Global Strategy for Diet and Physical Activity in May 2004. This commentary reports on the development of the strategy and its importance specifically for physical activity-related work of NGOs and researchers interested in increasing global physical activity participation. Sparked by its work on global efforts to target non-communicable disease prevention in 2000, the World Health Organization commissioned a global strategy on diet and physical activity. The physical activity interest followed efforts that had led to the initial global "Move for Health Day" in 2002. WHO assembled a reference group for the global strategy, and a regional consultation process with countries was undertaken. Underpinning the responses was the need for more physical activity advocacy; partnerships outside of health including urban planning; development of national activity guidelines; and monitoring of the implementation of the strategy. The consultation process was an important mechanism to confirm the importance and elevate the profile of physical activity within the global strategy. It is suggested that separate implementation strategies for diet and physical activity may be needed to work with partner agencies in disparate sectors (e.g. urban planning for physical activity, agriculture for diet). International professional societies are well situated to make an important contribution to global public health by advocating for the importance of physical activity among risk factors; developing international measures of physical activity and global impacts of inactivity; and developing a global research and intervention agenda. PMID:16120214

  12. The place of physical activity in the WHO Global Strategy on Diet and Physical Activity.

    PubMed

    Bauman, Adrian; Craig, Cora L

    2005-08-24

    In an effort to reduce the global burden of non-communicable disease, the World Health Organization released a Global Strategy for Diet and Physical Activity in May 2004. This commentary reports on the development of the strategy and its importance specifically for physical activity-related work of NGOs and researchers interested in increasing global physical activity participation. Sparked by its work on global efforts to target non-communicable disease prevention in 2000, the World Health Organization commissioned a global strategy on diet and physical activity. The physical activity interest followed efforts that had led to the initial global "Move for Health Day" in 2002. WHO assembled a reference group for the global strategy, and a regional consultation process with countries was undertaken. Underpinning the responses was the need for more physical activity advocacy; partnerships outside of health including urban planning; development of national activity guidelines; and monitoring of the implementation of the strategy. The consultation process was an important mechanism to confirm the importance and elevate the profile of physical activity within the global strategy. It is suggested that separate implementation strategies for diet and physical activity may be needed to work with partner agencies in disparate sectors (e.g. urban planning for physical activity, agriculture for diet). International professional societies are well situated to make an important contribution to global public health by advocating for the importance of physical activity among risk factors; developing international measures of physical activity and global impacts of inactivity; and developing a global research and intervention agenda.

  13. Strategies Targeting cAMP Signaling in the Treatment of Polycystic Kidney Disease

    PubMed Central

    Harris, Peter C.

    2014-01-01

    Polycystic kidney disease (PKD) is a leading cause of ESRD worldwide. In PKD, excessive cell proliferation and fluid secretion, pathogenic interactions of mutated epithelial cells with an abnormal extracellular matrix and alternatively activated interstitial macrophages, and the disruption of mechanisms controlling tubular diameter contribute to cyst formation. Studies with animal models suggest that several diverse pathophysiologic mechanisms, including dysregulation of intracellular calcium levels and cAMP signaling, mediate these cystogenic mechanisms. This article reviews the evidence implicating calcium and cAMP as central players in a network of signaling pathways underlying the pathogenesis of PKD and considers the therapeutic relevance of treatment strategies targeting cAMP signaling. PMID:24335972

  14. Small Molecule Inhibitors Targeting Activator Protein 1 (AP-1)

    PubMed Central

    2015-01-01

    Activator protein 1 (AP-1) is a pivotal transcription factor that regulates a wide range of cellular processes including proliferation, apoptosis, differentiation, survival, cell migration, and transformation. Accumulating evidence supports that AP-1 plays an important role in several severe disorders including cancer, fibrosis, and organ injury, as well as inflammatory disorders such as asthma, psoriasis, and rheumatoid arthritis. AP-1 has emerged as an actively pursued drug discovery target over the past decade. Excitingly, a selective AP-1 inhibitor T-5224 (51) has been investigated in phase II human clinical trials. Nevertheless, no effective AP-1 inhibitors have yet been approved for clinical use. Despite significant advances achieved in understanding AP-1 biology and function, as well as the identification of small molecules modulating AP-1 associated signaling pathways, medicinal chemistry efforts remain an urgent need to yield selective and efficacious AP-1 inhibitors as a viable therapeutic strategy for human diseases. PMID:24831826

  15. Small molecule inhibitors targeting activator protein 1 (AP-1).

    PubMed

    Ye, Na; Ding, Ye; Wild, Christopher; Shen, Qiang; Zhou, Jia

    2014-08-28

    Activator protein 1 (AP-1) is a pivotal transcription factor that regulates a wide range of cellular processes including proliferation, apoptosis, differentiation, survival, cell migration, and transformation. Accumulating evidence supports that AP-1 plays an important role in several severe disorders including cancer, fibrosis, and organ injury, as well as inflammatory disorders such as asthma, psoriasis, and rheumatoid arthritis. AP-1 has emerged as an actively pursued drug discovery target over the past decade. Excitingly, a selective AP-1 inhibitor T-5224 (51) has been investigated in phase II human clinical trials. Nevertheless, no effective AP-1 inhibitors have yet been approved for clinical use. Despite significant advances achieved in understanding AP-1 biology and function, as well as the identification of small molecules modulating AP-1 associated signaling pathways, medicinal chemistry efforts remain an urgent need to yield selective and efficacious AP-1 inhibitors as a viable therapeutic strategy for human diseases.

  16. Bioinspired Gold Nanorod Functionalization Strategies for MUC1-Targeted Imaging and Photothermal Therapy

    NASA Astrophysics Data System (ADS)

    Zelasko-Leon, Daria Cecylia

    . Together, these findings indicate that these may be clinically useful candidate therapeutics for photothermal therapy of epithelial cancers overexpressing MUC1. The stepwise AuNR modification strategy utilizing a polyphenolic adhesive primer for bioconjugation is approachable, practical, and highly adaptable to the use of alternative agents for adhesion, stabilization, and targeting, expanding the range of applications. Given the mounting body of literature describing the anticancer activities of plant polyphenols, the results establish the potential therapeutic use of tannic acid coatings for targeted cancer nanomedicine. Importantly, the modular design afforded by this strategy offers many opportunities to explore the influence of biointerfacially optimized targeting and therapy, underscoring a major novelty of this work.

  17. Targeted inhibition of STATs and IRFs as a potential treatment strategy in cardiovascular disease

    PubMed Central

    Szelag, Malgorzata; Piaszyk-Borychowska, Anna; Plens-Galaska, Martyna; Wesoly, Joanna; Bluyssen, Hans A.R.

    2016-01-01

    Key factors contributing to early stages of atherosclerosis and plaque development include the pro-inflammatory cytokines Interferon (IFN)α, IFNγ and Interleukin (IL)-6 and Toll-like receptor 4 (TLR4) stimuli. Together, they trigger activation of Signal Transducer and Activator of Transcription (STAT) and Interferon Regulatory Factor (IRF) families. In particular, STAT1, 2 and 3; IRF1 and 8 have recently been recognized as prominent modulators of inflammation, especially in immune and vascular cells during atherosclerosis. Moreover, inflammation-mediated activation of these STATs and IRFs coordinates a platform for synergistic amplification leading to pro-atherogenic responses. Searches for STAT3-targeting compounds, exploring the pTyr-SH2 interaction area of STAT3, yielded many small molecules including natural products. Only a few inhibitors for other STATs, but none for IRFs, are described. Promising results for several STAT3 inhibitors in recent clinical trials predicts STAT3-inhibiting strategies may find their way to the clinic. However, many of these inhibitors do not seem STAT-specific, display toxicity and are not very potent. This illustrates the need for better models, and screening and validation tools for novel STAT and IRF inhibitors. This review presents a summary of these findings. It postulates STAT1, STAT2 and STAT3 and IRF1 and IRF8 as interesting therapeutic targets and targeted inhibition could be a potential treatment strategy in CVDs. In addition, it proposes a pipeline approach that combines comparative in silico docking of STAT-SH2 and IRF-DBD models with in vitro STAT and IRF activation inhibition validation, as a novel tool to screen multi-million compound libraries and identify specific inhibitors for STATs and IRFs. PMID:27166190

  18. Highly sensitive and specific colorimetric detection of cancer cells via dual-aptamer target binding strategy.

    PubMed

    Wang, Kun; Fan, Daoqing; Liu, Yaqing; Wang, Erkang

    2015-11-15

    Simple, rapid, sensitive and specific detection of cancer cells is of great importance for early and accurate cancer diagnostics and therapy. By coupling nanotechnology and dual-aptamer target binding strategies, we developed a colorimetric assay for visually detecting cancer cells with high sensitivity and specificity. The nanotechnology including high catalytic activity of PtAuNP and magnetic separation & concentration plays a vital role on the signal amplification and improvement of detection sensitivity. The color change caused by small amount of target cancer cells (10 cells/mL) can be clearly distinguished by naked eyes. The dual-aptamer target binding strategy guarantees the detection specificity that large amount of non-cancer cells and different cancer cells (10(4) cells/mL) cannot cause obvious color change. A detection limit as low as 10 cells/mL with detection linear range from 10 to 10(5) cells/mL was reached according to the experimental detections in phosphate buffer solution as well as serum sample. The developed enzyme-free and cost effective colorimetric assay is simple and no need of instrument while still provides excellent sensitivity, specificity and repeatability, having potential application on point-of-care cancer diagnosis.

  19. Big brown bats (Eptesicus fuscus) reveal diverse strategies for sonar target tracking in clutter.

    PubMed

    Mao, Beatrice; Aytekin, Murat; Wilkinson, Gerald S; Moss, Cynthia F

    2016-09-01

    Bats actively adjust the acoustic features of their sonar calls to control echo information specific to a given task and environment. A previous study investigated how bats adapted their echolocation behavior when tracking a moving target in the presence of a stationary distracter at different distances and angular offsets. The use of only one distracter, however, left open the possibility that a bat could reduce the interference of the distracter by turning its head. Here, bats tracked a moving target in the presence of one or two symmetrically placed distracters to investigate adaptive echolocation behavior in a situation where vocalizing off-axis would result in increased interference from distracter echoes. Both bats reduced bandwidth and duration but increased sweep rate in more challenging distracter conditions, and surprisingly, made more head turns in the two-distracter condition compared to one, but only when distracters were placed at large angular offsets. However, for most variables examined, subjects showed distinct strategies to reduce clutter interference, either by (1) changing spectral or temporal features of their calls, or (2) producing large numbers of sonar sound groups and consistent head-turning behavior. The results suggest that individual bats can use different strategies for target tracking in cluttered environments.

  20. Induction of mitochondrial dysfunction as a strategy for targeting tumour cells in metabolically compromised microenvironments.

    PubMed

    Zhang, Xiaonan; Fryknäs, Mårten; Hernlund, Emma; Fayad, Walid; De Milito, Angelo; Olofsson, Maria Hägg; Gogvadze, Vladimir; Dang, Long; Påhlman, Sven; Schughart, Leoni A Kunz; Rickardson, Linda; D'Arcy, Padraig; Gullbo, Joachim; Nygren, Peter; Larsson, Rolf; Linder, Stig

    2014-01-01

    Abnormal vascularization of solid tumours results in the development of microenvironments deprived of oxygen and nutrients that harbour slowly growing and metabolically stressed cells. Such cells display enhanced resistance to standard chemotherapeutic agents and repopulate tumours after therapy. Here we identify the small molecule VLX600 as a drug that is preferentially active against quiescent cells in colon cancer 3-D microtissues. The anticancer activity is associated with reduced mitochondrial respiration, leading to bioenergetic catastrophe and tumour cell death. VLX600 shows enhanced cytotoxic activity under conditions of nutrient starvation. Importantly, VLX600 displays tumour growth inhibition in vivo. Our findings suggest that tumour cells in metabolically compromised microenvironments have a limited ability to respond to decreased mitochondrial function, and suggest a strategy for targeting the quiescent populations of tumour cells for improved cancer treatment.

  1. Bio and nanotechnological strategies for tumor-targeted gene therapy.

    PubMed

    Kang, Jeong-Hun; Toita, Riki; Katayama, Yoshiki

    2010-01-01

    Gene therapy is a new medical approach for the treatment of tumors. For safe and efficient gene therapy, therapeutic genes need to be delivered efficiently into the target tumor cells. Development of gene delivery systems to specifically recognize and target tumor cells and to distinguish them from normal cells, especially in the same tissue or organ, is one of the most important issues regarding the present gene delivery methodologies. The enhanced permeability and retention (EPR) effect using the characteristics of angiogenic tumor blood vessels, as well as gene delivery systems recognizing hyperactivated receptors or intracellular signals, is broadly applied to tumor-targeted gene therapy. In addition, bacterial vectors can be a useful means for targeting hypoxic or anoxic regions of a tumor.

  2. Thinking Patterns, Brain Activity and Strategy Choice

    NASA Astrophysics Data System (ADS)

    Nishimura, Kazuo; Okada, Akira; Inagawa, Michiyo; Tobinaga, Yoshikazu

    2012-03-01

    In this study we analyzed the relationship between thinking patterns, behavior and associated brain activity. Subjects completed a self-report assessing whether they could voluntarily stop thinking or not, and were then divided into two groups: those with the ability to stop thinking and those without. We measured subjects' brain activity using magnetoencephalography while giving them a series of tasks intended to encourage or discourage spontaneous thinking. Our findings revealed differences between the two groups in terms of which portions of the brain were active during the two types of task. A second questionnaire confirmed a relationship between the ability to stop thinking and strategy choices in a dilemma game. We found that subjects without the ability to stop thinking had a tendency to choose cooperative behavior.

  3. An adaptive strategy for active debris removal

    NASA Astrophysics Data System (ADS)

    White, Adam E.; Lewis, Hugh G.

    2014-04-01

    Many parameters influence the evolution of the near-Earth debris population, including launch, solar, explosion and mitigation activities, as well as other future uncertainties such as advances in space technology or changes in social and economic drivers that effect the utilisation of space activities. These factors lead to uncertainty in the long-term debris population. This uncertainty makes it difficult to identify potential remediation strategies, involving active debris removal (ADR), that will perform effectively in all possible future cases. Strategies that cannot perform effectively, because of this uncertainty, risk either not achieving their intended purpose, or becoming a hindrance to the efforts of spacecraft manufactures and operators to address the challenges posed by space debris. One method to tackle this uncertainty is to create a strategy that can adapt and respond to the space debris population. This work explores the concept of an adaptive strategy, in terms of the number of objects required to be removed by ADR, to prevent the low Earth orbit (LEO) debris population from growing in size. This was demonstrated by utilising the University of Southampton’s Debris Analysis and Monitoring Architecture to the Geosynchronous Environment (DAMAGE) tool to investigate ADR rates (number of removals per year) that change over time in response to the current space environment, with the requirement of achieving zero growth of the LEO population. DAMAGE was used to generate multiple Monte Carlo projections of the future LEO debris environment. Within each future projection, the debris removal rate was derived at five-year intervals, by a new statistical debris evolutionary model called the Computational Adaptive Strategy to Control Accurately the Debris Environment (CASCADE) model. CASCADE predicted the long-term evolution of the current DAMAGE population with a variety of different ADR rates in order to identify a removal rate that produced a zero net

  4. Biomaterial-mediated strategies targeting vascularization for bone repair.

    PubMed

    García, José R; García, Andrés J

    2016-04-01

    Repair of non-healing bone defects through tissue engineering strategies remains a challenging feat in the clinic due to the aversive microenvironment surrounding the injured tissue. The vascular damage that occurs following a bone injury causes extreme ischemia and a loss of circulating cells that contribute to regeneration. Tissue-engineered constructs aimed at regenerating the injured bone suffer from complications based on the slow progression of endogenous vascular repair and often fail at bridging the bone defect. To that end, various strategies have been explored to increase blood vessel regeneration within defects to facilitate both tissue-engineered and natural repair processes. Developments that induce robust vascularization will need to consolidate various parameters including optimization of embedded therapeutics, scaffold characteristics, and successful integration between the construct and the biological tissue. This review provides an overview of current strategies as well as new developments in engineering biomaterials to induce reparation of a functional vascular supply in the context of bone repair.

  5. Strategies and Challenges in Clinical Trials Targeting Human Aging

    PubMed Central

    Newman, John C.; Milman, Sofiya; Hashmi, Shahrukh K.; Austad, Steve N.; Kirkland, James L.; Halter, Jeffrey B.

    2016-01-01

    Interventions that target fundamental aging processes have the potential to transform human health and health care. A variety of candidate drugs have emerged from basic and translational research that may target aging processes. Some of these drugs are already in clinical use for other purposes, such as metformin and rapamycin. However, designing clinical trials to test interventions that target the aging process poses a unique set of challenges. This paper summarizes the outcomes of an international meeting co-ordinated by the NIH-funded Geroscience Network to further the goal of developing a translational pipeline to move candidate compounds through clinical trials and ultimately into use. We review the evidence that some drugs already in clinical use may target fundamental aging processes. We discuss the design principles of clinical trials to test such interventions in humans, including study populations, interventions, and outcomes. As examples, we offer several scenarios for potential clinical trials centered on the concepts of health span (delayed multimorbidity and functional decline) and resilience (response to or recovery from an acute health stress). Finally, we describe how this discussion helped inform the design of the proposed Targeting Aging with Metformin study. PMID:27535968

  6. Characterizing Types of Human Mobility to Inform Differential and Targeted Malaria Elimination Strategies in Northeast Cambodia

    PubMed Central

    Peeters Grietens, Koen; Gryseels, Charlotte; Dierickx, Susan; Bannister-Tyrrell, Melanie; Trienekens, Suzan; Uk, Sambunny; Phoeuk, Pisen; Suon, Sokha; Set, Srun; Gerrets, René; Hoibak, Sarah; Muela Ribera, Joan; Hausmann-Muela, Susanna; Tho, Sochantha; Durnez, Lies; Sluydts, Vincent; d’Alessandro, Umberto; Coosemans, Marc; Erhart, Annette

    2015-01-01

    Human population movements currently challenge malaria elimination in low transmission foci in the Greater Mekong Subregion. Using a mixed-methods design, combining ethnography (n = 410 interviews), malariometric data (n = 4996) and population surveys (n = 824 indigenous populations; n = 704 Khmer migrants) malaria vulnerability among different types of mobile populations was researched in the remote province of Ratanakiri, Cambodia. Different structural types of human mobility were identified, showing differential risk and vulnerability. Among local indigenous populations, access to malaria testing and treatment through the VMW-system and LLIN coverage was high but control strategies failed to account for forest farmers’ prolonged stays at forest farms/fields (61% during rainy season), increasing their exposure (p = 0.002). The Khmer migrants, with low acquired immunity, active on plantations and mines, represented a fundamentally different group not reached by LLIN-distribution campaigns since they were largely unregistered (79%) and unaware of the local VMW-system (95%) due to poor social integration. Khmer migrants therefore require control strategies including active detection, registration and immediate access to malaria prevention and control tools from which they are currently excluded. In conclusion, different types of mobility require different malaria elimination strategies. Targeting mobility without an in-depth understanding of malaria risk in each group challenges further progress towards elimination. PMID:26593245

  7. Learning to Create Ad Strategies for "Different" Target Audiences.

    ERIC Educational Resources Information Center

    Treise, Debbie; Wagner, Elaine

    1999-01-01

    Describes a focus group exercise used with advertising creative- and strategy-development students that was designed to cultivate awareness of the ethnic consumers' purchase-decision process. Offers an overview of the project's stages, describes the assignment, and notes that members of the original-product focus group also reviewed students'…

  8. Targeting Millennials: Social Media Strategies within Higher Education

    ERIC Educational Resources Information Center

    Sessa, Whitney L.

    2015-01-01

    Using a quantitative survey method with an online questionnaire as the data collection tool, the author surveyed 189 social media managers working at American Higher Education institutions to identify forms of social media in use, along with the most popular strategies that colleges and universities use with Facebook.

  9. Plant community and target species affect responses to restoration strategies

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Increases in Kentucky bluegrass and smooth brome on northern Great Plains rangelands have the potential to negatively impact ecosystem function, lower plant diversity and alter seasonal forage distribution, but control strategies are lacking in the region. A project was initiated on a heavily invad...

  10. Activating frataxin expression by repeat-targeted nucleic acids

    PubMed Central

    Li, Liande; Matsui, Masayuki; Corey, David R.

    2016-01-01

    Friedreich's ataxia is an incurable genetic disorder caused by a mutant expansion of the trinucleotide GAA within an intronic FXN RNA. This expansion leads to reduced expression of frataxin (FXN) protein and evidence suggests that transcriptional repression is caused by an R-loop that forms between the expanded repeat RNA and complementary genomic DNA. Synthetic agents that increase levels of FXN protein might alleviate the disease. We demonstrate that introducing anti-GAA duplex RNAs or single-stranded locked nucleic acids into patient-derived cells increases FXN protein expression to levels similar to analogous wild-type cells. Our data are significant because synthetic nucleic acids that target GAA repeats can be lead compounds for restoring curative FXN levels. More broadly, our results demonstrate that interfering with R-loop formation can trigger gene activation and reveal a new strategy for upregulating gene expression. PMID:26842135

  11. Infertile Partnersʼ Coping Strategies Are Interrelated – Implications for Targeted Psychological Counseling

    PubMed Central

    Volmer, L.; Rösner, S.; Toth, B.; Strowitzki, T.; Wischmann, T.

    2017-01-01

    Background Infertility patients often have high stress levels which, in some cases, represent a risk of developing depression or anxiety. The SCREENIVF questionnaire is a validated tool to evaluate such risks. Some coping strategies have been shown to be correlated with infertile couplesʼ levels of stress. Determining which strategies are correlated with higher levels of risk for depression or anxiety could be useful to offer targeted psychological counseling to reduce the risk of depression or anxiety. Materials and Methods A total of 296 women and men who attended the Fertility Center at Heidelberg University Hospital completed the SCREENIVF questionnaire and the COMPI coping scales. Data were analyzed first on an individual basis and focused on the couple, using the Actor Partner Interdependence Model. Results On an individual level, active avoidance coping was positively correlated with a higher risk of depression or anxiety in women, while meaning-based coping was negatively correlated with risk in men. When the results of couples were viewed together, women and men using active avoidance coping exhibited higher risk scores as individuals (actor effect), as did their partners (partner effect). Women who used meaning-based coping had positive actor and partner effects. Women using active-confronting coping had a negative partner effect (higher risk score for men). Conclusions These findings indicate that some coping strategies may have a protective effect while others may increase the risk of emotional maladjustment in infertile couples. Further analysis of coping strategies could help to identify new counseling approaches for infertile patients. PMID:28190889

  12. Overview on the target fabrication facilities at ELI-NP and ongoing strategies

    NASA Astrophysics Data System (ADS)

    Gheorghiu, C. C.; Leca, V.; Popa, D.; Cernaianu, M. O.; Stutman, D.

    2016-10-01

    Along with the development of petawatt class laser systems, the interaction between high power lasers and matter flourished an extensive research, with high-interest applications like: laser nuclear physics, proton radiography or cancer therapy. The new ELI-NP (Extreme Light Infrastructure - Nuclear Physics) petawatt laser facility, with 10PW and ~ 1023W/cm2 beam intensity, is one of the innovative projects that will provide novel research of fundamental processes during light-matter interaction. As part of the ELI-NP facility, Targets Laboratory will provide the means for in-house manufacturing and characterization of the required targets (mainly solid ones) for the experiments, in addition to the research activity carried out in order to develop novel target designs with improved performances. A description of the Targets Laboratory with the main pieces of equipment and their specifications are presented. Moreover, in view of the latest progress in the target design, one of the proposed strategies for the forthcoming experiments at ELI-NP is also described, namely: ultra-thin patterned foil of diamond-like carbon (DLC) coated with a carbon-based ultra-low density layer. The carbon foam which behaves as a near-critical density plasma, will allow the controlled-shaping of the laser pulse before the main interaction with the solid foil. Particular emphasis will be directed towards the target's design optimization, by simulation tests and tuning the key-properties (thickness/length, spacing, density foam, depth, periodicity etc.) which are expected to have a crucial effect on the laser-matter interaction process.

  13. MicroRNA-based Therapeutic Strategies for Targeting Mutant and Wild Type RAS in Cancer

    PubMed Central

    Sharma, Sriganesh B.; Ruppert, J. Michael

    2015-01-01

    MicroRNAs (miRs) have been causally implicated in the progression and development of a wide variety of cancers. miRs modulate the activity of key cell signaling networks by regulating the translation of pathway component proteins. Thus, the pharmacological targeting of miRs that regulate cancer cell signaling networks, either by promoting (using miR-supplementation) or by suppressing (using anti-sense oligonucleotide based strategies) miR activity is an area of intense research. The RAS-Extracellular signal regulated kinase (ERK) pathway represents a major miR-regulated signaling network that endows cells with some of the classical hallmarks of cancer, and is often inappropriately activated in malignancies by somatic genetic alteration through point mutation or alteration of gene copy number. In addition, recent progress indicates that many tumors may be deficient in GTPase activating proteins (GAPs) due to the collaborative action of oncogenic microRNAs. Recent studies also suggest that in tumors harboring a mutant RAS allele there is a critical role for wild type RAS proteins in determining overall RAS-ERK pathway activity. Together, these two advances comprise a new opportunity for therapeutic intervention. In this review, we evaluate miR-based therapeutic strategies for modulating RAS-ERK signaling in cancers, in particular for more direct modulation of RAS-GTP levels, with the potential to complement current strategies in order to yield more durable treatment responses. To this end, we discuss the potential for miR-based therapies focused on three prominent miRs including the pan-RAS regulator let-7 and the GAP regulator comprised of miR-206 and miR-21 (miR-206/21). PMID:26284568

  14. Modulation of actin dynamics as potential macrophage subtype-targeting anti-tumour strategy

    PubMed Central

    Pergola, Carlo; Schubert, Katrin; Pace, Simona; Ziereisen, Jana; Nikels, Felix; Scherer, Olga; Hüttel, Stephan; Zahler, Stefan; Vollmar, Angelika M.; Weinigel, Christina; Rummler, Silke; Müller, Rolf; Raasch, Martin; Mosig, Alexander; Koeberle, Andreas; Werz, Oliver

    2017-01-01

    Tumour-associated macrophages mainly comprise immunosuppressive M2 phenotypes that promote tumour progression besides anti-tumoural M1 subsets. Selective depletion or reprogramming of M2 may represent an innovative anti-cancer strategy. The actin cytoskeleton is central for cellular homeostasis and is targeted for anti-cancer chemotherapy. Here, we show that targeting G-actin nucleation using chondramide A (ChA) predominantly depletes human M2 while promoting the tumour-suppressive M1 phenotype. ChA reduced the viability of M2, with minor effects on M1, but increased tumour necrosis factor (TNF)α release from M1. Interestingly, ChA caused rapid disruption of dynamic F-actin filaments and polymerization of G-actin, followed by reduction of cell size, binucleation and cell division, without cellular collapse. In M1, but not in M2, ChA caused marked activation of SAPK/JNK and NFκB, with slight or no effects on Akt, STAT-1/-3, ERK-1/2, and p38 MAPK, seemingly accounting for the better survival of M1 and TNFα secretion. In a microfluidically-supported human tumour biochip model, circulating ChA-treated M1 markedly reduced tumour cell viability through enhanced release of TNFα. Together, ChA may cause an anti-tumoural microenvironment by depletion of M2 and activation of M1, suggesting induction of G-actin nucleation as potential strategy to target tumour-associated macrophages in addition to neoplastic cells. PMID:28134280

  15. Multi-target siRNA: Therapeutic Strategy for Hepatocellular Carcinoma

    PubMed Central

    Li, Tiejun; Xue, Yuwen; Wang, Guilan; Gu, Tingting; Li, Yunlong; Zhu, York Yuanyuan; Chen, Li

    2016-01-01

    Multiple targets RNAi strategy is a preferred way to treat multigenic diseases, especially cancers. In the study, multi-target siRNAs were designed to inhibit NET-1, EMS1 and VEGF genes in hepatocellular carcinoma (HCC) cells. And multi-target siRNAs showed better silencing effects on NET-1, EMS1 and VEGF, compared with single target siRNA. Moreover, multi-target siRNA showed greater suppression effects on proliferation, migration, invasion, angiogenesis and induced apoptosis in HCC cells. The results suggested that multi-target siRNA might be a preferred strategy for cancer therapy and NET-1, EMS1 and VEGF could be effective targets for HCC treatments. PMID:27390607

  16. Signaling Pathways in Schizophrenia: emerging targets and therapeutic strategies

    PubMed Central

    Karam, Caline S; Ballon, Jacob S; Bivens, Nancy M; Freyberg, Zachary; Girgis, Ragy R; Lizardi-Ortiz, Jose E; Markx, Sander; Lieberman, Jeffrey A; Javitch, Jonathan A

    2013-01-01

    Dopamine D2 receptor antagonism is a unifying property of all antipsychotic drugs in clinical use for schizophrenia. While often effective at ameliorating psychosis, these drugs are largely ineffective at treating negative and cognitive symptoms. Increasing attention is being focused on the complex genetics of the illness and the signaling pathways implicated in its pathophysiology. We review targeted approaches for pharmacotherapy involving the glutamatergic, GABAergic and cholinergic pathways. We also describe a number of the major genetic findings that identify signaling pathways representing potential targets for novel pharmacological intervention. These include genes in the 22q11 locus, DISC1, neuregulin/ERB4, and components of the Akt/GSK-3 pathway. PMID:20579747

  17. Extracellularly activated nanocarriers: A new paradigm of tumor targeted drug delivery

    PubMed Central

    Gullotti, Emily; Yeo, Yoon

    2009-01-01

    One of the main goals of nanomedicine is to develop a nanocarrier that can selectively deliver anti-cancer drugs to the targeted tumors. Extensive efforts have resulted in several tumor-targeted nanocarriers, some of which are approved for clinical use. Most nanocarriers achieve tumor-selective accumulation through the enhanced permeability and retention effect. Targeting molecules such as antibodies, peptides, ligands, or nucleic acids attached to the nanocarriers further enhance their recognition and internalization by the target tissues. While both the stealth and targeting features are important for effective and selective drug delivery to the tumors, achieving both features simultaneously is often found to be difficult. Some of the recent targeting strategies have the potential to overcome this challenge. These strategies utilize the unique extracellular environment of tumors to change the long-circulating nanocarriers to release the drug or interact with cells in a tumor-specific manner. This review discusses the new targeting strategies with recent examples, which utilize the environmental stimuli to activate the nanocarriers. Traditional strategies for tumor-targeted nanocarriers are briefly discussed with an emphasis on their achievements and challenges. PMID:19366234

  18. Integrative biology approach identifies cytokine targeting strategies for psoriasis.

    PubMed

    Perera, Gayathri K; Ainali, Chrysanthi; Semenova, Ekaterina; Hundhausen, Christian; Barinaga, Guillermo; Kassen, Deepika; Williams, Andrew E; Mirza, Muddassar M; Balazs, Mercedesz; Wang, Xiaoting; Rodriguez, Robert Sanchez; Alendar, Andrej; Barker, Jonathan; Tsoka, Sophia; Ouyang, Wenjun; Nestle, Frank O

    2014-02-12

    Cytokines are critical checkpoints of inflammation. The treatment of human autoimmune disease has been revolutionized by targeting inflammatory cytokines as key drivers of disease pathogenesis. Despite this, there exist numerous pitfalls when translating preclinical data into the clinic. We developed an integrative biology approach combining human disease transcriptome data sets with clinically relevant in vivo models in an attempt to bridge this translational gap. We chose interleukin-22 (IL-22) as a model cytokine because of its potentially important proinflammatory role in epithelial tissues. Injection of IL-22 into normal human skin grafts produced marked inflammatory skin changes resembling human psoriasis. Injection of anti-IL-22 monoclonal antibody in a human xenotransplant model of psoriasis, developed specifically to test potential therapeutic candidates, efficiently blocked skin inflammation. Bioinformatic analysis integrating both the IL-22 and anti-IL-22 cytokine transcriptomes and mapping them onto a psoriasis disease gene coexpression network identified key cytokine-dependent hub genes. Using knockout mice and small-molecule blockade, we show that one of these hub genes, the so far unexplored serine/threonine kinase PIM1, is a critical checkpoint for human skin inflammation and potential future therapeutic target in psoriasis. Using in silico integration of human data sets and biological models, we were able to identify a new target in the treatment of psoriasis.

  19. Targeting MIF in Cancer: Therapeutic Strategies, Current Developments, and Future Opportunities.

    PubMed

    O'Reilly, Ciaran; Doroudian, Mohammad; Mawhinney, Leona; Donnelly, Seamas C

    2016-05-01

    Strong evidence has been presented linking chronic inflammation to the onset and pathogenesis of cancer. The multifunctional pro-inflammatory protein macrophage migration inhibitory factor (MIF) occupies a central role in the inflammatory pathway and has been implicated in the tumorigenesis, angiogenesis, and metastasis of many cancer phenotypes. This review highlights the current state of the art, which presents MIF, and the second member of the MIF structural superfamily, D-DT (MIF2), as significant mediators in the inflammatory-cancer axis. Although the mechanism by which MIF asserts its biological activity has yet to be fully understood, it has become clear in recent years that for certain phenotypes of cancer, MIF represents a valid therapeutic target. Current research efforts have focused on small molecule approaches that target MIF's unique tautomerase active site and neutralization of MIF with anti-MIF antibodies. These approaches have yielded promising results in a number of preclinical murine cancer models and have helped to increase our understanding of MIF biological activity. More recently, MIF's involvement in a number of key protein-protein interactions, such as with CD74 and HSP90, has been highlighted and provides a novel platform for the development of anti-MIF chemotherapeutic strategies in the future.

  20. 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

  1. Bypassing Protein Corona Issue on Active Targeting: Zwitterionic Coatings Dictate Specific Interactions of Targeting Moieties and Cell Receptors.

    PubMed

    Safavi-Sohi, Reihaneh; Maghari, Shokoofeh; Raoufi, Mohammad; Jalali, Seyed Amir; Hajipour, Mohammad J; Ghassempour, Alireza; Mahmoudi, Morteza

    2016-09-07

    Surface functionalization strategies for targeting nanoparticles (NP) to specific organs, cells, or organelles, is the foundation for new applications of nanomedicine to drug delivery and biomedical imaging. Interaction of NPs with biological media leads to the formation of a biomolecular layer at the surface of NPs so-called as "protein corona". This corona layer can shield active molecules at the surface of NPs and cause mistargeting or unintended scavenging by the liver, kidney, or spleen. To overcome this corona issue, we have designed biotin-cysteine conjugated silica NPs (biotin was employed as a targeting molecule and cysteine was used as a zwitterionic ligand) to inhibit corona-induced mistargeting and thus significantly enhance the active targeting capability of NPs in complex biological media. To probe the targeting yield of our engineered NPs, we employed both modified silicon wafer substrates with streptavidin (i.e., biotin receptor) to simulate a target and a cell-based model platform using tumor cell lines that overexpress biotin receptors. In both cases, after incubation with human plasma (thus forming a protein corona), cellular uptake/substrate attachment of the targeted NPs with zwitterionic coatings were significantly higher than the same NPs without zwitterionic coating. Our results demonstrated that NPs with a zwitterionic surface can considerably facilitate targeting yield of NPs and provide a promising new type of nanocarriers in biological applications.

  2. A Plethora of Virulence Strategies Hidden Behind Nuclear Targeting of Microbial Effectors

    PubMed Central

    Rivas, Susana; Genin, Stéphane

    2011-01-01

    Plant immune responses depend on the ability to couple rapid recognition of the invading microbe to an efficient response. During evolution, plant pathogens have acquired the ability to deliver effector molecules inside host cells in order to manipulate cellular and molecular processes and establish pathogenicity. Following translocation into plant cells, microbial effectors may be addressed to different subcellular compartments. Intriguingly, a significant number of effector proteins from different pathogenic microorganisms, including viruses, oomycetes, fungi, nematodes, and bacteria, is targeted to the nucleus of host cells. In agreement with this observation, increasing evidence highlights the crucial role played by nuclear dynamics, and nucleocytoplasmic protein trafficking during a great variety of analyzed plant–pathogen interactions. Once in the nucleus, effector proteins are able to manipulate host transcription or directly subvert essential host components to promote virulence. Along these lines, it has been suggested that some effectors may affect histone packing and, thereby, chromatin configuration. In addition, microbial effectors may either directly activate transcription or target host transcription factors to alter their regular molecular functions. Alternatively, nuclear translocation of effectors may affect subcellular localization of their cognate resistance proteins in a process that is essential for resistance protein-mediated plant immunity. Here, we review recent progress in our field on the identification of microbial effectors that are targeted to the nucleus of host plant cells. In addition, we discuss different virulence strategies deployed by microbes, which have been uncovered through examination of the mechanisms that guide nuclear localization of effector proteins. PMID:22639625

  3. Targeting Nucleophosmin 1 Represents a Rational Strategy for Radiation Sensitization

    SciTech Connect

    Sekhar, Konjeti R.; Benamar, Mouadh; Venkateswaran, Amudhan; Sasi, Soumya; Penthala, Narsimha R.; Crooks, Peter A.; Hann, Stephen R.; Geng, Ling; Balusu, Ramesh; Abbas, Tarek; Freeman, Michael L.

    2014-08-01

    Purpose: To test the hypothesis that small molecule targeting of nucleophosmin 1 (NPM1) represents a rational approach for radiosensitization. Methods and Materials: Wilde-type and NPM1-deficient mouse embryo fibroblasts (MEFs) were used to determine whether radiosensitization produced by the small molecule YTR107 was NPM1 dependent. The stress response to ionizing radiation was assessed by quantifying pNPM1, γH2AX, and Rad51 foci, neutral comet tail moment, and colony formation. NPM1 levels in a human-derived non-small-cell lung cancer (NSCLC) tissue microarray (TMA) were determined by immunohistochemistry. YTR107-mediated radiosensitization was assessed in NSCLC cell lines and xenografts. Results: Use of NPM1-null MEFs demonstrated that NPM1 is critical for DNA double- strand break (DSB) repair, that loss of NPM1 increases radiation sensitivity, and that YTR107-mediated radiosensitization is NPM1 dependent. YTR107 was shown to inhibit NPM1 oligomerization and impair formation of pNPM1 irradiation-induced foci that colocalized with γH2AX foci. Analysis of the TMA demonstrated that NPM1 is overexpressed in subsets of NSCLC. YTR107 inhibited DNA DSB repair and radiosensitized NSCLC lines and xenografts. Conclusions: These data demonstrate that YTR107-mediated targeting of NPM1 impairs DNA DSB repair, an event that increases radiation sensitivity.

  4. Understanding L2 French Teaching Strategies in a Non-Target Language Classroom Context

    ERIC Educational Resources Information Center

    Sun, Peijian; Yuan, Rui; Teng, Lin

    2015-01-01

    This research explored the congruence and disparity between teachers' and students' attitudes towards French as a second language (L2) teaching strategies in a non-target language classroom context in the USA. The findings suggest students' and teachers' attitudes towards the direct and indirect teaching strategies were generally consistent, but…

  5. Strategies for active alignment of lenses

    NASA Astrophysics Data System (ADS)

    Langehanenberg, Patrik; Heinisch, Josef; Wilde, Chrisitan; Hahne, Felix; Lüerß, Bernd

    2015-10-01

    Today's optical systems require up-to-date assembly and joining technology. The trend of keeping dimensions as small as possible while maintaining or increasing optical imaging performance leaves little to no room for mechanical lens adjustment equipment that may remain in the final product. In this context active alignment of optical elements opens up possibilities for the fast and cost-economic manufacturing of lenses and lens assemblies with highest optical performance. Active alignment for lens manufacturing is the precise alignment of the optical axis of a lens with respect to an optical or mechanical reference axis (e.g. housing) including subsequent fixation by glue. In this contribution we will describe different approaches for active alignment and outline strengths and limitations of the different methods. Using the SmartAlign principle, highest quality cemented lenses can be manufactured without the need for high precision prealignment, while the reduction to a single alignment step greatly reduces the cycle time. The same strategies can also be applied to bonding processes. Lenses and lens groups can be aligned to both mechanical and optical axes to maximize the optical performance of a given assembly. In hybrid assemblies using both mechanical tolerances and active alignment, SmartAlign can be used to align critical lens elements anywhere inside the system for optimized total performance. Since all geometrical parameters are re-measured before each alignment, this process is especially suited for complex and time-consuming production processes where the stability of the reference axis would otherwise be critical. For highest performance, lenses can be actively aligned using up to five degrees of freedom. In this way, SmartAlign enables the production of ultra-precise mounted lenses with an alignment precision below 1 μm.

  6. Advancements in Tumor Targeting Strategies for Boron Neutron Capture Therapy.

    PubMed

    Luderer, Micah John; de la Puente, Pilar; Azab, Abdel Kareem

    2015-09-01

    Boron neutron capture therapy (BNCT) is a promising cancer therapy modality that utilizes the nuclear capture reaction of epithermal neutrons by boron-10 resulting in a localized nuclear fission reaction and subsequent cell death. Since cellular destruction is limited to approximately the diameter of a single cell, primarily only cells in the neutron field with significant boron accumulation will be damaged. However, the emergence of BNCT as a prominent therapy has in large part been hindered by a paucity of tumor selective boron containing agents. While L-boronophenylalanine and sodium borocaptate are the most commonly investigated clinical agents, new agents are desperately needed due to their suboptimal tumor selectivity. This review will highlight the various strategies to improve tumor boron delivery including: nucleoside and carbohydrate analogs, unnatural amino acids, porphyrins, antibody-dendrimer conjugates, cationic polymers, cell-membrane penetrating peptides, liposomes and nanoparticles.

  7. Targeting TNF: a therapeutic strategy for Alzheimer's disease.

    PubMed

    Cheng, Xin; Shen, Yong; Li, Rena

    2014-11-01

    Tumor necrosis factor (TNF), a ligand cytokine, is involved in systemic inflammation. Apart from the well-known pharmacological effects of TNF inhibitors on autoimmune disorders, interest in the effects of TNF in neurodegenerative disorders such as Alzheimer disease (AD) is increasing. TNF and its type 1 receptor (TNFRI) are not only involved in AD-related brain neuroinflammation, but also contribute to amyloidogenesis via β-secretase regulation, suggesting TNF as a promising candidate for future AD therapy. Although the potential adverse effects of TNF-based AD therapies have been of concerns, here we summarize recent discoveries relating to TNF and TNFRI-mediated signal transduction as potential therapeutic targets in AD pathology and clinical investigations.

  8. Strategies on the nuclear-targeted delivery of genes

    PubMed Central

    Yao, Jing; Fan, Ying; Li, Yuanke; Huang, Leaf

    2016-01-01

    To improve the nuclear-targeted delivery of non-viral vectors, extensive effort has been carried out on the development of smart vectors which could overcome multiple barriers. The nuclear envelope presents a major barrier to transgene delivery. Viruses are capable of crossing the nuclear envelope to efficiently deliver their genome into the nucleus through the specialized protein components. However, non-viral vectors are preferred over viral ones because of the safety concerns associated with the latter. Non-viral delivery systems have been designed to include various types of components to enable nuclear translocation at the periphery of the nucleus. This review summarizes the progress of research regarding nuclear transport mechanisms. “Smart” non-viral vectors that have been modified by peptides and other small molecules are able to facilitate the nuclear translocation and enhance the efficacy of gene expression. The resulting technology may also enhance delivery of other macromolecules to the nucleus. PMID:23964565

  9. Targeting the Central Pocket in Human Transcription Factor TEAD as a Potential Cancer Therapeutic Strategy

    PubMed Central

    Pobbati, Ajaybabu V.; Han, Xiao; Hung, Alvin W.; Weiguang, Seetoh; Huda, Nur; Chen, Guo-Ying; Kang, CongBao; Chia, Cheng San Brian; Luo, Xuelian; Hong, Wanjin; Poulsen, Anders

    2015-01-01

    SUMMARY The human TEAD family of transcription factors (TEAD1-4) is required for YAP-mediated transcription in the Hippo pathway. Hyperactivation of TEAD’s co-activator YAP contributes to tissue overgrowth and human cancers, suggesting that pharmacological interference of TEAD-YAP activity may be an effective strategy for anticancer therapy. Here we report the discovery of a central pocket in the YAP-binding domain (YBD) of TEAD that is targetable by small molecule inhibitors. Our X-ray crystallography studies reveal that flufenamic acid, a non-steroidal anti-inflammatory drug (NSAID), binds to the central pocket of TEAD2 YBD. Our biochemical and functional analyses further demonstrate that binding of NSAIDs to TEAD inhibits TEAD-YAP-dependent transcription, cell migration and proliferation, indicating that the central pocket is important for TEAD function. Therefore, our studies discover a novel way of targeting TEAD transcription factors and set the stage for therapeutic development of specific TEAD-YAP inhibitors against human cancers. PMID:26592798

  10. Tracking strategies for laser ranging to multiple satellite targets

    NASA Technical Reports Server (NTRS)

    Robbins, J. W.; Smith, D. E.; Kolenkiewicz, R.

    1994-01-01

    By the middle of the decade, several new Laser Geodynamic Satellites will be launched to join the current constellation comprised of the laser geodynamic satellite (LAGEOS) (US), Starlette (France), Ajisai (Japan), and Etalon I and II (USSR). The satellites to be launched, LAGEOS II and III (US & Italy), and Stella (France), will be injected into orbits that differ from the existing constellation so that geodetic and gravimetric quantities are sampled to enhance their resolution and accuracy. An examination of various possible tracking strategies adopted by the network of laser tracking stations has revealed that the recovery of precise geodetic parameters can be obtained over shorter intervals than is currently obtainable with the present constellation of satellites. This is particularly important in the planning of mobile laser tracking operations, given a network of permanently operating tracking sites. Through simulations, it is shown that laser tracking of certain satellite passes, pre-selected to provide optimal sky-coverage, provides the means to acquire a sufficient amount of data to allow the recovery of 1 cm station positions.

  11. Novel Strategies for Targeting Innate Immune Responses to Influenza

    PubMed Central

    Shirey, Kari Ann; Lai, Wendy; Patel, Mira C.; Pletneva, Lioubov M.; Pang, Catherine; Kurt-Jones, Evelyn; Lipsky, Michael; Roger, Thierry; Calandra, Thierry; Tracey, Kevin; Al-Abed, Yousef; Bowie, Andrew G.; Fasano, Alessio; Dinarello, Charles; Gusovsky, Fabian; Blanco, Jorge C.G.; Vogel, Stefanie N.

    2016-01-01

    We previously reported that TLR4-/- mice are refractory to mouse-adapted A/PR/8/34 (PR8) influenza-induced lethality and that therapeutic administration of the TLR4 antagonist, Eritoran, blocked PR8-induced lethality and acute lung injury (ALI) when given starting 2 days post-infection. Herein, we extend these findings: anti-TLR4- or TLR2-specific IgG therapy also conferred significant protection of wild-type (WT) mice from lethal PR8 infection. If treatment is initiated 3 h prior to PR8 infection and continued daily for 4 days, Eritoran failed to protect WT and TLR4-/- mice, implying that Eritoran must block a virus-induced, non-TLR4 signal that is required for protection. Mechanistically, we determined that (i) Eritoran blocks HMGB1-mediated, TLR4-dependent signaling in vitro and circulating HMGB1 in vivo, and an HMGB1 inhibitor protects against PR8; (ii) Eritoran inhibits pulmonary lung edema associated with ALI, (iii) IL-1β contributes significantly to PR8-induced lethality, as evidenced by partial protection by IL-1 receptor antagonist (IL-1Ra) therapy. Synergistic protection against PR8-induced lethality was achieved when Eritoran and the anti-viral drug, oseltamivir, were administered starting 4 days post-infection. Eritoran treatment does not prevent development of an adaptive immune response to subsequent PR8 challenge. Overall, our data support the potential of a host-targeted therapeutic approach to influenza infection. PMID:26813341

  12. Targeting cancer’s weaknesses (not its strengths): Therapeutic strategies suggested by the atavistic model

    PubMed Central

    Lineweaver, Charles H.; Davies, Paul C.W.; Vincent, Mark D.

    2014-01-01

    In the atavistic model of cancer progression, tumor cell dedifferentiation is interpreted as a reversion to phylogenetically earlier capabilities. The more recently evolved capabilities are compromised first during cancer progression. This suggests a therapeutic strategy for targeting cancer: design challenges to cancer that can only be met by the recently evolved capabilities no longer functional in cancer cells. We describe several examples of this target-the-weakness strategy. Our most detailed example involves the immune system. The absence of adaptive immunity in immunosuppressed tumor environments is an irreversible weakness of cancer that can be exploited by creating a challenge that only the presence of adaptive immunity can meet. This leaves tumor cells more vulnerable than healthy tissue to pathogenic attack. Such a target-the-weakness therapeutic strategy has broad applications, and contrasts with current therapies that target the main strength of cancer: cell proliferation. PMID:25043755

  13. Goldstone field test activities: Target search

    NASA Technical Reports Server (NTRS)

    Tarter, J.

    1986-01-01

    In March of this year prototype SETI equipment was installed at DSS13, the 26 meter research and development antenna at NASA's Goldstone complex of satellite tracking dishes. The SETI equipment will remain at this site at least through the end of the summer so that the hardware and software developed for signal detection and recognition can be fully tested in a dynamic observatory environment. The field tests are expected to help understand which strategies for observing and which signal recognition algorithms perform best in the presence of strong man-made interfering signals (RFI) and natural astronomical sources.

  14. A targeted quantitative proteomics strategy for global kinome profiling of cancer cells and tissues.

    PubMed

    Xiao, Yongsheng; Guo, Lei; Wang, Yinsheng

    2014-04-01

    Kinases are among the most intensively pursued enzyme superfamilies as targets for anti-cancer drugs. Large data sets on inhibitor potency and selectivity for more than 400 human kinases became available recently, offering the opportunity to design rationally novel kinase-based anti-cancer therapies. However, the expression levels and activities of kinases are highly heterogeneous among different types of cancer and even among different stages of the same cancer. The lack of effective strategy for profiling the global kinome hampers the development of kinase-targeted cancer chemotherapy. Here, we introduced a novel global kinome profiling method, based on our recently developed isotope-coded ATP-affinity probe and a targeted proteomic method using multiple-reaction monitoring (MRM), for assessing simultaneously the expression of more than 300 kinases in human cells and tissues. This MRM-based assay displayed much better sensitivity, reproducibility, and accuracy than the discovery-based shotgun proteomic method. Approximately 250 kinases could be routinely detected in the lysate of a single cell line. Additionally, the incorporation of iRT into MRM kinome library rendered our MRM kinome assay easily transferrable across different instrument platforms and laboratories. We further employed this approach for profiling kinase expression in two melanoma cell lines, which revealed substantial kinome reprogramming during cancer progression and demonstrated an excellent correlation between the anti-proliferative effects of kinase inhibitors and the expression levels of their target kinases. Therefore, this facile and accurate kinome profiling assay, together with the kinome-inhibitor interaction map, could provide invaluable knowledge to predict the effectiveness of kinase inhibitor drugs and offer the opportunity for individualized cancer chemotherapy.

  15. Novel strategies for targeting innate immune responses to influenza.

    PubMed

    Shirey, K A; Lai, W; Patel, M C; Pletneva, L M; Pang, C; Kurt-Jones, E; Lipsky, M; Roger, T; Calandra, T; Tracey, K J; Al-Abed, Y; Bowie, A G; Fasano, A; Dinarello, C A; Gusovsky, F; Blanco, J C G; Vogel, S N

    2016-09-01

    We previously reported that TLR4(-/-) mice are refractory to mouse-adapted A/PR/8/34 (PR8) influenza-induced lethality and that therapeutic administration of the TLR4 antagonist Eritoran blocked PR8-induced lethality and acute lung injury (ALI) when given starting 2 days post infection. Herein we extend these findings: anti-TLR4- or -TLR2-specific IgG therapy also conferred significant protection of wild-type (WT) mice from lethal PR8 infection. If treatment is initiated 3 h before PR8 infection and continued daily for 4 days, Eritoran failed to protect WT and TLR4(-/-) mice, implying that Eritoran must block a virus-induced, non-TLR4 signal that is required for protection. Mechanistically, we determined that (i) Eritoran blocks high-mobility group B1 (HMGB1)-mediated, TLR4-dependent signaling in vitro and circulating HMGB1 in vivo, and an HMGB1 inhibitor protects against PR8; (ii) Eritoran inhibits pulmonary lung edema associated with ALI; (iii) interleukin (IL)-1β contributes significantly to PR8-induced lethality, as evidenced by partial protection by IL-1 receptor antagonist (IL-1Ra) therapy. Synergistic protection against PR8-induced lethality was achieved when Eritoran and the antiviral drug oseltamivir were administered starting 4 days post infection. Eritoran treatment does not prevent development of an adaptive immune response to subsequent PR8 challenge. Overall, our data support the potential of a host-targeted therapeutic approach to influenza infection.

  16. Limited Sampling Strategy and Target Attainment Analysis for Levofloxacin in Patients with Tuberculosis

    PubMed Central

    Alsultan, Abdullah; An, Guohua

    2015-01-01

    There is an urgent need to improve and shorten the treatment of tuberculosis (TB) and multidrug resistant tuberculosis (MDR-TB). Levofloxacin, a newer fluoroquinolone, has potent activity against TB both in vitro and in vivo. Levofloxacin dosing can be optimized to improve the treatment of both TB and MDR-TB. Levofloxacin efficacy is linked primarily to the ratio of the area under the concentration-time curve for the free fraction of drug (fAUC) to the MIC. Since obtaining a full-time concentration profile is not feasible in the clinic, we developed a limited sampling strategy (LSS) to estimate the AUC. We also utilized Monte Carlo simulations to evaluate the dosing of levofloxacin. Pharmacokinetic data were obtained from 10 Brazilian TB patients. The pharmacokinetic data were fitted with a one-compartment model. LSSs were developed using two methods: linear regression and Bayesian approaches. Several LSSs predicted levofloxacin AUC with good accuracy and precision. The most accurate were the method using two samples collected at 4 and 6 h (R2 = 0.91 using linear regression and 0.97 using Bayesian approaches) and that using samples collected at 2 and 6 h (R2 = 0.90 using linear regression and 0.96 using Bayesian approaches). The 2-and-6-h approach also provides a good estimate of the maximum concentration of the drug in serum (Cmax). Our target attainment analysis showed that higher doses (17 to 20 mg/kg of body weight) of levofloxacin might be needed to improve its activity. Doses in the range of 17 to 20 mg/kg showed good target attainment for MICs from 0.25 to 0.50. At an MIC of 2, poor target attainment was observed across all doses. This LSS for levofloxacin can be used for therapeutic drug monitoring and for future pharmacokinetic/pharmacodynamic studies. PMID:25870068

  17. Limited sampling strategy and target attainment analysis for levofloxacin in patients with tuberculosis.

    PubMed

    Alsultan, Abdullah; An, Guohua; Peloquin, Charles A

    2015-07-01

    There is an urgent need to improve and shorten the treatment of tuberculosis (TB) and multidrug resistant tuberculosis (MDR-TB). Levofloxacin, a newer fluoroquinolone, has potent activity against TB both in vitro and in vivo. Levofloxacin dosing can be optimized to improve the treatment of both TB and MDR-TB. Levofloxacin efficacy is linked primarily to the ratio of the area under the concentration-time curve for the free fraction of drug (fAUC) to the MIC. Since obtaining a full-time concentration profile is not feasible in the clinic, we developed a limited sampling strategy (LSS) to estimate the AUC. We also utilized Monte Carlo simulations to evaluate the dosing of levofloxacin. Pharmacokinetic data were obtained from 10 Brazilian TB patients. The pharmacokinetic data were fitted with a one-compartment model. LSSs were developed using two methods: linear regression and Bayesian approaches. Several LSSs predicted levofloxacin AUC with good accuracy and precision. The most accurate were the method using two samples collected at 4 and 6 h (R(2) = 0.91 using linear regression and 0.97 using Bayesian approaches) and that using samples collected at 2 and 6 h (R(2) = 0.90 using linear regression and 0.96 using Bayesian approaches). The 2-and-6-h approach also provides a good estimate of the maximum concentration of the drug in serum (Cmax). Our target attainment analysis showed that higher doses (17 to 20 mg/kg of body weight) of levofloxacin might be needed to improve its activity. Doses in the range of 17 to 20 mg/kg showed good target attainment for MICs from 0.25 to 0.50. At an MIC of 2, poor target attainment was observed across all doses. This LSS for levofloxacin can be used for therapeutic drug monitoring and for future pharmacokinetic/pharmacodynamic studies.

  18. Recent Strategies Targeting HIV Glycans in Vaccine Design

    PubMed Central

    Horiya, Satoru; MacPherson, Iain S.; Krauss, Isaac J.

    2015-01-01

    Although efforts to develop a vaccine against HIV have so far met with little success, recent studies of HIV-positive patients with strongly neutralizing sera have shown that the human immune system is capable of producing potent and broadly-neutralizing antibodies (bnAbs), some of which neutralize up to 90 % of HIV strains. These antibodies bind to conserved vulnerable sites on the viral envelope glycoprotein gp120, and identification of these sites has provided tantalizing clues about the design of potentially effective vaccines. Carbohydrates play a key role in this field, as a large fraction of bnAbs bind to carbohydrates or combinations of carbohydrate and peptide elements on gp120. Additionally, carbohydrates partially mask some peptide surfaces recognized by bnAbs. The use of engineered glycoproteins and other glycostructures as vaccines to elicit antibodies with broad neutralizing activity is therefore a key area of interest in HIV vaccine design. PMID:25393493

  19. Nuclease Target Site Selection for Maximizing On-target Activity and Minimizing Off-target Effects in Genome Editing

    PubMed Central

    Lee, Ciaran M; Cradick, Thomas J; Fine, Eli J; Bao, Gang

    2016-01-01

    The rapid advancement in targeted genome editing using engineered nucleases such as ZFNs, TALENs, and CRISPR/Cas9 systems has resulted in a suite of powerful methods that allows researchers to target any genomic locus of interest. A complementary set of design tools has been developed to aid researchers with nuclease design, target site selection, and experimental validation. Here, we review the various tools available for target selection in designing engineered nucleases, and for quantifying nuclease activity and specificity, including web-based search tools and experimental methods. We also elucidate challenges in target selection, especially in predicting off-target effects, and discuss future directions in precision genome editing and its applications. PMID:26750397

  20. Targeted, noninvasive blockade of cortical neuronal activity

    NASA Astrophysics Data System (ADS)

    McDannold, Nathan; Zhang, Yongzhi; Power, Chanikarn; Arvanitis, Costas D.; Vykhodtseva, Natalia; Livingstone, Margaret

    2015-11-01

    Here we describe a novel method to noninvasively modulate targeted brain areas through the temporary disruption of the blood-brain barrier (BBB) via focused ultrasound, enabling focal delivery of a neuroactive substance. Ultrasound was used to locally disrupt the BBB in rat somatosensory cortex, and intravenous administration of GABA then produced a dose-dependent suppression of somatosensory-evoked potentials in response to electrical stimulation of the sciatic nerve. No suppression was observed 1-5 days afterwards or in control animals where the BBB was not disrupted. This method has several advantages over existing techniques: it is noninvasive; it is repeatable via additional GABA injections; multiple brain regions can be affected simultaneously; suppression magnitude can be titrated by GABA dose; and the method can be used with freely behaving subjects. We anticipate that the application of neuroactive substances in this way will be a useful tool for noninvasively mapping brain function, and potentially for surgical planning or novel therapies.

  1. A combined molecular docking-based and pharmacophore-based target prediction strategy with a probabilistic fusion method for target ranking.

    PubMed

    Li, Guo-Bo; Yang, Ling-Ling; Xu, Yong; Wang, Wen-Jing; Li, Lin-Li; Yang, Sheng-Yong

    2013-07-01

    Herein, a combined molecular docking-based and pharmacophore-based target prediction strategy is presented, in which a probabilistic fusion method is suggested for target ranking. Establishment and validation of the combined strategy are described. A target database, termed TargetDB, was firstly constructed, which contains 1105 drug targets. Based on TargetDB, the molecular docking-based target prediction and pharmacophore-based target prediction protocols were established. A probabilistic fusion method was then developed by constructing probability assignment curves (PACs) against a set of selected targets. Finally the workflow for the combined molecular docking-based and pharmacophore-based target prediction strategy was established. Evaluations of the performance of the combined strategy were carried out against a set of structurally different single-target compounds and a well-known multi-target drug, 4H-tamoxifen, which results showed that the combined strategy consistently outperformed the sole use of docking-based and pharmacophore-based methods. Overall, this investigation provides a possible way for improving the accuracy of in silico target prediction and a method for target ranking.

  2. Journey to the Center of the Cell: Current Nanocarrier Design Strategies Targeting Biopharmaceuticals to the Cytoplasm and Nucleus.

    PubMed

    Munsell, Erik V; Ross, Nikki L; Sullivan, Millicent O

    2016-01-01

    New biopharmaceutical molecules, potentially able to provide more personalized and effective treatments, are being identified through the advent of advanced synthetic biology strategies, sophisticated chemical synthesis approaches, and new analytical methods to assess biological potency. However, translation of many of these structures has been significantly limited due to the need for more efficient strategies to deliver macromolecular therapeutics to desirable intracellular sites of action. Engineered nanocarriers that encapsulate peptides, proteins, or nucleic acids are generally internalized into target cells via one of several endocytic pathways. These nanostructures, entrapped within endosomes, must navigate the intracellular milieu to orchestrate delivery to the intended destination, typically the cytoplasm or nucleus. For therapeutics active in the cytoplasm, endosomal escape continues to represent a limiting step to effective treatment, since a majority of nanocarriers trapped within endosomes are ultimately marked for enzymatic degradation in lysosomes. Therapeutics active in the nucleus have the added challenges of reaching and penetrating the nuclear envelope, and nuclear delivery remains a preeminent challenge preventing clinical translation of gene therapy applications. Herein, we review cutting-edge peptide- and polymer-based design strategies with the potential to enable significant improvements in biopharmaceutical efficacy through improved intracellular targeting. These strategies often mimic the activities of pathogens, which have developed innate and highly effective mechanisms to penetrate plasma membranes and enter the nucleus of host cells. Understanding these mechanisms has enabled advances in synthetic peptide and polymer design that may ultimately improve intracellular trafficking and bioavailability, leading to increased access to new classes of biotherapeutics.

  3. Journey to the Center of the Cell: Current Nanocarrier Design Strategies Targeting Biopharmaceuticals to the Cytoplasm and Nucleus

    PubMed Central

    Munsell, Erik V.; Ross, Nikki L.; Sullivan, Millicent O.

    2016-01-01

    New biopharmaceutical molecules, potentially able to provide more personalized and effective treatments, are being identified through the advent of advanced synthetic biology strategies, sophisticated chemical synthesis approaches, and new analytical methods to assess biological potency. However, translation of many of these structures has been significantly limited due to the need for more efficient strategies to deliver macromolecular therapeutics to desirable intracellular sites of action. Engineered nanocarriers that encapsulate peptides, proteins, or nucleic acids are generally internalized into target cells via one of several endocytic pathways. These nanostructures, entrapped within endosomes, must navigate the intracellular milieu to orchestrate delivery to the intended destination, typically the cytoplasm or nucleus. For therapeutics active in the cytoplasm, endosomal escape continues to represent a limiting step to effective treatment, since a majority of nanocarriers trapped within endosomes are ultimately marked for enzymatic degradation in lysosomes. Therapeutics active in the nucleus have the added challenges of reaching and penetrating the nuclear envelope, and nuclear delivery remains a preeminent challenge preventing clinical translation of gene therapy applications. Herein, we review cutting-edge peptide- and polymer-based design strategies with the potential to enable significant improvements in biopharmaceutical efficacy through improved intracellular targeting. These strategies often mimic the activities of pathogens, which have developed innate and highly effective mechanisms to penetrate plasma membranes and enter the nucleus of host cells. Understanding these mechanisms has enabled advances in synthetic peptide and polymer design that may ultimately improve intracellular trafficking and bioavailability, leading to increased access to new classes of biotherapeutics. PMID:26675220

  4. Structures of Cryptococcus neoformans protein farnesyltransferase reveal strategies for developing inhibitors that target fungal pathogens.

    PubMed

    Hast, Michael A; Nichols, Connie B; Armstrong, Stephanie M; Kelly, Shannon M; Hellinga, Homme W; Alspaugh, J Andrew; Beese, Lorena S

    2011-10-07

    Cryptococcus neoformans is a fungal pathogen that causes life-threatening infections in immunocompromised individuals, including AIDS patients and transplant recipients. Few antifungals can treat C. neoformans infections, and drug resistance is increasing. Protein farnesyltransferase (FTase) catalyzes post-translational lipidation of key signal transduction proteins and is essential in C. neoformans. We present a multidisciplinary study validating C. neoformans FTase (CnFTase) as a drug target, showing that several anticancer FTase inhibitors with disparate scaffolds can inhibit C. neoformans and suggesting structure-based strategies for further optimization of these leads. Structural studies are an essential element for species-specific inhibitor development strategies by revealing similarities and differences between pathogen and host orthologs that can be exploited. We, therefore, present eight crystal structures of CnFTase that define the enzymatic reaction cycle, basis of ligand selection, and structurally divergent regions of the active site. Crystal structures of clinically important anticancer FTase inhibitors in complex with CnFTase reveal opportunities for optimization of selectivity for the fungal enzyme by modifying functional groups that interact with structurally diverse regions. A substrate-induced conformational change in CnFTase is observed as part of the reaction cycle, a feature that is mechanistically distinct from human FTase. Our combined structural and functional studies provide a framework for developing FTase inhibitors to treat invasive fungal infections.

  5. Structures of Cryptococcus neoformans Protein Farnesyltransferase Reveal Strategies for Developing Inhibitors That Target Fungal Pathogens

    SciTech Connect

    Hast, Michael A.; Nichols, Connie B.; Armstrong, Stephanie M.; Kelly, Shannon M.; Hellinga, Homme W.; Alspaugh, J. Andrew; Beese, Lorena S.

    2012-09-17

    Cryptococcus neoformans is a fungal pathogen that causes life-threatening infections in immunocompromised individuals, including AIDS patients and transplant recipients. Few antifungals can treat C. neoformans infections, and drug resistance is increasing. Protein farnesyltransferase (FTase) catalyzes post-translational lipidation of key signal transduction proteins and is essential in C. neoformans. We present a multidisciplinary study validating C. neoformans FTase (CnFTase) as a drug target, showing that several anticancer FTase inhibitors with disparate scaffolds can inhibit C. neoformans and suggesting structure-based strategies for further optimization of these leads. Structural studies are an essential element for species-specific inhibitor development strategies by revealing similarities and differences between pathogen and host orthologs that can be exploited. We, therefore, present eight crystal structures of CnFTase that define the enzymatic reaction cycle, basis of ligand selection, and structurally divergent regions of the active site. Crystal structures of clinically important anticancer FTase inhibitors in complex with CnFTase reveal opportunities for optimization of selectivity for the fungal enzyme by modifying functional groups that interact with structurally diverse regions. A substrate-induced conformational change in CnFTase is observed as part of the reaction cycle, a feature that is mechanistically distinct from human FTase. Our combined structural and functional studies provide a framework for developing FTase inhibitors to treat invasive fungal infections.

  6. Community-Engaged Strategies to Promote Relevance of Research Capacity-Building Efforts Targeting Community Organizations

    PubMed Central

    Cunningham, Jennifer; Miller, Stephania T.; Joosten, Yvonne; Elzey, Jared D.; Israel, Tiffany; King, Christine; Luther, Patrick; Vaughn, Yolanda; Wilkins, Consuelo H.

    2015-01-01

    Objective The study goal is to highlight strategies for promoting relevance of research capacity-building efforts targeting community organizations (CO)s. Methods Two community partners, representing two COs, were invited to participate in CO research development trainings, Community Research Forums (Forum)s. Their contributions were documented via Forum document review. Forum participants, representatives from other COs, completed post-Forum surveys to identify additional training needs and rate Forum impact relative to their training expectations. A content-based analysis and descriptive statistics were used to summarize needs assessment- and impact-related survey responses, respectively. Results Community partners were involved in eight Forum-related activities including marketing (planning), facilitation (implementation), and manuscript co-authorship (dissemination). Eighty-one individuals, representing 55 COs, attended the Forums. Needs assessment responses revealed a desire for additional assistance with existing Forum topics (e.g., defining research priorities) and a need for new ones (e.g., promoting organizational buy-in for research). Ninety-one percent of participants agreed that the Forum demonstrated the value of research to COs and how to create a research agenda. Conclusions Including community partners in all Forum phases ensured that CO perspectives were integrated throughout. Post-forum needs and impact assessment results will help in tailoring, where needed, future training topics and strategies, respectively. PMID:25951171

  7. Fighting Cancer with Transition Metal Complexes: From Naked DNA to Protein and Chromatin Targeting Strategies

    PubMed Central

    Palermo, Giulia; Magistrato, Alessandra; Riedel, Tina; von Erlach, Thibaud; Davey, Curt A.; Dyson, Paul J.

    2015-01-01

    Abstract Many transition metal complexes have unique physicochemical properties that can be efficiently exploited in medicinal chemistry for cancer treatment. Traditionally, double‐stranded DNA has been assumed to be the main binding target; however, recent studies have shown that nucleosomal DNA as well as proteins can act as dominant molecular binding partners. This has raised new questions about the molecular determinants that govern DNA versus protein binding selectivity, and has offered new ways to rationalize their biological activity and possible side effects. To address these questions, molecular simulations at an atomistic level of detail have been used to complement, support, and rationalize experimental data. Herein we review some relevant studies—focused on platinum and ruthenium compounds—to illustrate the power of state‐of‐the‐art molecular simulation techniques and to demonstrate how the interplay between molecular simulations and experiments can make important contributions to elucidating the target preferences of some promising transition metal anticancer agents. This contribution aims at providing relevant information that may help in the rational design of novel drug‐discovery strategies. PMID:26634638

  8. Utilizing G2/M retention effect to enhance tumor accumulation of active targeting nanoparticles

    PubMed Central

    Hu, Guanlian; Cun, Xingli; Ruan, Shaobo; Shi, Kairong; Wang, Yang; Kuang, Qifang; Hu, Chuan; Xiao, Wei; He, Qin; Gao, Huile

    2016-01-01

    In recent years, active targeting strategies by ligand modification have emerged to enhance tumor accumulation of NP, but their clinical application was strictly restricted due to the complex preparation procedures, poor stability and serious toxicity. An effective and clinical translational strategy is required to satisfy the current problems. Interestingly, the internalization of NP is intimately related with cell cycle and the expression of receptors is not only related with cancer types but also cell cycle progression. So the cellular uptake of ligand modified NP may be related with cell cycle. However, few investigations were reported about the relationship between cell cycle and the internalization of ligand modified NP. Herein, cellular uptake of folic acid (FA) modified NP after utilizing chemotherapeutic to retain the tumor cells in G2/M phase was studied and a novel strategy was designed to enhance the active targeting effect. In our study, docetaxel (DTX) notably synchronized cells in G2/M phase and pretreatment with DTX highly improved in vitro and in vivo tumor cell targeting effect of FA decorated NP (FANP). Since FA was a most common used tumor active targeting ligand, we believe that this strategy possesses broader prospects in clinical application for its simplicity and effectiveness. PMID:27273770

  9. Active Learning Strategies and Assessment in World Geography Classes

    ERIC Educational Resources Information Center

    Klein, Phil

    2003-01-01

    Active learning strategies include a variety of methods, such as inquiry and discovery, in which students are actively engaged in the learning process. This article describes several strategies that can be used in secondary-or college-level world geography courses. The goal of these activities is to foster development of a spatial perspective in…

  10. Active Learning: 101 Strategies To Teach Any Subject.

    ERIC Educational Resources Information Center

    Silberman, Mel

    This book contains specific, practical strategies that can be used for almost any subject matters to promote active learning. It brings together in one source a comprehensive collection of instructional strategies, with ways to get students to be active from the beginning through activities that build teamwork and get students thinking about the…

  11. Improving fold activation of small transcription activating RNAs (STARs) with rational RNA engineering strategies.

    PubMed

    Meyer, Sarai; Chappell, James; Sankar, Sitara; Chew, Rebecca; Lucks, Julius B

    2016-01-01

    Regulatory RNAs have become integral components of the synthetic biology and bioengineering toolbox for controlling gene expression. We recently expanded this toolbox by creating small transcription activating RNAs (STARs) that act by disrupting the formation of a target transcriptional terminator hairpin placed upstream of a gene. While STARs are a promising addition to the repertoire of RNA regulators, much work remains to be done to optimize the fold activation of these systems. Here we apply rational RNA engineering strategies to improve the fold activation of two STAR regulators. We demonstrate that a combination of promoter strength tuning and multiple RNA engineering strategies can improve fold activation from 5.4-fold to 13.4-fold for a STAR regulator derived from the pbuE riboswitch terminator. We then validate the generality of our approach and show that these same strategies improve fold activation from 2.1-fold to 14.6-fold for an unrelated STAR regulator, opening the door to creating a range of additional STARs to use in a broad array of biotechnologies. We also establish that the optimizations preserve the orthogonality of these STARs between themselves and a set of RNA transcriptional repressors, enabling these optimized STARs to be used in sophisticated circuits.

  12. Active calibration target for bistatic radar cross-section measurements

    NASA Astrophysics Data System (ADS)

    Pienaar, M.; Odendaal, J. W.; Joubert, J.; Cilliers, J. E.; Smit, J. C.

    2016-05-01

    Either passive calibration targets are expensive and complex to manufacture or their bistatic radar cross section (RCS) levels are significantly lower than the monostatic RCS levels of targets such as spheres, dihedral, and trihedral corner reflectors. In this paper the performance of an active calibration target with relative high bistatic RCS values is illustrated as a reference target for bistatic RCS measurements. The reference target is simple to manufacture, operates over a wide frequency range, and can be configured to calibrate all four polarizations (VV, HH, HV, and VH). Bistatic RCS measurements of canonical targets, performed in a controlled environment, are calibrated with the reference target and the results are compared to simulated results using FEKO.

  13. Optimal marker-strategy clinical trial design to detect predictive markers for targeted therapy.

    PubMed

    Zang, Yong; Liu, Suyu; Yuan, Ying

    2016-07-01

    In developing targeted therapy, the marker-strategy design (MSD) provides an important approach to evaluate the predictive marker effect. This design first randomizes patients into non-marker-based or marker-based strategies. Patients allocated to the non-marker-based strategy are then further randomized to receive either the standard or targeted treatments, while patients allocated to the marker-based strategy receive treatments based on their marker statuses. Little research has been done on the statistical properties of the MSD, which has led to some widespread misconceptions and placed clinical researchers at high risk of using inefficient designs. In this article, we show that the commonly used between-strategy comparison has low power to detect the predictive effect and is valid only under a restrictive condition that the randomization ratio within the non-marker-based strategy matches the marker prevalence. We propose a Wald test that is generally valid and also uniformly more powerful than the between-strategy comparison. Based on that, we derive an optimal MSD that maximizes the power to detect the predictive marker effect by choosing the optimal randomization ratios between the two strategies and treatments. Our numerical study shows that using the proposed optimal designs can substantially improve the power of the MSD to detect the predictive marker effect. We use a lung cancer trial to illustrate the proposed optimal designs.

  14. Dual cancer-specific targeting strategy cures primary and distant breast carcinomas in nude mice.

    PubMed

    Sarkar, Devanand; Su, Zao-Zhong; Vozhilla, Nicolaq; Park, Eun Sook; Gupta, Pankaj; Fisher, Paul B

    2005-09-27

    Limitations of current viral-based gene therapies for malignant tumors include lack of cancer-specific targeting and insufficient tumor delivery. To ameliorate these problems and develop a truly effective adenovirus gene-based therapy for cancer, we constructed a conditionally replication competent adenovirus (CRCA) manifesting the unique properties of tumor-specific virus replication in combination with production of a cancer-selective cytotoxic cytokine, melanoma differentiation associated gene-7/interleukin-24 (mda-7/IL-24), which embodies potent bystander antitumor activity. Cancer cell selective tropism was ensured by engineering the expression of the adenoviral E1A protein, necessary for viral replication, under the control of a minimal promoter region of progression elevated gene-3 (PEG-3), which functions selectively in diverse cancer cells with minimal activity in normal cells. In the E3 region of this CRCA, we introduced the mda-7/IL-24 gene, thereby mediating robust production of this cytokine as a function of adenovirus replication. Infection of this CRCA (designated Ad.PEG-E1A-mda-7) in normal mammary epithelial cells and breast cancer cells confirmed cancer cell selective adenoviral replication, mda-7/IL-24 expression, growth inhibition, and apoptosis induction. Injecting Ad.PEG-E1A-mda-7 into human breast cancer xenografts in athymic nude mice completely eradicated not only the primary tumor but also distant tumors (established on the opposite flank of the animal) thereby implementing a cure. This dual cancer-specific targeting strategy provides an effective approach for treating breast and other human neoplasms with the potential for eradicating both primary tumors and metastatic disease. Additionally, these studies support the potential use of mda-7/IL-24 in the therapy of malignant cancers.

  15. Developments of thick solid neon as an active target

    NASA Astrophysics Data System (ADS)

    Kamiguchi, Nagaaki; Moriguchi, Tetsurou; Ozawa, Akira; Isimoto, Sigeru

    2009-10-01

    One of research subjects in our group is to measure reaction cross sections (σR) of RI beams. By measuring σR, we can deduce root mean square radii of unstable nuclei. In the measurements of σR, we usually used a carbon as the reaction targets (a few cm thickness). If we use the reaction target as a detector (active target), there are some advantages in the measurements; (1)The events only colliding with the reaction target can be selected. (2)If position information is available, we may define the colliding point inside the target. (3)If energy information is available, we may measure the energy loss of the beams inside the target. As the active target in the σR measurements, we noticed the solid neon. Since the neon is a noble gas, it is predicted to emit scintillations and work as an ionization chamber for charged particles. Indeed, scintillations from liquid and solid neon have been already observed. We will present production of the thick solid neon (˜30mm thickness), and observations of scintillations and ionization signals from the solid neon. We will also discuss possibility to use the sold neon as the active target in the σR measurements.

  16. Understanding the fate of chlorogenic acids in coffee roasting using mass spectrometry based targeted and non-targeted analytical strategies.

    PubMed

    Jaiswal, Rakesh; Matei, Marius F; Golon, Agnieszka; Witt, Matthias; Kuhnert, Nikolai

    2012-09-01

    Coffee is one of mankind's most popular beverages obtained from green coffee beans by roasting. Much effort has been expended towards the chemical characterisation of the components of the roasted coffee bean, frequently termed melanoidines, which are dominated byproducts formed from its most relevant secondary metabolites - chlorogenic acids. However, impeded by a lack of suitable authentic reference standards and analytical techniques sufficiently powerful for providing insight into an extraordinarily complex enigmatic material, unsurprisingly little structural and mechanistic information about the products of coffee roasting is available. Here we report on the characterisation of low molecular weight melanoidine fractions of roasted coffee using a conceptually novel combination of targeted and non-targeted mass spectrometrical techniques. We provide an unprecedented account of the chemical composition of roasted coffee beans. Using a targeted analytical approach we show for the first time, by comparison to authentic reference standards obtained by chemical synthesis, that chlorogenic acids follow four distinct reaction pathways including epimerization, acyl migration, lactonisation and dehydration. The analytical strategy employed in a non-targeted approach uses high resolution mass spectrometry to identify the most abundant molecular formulas present in roasted coffee samples and model roasts followed by van Krevelen and homologous series analysis. We identified the molecular formulas formed from reactions of chlorogenic acids, carbohydrates and proteins, both between classes of compounds and within same classes of compounds. Furthermore, we identified two new classes of compounds formed from chlorogenic acids during roasting, chlorogenic acid acetates and O-phenolic quinoyl and shikimoyl esters of chlorogenic acids.

  17. Tobramycin variants with enhanced ribosome-targeting activity

    PubMed Central

    Fosso, Marina Y.; Zhu, Hongkun; Green, Keith D.

    2015-01-01

    With the increased evolution of aminoglycoside (AG)-resistant bacterial strains, the need to develop AGs with (i) enhanced antimicrobial activity, (ii) the ability to evade resistance mechanisms, and (iii) the capability of targeting the ribosome with higher efficiency, is more and more pressing. The chemical derivatization of the naturally occurring tobramycin (TOB) by attachment of 37 different thioethers groups at the 6″-position led to the identification of generally poorer substrates of TOB-targeting AG-modifying enzymes (AMEs). Thirteen of these displayed better antibacterial activity than the parental TOB while retaining ribosome-targeting specificity. Analysis of these compounds in vitro shed light on the mechanism by which they act and revealed three with clearly enhanced ribosome-targeting activity. PMID:26033429

  18. Peroxisome proliferator-activated receptor alpha target genes.

    PubMed

    Rakhshandehroo, Maryam; Knoch, Bianca; Müller, Michael; Kersten, Sander

    2010-01-01

    The peroxisome proliferator-activated receptor alpha (PPARα) is a ligand-activated transcription factor involved in the regulation of a variety of processes, ranging from inflammation and immunity to nutrient metabolism and energy homeostasis. PPARα serves as a molecular target for hypolipidemic fibrates drugs which bind the receptor with high affinity. Furthermore, PPARα binds and is activated by numerous fatty acids and fatty acid-derived compounds. PPARα governs biological processes by altering the expression of a large number of target genes. Accordingly, the specific role of PPARα is directly related to the biological function of its target genes. Here, we present an overview of the involvement of PPARα in lipid metabolism and other pathways through a detailed analysis of the different known or putative PPARα target genes. The emphasis is on gene regulation by PPARα in liver although many of the results likely apply to other organs and tissues as well.

  19. Peroxisome Proliferator-Activated Receptor Alpha Target Genes

    PubMed Central

    Rakhshandehroo, Maryam; Knoch, Bianca; Müller, Michael; Kersten, Sander

    2010-01-01

    The peroxisome proliferator-activated receptor alpha (PPARα) is a ligand-activated transcription factor involved in the regulation of a variety of processes, ranging from inflammation and immunity to nutrient metabolism and energy homeostasis. PPARα serves as a molecular target for hypolipidemic fibrates drugs which bind the receptor with high affinity. Furthermore, PPARα binds and is activated by numerous fatty acids and fatty acid-derived compounds. PPARα governs biological processes by altering the expression of a large number of target genes. Accordingly, the specific role of PPARα is directly related to the biological function of its target genes. Here, we present an overview of the involvement of PPARα in lipid metabolism and other pathways through a detailed analysis of the different known or putative PPARα target genes. The emphasis is on gene regulation by PPARα in liver although many of the results likely apply to other organs and tissues as well. PMID:20936127

  20. 78 FR 14121 - Notice of Availability of Funds and Solicitation for Grant Applications for Strategies Targeting...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-03-04

    ... Investment Act to serve adult and youth ex-offenders. Services for ex-offenders will be targeted to females... grants will include an integrated strategy of recruitment and assessment, empowerment and self... . The Web sites provide application information, eligibility requirements, review and...

  1. MET/HGF pathway activation as a paradigm of resistance to targeted therapies.

    PubMed

    Ko, Brian; He, Tianfang; Gadgeel, Shirish; Halmos, Balazs

    2017-01-01

    Resistance to targeted therapeutics is a key issue limiting the long-term utility of these medications in the management of molecularly selected subsets of cancer patients, including patients with non-small cell lung cancer harboring oncogenic alterations affecting EGFR, ALK and other genes. Bypass resistance mediated by activation of MET kinase has emerged as a frequent, validated and pivotal resistance mechanism in multiple types of cancers. Biochemical understanding is accumulating to explain the unique role of MET in such bypass pathways, providing alternate downstream activation opportunities and intricate interactions during epithelial-mesenchymal transitions. Multiple diagnostic testing platforms have become available for selecting appropriate patients for MET targeting in a variety of settings. Importantly, in light of the failures of several earlier clinical studies of MET targeting agents, a large array of recent and current MET-focused trials are incorporating stricter patient selection and more robust predictive biomarkers providing hope for validation of MET targeting as a clinically impactful strategy.

  2. 78 FR 70537 - Takes of Marine Mammals Incidental to Specified Activities; Target and Missile Launch Activities...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-11-26

    ... U.S. Navy (Navy), Naval Air Warfare Center Weapons Division (NAWCWD) for authorization to take... conducted for testing new types of targets. Missiles vary from tactical and developmental weapons to target missiles used to test defensive strategies and other weapons systems. Up to 200 missiles may be...

  3. Amplification of TRIM44: Pairing a Prognostic Target With Potential Therapeutic Strategy

    PubMed Central

    Ong, Chin-Ann Johnny; Shannon, Nicholas B.; Ross-Innes, Caryn S.; O’Donovan, Maria; Rueda, Oscar M.; Hu, De-en; Kettunen, Mikko I.; Walker, Christina Elaine; Noorani, Ayesha; Hardwick, Richard H.; Caldas, Carlos; Brindle, Kevin

    2014-01-01

    Background Many prognostic biomarkers have been proposed recently. However, there is a lack of therapeutic strategies exploiting novel prognostic biomarkers. We aimed to propose therapeutic options in patients with overexpression of TRIM44, a recently identified prognostic gene. Methods Genomic and transcriptomic data of epithelial cancers (n = 1932), breast cancers (BCs; n = 1980) and esophago-gastric cancers (EGCs; n = 163) were used to identify genomic aberrations driving TRIM44 overexpression. The driver gene status of TRIM44 was determined using a small interfering RNA (siRNA) screen of the 11p13 amplicon. Integrative analysis was applied across multiple datasets to identify pathway activation and potential therapeutic strategies. Validation of the in silico findings were performed using in vitro assays, xenografts, and patient samples (n = 160). Results TRIM44 overexpression results from genomic amplification in 16.1% of epithelial cancers, including 8.1% of EGCs and 6.1% of BCs. This was confirmed using fluorescent in situ hybridization. The siRNA screen confirmed TRIM44 to be a driver of the amplicon. In silico analysis revealed an association between TRIM44 and mTOR signalling, supported by a decrease in mTOR signalling after siRNA knockdown of TRIM44 in cell lines and colocalization of TRIM44 and p-mTOR in patient samples. In vitro inhibition studies using an mTOR inhibitor (everolimus) decreased cell viability in two TRIM44-amplified cells lines by 88% and 70% compared with 35% in the control cell line. These findings were recapitulated in xenograft models. Conclusions Genomic amplification drives TRIM44 overexpression in EGCs and BCs. Targeting the mTOR pathway provides a potential therapeutic option for TRIM44-amplified tumors. PMID:24777112

  4. Ligand-based targeted therapy: a novel strategy for hepatocellular carcinoma

    PubMed Central

    Li, Min; Zhang, Weiyue; Wang, Birong; Gao, Yang; Song, Zifang; Zheng, Qi Chang

    2016-01-01

    Hepatocellular carcinoma (HCC) is the most common primary liver cancer with high morbidity and mortality worldwide. Chemotherapy is recommended to patients with intermediate or advanced stage cancer. However, the conventional chemotherapy yields low desired response rates due to multidrug resistance, fast clearance rate, nonspecific delivery, severe side effects, low drug concentration in cancer cells, and so on. Nanoparticle-mediated targeted drug delivery system can surmount the aforementioned obstacles through enhanced permeability and retention effect and active targeting as a novel approach of therapeutics for HCC in recent years. The active targeting is triggered by ligands on the delivery system, which recognize with and internalize into hepatoma cells with high specificity and efficiency. This review focuses on the latest targeted delivery systems for HCC and summarizes the ligands that can enhance the capacity of active targeting, to provide some insight into future research in nanomedicine for HCC. PMID:27920520

  5. Clear speech production of Korean stops: changing phonetic targets and enhancement strategies.

    PubMed

    Kang, Kyoung-Ho; Guion, Susan G

    2008-12-01

    The proposal that phonological contrast is enhanced through greater approximation of phonetic targets was investigated by comparing clear speech to conversational and citation-form speech produced by Korean speakers. The stop system of Korean is undergoing a sound change in which younger speakers produce the aspirated-lenis stop contrast differently from previous generations. Older speakers differentiate this contrast primarily with the acoustic correlate of voice onset time (VOT) and secondarily with F0. Younger speakers are merging VOT values for this contrast. As a result, the primary acoustic correlate is now F0 for younger speakers. These production differences likely indicate that younger speakers have developed different phonetic targets for stop production. These different phonetic targets were predicted to result in different enhancement patterns in clear speech: Younger speakers were predicted to enhance F0 differences, whereas older speakers were predicted to enhance VOT differences in clear speech. Results indicated that the older group solely used VOT to enhance the contrast in clear speech, whereas the younger group primarily used F0 but also demonstrated small VOT enhancement. These results indicate that clear speech enhancement strategies reflect phonetic targets. Older and younger speakers have different F0 and VOT targets and these different targets conditioned different enhancement strategies.

  6. Implications of structural genomics target selection strategies: Pfam5000, whole genome, and random approaches

    SciTech Connect

    Chandonia, John-Marc; Brenner, Steven E.

    2004-07-14

    The structural genomics project is an international effort to determine the three-dimensional shapes of all important biological macromolecules, with a primary focus on proteins. Target proteins should be selected according to a strategy which is medically and biologically relevant, of good value, and tractable. As an option to consider, we present the Pfam5000 strategy, which involves selecting the 5000 most important families from the Pfam database as sources for targets. We compare the Pfam5000 strategy to several other proposed strategies that would require similar numbers of targets. These include including complete solution of several small to moderately sized bacterial proteomes, partial coverage of the human proteome, and random selection of approximately 5000 targets from sequenced genomes. We measure the impact that successful implementation of these strategies would have upon structural interpretation of the proteins in Swiss-Prot, TrEMBL, and 131 complete proteomes (including 10 of eukaryotes) from the Proteome Analysis database at EBI. Solving the structures of proteins from the 5000 largest Pfam families would allow accurate fold assignment for approximately 68 percent of all prokaryotic proteins (covering 59 percent of residues) and 61 percent of eukaryotic proteins (40 percent of residues). More fine-grained coverage which would allow accurate modeling of these proteins would require an order of magnitude more targets. The Pfam5000 strategy may be modified in several ways, for example to focus on larger families, bacterial sequences, or eukaryotic sequences; as long as secondary consideration is given to large families within Pfam, coverage results vary only slightly. In contrast, focusing structural genomics on a single tractable genome would have only a limited impact in structural knowledge of other proteomes: a significant fraction (about 30-40 percent of the proteins, and 40-60 percent of the residues) of each proteome is classified in small

  7. Developing, implementing, and evaluating a condom promotion program targeting sexually active adolescents.

    PubMed

    Alstead, M; Campsmith, M; Halley, C S; Hartfield, K; Goldbaum, G; Wood, R W

    1999-12-01

    This article describes the development, implementation, and evaluation of the Condom Campaign, a 1995 HIV prevention program promoting condom use among sexually active adolescents in three King County, Washington, urban communities. This program employed three main strategies: (a) mobilizing all levels of the target communities to support and guide program development and implementation; (b) creating and implementing a mass media campaign targeting sexually active teenagers that promoted correct condom use and favorable attitudes toward condoms; and (c) recruiting public agencies, community organizations, and businesses to distribute condoms from bins and vending machines. We evaluated the program through a series of cross-sectional interviews conducted in the three communities chosen for their elevated levels of adolescent sexual risk behavior. Overall, 73% of target youth reported exposure to the Condom Campaign; exposure did not differ by age, gender, race, or level of sexual experience. Levels of sexual activity remained stable throughout the media campaign.

  8. Integration of phosphoproteomic, chemical, and biological strategies for the functional analysis of targeted protein phosphorylation.

    PubMed

    Guo, Mingquan; Huang, Bill X

    2013-02-01

    Reversible phosphorylation, tightly controlled by protein kinases and phosphatases, plays a central role in mediating biological processes, such as protein-protein interactions, subcellular translocation, and activation of cellular enzymes. MS-based phosphoproteomics has now allowed the detection and quantification of tens of thousands of phosphorylation sites from a typical biological sample in a single experiment, which has posed new challenges in functional analysis of each and every phosphorylation site on specific signaling phosphoproteins of interest. In this article, we review recent advances in the functional analysis of targeted phosphorylation carried out by various chemical and biological approaches in combination with the MS-based phosphoproteomics. This review focuses on three types of strategies, including forward functional analysis, defined for the result-driven phosphoproteomics efforts in determining the substrates of a specific protein kinase; reverse functional analysis, defined for tracking the kinase(s) for specific phosphosite(s) derived from the discovery-driven phosphoproteomics efforts; and MS-based analysis on the structure-function relationship of phosphoproteins. It is expected that this review will provide a state-of-the-art overview of functional analysis of site-specific phosphorylation and explore new perspectives and outline future challenges.

  9. Biomimicking Platelet-Monocyte Interactions as a Novel Targeting Strategy for Heart Healing.

    PubMed

    Cheng, Bill; Toh, Elsie K W; Chen, Kun-Hung; Chang, Yuan-Chih; Hu, Che-Ming J; Wu, Han-Chung; Chau, Lee-Young; Chen, Peilin; Hsieh, Patrick C H

    2016-10-01

    In patients who survive myocardial infarction, many go on to develop congestive heart failure (CHF). Despite ongoing efforts to develop new approaches for postinfarction therapy, there are still no effective therapeutic options available to CHF patients. Currently, the delivery of cardioprotective drugs relies entirely on passive uptake via the enhanced permeability and retention (EPR) effect which occurs in proximity to the infarction site. However, in ischemic disease, unlike in cancer, the EPR effect only exists for a short duration postinfarction and thus insufficient for meaningful cardioprotection. Splenic monocytes are recruited to the heart in large numbers postinfarction, and are known to interact with platelets during circulation. Therefore, the strategy is to exploit this interaction by developing platelet-like proteoliposomes (PLPs), biomimicking platelet interactions with circulating monocytes. PLPs show strong binding affinity for monocytes but not for endothelial cells in vitro, mimicking normal platelet activity. Furthermore, intravital multiphoton imaging shows that comparing to plain liposomes, PLPs do not aggregate on uninjured endothelium but do accumulate at the injury site 72 h postinfarction. Importantly, PLPs enhance the targeting of anti-inflammatory drug, cobalt protoporphyrin, to the heart in an EPR-independent manner, which result in better therapeutic outcome.

  10. Assessment of soil sealing management responses, strategies, and targets toward ecologically sustainable urban land use management.

    PubMed

    Artmann, Martina

    2014-05-01

    Soil sealing has negative impacts on ecosystem services since urban green and soil get lost. Although there is political commitment to stop further sealing, no reversal of this trend can be observed in Europe. This paper raises the questions (1) which strategies can be regarded as being efficient toward ecologically sustainable management of urban soil sealing and (2) who has competences and should take responsibility to steer soil sealing? The analyses are conducted in Germany. The assessment of strategies is carried out using indicators as part of a content analysis. Legal-planning, informal-planning, economic-fiscal, co-operative, and informational strategies are analyzed. Results show that there is a sufficient basis of strategies to secure urban ecosystem services by protecting urban green and reducing urban gray where microclimate regulation is a main target. However, soil sealing management lacks a spatial strategically overview as well as the consideration of services provided by fertile soils.

  11. Therapeutic strategies of drug repositioning targeting autophagy to induce cancer cell death: from pathophysiology to treatment.

    PubMed

    Yoshida, Go J

    2017-03-09

    The 2016 Nobel Prize in Physiology or Medicine was awarded to the researcher that discovered autophagy, which is an evolutionally conserved catabolic process which degrades cytoplasmic constituents and organelles in the lysosome. Autophagy plays a crucial role in both normal tissue homeostasis and tumor development and is necessary for cancer cells to adapt efficiently to an unfavorable tumor microenvironment characterized by hypo-nutrient conditions. This protein degradation process leads to amino acid recycling, which provides sufficient amino acid substrates for cellular survival and proliferation. Autophagy is constitutively activated in cancer cells due to the deregulation of PI3K/Akt/mTOR signaling pathway, which enables them to adapt to hypo-nutrient microenvironment and exhibit the robust proliferation at the pre-metastatic niche. That is why just the activation of autophagy with mTOR inhibitor often fails in vain. In contrast, disturbance of autophagy-lysosome flux leads to endoplasmic reticulum (ER) stress and an unfolded protein response (UPR), which finally leads to increased apoptotic cell death in the tumor tissue. Accumulating evidence suggests that autophagy has a close relationship with programmed cell death, while uncontrolled autophagy itself often induces autophagic cell death in tumor cells. Autophagic cell death was originally defined as cell death accompanied by large-scale autophagic vacuolization of the cytoplasm. However, autophagy is a "double-edged sword" for cancer cells as it can either promote or suppress the survival and proliferation in the tumor microenvironment. Furthermore, several studies of drug re-positioning suggest that "conventional" agents used to treat diseases other than cancer can have antitumor therapeutic effects by activating/suppressing autophagy. Because of ever increasing failure rates and high cost associated with anticancer drug development, this therapeutic development strategy has attracted increasing

  12. Aptamer-mediated universal enzyme assay based on target-triggered DNA polymerase activity.

    PubMed

    Park, Ki Soo; Lee, Chang Yeol; Kang, Kyoung Suk; Park, Hyun Gyu

    2017-02-15

    We herein describe an innovative method for a universal fluorescence turn-on enzyme assay, which relies on the target enzyme-triggered DNA polymerase activity. In the first target recognition step, the target enzyme is designed to destabilize detection probe derived from an aptamer specific to DNA polymerase containing the overhang sequence and the complementary blocker DNA, which consequently leads to the recovery of DNA polymerase activity inhibited by the detection probe. This target-triggered polymerase activity is monitored in the second signal transduction step based on primer extension reaction coupled with TaqMan probe. Utilizing this design principle, we have successfully detected the activities of two model enzymes, exonuclease I and uracil DNA glycosylase with high sensitivity and selectivity. Since this strategy is composed of separated target recognition and signal transduction modules, it could be universally employed for the sensitive determination of numerous different target enzymes by simply redesigning the overhang sequence of detection probe, while keeping TaqMan probe-based signal transduction module as a universal signaling tool.

  13. Viral microRNAs Target a Gene Network, Inhibit STAT Activation, and Suppress Interferon Responses

    PubMed Central

    Ramalingam, Dhivya; Ziegelbauer, Joseph M.

    2017-01-01

    Kaposi’s sarcoma-associated herpesvirus (KSHV) encodes 12 pre-microRNAs during latency that are processed to yield ~25 mature microRNAs (miRNAs). We were interested in identifying cellular networks that were targeted by KSHV-miRNAs and employed network building strategies using validated KSHV miRNA targets. Here, we report the identification of a gene network centering on the transcription factor- signal transducer and activator of transcription 3 (STAT3) that is targeted by KSHV miRNAs. KSHV miRNAs suppressed STAT3 and STAT5 activation and inhibited STAT3-dependent reporter activation upon IL6-treatment. KSHV miRNAs also repressed the induction of antiviral interferon-stimulated genes upon IFNα- treatment. Finally, we observed increased lytic reactivation of KSHV from latently infected cells upon STAT3 repression with siRNAs or a small molecule inhibitor. Our data suggest that treatment of infected cells with a STAT3 inhibitor and a viral replication inhibitor, ganciclovir, represents a possible strategy to eliminate latently infected cells without increasing virion production. Together, we show that KSHV miRNAs suppress a network of targets associated with STAT3, deregulate cytokine-mediated gene activation, suppress an interferon response, and influence the transition into the lytic phase of viral replication. PMID:28102325

  14. Transcriptionally active genome regions are preferred targets for retrovirus integration.

    PubMed Central

    Scherdin, U; Rhodes, K; Breindl, M

    1990-01-01

    We have analyzed the transcriptional activity of cellular target sequences for Moloney murine leukemia virus integration in mouse fibroblasts. At least five of the nine random, unselected integration target sequences studied showed direct evidence for transcriptional activity by hybridization to nuclear run-on transcripts prepared from uninfected cells. At least four of the sequences contained multiple recognition sites for several restriction enzymes that cut preferentially in CpG-rich islands, indicating integration into 5' or 3' ends or flanking regions of genes. Assuming that only a minor fraction (less than 20%) of the genome is transcribed in mammalian cells, we calculated the probability that this association of retroviral integration sites with transcribed sequences is due to chance to be very low (1.6 x 10(-2]. Thus, our results strongly suggest that transcriptionally active genome regions are preferred targets for retrovirus integration. Images PMID:2296087

  15. Optimal Strategies for Controlling Riverine Tsetse Flies Using Targets: A Modelling Study

    PubMed Central

    Vale, Glyn A.; Hargrove, John W.; Lehane, Michael J.; Solano, Philippe; Torr, Stephen J.

    2015-01-01

    Background Tsetse flies occur in much of sub-Saharan Africa where they transmit the trypanosomes that cause the diseases of sleeping sickness in humans and nagana in livestock. One of the most economical and effective methods of tsetse control is the use of insecticide-treated screens, called targets, that simulate hosts. Targets have been ~1m2, but recently it was shown that those tsetse that occupy riverine situations, and which are the main vectors of sleeping sickness, respond well to targets only ~0.06m2. The cheapness of these tiny targets suggests the need to reconsider what intensity and duration of target deployments comprise the most cost-effective strategy in various riverine habitats. Methodology/Principal Findings A deterministic model, written in Excel spreadsheets and managed by Visual Basic for Applications, simulated the births, deaths and movement of tsetse confined to a strip of riverine vegetation composed of segments of habitat in which the tsetse population was either self-sustaining, or not sustainable unless supplemented by immigrants. Results suggested that in many situations the use of tiny targets at high density for just a few months per year would be the most cost-effective strategy for rapidly reducing tsetse densities by the ~90% expected to have a great impact on the incidence of sleeping sickness. Local elimination of tsetse becomes feasible when targets are deployed in isolated situations, or where the only invasion occurs from populations that are not self-sustaining. Conclusion/Significance Seasonal use of tiny targets deserves field trials. The ability to recognise habitat that contains tsetse populations which are not self-sustaining could improve the planning of all methods of tsetse control, against any species, in riverine, savannah or forest situations. Criteria to assist such recognition are suggested. PMID:25803871

  16. A reduced energy supply strategy in active vibration control

    NASA Astrophysics Data System (ADS)

    Ichchou, M. N.; Loukil, T.; Bareille, O.; Chamberland, G.; Qiu, J.

    2011-12-01

    In this paper, a control strategy is presented and numerically tested. This strategy aims to achieve the potential performance of fully active systems with a reduced energy supply. These energy needs are expected to be comparable to the power demands of semi-active systems, while system performance is intended to be comparable to that of a fully active configuration. The underlying strategy is called 'global semi-active control'. This control approach results from an energy investigation based on management of the optimal control process. Energy management encompasses storage and convenient restitution. The proposed strategy monitors a given active law without any external energy supply by considering purely dissipative and energy-demanding phases. Such a control law is offered here along with an analysis of its properties. A suboptimal form, well adapted for practical implementation steps, is also given. Moreover, a number of numerical experiments are proposed in order to validate test findings.

  17. Development of an improved active gas target design for ANASEN

    NASA Astrophysics Data System (ADS)

    Schill, Sabina; Blackmon, J. C.; Deibel, C. M.; Macon, K. T.; Rasco, B. C.; Wiedenhoever, I.

    2014-09-01

    The Array for Nuclear Astrophysics and Structure with Exotic Nuclei (ANASEN) is a charged particle detector array with an active gas target-detector capability for sensitive measurements using radioactive ion beams. One of the main goals is to improve our understanding of nuclear reactions important in stellar explosions. Following initial experimental campaigns with ANASEN, we have been developing an improved active gas target design for ANASEN that incorporates an innovative cylindrical gas ionization detector for heavy ions surrounding the beam axis inside of the other ANASEN charged particle detectors. The detection of heavy ions in coincidence with lighter ions in a redesigned proportional counter will provide greater discriminating power. The new active gas target design will be presented, and its simulated performance will be compared with test data. The Array for Nuclear Astrophysics and Structure with Exotic Nuclei (ANASEN) is a charged particle detector array with an active gas target-detector capability for sensitive measurements using radioactive ion beams. One of the main goals is to improve our understanding of nuclear reactions important in stellar explosions. Following initial experimental campaigns with ANASEN, we have been developing an improved active gas target design for ANASEN that incorporates an innovative cylindrical gas ionization detector for heavy ions surrounding the beam axis inside of the other ANASEN charged particle detectors. The detection of heavy ions in coincidence with lighter ions in a redesigned proportional counter will provide greater discriminating power. The new active gas target design will be presented, and its simulated performance will be compared with test data. This work was supported by the U.S. National Science Foundation and the Dept of Energy's Office of Science.

  18. Potent and Targeted Activation of Latent HIV-1 Using the CRISPR/dCas9 Activator Complex.

    PubMed

    Saayman, Sheena M; Lazar, Daniel C; Scott, Tristan A; Hart, Jonathan R; Takahashi, Mayumi; Burnett, John C; Planelles, Vicente; Morris, Kevin V; Weinberg, Marc S

    2016-03-01

    HIV-1 provirus integration results in a persistent latently infected reservoir that is recalcitrant to combined antiretroviral therapy (cART) with lifelong treatment being the only option. The "shock and kill" strategy aims to eradicate latent HIV by reactivating proviral gene expression in the context of cART treatment. Gene-specific transcriptional activation can be achieved using the RNA-guided CRISPR-Cas9 system comprising single guide RNAs (sgRNAs) with a nuclease-deficient Cas9 mutant (dCas9) fused to the VP64 transactivation domain (dCas9-VP64). We engineered this system to target 23 sites within the long terminal repeat promoter of HIV-1 and identified a "hotspot" for activation within the viral enhancer sequence. Activating sgRNAs transcriptionally modulated the latent proviral genome across multiple different in vitro latency cell models including T cells comprising a clonally integrated mCherry-IRES-Tat (LChIT) latency system. We detected consistent and effective activation of latent virus mediated by activator sgRNAs, whereas latency reversal agents produced variable activation responses. Transcriptomic analysis revealed dCas9-VP64/sgRNAs to be highly specific, while the well-characterized chemical activator TNFα induced widespread gene dysregulation. CRISPR-mediated gene activation represents a novel system which provides enhanced efficiency and specificity in a targeted latency reactivation strategy and represents a promising approach to a "functional cure" of HIV/AIDS.

  19. An efficient strategy for gene targeting and phenotypic assessment in the Plasmodium yoelii rodent malaria model.

    PubMed

    Mikolajczak, Sebastian A; Aly, Ahmed S I; Dumpit, Ronald F; Vaughan, Ashley M; Kappe, Stefan H I

    2008-04-01

    In this report, we describe a cloning procedure for gene replacement by double homologous recombination in Plasmodium yoelii, which requires only one digestion and ligation step. This significantly shortens the time required to complete the production of the targeting vector. Furthermore, for more efficient phenotypic evaluation of the gene knockout parasites, we have also introduced a fluorescent protein cassette into the targeting vector. This allows for a more rapid assessment of parasite growth in all of its developmental stages. In addition, the introduction of the fluorescent marker via the replacement strategy confers the stable integration of the marker.

  20. Notetaking Activity as a Logical Classroom Learning Strategy.

    ERIC Educational Resources Information Center

    Taylor, William; And Others

    The impact on learning performance of a notetaking strategy called the Directed Overt Activity Strategy (DOA) was evaluated on three types of instructional tasks: spatial learning, simple concept learning, and complex concept learning. One hundred volunteer freshman psychology students from Ohio State University used either the DOA or their own…

  1. Do Active-Learning Strategies Improve Students' Critical Thinking?

    ERIC Educational Resources Information Center

    Nelson, Larry P.; Crow, Mary L.

    2014-01-01

    Improving students' ability to recognize work-related problems and apply effective strategies and solutions to fundamental challenges in the field is at the crux of a good college preparation. This paper attempts to investigate if active-learning strategies improve students' critical thinking ability in this regard. Participants were pre-service…

  2. A Manual of Classroom Strategies/Activities for Basic Business.

    ERIC Educational Resources Information Center

    Wyoming Univ., Laramie. Coll. of Education.

    This manual contains 75 strategies or classroom activities for teaching basic business education. All activities can be adapted for special needs students. The activities were prepared by 19 business education teachers during a 3-weekend continuing education course for business education teachers at the University of Wyoming. Examples of…

  3. Targeting glycoprotein VI and the immunoreceptor tyrosine-based activation motif signaling pathway.

    PubMed

    Stegner, David; Haining, Elizabeth J; Nieswandt, Bernhard

    2014-08-01

    Coronary artery thrombosis and ischemic stroke are often initiated by the disruption of an atherosclerotic plaque and consequent intravascular platelet activation. Thus, antiplatelet drugs are central in the treatment and prevention of the initial, and subsequent, vascular events. However, novel pharmacological targets for platelet inhibition remain an important goal of cardiovascular research because of the negative effect of existing antiplatelet drugs on primary hemostasis. One promising target is the platelet collagen receptor glycoprotein VI. Blockade or antibody-mediated depletion of this receptor in circulating platelets is beneficial in experimental models of thrombosis and thrombo-inflammatory diseases, such as stroke, without impairing hemostasis. In this review, we summarize the importance of glycoprotein VI and (hem)immunoreceptor tyrosine-based activation motif signaling in hemostasis, thrombosis, and thrombo-inflammatory processes and discuss the targeting strategies currently under development for inhibiting glycoprotein VI and its signaling.

  4. Fortification of foods with vitamin D in India: strategies targeted at children.

    PubMed

    G, Ritu; Gupta, Ajay

    2015-01-01

    Vitamin D deficiency is endemic in India, despite abundant sunshine, due to several socioeconomic and cultural constraints. Fortification of staple foods with vitamin D is a viable population-based strategy for the general population in India. These strategies are discussed in the review article entitled, "Fortification of Foods With Vitamin D in India" [1]. The quantity of foods consumed by children is much smaller compared to adults. Therefore, children need energy-dense and micronutrient-dense foods to meet their daily nutritional requirements. Targeted food fortification programs are needed to meet the special needs of children. This review explores potential strategies that could be used for fortification of foods with vitamin D for children in India. Sattu has the potential to be a valuable vehicle for vitamin D fortification in India. The salient characteristics and merits of sattu as an ideal food to be fortified with micronutrients, especially vitamin D, are reviewed here. Key teaching points: • Fortification of foods with vitamin D, specifically targeted towards the nutritional requirements of infants and children, is a viable strategy in the Indian scenario. •Government programs targeting the nutritional needs of children in India, especially via midday meal programs in schools, should incorporate indigenous ready-to-eat foods fortified with micronutrients including vitamin D. These foods would need to have longer shelf life, require minimal preparation, and have economic and technological feasibility. • Sattu, a protein rich Indian fast food, comprised of roasted flour made from cereals and legumes, has immense potential to serve as an economically and technologically feasible fortification vehicle for vitamin D fortification strategies.

  5. MTTE: an innovative strategy for the evaluation of targeted/exome enrichment efficiency

    PubMed Central

    Klonowska, Katarzyna; Handschuh, Luiza; Swiercz, Aleksandra; Figlerowicz, Marek; Kozlowski, Piotr

    2016-01-01

    Although currently available strategies for the preparation of exome-enriched libraries are well established, a final validation of the libraries in terms of exome enrichment efficiency prior to the sequencing step is of considerable importance. Here, we present a strategy for the evaluation of exome enrichment, i.e., the Multipoint Test for Targeted-enrichment Efficiency (MTTE), PCR-based approach utilizing multiplex ligation-dependent probe amplification with capillary electrophoresis separation. We used MTTE for the analysis of subsequent steps of the Illumina TruSeq Exome Enrichment procedure. The calculated values of enrichment-associated parameters (i.e., relative enrichment, relative clearance, overall clearance, and fold enrichment) and the comparison of MTTE results with the actual enrichment revealed the high reliability of our assay. Additionally, the MTTE assay enabled the determination of the sequence-associated features that may confer bias in the enrichment of different targets. Importantly, the MTTE is low cost method that can be easily adapted to the region of interest important for a particular project. Thus, the MTTE strategy is attractive for post-capture validation in a variety of targeted/exome enrichment NGS projects. PMID:27572310

  6. Nanomedicine strategies for sustained, controlled, and targeted treatment of cancer stem cells of the digestive system

    PubMed Central

    Xie, Fang-Yuan; Xu, Wei-Heng; Yin, Chuan; Zhang, Guo-Qing; Zhong, Yan-Qiang; Gao, Jie

    2016-01-01

    Cancer stem cells (CSCs) constitute a small proportion of the cancer cells that have self-renewal capacity and tumor-initiating ability. They have been identified in a variety of tumors, including tumors of the digestive system. CSCs exhibit some unique characteristics, which are responsible for cancer metastasis and recurrence. Consequently, the development of effective therapeutic strategies against CSCs plays a key role in increasing the efficacy of cancer therapy. Several potential approaches to target CSCs of the digestive system have been explored, including targeting CSC surface markers and signaling pathways, inducing the differentiation of CSCs, altering the tumor microenvironment or niche, and inhibiting ATP-driven efflux transporters. However, conventional therapies may not successfully eradicate CSCs owing to various problems, including poor solubility, stability, rapid clearance, poor cellular uptake, and unacceptable cytotoxicity. Nanomedicine strategies, which include drug, gene, targeted, and combinational delivery, could solve these problems and significantly improve the therapeutic index. This review briefly summarizes the ongoing development of strategies and nanomedicine-based therapies against CSCs of the digestive system. PMID:27795813

  7. Eliciting Production of L2 Target Structures through Priming Activities

    ERIC Educational Resources Information Center

    McDonough, Kim; Trofimovich, Pavel; Neumann, Heike

    2015-01-01

    This study focuses on the pedagogical applications of structural priming research in an English for academic purposes (EAP) context, investigating whether priming activities are an effective tool for eliciting production of target grammatical structures. University students across four EAP classes carried out a total of 6 information-exchange…

  8. Quantitative control of active targeting of nanocarriers to tumor cells through optimization of folate ligand density.

    PubMed

    Tang, Zhaomin; Li, Dan; Sun, Huili; Guo, Xing; Chen, Yuping; Zhou, Shaobing

    2014-09-01

    The active targeting delivery system has been widely studied in cancer therapy by utilizing folate (FA) ligands to generate specific interaction between nanocarriers and folate receptors (FRs) on tumor cell. However, there is little work that has been published to investigate the influence of the definite density of the FA ligands on the active targeting of nanocarriers. In this study, we have combined magnetic-guided iron oxide nanoparticles with FA ligands, adjusted the FA ligand density and then studied the resulting effects on the active targeting ability of this dual-targeting drug delivery system to tumor cells. We have also optimized the FA ligand density of the drug delivery system for their active targeting to FR-overexpressing tumor cells in vitro. Prussian blue staining, semi-thin section of cells observed with transmission electron microscopy (TEM) and inductively coupled plasma-atomic emission spectroscopy (ICP-AES) have shown that the optimal FA density is from 2.3 × 10(18) to 2.5 × 10(18) per gram nanoparticles ((g·NPs)(-1)). We have further tried to qualitatively and quantitatively control the active targeting and delivering of drugs to tumors on 4T1-bearing BALB/c mice. As expected, the in vivo experimental results have also demonstrated that the FA density of the magnetic nanoparticles (MNPs) could be optimized for a more easily binding to tumor cells via the multivalent linkages and more readily internalization through the FR-mediated endocytosis. Our study can provide a strategy to quantitatively control the active targeting of nanocarriers to tumor cells for cancer therapy.

  9. Mammalian Target of Rapamycin (mTOR) Activation Increases Axonal Growth Capacity of Injured Peripheral Nerves*

    PubMed Central

    Abe, Namiko; Borson, Steven H.; Gambello, Michael J.; Wang, Fan; Cavalli, Valeria

    2010-01-01

    Unlike neurons in the central nervous system (CNS), injured neurons in the peripheral nervous system (PNS) can regenerate their axons and reinnervate their targets. However, functional recovery in the PNS often remains suboptimal, especially in cases of severe damage. The lack of regenerative ability of CNS neurons has been linked to down-regulation of the mTOR (mammalian target of rapamycin) pathway. We report here that PNS dorsal root ganglial neurons (DRGs) activate mTOR following damage and that this activity enhances axonal growth capacity. Furthermore, genetic up-regulation of mTOR activity by deletion of tuberous sclerosis complex 2 (TSC2) in DRGs is sufficient to enhance axonal growth capacity in vitro and in vivo. We further show that mTOR activity is linked to the expression of GAP-43, a crucial component of axonal outgrowth. However, although TSC2 deletion in DRGs facilitates axonal regrowth, it leads to defects in target innervation. Thus, whereas manipulation of mTOR activity could provide new strategies to stimulate nerve regeneration in the PNS, fine control of mTOR activity is required for proper target innervation. PMID:20615870

  10. Active Learning Strategies in Physics Teaching

    ERIC Educational Resources Information Center

    Karamustafaoglu, Orhan

    2009-01-01

    The purpose of this study was to determine physics teachers' opinions about student-centered activities applicable in physics teaching and learning in context. A case study approach was used in this research. First, semi-structured interviews were carried out with 6 physics teachers. Then, a questionnaire was developed based on the data obtained…

  11. PP2A targeting by viral proteins: a widespread biological strategy from DNA/RNA tumor viruses to HIV-1.

    PubMed

    Guergnon, Julien; Godet, Angélique N; Galioot, Amandine; Falanga, Pierre Barthélémy; Colle, Jean-Hervé; Cayla, Xavier; Garcia, Alphonse

    2011-11-01

    Protein phosphatase 2A (PP2A) is a large family of holoenzymes that comprises 1% of total cellular proteins and accounts for the majority of Ser/Thr phosphatase activity in eukaryotic cells. Although initially viewed as constitutive housekeeping enzymes, it is now well established that PP2A proteins represent a family of highly and sophistically regulated phosphatases. The past decade, multiple complementary studies have improved our knowledge about structural and functional regulation of PP2A holoenzymes. In this regard, after summarizing major cellular regulation, this review will mainly focus on discussing a particulate biological strategy, used by various viruses, which is based on the targeting of PP2A enzymes by viral proteins in order to specifically deregulate, for their own benefit, cellular pathways of their hosts. The impact of such PP2A targeting for research in human diseases, and in further therapeutic developments, is also discussed.

  12. Targeting Strategies for Renal Cell Carcinoma: From Renal Cancer Cells to Renal Cancer Stem Cells.

    PubMed

    Yuan, Zhi-Xiang; Mo, Jingxin; Zhao, Guixian; Shu, Gang; Fu, Hua-Lin; Zhao, Wei

    2016-01-01

    Renal cell carcinoma (RCC) is a common form of urologic tumor that originates from the highly heterogeneous epithelium of renal tubules. Over the last decade, targeting therapies to renal cancer cells have transformed clinical care for RCC. Recently, it was proposed that renal cancer stem cells (CSCs) isolated from renal carcinomas were responsible for driving tumor growth and resistance to conventional chemotherapy and radiotherapy, according to the theory of CSCs; this has provided the rationale for therapies targeting this aggressive cell population. Precise identification of renal CSC populations and the complete cell hierarchy will accurately inform characterization of disease subtypes. This will ultimately contribute to more personalized and targeted therapies. Here, we summarize potential targeting strategies for renal cancer cells and renal CSCs, including tyrosine kinase inhibitors, mammalian target of rapamycin inhibitors (mTOR), interleukins, CSC marker inhibitors, bone morphogenetic protein-2, antibody drug conjugates, and nanomedicine. In conclusion, targeting therapies for RCC represent new directions for exploration and clinical investigation and they plant a seed of hope for advanced clinical care.

  13. Targeting Strategies for Renal Cell Carcinoma: From Renal Cancer Cells to Renal Cancer Stem Cells

    PubMed Central

    Yuan, Zhi-xiang; Mo, Jingxin; Zhao, Guixian; Shu, Gang; Fu, Hua-lin; Zhao, Wei

    2016-01-01

    Renal cell carcinoma (RCC) is a common form of urologic tumor that originates from the highly heterogeneous epithelium of renal tubules. Over the last decade, targeting therapies to renal cancer cells have transformed clinical care for RCC. Recently, it was proposed that renal cancer stem cells (CSCs) isolated from renal carcinomas were responsible for driving tumor growth and resistance to conventional chemotherapy and radiotherapy, according to the theory of CSCs; this has provided the rationale for therapies targeting this aggressive cell population. Precise identification of renal CSC populations and the complete cell hierarchy will accurately inform characterization of disease subtypes. This will ultimately contribute to more personalized and targeted therapies. Here, we summarize potential targeting strategies for renal cancer cells and renal CSCs, including tyrosine kinase inhibitors, mammalian target of rapamycin inhibitors (mTOR), interleukins, CSC marker inhibitors, bone morphogenetic protein-2, antibody drug conjugates, and nanomedicine. In conclusion, targeting therapies for RCC represent new directions for exploration and clinical investigation and they plant a seed of hope for advanced clinical care. PMID:27891093

  14. Strategies and Advancement in Antibody-Drug Conjugate Optimization for Targeted Cancer Therapeutics

    PubMed Central

    Kim, Eunhee G.; Kim, Kristine M.

    2015-01-01

    Antibody-drug conjugates utilize the antibody as a delivery vehicle for highly potent cytotoxic molecules with specificity for tumor-associated antigens for cancer therapy. Critical parameters that govern successful antibody-drug conjugate development for clinical use include the selection of the tumor target antigen, the antibody against the target, the cytotoxic molecule, the linker bridging the cytotoxic molecule and the antibody, and the conjugation chemistry used for the attachment of the cytotoxic molecule to the antibody. Advancements in these core antibody-drug conjugate technology are reflected by recent approval of Adectris® (anti-CD30-drug conjugate) and Kadcyla® (anti-HER2 drug conjugate). The potential approval of an anti-CD22 conjugate and promising new clinical data for anti-CD19 and anti-CD33 conjugates are additional advancements. Enrichment of antibody-drug conjugates with newly developed potent cytotoxic molecules and linkers are also in the pipeline for various tumor targets. However, the complexity of antibody-drug conjugate components, conjugation methods, and off-target toxicities still pose challenges for the strategic design of antibody-drug conjugates to achieve their fullest therapeutic potential. This review will discuss the emergence of clinical antibody-drug conjugates, current trends in optimization strategies, and recent study results for antibody-drug conjugates that have incorporated the latest optimization strategies. Future challenges and perspectives toward making antibody-drug conjugates more amendable for broader disease indications are also discussed. PMID:26535074

  15. Targeting stemness is an effective strategy to control EML4-ALK+ non-small cell lung cancer cells.

    PubMed

    Oh, Se Jin; Noh, Kyung Hee; Lee, Young-Ho; Hong, Soon-Oh; Song, Kwon-Ho; Lee, Hyo-Jung; Kim, Soyeon; Kim, Tae Min; Jeon, Ju-Hong; Seo, Jae Hong; Kim, Dong-Wan; Kim, Tae Woo

    2015-11-24

    The fusion between anaplastic lymphoma kinase (ALK) and echinoderm microtubule-associated protein-like 4 (EML4) is a causative factor in a unique subset of patients with non-small cell lung carcinoma (NSCLC). Although the inhibitor crizotinib, as it blocks the kinase activity of the resulting EML4-ALK fusion protein, displays remarkable initial responses, a fraction of NSCLC cases eventually become resistant to crizotinib by acquiring mutations in the ALK domain or activating bypass pathways via EGFR, KIT, or KRAS. Cancer stem cell (CSC) theory provides a plausible explanation for acquisition of tumorigenesis and resistance. However, the question as to whether EML4-ALK-driven tumorigenesis is linked with the stem-like property and whether the stemness is an effective target in controlling EML4-ALK+ NSCLC including crizotinib-resistant NSCLC cells has not been addressed. Here, we report that stem-like properties stem from ALK activity in EML4-ALK+ NSCLC cells. Notably, treatment with rapamycin, a CSC targeting agent, attenuates stem-like phenotypes of the EML4-ALK+ cells, which increased capability of tumor formation and higher expression of stemness-associated molecules such as ALDH, NANOG, and OCT4. Importantly, combinational treatment with rapamycin and crizotinib leads to synergistic anti-tumor effects on EML4-ALK+ NSCLC cells as well as on those resistant to crizotinib. Thus, we provide a proof of principle that targeting stemness would be a novel strategy to control intractable EML4-ALK+ NSCLC.

  16. HSP90 Inhibitor-SN-38 Conjugate Strategy for Targeted Delivery of Topoisomerase I Inhibitor to Tumors.

    PubMed

    Proia, David A; Smith, Donald L; Zhang, Junyi; Jimenez, John-Paul; Sang, Jim; Ogawa, Luisa Shin; Sequeira, Manuel; Acquaviva, Jaime; He, Suqin; Zhang, Chaohua; Khazak, Vladimir; Astsaturov, Igor; Inoue, Takayo; Tatsuta, Noriaki; Osman, Sami; Bates, Richard C; Chimmanamada, Dinesh; Ying, Weiwen

    2015-11-01

    The clinical benefits of chemotherapy are commonly offset by insufficient drug exposures, narrow safety margins, and/or systemic toxicities. Over recent decades, a number of conjugate-based targeting approaches designed to overcome these limitations have been explored. Here, we report on an innovative strategy that utilizes HSP90 inhibitor-drug conjugates (HDC) for directed tumor targeting of chemotherapeutic agents. STA-12-8666 is an HDC that comprises an HSP90 inhibitor fused to SN-38, the active metabolite of irinotecan. Mechanistic analyses in vitro established that high-affinity HSP90 binding conferred by the inhibitor backbone could be exploited for conjugate accumulation within tumor cells. In vivo modeling showed that the HSP90 inhibitor moiety was required for selective retention of STA-12-8666, and this enrichment promoted extended release of active SN-38 within the tumor compartment. Indeed, controlled intratumoral payload release by STA-12-8666 contributed to a broad therapeutic window, sustained biomarker activity, and remarkable degree of efficacy and durability of response in multiple cell line and patient-derived xenograft models. Overall, STA-12-8666 has been developed as a unique HDC agent that employs a distinct mechanism of targeted drug delivery to achieve potent and sustained antitumor effects. These findings identify STA-12-8666 as a promising new candidate for evaluation as novel anticancer therapeutic.

  17. How to Target Activated Ras Proteins: Direct Inhibition vs. Induced Mislocalization

    PubMed Central

    Brock, Ethan J.; Ji, Kyungmin; Reiners, John J.; Mattingly, Raymond R.

    2016-01-01

    Oncogenic Ras proteins are a driving force in a significant set of human cancers and wild-type, unmutated Ras proteins likely contribute to the malignant phenotype of many more. The overall challenge of targeting activated Ras proteins has great promise to treat cancer, but this goal has yet to be achieved. Significant efforts and resources have been committed to inhibiting Ras, but these energies have so far made little impact in the clinic. Direct attempts to target activated Ras proteins have faced many obstacles, including the fundamental nature of the gain-of-function oncogenic activity being produced by a loss-of-function at the biochemical level. Nevertheless, there has been very promising recent pre-clinical progress. The major strategy that has so far reached the clinic aimed to inhibit activated Ras indirectly through blocking its post-translational modification and inducing its mislocalization. While these efforts to indirectly target Ras through inhibition of farnesyl transferase (FTase) were rationally designed, this strategy suffered from insufficient attention to the distinctions between the isoforms of Ras. This led to subsequent failures in large-scale clinical trials targeting K-Ras driven lung, colon, and pancreatic cancers. Despite these setbacks, efforts to indirectly target activated Ras through inducing its mislocalization have persisted. It is plausible that FTase inhibitors may still have some utility in the clinic, perhaps in combination with statins or other agents. Alternative approaches for inducing mislocalization of Ras through disruption of its palmitoylation cycle or interaction with chaperone proteins are in early stages of development. PMID:26423696

  18. Using active learning strategies to present bloodborne pathogen programs.

    PubMed

    Weaver, Mary G

    2003-06-01

    Every year, school nurses have the responsibility for developing and presenting a bloodborne pathogen presentation to the education and clerical staff of their buildings. Although the information is similar from year to year, the manner in which the information is presented can be altered. Teachers are using active learning strategies in a variety of learning environments, engaging students in the learning process by having them play an active role. With some planning, preparation, and imagination, active learning strategies can be incorporated into bloodborne pathogen presentations. The purpose of this article is to define active learning, describe how to develop a program using active learning strategies, and provide some examples of bloodborne pathogen presentations that have already been developed. Several sources are identified that can provide the school nurse with information regarding bloodborne pathogens. Information about how computers can be integrated into the bloodborne pathogen presentation is also presented.

  19. Targeting GH-1 splicing as a novel pharmacological strategy for growth hormone deficiency type II.

    PubMed

    Miletta, Maria Consolata; Flück, Christa E; Mullis, Primus-E

    2017-01-15

    Isolated growth hormone deficiency type II (IGHD II) is a rare genetic splicing disorder characterized by reduced growth hormone (GH) secretion and short stature. It is mainly caused by autosomal dominant-negative mutations within the growth hormone gene (GH-1) which results in missplicing at the mRNA level and the subsequent loss of exon 3, producing the 17.5-kDa GH isoform: a mutant and inactive GH protein that reduces the stability and the secretion of the 22-kDa GH isoform, the main biologically active GH form. At present, patients suffering from IGHD II are treated with daily injections of recombinant human GH (rhGH) in order to reach normal height. However, this type of replacement therapy, although effective in terms of growth, does not prevent the toxic effects of the 17.5-kDa mutant on the pituitary gland, which may eventually lead to other hormonal deficiencies. As the severity of the disease inversely correlates with the 17.5-kDa/22-kDa ratio, increasing the inclusion of exon 3 is expected to ameliorate disease symptoms. This review focuses on the recent advances in experimental and therapeutic strategies applicable to treat IGHD II in clinical and preclinical contexts. Several avenues for alternative IGHD II therapy will be discussed including the use of small interfering RNA (siRNA) and short hairpin RNA (shRNA) constructs that specifically target the exon 3-deleted transcripts as well as the application of histone deacetylase inhibitors (HDACi) and antisense oligonucleotides (AONs) to enhance full-length GH-1 transcription, correct GH-1 exon 3 splicing and manipulate GH pathway.

  20. Active helium target: Neutron scalar polarizability extraction via Compton scattering

    SciTech Connect

    Morris, Meg Hornidge, David; Annand, John; Strandberg, Bruno

    2015-12-31

    Precise measurement of the neutron scalar polarizabilities has been a lasting challenge because of the lack of a free-neutron target. Led by the University of Glasgow and the Mount Allison University groups of the A2 collaboration in Mainz, Germany, preparations have begun to test a recent theoretical model with an active helium target with the hope of determining these elusive quantities with small statistical, systematic, and model-dependent errors. Apparatus testing and background-event simulations have been carried out, with the full experiment projected to run in 2015. Once determined, these values can be applied to help understand quantum chromodynamics in the nonperturbative region.

  1. Reversible, activity-dependent targeting of profilin to neuronal nuclei

    SciTech Connect

    Birbach, Andreas . E-mail: andreas.birbach@lbicr.lbg.ac.at; Verkuyl, J. Martin; Matus, Andrew . E-mail: aim@fmi.ch

    2006-07-15

    The actin cytoskeleton in pyramidal neurons plays a major role in activity-dependent processes underlying neuronal plasticity. The small actin-binding protein profilin shows NMDA receptor-dependent accumulation in dendritic spines, which is correlated with suppression of actin dynamics and long-term stabilization of synaptic morphology. Here we show that following NMDA receptor activation profilin also accumulates in the nucleus of hippocampal neurons via a process involving rearrangement of the actin cytoskeleton. This simultaneous targeting to dendritic spines and the cell nucleus suggests a novel mechanism of neuronal plasticity in which profilin both tags activated synapses and influences nuclear events.

  2. Epidermal Growth Factor Receptor targeting in non-small cell lung cancer: revisiting different strategies against the same target.

    PubMed

    Castañón, Eduardo; Martín, Patricia; Rolfo, Christian; Fusco, Juan P; Ceniceros, Lucía; Legaspi, Jairo; Santisteban, Marta; Gil-Bazo, Ignacio

    2014-01-01

    Epidermal Growth Factor Receptor (EGFR) tyrosine kinase inhibitors (TKIs) have changed the paradigm of treatment in non-small cell lung cancer (NSCLC). The molecular biology study of EGFR has led to clinical trials that select patients more accurately, regarding the presence of EGFR activating mutations. Nonetheless, a lack of response or a temporary condition of the response has been detected in patients on EGFR TKIs. This has urged to study potential resistance mechanisms underneath. The most important ones are the presence of secondary mutations in EGFR, such as T790M, or the overexpression of mesenchymal-epithelial transition factor (MET) that may explain why patients who initially respond to EGFR TKIs, may ultimately become refractory. Several approaches have been taken and new drugs both targeting EGFR resistance-mutation or MET are currently being developed. Here we review and update the EGFR biological pathway as well as the clinical data leading to approval of the EGFR TKIs currently in the market. New compounds under investigation targeting resistance mutations or dually targeting EGFR and other relevant receptors are also reviewed and discussed.

  3. Active tectonics and human survival strategies

    NASA Astrophysics Data System (ADS)

    King, Geoffrey; Bailey, Geoffrey; Sturdy, Derek

    1994-10-01

    Tectonic movements continuously remould the surface of Earth in response to plate motion. Yet such deformation is rarely taken into account when assessing landscape change and its impact on human land use, except perhaps as an occasional hazard to human life or a temporary disruption in the longer term patterns of human history. However, active tectonics also create and sustain landscapes that can be beneficial to human survival, forming a complex topography of potentially fertile sedimentary basins enclosed by mountain barriers that can facilitate the control and explotation of food resources, especially animal prey. We discuss the tectonic history of northwest Greece and show how the Paleolithic sites of the region are located to take advantage of tectonically created features at both a local and a regional scale. We suggest that the association of significant concentrations of early Paleolithic sites with tectonically acitve regions is not coincidental and that on the longer time spans of human biological evolution, active tectonics has been an important selective agent contributing to the development of the human species as an intelligent predator.

  4. Tropism-Modification Strategies for Targeted Gene Delivery Using Adenoviral Vectors

    PubMed Central

    Coughlan, Lynda; Alba, Raul; Parker, Alan L.; Bradshaw, Angela C.; McNeish, Iain A.; Nicklin, Stuart A.; Baker, Andrew H.

    2010-01-01

    Achieving high efficiency, targeted gene delivery with adenoviral vectors is a long-standing goal in the field of clinical gene therapy. To achieve this, platform vectors must combine efficient retargeting strategies with detargeting modifications to ablate native receptor binding (i.e. CAR/integrins/heparan sulfate proteoglycans) and “bridging” interactions. “Bridging” interactions refer to coagulation factor binding, namely coagulation factor X (FX), which bridges hepatocyte transduction in vivo through engagement with surface expressed heparan sulfate proteoglycans (HSPGs). These interactions can contribute to the off-target sequestration of Ad5 in the liver and its characteristic dose-limiting hepatotoxicity, thereby significantly limiting the in vivo targeting efficiency and clinical potential of Ad5-based therapeutics. To date, various approaches to retargeting adenoviruses (Ad) have been described. These include genetic modification strategies to incorporate peptide ligands (within fiber knob domain, fiber shaft, penton base, pIX or hexon), pseudotyping of capsid proteins to include whole fiber substitutions or fiber knob chimeras, pseudotyping with non-human Ad species or with capsid proteins derived from other viral families, hexon hypervariable region (HVR) substitutions and adapter-based conjugation/crosslinking of scFv, growth factors or monoclonal antibodies directed against surface-expressed target antigens. In order to maximize retargeting, strategies which permit detargeting from undesirable interactions between the Ad capsid and components of the circulatory system (e.g. coagulation factors, erythrocytes, pre-existing neutralizing antibodies), can be employed simultaneously. Detargeting can be achieved by genetic ablation of native receptor-binding determinants, ablation of “bridging interactions” such as those which occur between the hexon of Ad5 and coagulation factor X (FX), or alternatively, through the use of polymer-coated

  5. Chetomin, targeting HIF-1α/p300 complex, exhibits antitumour activity in multiple myeloma

    PubMed Central

    Viziteu, Elena; Grandmougin, Camille; Goldschmidt, Hartmut; Seckinger, Anja; Hose, Dirk; Klein, Bernard; Moreaux, Jerome

    2016-01-01

    Background: Multiple myeloma (MM) is an incurable clonal plasma cell malignancy. The constitutive expression of HIF-1α in MM suggests that inhibition of HIF-1α-mediated transcription represents an interesting target in MM. Methods: As p300 is a crucial co-activator of hypoxia-inducible transcription, disrupting the complex HIF-1α/p300 to target HIF activity appears to be an attractive strategy. Results: We reported that chetomin, an inhibitor of HIF-1α/p300 interaction, exhibits antitumour activity in human myeloma cell lines and primary MM cells from patients. Conclusions: Our data suggest that chetomin may be of clinical value in MM and especially for patients characterised by a high EP300/HIF-1α expression and a poor prognosis. PMID:26867162

  6. Statistical algorithms for target detection in coherent active polarimetric images.

    PubMed

    Goudail, F; Réfrégier, P

    2001-12-01

    We address the problem of small-target detection with a polarimetric imager that provides orthogonal state contrast images. Such active systems allow one to measure the degree of polarization of the light backscattered by purely depolarizing isotropic materials. To be independent of the spatial nonuniformities of the illumination beam, small-target detection on the orthogonal state contrast image must be performed without using the image of backscattered intensity. We thus propose and develop a simple and efficient target detection algorithm based on a nonlinear pointwise transformation of the orthogonal state contrast image followed by a maximum-likelihood algorithm optimal for additive Gaussian perturbations. We demonstrate the efficiency of this suboptimal technique in comparison with the optimal one, which, however, assumes a priori knowledge about the scene that is not available in practice. We illustrate the performance of this approach on both simulated and real polarimetric images.

  7. Radiation damage/activity calculation for CSNS target station

    NASA Astrophysics Data System (ADS)

    Yin, W.; Liang, T. J.; Yu, Q. Z.; Jia, X. J.

    2010-03-01

    The radiation damages have been performed for Chinese spallation neutron source (CSNS) target center components that relies on Monte Carlo simulation code MCNPX. During the calculation, Bertini intranuclear cascade model, three level-density formulation GCCI, and multistage pre-equilibrium model MPM on which are provided within MCNPX are employed. We calculate the displacement per atom (DPA) and afterheat of the tungsten target, the stainless steel target vessel window and the aluminum alloy moderator vessel. As a hundred kW-level source, these spallation center components have the lifetime more than 5 year. We also give the activity for the T0 chopper of the beam line HIPD to get the primary data for making out a maintenance scenario.

  8. The importance of search strategy for finding targets in open terrain.

    PubMed

    Riggs, Charlotte A; Cornes, Katherine; Godwin, Hayward J; Liversedge, Simon P; Guest, Richard; Donnelly, Nick

    2017-01-01

    A number of real-world search tasks (i.e. police search, detection of improvised explosive devices (IEDs)) require searchers to search exhaustively across open ground. In the present study, we simulated this problem by asking individuals (Experiments 1a and 1b) and dyads (Experiment 2) to search for coin targets pseudo-randomly located in a bounded area of open grassland terrain. In Experiment 1a, accuracy, search time, and the route used to search an area were measured. Participants tended to use an 'S'-shaped pattern with a common width of search lane. Increased accuracy was associated with slower, but also variable, search speed, though only when participants moved along the length (as opposed to across the width) of the search area. Experiment 1b varied the number of targets available within the bounded search area and in doing so varied target prevalence and density. The results confirmed that the route taken in Experiment 1a generalizes across variations in target prevalence/density. In Experiment 2, accuracy, search time, and the search strategy used by dyads was measured. While dyads were more accurate than individuals, dyads that opted to conduct two independent searches were more accurate than those who opted to split the search space. The implications of these results for individuals and dyads when searching for targets in open space are discussed.

  9. Targeting strategies on miRNA-21 and PDCD4 for glioblastoma.

    PubMed

    Wang, Gang; Wang, Jun Jie; Tang, Hong Ming; To, Shing Shun Tony

    2015-08-15

    MicroRNAs (miRNAs) are often deregulated in glioblastoma multiforme (GBM). Downregulation of microRNA-21 (miR-21), especially in GBM, is responsible for increased apoptosis, decreased cell proliferation and invasion, increased G0/G1 cell cycle arrest, and reduced chemotherapeutic resistance to doxorubicin. Furthermore, it is a critical regulator of multiple downstream genes and signaling pathways involved in gliomagenesis. Programmed cell death 4 (PDCD4) is critical in mediating apoptosis in GBM, and is downregulated by miR-21, which may mediate the resistance of glioblastoma cells against chemotherapy or radiation via its target genes PDCD4. Evidence is mounting that how alterations of these miRNAs transcription factors provide initiation, maintenance, or progression of tumors. This review will focus on the roles of miRNAs family members (particularly miR-21 and its target gene PDCD4) in tumors like glioblastoma and new targeting strategies, as examples some new targeting therapeutic methods and molecular mechanisms of signal pathways in glioblastoma therapeutics, to give the reader the current trends of approach to target regulation of these miRNA and genes for future glioma therapies.

  10. Alkynol natural products target ALDH2 in cancer cells by irreversible binding to the active site.

    PubMed

    Heydenreuter, Wolfgang; Kunold, Elena; Sieber, Stephan A

    2015-11-11

    Falcarinol and stipudiol are natural products with potent anti-cancer activity found in several vegetables. Here, we use a chemical proteomic strategy to identify ALDH2 as a molecular target of falcarinol in cancer cells and confirm enzyme inhibition via covalent alkylation of the active site. Furthermore, the synthesis of stipudiol led to the observation that ALDH2 exhibits preference for alkynol-based binders. Inhibition of ALDH2 impairs detoxification of reactive aldehydes and limits oxidative stress response, two crucial pathways for cellular viability.

  11. Buoyancy-activated cell sorting using targeted biotinylated albumin microbubbles.

    PubMed

    Liou, Yu-Ren; Wang, Yu-Hsin; Lee, Chia-Ying; Li, Pai-Chi

    2015-01-01

    Cell analysis often requires the isolation of certain cell types. Various isolation methods have been applied to cell sorting, including fluorescence-activated cell sorting and magnetic-activated cell sorting. However, these conventional approaches involve exerting mechanical forces on the cells, thus risking cell damage. In this study we applied a novel isolation method called buoyancy-activated cell sorting, which involves using biotinylated albumin microbubbles (biotin-MBs) conjugated with antibodies (i.e., targeted biotin-MBs). Albumin MBs are widely used as contrast agents in ultrasound imaging due to their good biocompatibility and stability. For conjugating antibodies, biotin is conjugated onto the albumin MB shell via covalent bonds and the biotinylated antibodies are conjugated using an avidin-biotin system. The albumin microbubbles had a mean diameter of 2 μm with a polydispersity index of 0.16. For cell separation, the MDA-MB-231 cells are incubated with the targeted biotin-MBs conjugated with anti-CD44 for 10 min, centrifuged at 10 g for 1 min, and then allowed 1 hour at 4 °C for separation. The results indicate that targeted biotin-MBs conjugated with anti-CD44 antibodies can be used to separate MDA-MB-231 breast cancer cells; more than 90% of the cells were collected in the MB layer when the ratio of the MBs to cells was higher than 70:1. Furthermore, we found that the separating efficiency was higher for targeted biotin-MBs than for targeted avidin-incorporated albumin MBs (avidin-MBs), which is the most common way to make targeted albumin MBs. We also demonstrated that the recovery rate of targeted biotin-MBs was up to 88% and the sorting purity was higher than 84% for a a heterogenous cell population containing MDA-MB-231 cells (CD44(+)) and MDA-MB-453 cells (CD44-), which are classified as basal-like breast cancer cells and luminal breast cancer cells, respectively. Knowing that the CD44(+) is a commonly used cancer-stem-cell biomarker, our

  12. Active radar guides missile to its target: receptor-based targeted treatment of hepatocellular carcinoma by nanoparticulate systems.

    PubMed

    Yan, Jing-Jun; Liao, Jia-Zhi; Lin, Ju-Sheng; He, Xing-Xing

    2015-01-01

    Patients with hepatocellular carcinoma (HCC) usually present at advanced stages and do not benefit from surgical resection, so drug therapy should deserve a prominent place in unresectable HCC treatment. But chemotherapy agents, such as doxorubicin, cisplatin, and paclitaxel, frequently encounter important problems such as low specificity and non-selective biodistribution. Recently, the development of nanotechnology led to significant breakthroughs to overcome these problems. Decorating the surfaces of nanoparticulate-based drug carriers with homing devices has demonstrated its potential in concentrating chemotherapy agents specifically to HCC cells. In this paper, we reviewed the current status of active targeting strategies for nanoparticulate systems based on various receptors such as asialoglycoprotein receptor, transferrin receptor, epidermal growth factor receptor, folate receptor, integrin, and CD44, which are abundantly expressed on the surfaces of hepatocytes or liver cancer cells. Furthermore, we pointed out their merits and defects and provided theoretical references for further research.

  13. A strategy to correct for intrafraction target translation in conformal prostate radiotherapy: simulation results.

    PubMed

    Keall, P J; Lauve, A D; Hagan, M P; Siebers, J V

    2007-06-01

    A strategy is proposed in which intrafraction internal target translation is corrected for by repositioning the multileaf collimator position aperture to conform to the new target pose in the beam projection, and the beam monitor units are adjusted to account for the change in the geometric relationship between the target and the beam. The purpose of this study was to investigate the dosimetric stability of the prostate and critical structures in the presence of internal target translation using the dynamic compensation strategy. Twenty-five previously treated prostate cancer patients were replanned using a four-field conformal technique to deliver 72 Gy to 95% of the planning target volume (PTV). Internal translation was introduced by displacing the prostate PTV (no rotation or deformation was considered). Thirty-six randomly selected isotropic displacements of magnitude 0.5, 1.0, 1.5 and 2.0 cm were sampled for each patient, for a total of 3600 errors. Due to their anatomic relation to the prostate, the rectum and bladder contours were also moved with the same magnitude and direction as the prostate. The dynamic compensation strategy was used to correct each of these errors by conforming the beam apertures to the new target pose and adjusting the monitor units using inverse-square and off-axis factor corrections. The dynamic compensation strategy plans were then compared to the original treatment plans via dose-volume histogram (DVH) analysis. Changes of more than 5% of the prescription dose (3.6 Gy) were deemed clinically significant. Compared to the original treatment plans, the dynamic compensation strategy produced small discrepancies in isodose distributions and DVH analyses for all structures considered apart from the femoral heads. These differences increased with the magnitude of the internal motion. Coverage of the PTV was excellent: D5, D95, and Dmean were not increased or decreased by more than 5% of the prescription dose for any of the 3600 simulated

  14. Update on the Pfam5000 Strategy for Selection of StructuralGenomics Targets

    SciTech Connect

    Chandonia, John-Marc; Brenner, Steven E.

    2005-06-27

    Structural Genomics is an international effort to determine the three-dimensional shapes of all important biological macromolecules, with a primary focus on proteins. Target proteins should be selected according to a strategy that is medically and biologically relevant, of good financial value, and tractable. In 2003, we presented the ''Pfam5000'' strategy, which involves selecting the 5,000 most important families from the Pfam database as sources for targets. In this update, we show that although both the Pfam database and the number of sequenced genomes have increased in size, the expected benefits of the Pfam5000 strategy have not changed substantially. Solving the structures of proteins from the 5,000 largest Pfam families would allow accurate fold assignment for approximately 65 percent of all prokaryotic proteins (covering 54 percent of residues) and 63 percent of eukaryotic proteins (42 percent of residues). Fewer than 2,300 of the largest families on this list remain to be solved, making the project feasible in the next five years given the expected throughput to be achieved in the production phase of the Protein Structure Initiative.

  15. Target identification with quantitative activity based protein profiling (ABPP).

    PubMed

    Chen, Xiao; Wong, Yin Kwan; Wang, Jigang; Zhang, Jianbin; Lee, Yew-Mun; Shen, Han-Ming; Lin, Qingsong; Hua, Zi-Chun

    2017-02-01

    As many small bioactive molecules fulfill their functions through interacting with protein targets, the identification of such targets is crucial in understanding their mechanisms of action (MOA) and side effects. With technological advancements in target identification, it has become possible to accurately and comprehensively study the MOA and side effects of small molecules. While small molecules with therapeutic potential were derived solely from nature in the past, the remodeling and synthesis of such molecules have now been made possible. Presently, while some small molecules have seen successful application as drugs, the majority remain undeveloped, requiring further understanding of their MOA and side effects to fully tap into their potential. Given the typical promiscuity of many small molecules and the complexity of the cellular proteome, a high-flux and high-accuracy method is necessary. While affinity chromatography approaches combined with MS have had successes in target identification, limitations associated with nonspecific results remain. To overcome these complications, quantitative chemical proteomics approaches have been developed including metabolic labeling, chemical labeling, and label-free methods. These new approaches are adopted in conjunction with activity-based protein profiling (ABPP), allowing for a rapid process and accurate results. This review will briefly introduce the principles involved in ABPP, then summarize current advances in quantitative chemical proteomics approaches as well as illustrate with examples how ABPP coupled with quantitative chemical proteomics has been used to detect the targets of drugs and other bioactive small molecules including natural products.

  16. A diamond active target for the PADME experiment

    NASA Astrophysics Data System (ADS)

    Chiodini, G.

    2017-02-01

    The PADME (Positron Annihilation into Dark Mediator Experiment) collaboration searches for dark photons produced in the annihilation e++e-→γ+A' of accelerated positrons with atomic electrons of a fixed target at the Beam Test Facility of Laboratori Nazionali di Frascati. The apparatus can detect dark photons decaying into visible A'→e+e- and invisible A'→χχ channels, where χ's are particles of a secluded sector weakly interacting and therefore undetected. In order to improve the missing mass resolution and to measure the beam flux, PADME has an active target able to reconstruct the beam spot position and the bunch multiplicity. In this work the active target is described, which is made of a detector grade polycrystalline synthetic diamond with strip electrodes on both surfaces. The electrodes segmentation allows to measure the beam profile along X and Y and evaluate the average beam position bunch per bunch. The results of beam tests for the first two diamond detector prototypes are shown. One of them holds innovative graphitic electrodes built with a custom process developed in the laboratory, and the other one with commercially available traditional Cr-Au electrodes. The front-end electronics used in the test beam is discussed and the performance observed is presented. Finally, the final design of the target to be realized at the beginning of 2017 to be ready for data taking in 2018 is illustrated.

  17. Macrophage Polarization: Anti-cancer Strategies to Target Tumor-associated Macrophage in Breast Cancer.

    PubMed

    Tariq, Muhammad; Zhang, Jieqiong; Liang, Guikai; Ding, Ling; He, Qiaojun; Yang, Bo

    2017-01-20

    Tumor-associated macrophages (TAMs) are the most abundant inflammatory cells and orchestrate different stages of breast cancer development. TAMs participate in the tumor angiogenesis, matrix remodeling, invasion, immunosuppression, metastasis, and chemoresistance in breast cancer. Several clinical studies indicate the association between the high influx of TAMs in tumor with poor prognosis in hepatocellular, ovarian, cervical, and breast cancer. Previously developed hypotheses have proposed that TAMs participate in antitumor responses of the body, while recently many clinical and experimental studies have revealed that TAMs in tumor microenvironment predominantly resemble with M2-like polarized macrophages and produce a high amount of anti-inflammatory factors which are directly responsible for the development of tumor. Various studies have shown that TAMs in tumor either enhance or antagonize the anti-tumor efficacy of cytotoxic agents, antibodies-targeting cancer cells, and therapeutic agents depending on the nature of treatment. Thereby, multiple roles of TAMs suggests that it is very important to develop novel therapeutic strategies to target TAMs in breast tumor. In this review, we have discussed the functional role of TAMs in breast cancer and summarized available recent advances potential therapeutic strategies that effectively target to TAMs cells. This article is protected by copyright. All rights reserved.

  18. Molecular pathways: targeting MALT1 paracaspase activity in lymphoma.

    PubMed

    Fontán, Lorena; Melnick, Ari

    2013-12-15

    MALT1 mediates the activation of NF-κB in response to antigen receptor signaling. MALT1, in association with BCL10 and CARD11, functions as a scaffolding protein to activate the inhibitor of IκB kinase (IKK) complex. In addition, MALT1 is a paracaspase that targets key proteins in a feedback loop mediating termination of the NF-κB response, thus promoting activation of NF-κB signaling. Activated B-cell subtype of diffuse large B-cell lymphomas (ABC-DLBCL), which tend to be more resistant to chemotherapy, are often biologically dependent on MALT1 activity. Newly developed MALT1 small-molecule inhibitors suppress the growth of ABC-DLBCLs in vitro and in vivo. This review highlights the recent advances in the normal and disease-related functions of MALT1. Furthermore, recent progress targeting MALT1 proteolytic activity raises the possibility of deploying MALT1 inhibitors for the treatment of B-cell lymphomas and perhaps autoimmune diseases that involve increased B- or T-cell receptor signaling.

  19. AMPK activation: a therapeutic target for type 2 diabetes?

    PubMed

    Coughlan, Kimberly A; Valentine, Rudy J; Ruderman, Neil B; Saha, Asish K

    2014-01-01

    Type 2 diabetes (T2D) is a metabolic disease characterized by insulin resistance, β-cell dysfunction, and elevated hepatic glucose output. Over 350 million people worldwide have T2D, and the International Diabetes Federation projects that this number will increase to nearly 600 million by 2035. There is a great need for more effective treatments for maintaining glucose homeostasis and improving insulin sensitivity. AMP-activated protein kinase (AMPK) is an evolutionarily conserved serine/threonine kinase whose activation elicits insulin-sensitizing effects, making it an ideal therapeutic target for T2D. AMPK is an energy-sensing enzyme that is activated when cellular energy levels are low, and it signals to stimulate glucose uptake in skeletal muscles, fatty acid oxidation in adipose (and other) tissues, and reduces hepatic glucose production. There is substantial evidence suggesting that AMPK is dysregulated in animals and humans with metabolic syndrome or T2D, and that AMPK activation (physiological or pharmacological) can improve insulin sensitivity and metabolic health. Numerous pharmacological agents, natural compounds, and hormones are known to activate AMPK, either directly or indirectly - some of which (for example, metformin and thiazolidinediones) are currently used to treat T2D. This paper will review the regulation of the AMPK pathway and its role in T2D, some of the known AMPK activators and their mechanisms of action, and the potential for future improvements in targeting AMPK for the treatment of T2D.

  20. Novel p53-dependent anticancer strategy by targeting iron signaling and BNIP3L-induced mitophagy

    PubMed Central

    Wilfinger, Nastasia; Austin, Shane; Scheiber-Mojdehkar, Barbara; Berger, Walter; Reipert, Siegfried; Praschberger, Monika; Paur, Jakob; Trondl, Robert; Keppler, Bernhard K.; Zielinski, Christoph C.; Nowikovsky, Karin

    2016-01-01

    This study identifies BNIP3L as the key regulator of p53-dependent cell death mechanism in colon cancer cells targeted by the novel gallium based anticancer drug, KP46. KP46 specifically accumulated into mitochondria where it caused p53-dependent morphological and functional damage impairing mitochondrial dynamics and bioenergetics. Furthermore, competing with iron for cellular uptake, KP46 lowered the intracellular labile iron pools and intracellular heme. Accordingly, p53 accumulated in the nucleus where it activated its transcriptional target BNIP3L, a BH3 only domain protein with functions in apoptosis and mitophagy. Upregulated BNIP3L sensitized the mitochondrial permeability transition and strongly induced PARKIN-mediated mitochondrial clearance and cellular vacuolization. Downregulation of BNIP3L entirely rescued cell viability caused by exposure of KP46 for 24 hours, confirming that early induced cell death was regulated by BNIP3L. Altogether, targeting BNIP3L in wild-type p53 colon cancer cells is a novel anticancer strategy activating iron depletion signaling and the mitophagy-related cell death pathway. PMID:26517689

  1. Expression, characterization, and evaluation of a RANK-binding single chain fraction variable: an osteoclast targeting drug delivery strategy.

    PubMed

    Newa, Madhuri; Lam, Michael; Bhandari, Krishna Hari; Xu, Biwen; Doschak, Michael R

    2014-01-06

    A single chain Fraction variable (scFv) employs antibody-like target recognition specificity. Osteoclasts, responsible for bone resorption, express Receptor Activator of Nuclear factor Kappa B (RANK) receptors. This study aimed to express, characterize, and evaluate scFv against RANK receptors that may serve as a platform to target osteoclasts. Using phage display technology, scFv against RANK receptor was expressed and characterized by DNA sequencing, sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), matrix-assisted laser desorption-ionization time-of-flight (MALDI TOF), enzyme-linked immunosorbent assay (ELISA), Western blot, and immunocytochemistry. The potential for cytotoxicity was evaluated using an MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide) assay, and its cross reactivity was evaluated using ELISA. Osteoclast-like cells were generated from RAW 264.7 cells, and the osteoclast targeting ability of scFv was evaluated using immunocytochemistry. ScFv's antiresorptive efficacy was studied using a tartrate-resistant acid phosphatase (TRAP) assay and resorption assay. Anti-RANK scFv was successfully expressed and characterized. No cross reactivity with other tumor necrosis factor receptor (TNFR) members and no cytotoxic effect on a non-RANK bearing cell line were observed. It showed specificity toward a RANK receptor and an inhibitory effect on osteoclast activity. With the increase in development trends for biologics as therapeutics and growing knowledge on the importance of osteoclast targeted therapy, this study may provide a drug delivery strategy to target osteoclasts, thereby leading to a promising therapy for resorptive bone diseases.

  2. [Current strategies in the treatment of renal-cell cancer: targeted therapies].

    PubMed

    Trigo, José Manuel; Bellmunt, Joaquim

    2008-03-22

    Renal-cell carcinoma represents 95% of all renal tumours. The Von Hippel-Lindau (VHL) tumor-suppressor gene is mutated or silenced in most clear cell renal carcinomas. pVHL loss results in the stabilization of the heterodimeric transcription factor hypoxia-inducible factor (HIF) and enhanced transactivation of HIF target genes. HIF itself has been difficult to inhibit with drug-like molecules although a number of agents that indirectly inhibit HIF, including mTOR (mammalian target of rapamycin) inhibitors, have been identified. Moreover, a number of drugs have been developed that target HIF-responsive gene products, such as vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF), implicated in tumor angiogenesis. Many of these targeted therapies, especially sunitinib, have demonstrated significant activity in kidney cancer clinical trials and represent a substantive advance in the treatment of this disease.

  3. Brain Activation Underlying Threat Detection to Targets of Different Races

    PubMed Central

    Senholzi, Keith B.; Depue, Brendan E.; Correll, Joshua; Banich, Marie T.; Ito, Tiffany A.

    2016-01-01

    The current study examined blood oxygen level dependent (BOLD) signal underlying racial differences in threat detection. During fMRI, participants determined whether pictures of Black or White individuals held weapons. They were instructed to make shoot responses when the picture showed armed individuals but don’t shoot responses to unarmed individuals, with the cost of not shooting armed individuals being greater than that of shooting unarmed individuals. Participants were faster to shoot armed Blacks than Whites, but faster in making don’t shoot responses to unarmed Whites than Blacks. Brain activity differed to armed versus unarmed targets depending on target race, suggesting different mechanisms underlying threat versus safety decisions. Anterior cingulate cortex was preferentially engaged for unarmed Whites than Blacks. Parietal and visual cortical regions exhibited greater activity for armed Blacks than Whites. Seed-based functional connectivity of the amygdala revealed greater coherence with parietal and visual cortices for armed Blacks than Whites. Furthermore, greater implicit Black-danger associations were associated with increased amygdala activation to armed Blacks, compared to armed Whites. Our results suggest that different neural mechanisms may underlie racial differences in responses to armed versus unarmed targets. PMID:26357911

  4. Need for Optimisation of Immunisation Strategies Targeting Invasive Meningococcal Disease in the Netherlands

    PubMed Central

    Bousema, Josefien Cornelie Minthe; Ruitenberg, Joost

    2015-01-01

    Invasive meningococcal disease (IMD) is a severe bacterial infectious disease with high mortality and morbidity rates worldwide. In recent years, industrialised countries have implemented vaccines targeting IMD in their National Immunisation Programmes (NIPs). In 2002, the Netherlands successfully implemented a single dose of meningococcal serogroup C conjugate vaccine at the age of 14 months and performed a single catch-up for children ≤18 years of age. Since then the disease disappeared in vaccinated individuals. Furthermore, herd protection was induced, leading to a significant IMD reduction in non-vaccinated individuals. However, previous studies revealed that the current programmatic immunisation strategy was insufficient to protect the population in the foreseeable future. In addition, vaccines that provide protection against additional serogroups are now available. This paper describes to what extent the current strategy to prevent IMD in the Netherlands is still sufficient, taking into account the burden of disease and the latest scientific knowledge related to IMD and its prevention. In particular, primary MenC immunisation seems not to provide long-term protection, indicating a risk for possible recurrence of the disease. This can be combatted by implementing a MenC or MenACWY adolescent booster vaccine. Additional health benefits can be achieved by replacing the primary MenC by a MenACWY vaccine. By implementation of a recently licensed MenB vaccine for infants in the NIP, the greatest burden of disease would be targeted. This paper shows that optimisation of the immunisation strategy targeting IMD in the Netherlands should be considered and contributes to create awareness concerning prevention optimisation in other countries. PMID:26673336

  5. Need for Optimisation of Immunisation Strategies Targeting Invasive Meningococcal Disease in the Netherlands.

    PubMed

    Bousema, Josefien Cornelie Minthe; Ruitenberg, Joost

    2015-09-13

    Invasive meningococcal disease (IMD) is a severe bacterial infectious disease with high mortality and morbidity rates worldwide. In recent years, industrialised countries have implemented vaccines targeting IMD in their National Immunisation Programmes (NIPs). In 2002, the Netherlands successfully implemented a single dose of meningococcal serogroup C conjugate vaccine at the age of 14 months and performed a single catch-up for children ≤18 years of age. Since then the disease disappeared in vaccinated individuals. Furthermore, herd protection was induced, leading to a significant IMD reduction in non-vaccinated individuals. However, previous studies revealed that the current programmatic immunisation strategy was insufficient to protect the population in the foreseeable future. In addition, vaccines that provide protection against additional serogroups are now available. This paper describes to what extent the current strategy to prevent IMD in the Netherlands is still sufficient, taking into account the burden of disease and the latest scientific knowledge related to IMD and its prevention. In particular, primary MenC immunisation seems not to provide long-term protection, indicating a risk for possible recurrence of the disease. This can be combatted by implementing a MenC or MenACWY adolescent booster vaccine. Additional health benefits can be achieved by replacing the primary MenC by a MenACWY vaccine. By implementation of a recently licensed MenB vaccine for infants in the NIP, the greatest burden of disease would be targeted. This paper shows that optimisation of the immunisation strategy targeting IMD in the Netherlands should be considered and contributes to create awareness concerning prevention optimisation in other countries.

  6. 13 CFR 124.509 - What are non-8(a) business activity targets?

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... reasonable marketing strategy, to attain the targeted dollar levels of non-8(a) revenue established in its..., business development, financing, marketing, accounting, or proposal preparation. (5) SBA may...

  7. 13 CFR 124.509 - What are non-8(a) business activity targets?

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... reasonable marketing strategy, to attain the targeted dollar levels of non-8(a) revenue established in its..., business development, financing, marketing, accounting, or proposal preparation. (5) SBA may...

  8. 13 CFR 124.509 - What are non-8(a) business activity targets?

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... following a reasonable marketing strategy, to attain the targeted dollar levels of non-8(a) revenue..., business development, financing, marketing, accounting, or proposal preparation. (5) SBA may...

  9. 13 CFR 124.509 - What are non-8(a) business activity targets?

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... following a reasonable marketing strategy, to attain the targeted dollar levels of non-8(a) revenue..., business development, financing, marketing, accounting, or proposal preparation. (5) SBA may...

  10. 13 CFR 124.509 - What are non-8(a) business activity targets?

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... following a reasonable marketing strategy, to attain the targeted dollar levels of non-8(a) revenue..., business development, financing, marketing, accounting, or proposal preparation. (5) SBA may...

  11. Potential Therapeutic Strategies for Alzheimer's Disease Targeting or Beyond β-Amyloid: Insights from Clinical Trials

    PubMed Central

    Jia, Qiutian; Qing, Hong

    2014-01-01

    Alzheimer's disease (AD) is a progressive neurodegenerative disorder with two hallmarks: β-amyloid plagues and neurofibrillary tangles. It is one of the most alarming illnesses to elderly people. No effective drugs and therapies have been developed, while mechanism-based explorations of therapeutic approaches have been intensively investigated. Outcomes of clinical trials suggested several pitfalls in the choice of biomarkers, development of drug candidates, and interaction of drug-targeted molecules; however, they also aroused concerns on the potential deficiency in our understanding of pathogenesis of AD, and ultimately stimulated the advent of novel drug targets tests. The anticipated increase of AD patients in next few decades makes development of better therapy an urgent issue. Here we attempt to summarize and compare putative therapeutic strategies that have completed clinical trials or are currently being tested from various perspectives to provide insights for treatments of Alzheimer's disease. PMID:25136630

  12. Successful Targeted Treatment of Mast Cell Activation Syndrome with Tofacitinib.

    PubMed

    Afrin, Lawrence B; Fox, Roger W; Zito, Susan L; Choe, Leo; Glover, Sarah C

    2017-04-06

    Mast cell (MC) activation syndrome (MCAS) is a collection of illnesses of inappropriate MC activation with little to no neoplastic MC proliferation, distinguishing it from mastocytosis. MCAS presents as chronic, generally inflammatory multisystem polymorbidity likely driven in most by heterogeneous patterns of constitutively activating mutations in MC regulatory elements, posing challenges for identifying optimal mutation-targeted treatment in individual patients. Targeting commonly affected downstream effectors may yield clinical benefit independent of upstream mutational profile. For example, both activated KIT and numerous cytokine receptors activate the Janus kinases (JAKs). Thus, JAK-inhibiting therapies may be useful against the downstream inflammatory effects of MCAS. The oral JAK1/JAK3 inhibitor, tofacitinib, is currently approved for rheumatoid arthritis and is in clinical trials for other chronic inflammatory disorders. Herein, we report two MCAS patients who rapidly gained substantial symptomatic response to tofacitinib. Their improvement suggests need for further evaluation of this class of drugs in MCAS treatment. This article is protected by copyright. All rights reserved.

  13. Treatment Strategies that Enhance the Efficacy and Selectivity of Mitochondria-Targeted Anticancer Agents

    PubMed Central

    Modica-Napolitano, Josephine S.; Weissig, Volkmar

    2015-01-01

    Nearly a century has passed since Otto Warburg first observed high rates of aerobic glycolysis in a variety of tumor cell types and suggested that this phenomenon might be due to an impaired mitochondrial respiratory capacity in these cells. Subsequently, much has been written about the role of mitochondria in the initiation and/or progression of various forms of cancer, and the possibility of exploiting differences in mitochondrial structure and function between normal and malignant cells as targets for cancer chemotherapy. A number of mitochondria-targeted compounds have shown efficacy in selective cancer cell killing in pre-clinical and early clinical testing, including those that induce mitochondria permeability transition and apoptosis, metabolic inhibitors, and ROS regulators. To date, however, none has exhibited the standards for high selectivity and efficacy and low toxicity necessary to progress beyond phase III clinical trials and be used as a viable, single modality treatment option for human cancers. This review explores alternative treatment strategies that have been shown to enhance the efficacy and selectivity of mitochondria-targeted anticancer agents in vitro and in vivo, and may yet fulfill the clinical promise of exploiting the mitochondrion as a target for cancer chemotherapy. PMID:26230693

  14. Gastric cancer in the era of molecularly targeted agents: current drug development strategies.

    PubMed

    Arkenau, Hendrik-Tobias

    2009-07-01

    Gastric cancer is the second most common cause of cancer death worldwide with approximately one million cases diagnosed annually. Despite considerable improvements in surgical techniques, innovations in clinical diagnostics and the development of new chemotherapy regimens, the clinical outcome for patients with advanced gastric cancer and cancer of the GEJ is generally poor with 5-year survival rates ranging between 5 and 15%. The understanding of cancer relevant events has resulted in new therapeutic strategies, particularly in developing of new molecular targeted agents. These agents have the ability to target a variety of cancer relevant receptors and downstream pathways including the epidermal growth factor receptor (EGFR), the vascular endothelial growth factor receptor (VEGFR), the insulin-like growth factor receptor (IGFR), the c-Met pathway, cell-cycle pathways, and down-stream signalling pathways such as the Akt-PI3k-mTOR pathway. In the era of new molecularly targeted agents this review focuses on recent developments of targeting relevant pathways involved in gastric cancer and cancer of the GEJ.

  15. Diacylglycerol Kinases (DGKs): Novel Targets for Improving T Cell Activity in Cancer

    PubMed Central

    Riese, Matthew J.; Moon, Edmund K.; Johnson, Bryon D.; Albelda, Steven M.

    2016-01-01

    Diacylglycerol kinases (DGKs) are a family of enzymes that catalyze the metabolism of diacylglycerol (DAG). Two isoforms of DGK, DGKα, and DGKζ, specifically regulate the pool of DAG that is generated as a second messenger after stimulation of the T cell receptor (TCR). Deletion of either isoform in mouse models results in T cells bearing a hyperresponsive phenotype and enhanced T cell activity against malignancy. Whereas, DGKζ appears to be the dominant isoform in T cells, rationale exists for targeting both isoforms individually or coordinately. Additional work is needed to rigorously identify the molecular changes that result from deletion of DGKs in order to understand how DAG contributes to T cell activation, the effect of DGK inhibition in human T cells, and to rationally develop combined immunotherapeutic strategies that target DGKs. PMID:27800476

  16. Factor XI and Contact Activation as Targets for Antithrombotic Therapy

    PubMed Central

    Gailani, David; Bane, Charles E.; Gruber, Andras

    2015-01-01

    Summary The most commonly used anticoagulants produce therapeutic antithrombotic effects either by inhibiting thrombin or factor Xa, or by lowering the plasma levels of the precursors of these key enzymes, prothrombin and factor X. These drugs do not distinguish between thrombin generation contributing to thrombosis from thrombin generation required for hemostasis. Thus, anticoagulants increase bleeding risk, and many patients who would benefit from therapy go untreated because of comorbidities that place them at unacceptable risk for hemorrhage. Studies in animals demonstrate that components of the plasma contact activation system contribute to experimentally-induced thrombosis, despite playing little or no role in hemostasis. Attention has focused on factor XII, the zymogen of a protease (factor XIIa) that initiates contact activation when blood is exposed to foreign surfaces; and factor XI, the zymogen of the protease factor XIa, which links contact activation to the thrombin generation mechanism. In the case of factor XI, epidemiologic data indicate this protein contributes to stroke and venous thromboembolism, and perhaps myocardial infarction, in humans. A phase 2 trial showing that reduction of factor XI may be more effective than low-molecular-weight heparin at preventing venous thrombosis during knee replacement surgery provides proof of concept for the premise that an antithrombotic effect can be uncoupled from an anticoagulant effect in humans by targeting components of contact activation. Here we review data on the role of factor XI and factor XII in thrombosis, and results of pre-clinical and human trials for therapies targeting these proteins. PMID:25976012

  17. Factor XI and contact activation as targets for antithrombotic therapy.

    PubMed

    Gailani, D; Bane, C E; Gruber, A

    2015-08-01

    The most commonly used anticoagulants produce therapeutic antithrombotic effects either by inhibiting thrombin or factor Xa (FXa) or by lowering the plasma levels of the precursors of these key enzymes, prothrombin and FX. These drugs do not distinguish between thrombin generation contributing to thrombosis from thrombin generation required for hemostasis. Thus, anticoagulants increase bleeding risk, and many patients who would benefit from therapy go untreated because of comorbidities that place them at unacceptable risk for hemorrhage. Studies in animals demonstrate that components of the plasma contact activation system contribute to experimentally induced thrombosis, despite playing little or no role in hemostasis. Attention has focused on FXII, the zymogen of a protease (FXIIa) that initiates contact activation when blood is exposed to foreign surfaces, and FXI, the zymogen of the protease FXIa, which links contact activation to the thrombin generation mechanism. In the case of FXI, epidemiologic data indicate this protein contributes to stroke and venous thromboembolism, and perhaps myocardial infarction, in humans. A phase 2 trial showing that reduction of FXI may be more effective than low molecular weight heparin at preventing venous thrombosis during knee replacement surgery provides proof of concept for the premise that an antithrombotic effect can be uncoupled from an anticoagulant effect in humans by targeting components of contact activation. Here, we review data on the role of FXI and FXII in thrombosis and results of preclinical and human trials for therapies targeting these proteins.

  18. Effects of organic carbon sequestration strategies on soil enzymatic activities

    NASA Astrophysics Data System (ADS)

    Puglisi, E.; Suciu, N.; Botteri, L.; Ferrari, T.; Coppolecchia, D.; Trevisan, M.; Piccolo, A.

    2009-04-01

    Greenhouse gases emissions can be counterbalanced with proper agronomical strategies aimed at sequestering carbon in soils. These strategies must be tested not only for their ability in reducing carbon dioxide emissions, but also for their impact on soil quality: enzymatic activities are related to main soil ecological quality, and can be used as early and sensitive indicators of alteration events. Three different strategies for soil carbon sequestration were studied: minimum tillage, protection of biodegradable organic fraction by compost amendment and oxidative polimerization of soil organic matter catalyzed by biometic porfirins. All strategies were compared with a traditional agricultural management based on tillage and mineral fertilization. Experiments were carried out in three Italian soils from different pedo-climatic regions located respectively in Piacenza, Turin and Naples and cultivated with maize or wheat. Soil samples were taken for three consecutive years after harvest and analyzed for their content in phosphates, ß-glucosidase, urease and invertase. An alteration index based on these enzymatic activities levels was applied as well. The biomimetic porfirin application didn't cause changes in enzymatic activities compared to the control at any treatment or location. Enzymatic activities were generally higher in the minimum tillage and compost treatment, while differences between location and date of samplings were limited. Application of the soil alteration index based on enzymatic activities showed that soils treated with compost or subjected to minimum tillage generally have a higher biological quality. The work confirms the environmental sustainability of the carbon sequestering agronomical practices studied.

  19. Combining Untargeted and Targeted Proteomic Strategies for Discrimination and Quantification of Cashmere Fibers

    PubMed Central

    Li, Shanshan; Zhang, Yong; Wang, Jihua; Yang, Yunfei; Miao, Chen; Guo, Yufeng; Zhang, Zhidan; Cao, Qichen; Shui, Wenqing

    2016-01-01

    Cashmere is regarded as a specialty and luxury fiber due to its scarcity and high economic value. For fiber quality assessment, it is technically very challenging to distinguish and quantify the cashmere fiber from yak or wool fibers because of their highly similar physical appearance and substantial protein sequence homology. To address this issue, we propose a workflow combining untargeted and targeted proteomics strategies for selecting, verifying and quantifying biomarkers for cashmere textile authentication. Untargeted proteomic surveys were first applied to identify 174, 157, and 156 proteins from cashmere, wool and yak fibers, respectively. After marker selection at different levels, peptides turned out to afford much higher selectivity than proteins for fiber species discrimination. Subsequently, parallel reaction monitoring (PRM) methods were developed for ten selected peptide markers. The PRM-based targeted analysis of peptide markers enabled accurate determination of fiber species and cashmere percentages in different fiber mixtures. Furthermore, collective use of these peptide makers allowed us to discriminate and quantify cashmere fibers in commercial finished fabrics that have undergone heavy chemical treatments. Cashmere proportion measurement in fabric samples using our proteomic approach was in good agreement with results from traditional light microscopy, yet our method can be more readily standardized to become an objective and robust assay for assessing authenticity of fibers and textiles. We anticipate that the proteomic strategies presented in our study could be further implicated in discovery of quality trait markers for other products containing highly homologous proteomes. PMID:26789629

  20. Haem-activated promiscuous targeting of artemisinin in Plasmodium falciparum

    PubMed Central

    Wang, Jigang; Zhang, Chong-Jing; Chia, Wan Ni; Loh, Cheryl C. Y.; Li, Zhengjun; Lee, Yew Mun; He, Yingke; Yuan, Li-Xia; Lim, Teck Kwang; Liu, Min; Liew, Chin Xia; Lee, Yan Quan; Zhang, Jianbin; Lu, Nianci; Lim, Chwee Teck; Hua, Zi-Chun; Liu, Bin; Shen, Han-Ming; Tan, Kevin S. W.; Lin, Qingsong

    2015-01-01

    The mechanism of action of artemisinin and its derivatives, the most potent of the anti-malarial drugs, is not completely understood. Here we present an unbiased chemical proteomics analysis to directly explore this mechanism in Plasmodium falciparum. We use an alkyne-tagged artemisinin analogue coupled with biotin to identify 124 artemisinin covalent binding protein targets, many of which are involved in the essential biological processes of the parasite. Such a broad targeting spectrum disrupts the biochemical landscape of the parasite and causes its death. Furthermore, using alkyne-tagged artemisinin coupled with a fluorescent dye to monitor protein binding, we show that haem, rather than free ferrous iron, is predominantly responsible for artemisinin activation. The haem derives primarily from the parasite's haem biosynthesis pathway at the early ring stage and from haemoglobin digestion at the latter stages. Our results support a unifying model to explain the action and specificity of artemisinin in parasite killing. PMID:26694030

  1. [The Spanish strategy for nutrition, physical activity and the prevention of obesity (NAOS Strategy)].

    PubMed

    Ballesteros Arribas, Juan Manuel; Dal-Re Saavedra, Marián; Pérez-Farinós, Napoleón; Villar Villalba, Carmen

    2007-01-01

    Obesity, the prevalence of which is still on the rise, is related to the main chronic diseases affecting the health of the population. Therefore, in 2004, the World Health Assembly approved the Global Strategy on Diet, Physical Activity and Health with the aim of reducing the risk factors of nontransmittable diseases related to unhealthy diets and physical inactivity. Along this same line, the Spanish Ministry of Health and Consumer Affairs began implementing the NAOS Strategy in 2005 as a platform from which to include and promote all those initiatives contributing to achieving the necessary social change in the promotion of healthy eating and the prevention of a sedentary lifestyle by meeting certain specific challenges within different scopes of action. The NAOS Strategy extends far beyond the healthcare and educational areas, by combining actions in all those sectors of society playing a role in preventing obesity. Informative campaigns, agreements with public and private institutions, voluntary working agreements, educational programs and supporting health promotion initiatives are some of the activities being carried out as part of the NAOS Strategy. Carrying out these activities and incorporating yet others, in conjunction with the work of evaluating and monitoring all of these activities, will be what is going to make it possible to maintain a high degree of effectiveness in preventing obesity.

  2. Active Anti-erosion Protection Strategy in Tamarisk (Tamarix aphylla)

    NASA Astrophysics Data System (ADS)

    Han, Zhiwu; Yin, Wei; Zhang, Junqiu; Niu, Shichao; Ren, Luquan

    2013-12-01

    Plants have numerous active protection strategies for adapting to complex and severe environments. These strategies provide endless inspiration for extending the service life of materials and machines. Tamarisk (Tamarix aphylla), a tree that thrives in raging sandstorm regions, has adapted to blustery conditions by evolving extremely effective and robust erosion resistant characteristics. However, the relationships among its surface cracks, internal histology and biomechanics, such as cracks, rings, cells, elasticity modulus and growth stress, which account for its erosion resistance, remain unclear. This present study reveals that the directionally eccentric growth rings of tamarisk, which are attributed to reduced stress and accelerated cell division, promote the formation of surface cracks. The windward rings are more extensive than the leeward side rings. The windward surfaces are more prone to cracks, which improves erosion resistance. Our data provide insight into the active protection strategy of the tamarisk against wind-sand erosion.

  3. Active anti-erosion protection strategy in tamarisk (Tamarix aphylla).

    PubMed

    Han, Zhiwu; Yin, Wei; Zhang, Junqiu; Niu, Shichao; Ren, Luquan

    2013-12-05

    Plants have numerous active protection strategies for adapting to complex and severe environments. These strategies provide endless inspiration for extending the service life of materials and machines. Tamarisk (Tamarix aphylla), a tree that thrives in raging sandstorm regions, has adapted to blustery conditions by evolving extremely effective and robust erosion resistant characteristics. However, the relationships among its surface cracks, internal histology and biomechanics, such as cracks, rings, cells, elasticity modulus and growth stress, which account for its erosion resistance, remain unclear. This present study reveals that the directionally eccentric growth rings of tamarisk, which are attributed to reduced stress and accelerated cell division, promote the formation of surface cracks. The windward rings are more extensive than the leeward side rings. The windward surfaces are more prone to cracks, which improves erosion resistance. Our data provide insight into the active protection strategy of the tamarisk against wind-sand erosion.

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

    PubMed

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

    2010-05-26

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

  5. Genome-based cancer therapeutics: targets, kinase drug resistance and future strategies for precision oncology.

    PubMed

    Workman, Paul; Al-Lazikani, Bissan; Clarke, Paul A

    2013-08-01

    Extraordinary progress has been made in our detailed understanding of the genetic and epigenetic mechanisms responsible for oncogenesis and cancer progression. Empowered by next-generation sequencing, many new targets and pathways have been identified to exploit oncogene and non-oncogene addiction and synthetic lethality. Kinase inhibitors feature strongly in the druggable cancer genome and 19 have been approved in oncology. While survival gains are valuable, drug resistance has emerged as the major challenge. The clonal heterogeneity and evolution of cancers is an intrinsic problem, together with feedback loops, kinase switching and activation of alternative targets and pathways. The solution to drug resistance will require the use of rationally targeted combinational regimens. The application of adaptive treatment cycles based on ongoing multi-technology profiling will be the key to long-term therapeutic success.

  6. Targeting of gastrointestinal tract for amended delivery of protein/peptide therapeutics: strategies and industrial perspectives.

    PubMed

    Pawar, Vivek K; Meher, Jaya Gopal; Singh, Yuvraj; Chaurasia, Mohini; Surendar Reddy, B; Chourasia, Manish K

    2014-12-28

    Delivery of proteins/peptides to the gastrointestinal (GI) tract via peroral/oral route involves tremendous challenges due to unfavorable environmental conditions like harsh pH, presence of proteolytic enzymes and absorption barriers. Detailed research is being conducted at the academic and industrial levels to diminish these troubles and various products are under clinical trials. Several approaches have been established to optimize oral delivery of proteins and peptides and can be broadly categorized into chemical and physical strategies. Chemical strategies include site specific mutagenesis, proteinylation, glycosylation, PEGylation and prodrug approaches, whereas physical strategies comprise formulation based approaches including application of absorption enhancers and metabolism modifiers along with delivering them via colloidal carrier systems such as nanoparticles, liposomes, microparticles, and micro- and nano-emulsions. This review stands to accomplish the diverse aspects of oral delivery of proteins/peptides and summarizes the key concepts involved in targeting the biodrugs to specific sites of the GI tract such as the intestine and colon. Furthermore some light has also been shed on the current industrial practices followed in developing oral formulations of such bioactives.

  7. IdealKnock: A framework for efficiently identifying knockout strategies leading to targeted overproduction.

    PubMed

    Gu, Deqing; Zhang, Cheng; Zhou, Shengguo; Wei, Liujing; Hua, Qiang

    2016-04-01

    In recent years, computer aided redesigning methods based on genome-scale metabolic network models (GEMs) have played important roles in metabolic engineering studies; however, most of these methods are hindered by intractable computing times. In particular, methods that predict knockout strategies leading to overproduction of desired biochemical are generally unable to do high level prediction because the computational time will increase exponentially. In this study, we propose a new framework named IdealKnock, which is able to efficiently evaluate potentials of the production for different biochemical in a system by merely knocking out pathways. In addition, it is also capable of searching knockout strategies when combined with the OptKnock or OptGene framework. Furthermore, unlike other methods, IdealKnock suggests a series of mutants with targeted overproduction, which enables researchers to select the one of greatest interest for experimental validation. By testing the overproduction of a large number of native metabolites, IdealKnock showed its advantage in successfully breaking through the limitation of maximum knockout number in reasonable time and suggesting knockout strategies with better performance than other methods. In addition, gene-reaction relationship is well considered in the proposed framework.

  8. Perceived Strategies and Activities for Successful Later Aging

    ERIC Educational Resources Information Center

    Holahan, Carole K.; Velasquez, Katherine S.

    2011-01-01

    This study investigated perceived strategies and activities for successful later aging. Participants were 242 members of the Terman Study of the Gifted who responded to an open-ended question concerning how they make the most of their aging years. Data were collected in 1996 and 1999, when the participants were average ages of 84 and 86.…

  9. Strategies for active learning in online continuing education.

    PubMed

    Phillips, Janet M

    2005-01-01

    Online continuing education and staff development is on the rise as the benefits of access, convenience, and quality learning are continuing to take shape. Strategies to enhance learning call for learner participation that is self-directed and independent, thus changing the educator's role from expert to coach and facilitator. Good planning of active learning strategies promotes optimal learning whether the learning content is presented in a course or a just-in-time short module. Active learning strategies can be used to enhance online learning during all phases of the teaching-learning process and can accommodate a variety of learning styles. Feedback from peers, educators, and technology greatly influences learner satisfaction and must be harnessed to provide effective learning experiences. Outcomes of active learning can be assessed online and implemented conveniently and successfully from the initiation of the course or module planning to the end of the evaluation process. Online learning has become accessible and convenient and allows the educator to track learner participation. The future of online education will continue to grow, and using active learning strategies will ensure that quality learning will occur, appealing to a wide variety of learning needs.

  10. Using Active Learning Strategies to Present Bloodborne Pathogen Programs

    ERIC Educational Resources Information Center

    Cooper, Leslie; Weaver, Mary G.

    2003-01-01

    Every year, school nurses have the responsibility for developing and presenting a bloodborne pathogen presentation to the education and clerical staff of their buildings. Although the information is similar from year to year, the manner in which the information is presented can be altered. Teachers are using active learning strategies in a variety…

  11. Multiple strategies to activate gold nanoparticles as antibiotics

    NASA Astrophysics Data System (ADS)

    Zhao, Yuyun; Jiang, Xingyu

    2013-08-01

    Widespread antibiotic resistance calls for new strategies. Nanotechnology provides a chance to overcome antibiotic resistance by multiple antibiotic mechanisms. This paper reviews the progress in activating gold nanoparticles with nonantibiotic or antibiotic molecules to combat bacterial resistance, analyzes the gap between experimental achievements and real clinical application, and suggests some potential directions in developing antibacterial nanodrugs.

  12. Brazilian physical activity guidelines as a strategy for health promotion

    PubMed Central

    Sebastião, Emerson; Schwingel, Andiara; Chodzko-Zajko, Wojtek

    2014-01-01

    Public health actions endorsed by the federal government, for instance, health promotion initiatives, usually have greater impact at population level compared to other types of initiatives. This commentary aims to instigate debate on the importance and necessity of producing federally endorsed brazilian physical activity guidelines as a strategy for health promotion. PMID:25210830

  13. Brazilian physical activity guidelines as a strategy for health promotion.

    PubMed

    Sebastião, Emerson; Schwingel, Andiara; Chodzko-Zajko, Wojtek

    2014-08-01

    Public health actions endorsed by the federal government, for instance, health promotion initiatives, usually have greater impact at population level compared to other types of initiatives. This commentary aims to instigate debate on the importance and necessity of producing federally endorsed brazilian physical activity guidelines as a strategy for health promotion.

  14. Revealing potential molecular targets bridging colitis and colorectal cancer based on multidimensional integration strategy

    PubMed Central

    Hu, Yongfei; Li, Xiaobo; Wang, Xishan; Fan, Huihui; Wang, Guiyu; Wang, Dong

    2015-01-01

    Chronic inflammation may play a vital role in the pathogenesis of inflammation-associated tumors. However, the underlying mechanisms bridging ulcerative colitis (UC) and colorectal cancer (CRC) remain unclear. Here, we integrated multidimensional interaction resources, including gene expression profiling, protein-protein interactions (PPIs), transcriptional and post-transcriptional regulation data, and virus-host interactions, to tentatively explore potential molecular targets that functionally link UC and CRC at a systematic level. In this work, by deciphering the overlapping genes, crosstalking genes and pivotal regulators of both UC- and CRC-associated functional module pairs, we revealed a variety of genes (including FOS and DUSP1, etc.), transcription factors (including SMAD3 and ETS1, etc.) and miRNAs (including miR-155 and miR-196b, etc.) that may have the potential to complete the connections between UC and CRC. Interestingly, further analyses of the virus-host interaction network demonstrated that several virus proteins (including EBNA-LP of EBV and protein E7 of HPV) frequently inter-connected to UC- and CRC-associated module pairs with their validated targets significantly enriched in both modules of the host. Together, our results suggested that multidimensional integration strategy provides a novel approach to discover potential molecular targets that bridge the connections between UC and CRC, which could also be extensively applied to studies on other inflammation-related cancers. PMID:26461477

  15. Targeting Hsp90-Cdc37: a promising therapeutic strategy by inhibiting Hsp90 chaperone function.

    PubMed

    Wang, Lei; Li, Li; Gu, Kai; Xu, Xiao-Li; You, Qi-Dong; Sun, Hao-Peng

    2016-05-27

    The Hsp90 chaperone protein regulates the folding, maturation and stability of a wide variety of oncoproteins. In recent years, many Hsp90 inhibitors have entered into the clinical trials while all of them target ATPase showing similar binding capacity and kinds of side-effects so that none have reached to the market. During the regulation progress, numerous protein-protein interactions (PPI) such as Hsp90 and client proteins or cochaperones are involved. With the Hsp90-cochaperones PPI networks being more and more clear, many cancerous proteins have been reported to be tightly correlated to Hsp90-cochaperones PPI. Among them, Hsp90-Cdc37 PPI has been widely reported to associate with numerous protein kinases, making it a novel target for the treatment of cancers. In this paper, we briefly review the strategies and modulators targeting Hsp90-Cdc37 complex including direct and indirect regulation mechanism. Through these discussions we expect to present inspirations for new insights into an alternative way to inhibit Hsp90 chaperone function.

  16. A targeted enrichment strategy for massively parallel sequencing of angiosperm plastid genomes1

    PubMed Central

    Stull, Gregory W.; Moore, Michael J.; Mandala, Venkata S.; Douglas, Norman A.; Kates, Heather-Rose; Qi, Xinshuai; Brockington, Samuel F.; Soltis, Pamela S.; Soltis, Douglas E.; Gitzendanner, Matthew A.

    2013-01-01

    • Premise of the study: We explored a targeted enrichment strategy to facilitate rapid and low-cost next-generation sequencing (NGS) of numerous complete plastid genomes from across the phylogenetic breadth of angiosperms. • Methods and Results: A custom RNA probe set including the complete sequences of 22 previously sequenced eudicot plastomes was designed to facilitate hybridization-based targeted enrichment of eudicot plastid genomes. Using this probe set and an Agilent SureSelect targeted enrichment kit, we conducted an enrichment experiment including 24 angiosperms (22 eudicots, two monocots), which were subsequently sequenced on a single lane of the Illumina GAIIx with single-end, 100-bp reads. This approach yielded nearly complete to complete plastid genomes with exceptionally high coverage (mean coverage: 717×), even for the two monocots. • Conclusions: Our enrichment experiment was highly successful even though many aspects of the capture process employed were suboptimal. Hence, significant improvements to this methodology are feasible. With this general approach and probe set, it should be possible to sequence more than 300 essentially complete plastid genomes in a single Illumina GAIIx lane (achieving ∼50× mean coverage). However, given the complications of pooling numerous samples for multiplex sequencing and the limited number of barcodes (e.g., 96) available in commercial kits, we recommend 96 samples as a current practical maximum for multiplex plastome sequencing. This high-throughput approach should facilitate large-scale plastid genome sequencing at any level of phylogenetic diversity in angiosperms. PMID:25202518

  17. Host target modification as a strategy to counter pathogen hijacking of the jasmonate hormone receptor

    PubMed Central

    Zhang, Li; Yao, Jian; Withers, John; Xin, Xiu-Fang; Banerjee, Rahul; Fariduddin, Qazi; Nakamura, Yoko; Nomura, Kinya; Howe, Gregg A.; Boland, Wilhelm; Yan, Honggao; He, Sheng Yang

    2015-01-01

    In the past decade, characterization of the host targets of pathogen virulence factors took a center stage in the study of pathogenesis and disease susceptibility in plants and humans. However, the impressive knowledge of host targets has not been broadly exploited to inhibit pathogen infection. Here, we show that host target modification could be a promising new approach to “protect” the disease-vulnerable components of plants. In particular, recent studies have identified the plant hormone jasmonate (JA) receptor as one of the common targets of virulence factors from highly evolved biotrophic/hemibiotrophic pathogens. Strains of the bacterial pathogen Pseudomonas syringae, for example, produce proteinaceous effectors, as well as a JA-mimicking toxin, coronatine (COR), to activate JA signaling as a mechanism to promote disease susceptibility. Guided by the crystal structure of the JA receptor and evolutionary clues, we succeeded in modifying the JA receptor to allow for sufficient endogenous JA signaling but greatly reduced sensitivity to COR. Transgenic Arabidopsis expressing this modified receptor not only are fertile and maintain a high level of insect defense, but also gain the ability to resist COR-producing pathogens Pseudomonas syringae pv. tomato and P. syringae pv. maculicola. Our results provide a proof-of-concept demonstration that host target modification can be a promising new approach to prevent the virulence action of highly evolved pathogens. PMID:26578782

  18. Targeting MKK3 as a novel anticancer strategy: molecular mechanisms and therapeutical implications

    PubMed Central

    Baldari, S; Ubertini, V; Garufi, A; D'Orazi, G; Bossi, G

    2015-01-01

    Mitogen-activated protein kinase kinase 3 (MAP2K3, MKK3) is a member of the dual specificity protein kinase group that belongs to the MAP kinase kinase family. This kinase is activated by mitogenic or stress-inducing stimuli and participates in the MAP kinase-mediated signaling cascade, leading to cell proliferation and survival. Several studies highlighted a critical role for MKK3 in tumor progression and invasion, and we previously identified MKK3 as transcriptional target of mutant (mut) p53 to sustain cell proliferation and survival, thus rendering MKK3 a promising target for anticancer therapies. Here, we found that targeting MKK3 with RNA interference, in both wild-type (wt) and mutp53-carrying cells, induced endoplasmic reticulum stress and autophagy that, respectively, contributed to stabilize wtp53 and degrade mutp53. MKK3 depletion reduced cancer cell proliferation and viability, whereas no significant effects were observed in normal cellular context. Noteworthy, MKK3 depletion in combination with chemotherapeutic agents increased tumor cell response to the drugs, in both wtp53 and mutp53 cancer cells, as demonstrated by enhanced poly (ADP-ribose) polymerase cleavage and reduced clonogenic ability in vitro. In addition, MKK3 depletion reduced tumor growth and improved biological response to chemotherapeutic in vivo. The overall results indicate MKK3 as a novel promising molecular target for the development of more efficient anticancer treatments in both wtp53- and mutp53-carrying tumors. PMID:25633290

  19. Utilization of a BGO detector as an active oxygen target

    NASA Astrophysics Data System (ADS)

    Loveman, R.; Gozani, T.; Bendahan, J.; Krivicich, J.; Elias, E.; Altschuler, E.

    1994-12-01

    The (n, n'γx) cross section for the 6.13 MeV state in oxygen has recently become of general interest because of the possibility of using this process to assay oxygen as a part of non-intrusive inspections. Localized densities of carbon, oxygen, and nitrogen are particularly useful in determining the presence of explosives and/or drugs in containers of all sizes, from suitcases to cargo containers. The presence of oxygen in BGO (Bi 4Ge 3O 12) scintillator makes this detector suitable for use as an active target for the measurement of the energy dependence of the excitation, of the first (6.049 MeV O +) and second (6.130 MeV 3 -) excited states in 16O by fast neutron interactions. An active target functions as both a target and an active device such as a detector. The de-excitations of the 6.049 and 6.130 states take place by nuclear pair production and γ-ray emission respectively. There is a large probability of absorbing all of the de-excitation energy in the scintillator in either of these cases. Since the energies deposited in the scintillator by these transitions are very close, the de-excitations are indistinguishable. However, since the cross section for the excitation of the 6.13 MeV state is believed to be larger than that of the 6.049 MeV, the major measured features of the energy variations are those related to the second state. The validity of the technique was initially tested using (MCNP) calculations. The calculations established that the detected neutron count rate in the crystal was proportional to the cross-sections used as input for the calculations, and that the constant of proportionality did not vary with neutron energy. Subsequently, measurements were made with a BGO detector as an active oxygen target. The results clearly show a strong energy dependence including several resonances.

  20. Targeting ASC in NLRP3 inflammasome by caffeic acid phenethyl ester: a novel strategy to treat acute gout

    PubMed Central

    Lee, Hye Eun; Yang, Gabsik; Kim, Nam Doo; Jeong, Seongkeun; Jung, Yunjin; Choi, Jae Young; Park, Hyun Ho; Lee, Joo Young

    2016-01-01

    Gouty arthritis is caused by the deposition of uric acid crystals, which induce the activation of NOD-like receptor family, pyrin domain containing 3(NLRP3) inflammasome. The NLRP3 inflammasome, composed of NLRP3, the adaptor protein ASC, and caspase-1, is closely linked to the pathogenesis of various metabolic diseases including gouty arthritis. We investigated whether an orally administrable inhibitor of NLRP3 inflammasome was effective for alleviating the pathological symptoms of gouty arthritis and what was the underlying mechanism. In primary mouse macrophages, caffeic acid phenethyl ester(CAPE) blocked caspase-1 activation and IL-1β production induced by MSU crystals, showing that CAPE suppresses NLRP3 inflammasome activation. In mouse gouty arthritis models, oral administration of CAPE suppressed MSU crystals-induced caspase-1 activation and IL-1β production in the air pouch exudates and the foot tissues, correlating with attenuation of inflammatory symptoms. CAPE directly associated with ASC as shown by SPR analysis and co-precipitation, resulting in blockade of NLRP3-ASC interaction induced by MSU crystals. Our findings provide a novel regulatory mechanism by which small molecules harness the activation of NLRP3 inflammasome by presenting ASC as a new target. Furthermore, the results suggest the preventive or therapeutic strategy for NLRP3-related inflammatory diseases such as gouty arthritis using orally available small molecules. PMID:27934918

  1. Targeting ASC in NLRP3 inflammasome by caffeic acid phenethyl ester: a novel strategy to treat acute gout.

    PubMed

    Lee, Hye Eun; Yang, Gabsik; Kim, Nam Doo; Jeong, Seongkeun; Jung, Yunjin; Choi, Jae Young; Park, Hyun Ho; Lee, Joo Young

    2016-12-09

    Gouty arthritis is caused by the deposition of uric acid crystals, which induce the activation of NOD-like receptor family, pyrin domain containing 3(NLRP3) inflammasome. The NLRP3 inflammasome, composed of NLRP3, the adaptor protein ASC, and caspase-1, is closely linked to the pathogenesis of various metabolic diseases including gouty arthritis. We investigated whether an orally administrable inhibitor of NLRP3 inflammasome was effective for alleviating the pathological symptoms of gouty arthritis and what was the underlying mechanism. In primary mouse macrophages, caffeic acid phenethyl ester(CAPE) blocked caspase-1 activation and IL-1β production induced by MSU crystals, showing that CAPE suppresses NLRP3 inflammasome activation. In mouse gouty arthritis models, oral administration of CAPE suppressed MSU crystals-induced caspase-1 activation and IL-1β production in the air pouch exudates and the foot tissues, correlating with attenuation of inflammatory symptoms. CAPE directly associated with ASC as shown by SPR analysis and co-precipitation, resulting in blockade of NLRP3-ASC interaction induced by MSU crystals. Our findings provide a novel regulatory mechanism by which small molecules harness the activation of NLRP3 inflammasome by presenting ASC as a new target. Furthermore, the results suggest the preventive or therapeutic strategy for NLRP3-related inflammatory diseases such as gouty arthritis using orally available small molecules.

  2. Energy Monitoring and Targeting as diagnosis; Applying work analysis to adapt a statistical change detection strategy using representation aiding

    NASA Astrophysics Data System (ADS)

    Hilliard, Antony

    Energy Monitoring and Targeting is a well-established business process that develops information about utility energy consumption in a business or institution. While M&T has persisted as a worthwhile energy conservation support activity, it has not been widely adopted. This dissertation explains M&T challenges in terms of diagnosing and controlling energy consumption, informed by a naturalistic field study of M&T work. A Cognitive Work Analysis of M&T identifies structures that diagnosis can search, information flows un-supported in canonical support tools, and opportunities to extend the most popular tool for MM&T: Cumulative Sum of Residuals (CUSUM) charts. A design application outlines how CUSUM charts were augmented with a more contemporary statistical change detection strategy, Recursive Parameter Estimates, modified to better suit the M&T task using Representation Aiding principles. The design was experimentally evaluated in a controlled M&T synthetic task, and was shown to significantly improve diagnosis performance.

  3. Improving Listening Skills through the Use of Active Listening Strategies.

    ERIC Educational Resources Information Center

    Engraffia, Margie; Graff, Nora; Jezuit, Sue; Schall, Leslie

    This report describes a program for improving active and critical listening skills for elementary age students. The targeted population consists of middle school children located near a large midwestern city. The problems of poor listening skills are documented through data revealing the need for attending interventions that have been put in…

  4. Improved drug targeting of cancer cells by utilizing actively targetable folic acid-conjugated albumin nanospheres.

    PubMed

    Shen, Zheyu; Li, Yan; Kohama, Kazuhiro; Oneill, Brian; Bi, Jingxiu

    2011-01-01

    Folic acid-conjugated albumin nanospheres (FA-AN) have been developed to provide an actively targetable drug delivery system for improved drug targeting of cancer cells with reduced side effects. The nanospheres were prepared by conjugating folic acid onto the surface of albumin nanospheres using 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDAC) as a catalyst. To test the efficacy of these nanospheres as a potential delivery platform, doxorubicin-loaded albumin nanospheres (DOX-AN) and doxorubicin-loaded FA-AN (FA-DOX-AN) were prepared by entrapping DOX (an anthracycline, antibiotic drug widely used in cancer chemotherapy that works by intercalating DNA) into AN and FA-AN nanoparticles. Cell uptake of the DOX was then measured. The results show that FA-AN was incorporated into HeLa cells (tumor cells) only after 2.0h incubation, whereas HeLa cells failed to incorporate albumin nanospheres without conjugated folic acid after 4.0h incubation. When HeLa cells were treated with the DOX-AN, FA-DOX-AN nanoparticles or free DOX, cell viability decreased with increasing culture time (i.e. cell death increases with time) over a 70h period. Cell viability was always the lowest for free DOX followed by FA-DOX-AN4 and then DOX-AN. In a second set of experiments, HeLa cells washed to remove excess DOX after an initial incubation for 2h were incubated for 70h. The corresponding cell viability was slightly higher when the cells were treated with FA-DOX-AN or free DOX whilst cells treated with DOX-AN nanoparticles remained viable. The above experiments were repeated for non-cancerous, aortic smooth muscle cells (AoSMC). As expected, cell viability of the HeLa cells (with FA receptor alpha, FRα) and AoSMC cells (without FRα) decreased rapidly with time in the presence of free DOX, but treatment with FA-DOX-AN resulted in selective killing of the tumor cells. These results indicated that FA-AN may be used as a promising actively targetable drug delivery system to improve drug

  5. A novel immunomodulatory and molecularly targeted strategy for refractory Hodgkin's lymphoma

    PubMed Central

    McGuire, Mary F.; Buryanek, Jamie; Janku, Filip; Younes, Anas; Hong, David

    2014-01-01

    Although Hodgkin's lymphoma (HL) was one of the first human cancers to be cured by chemotherapy, no new agents other than brentuximab vedotin (Adcetris®, CD 30 directed antibody drug conjugate) have received US Food and Drug Administration (FDA) approval for HL since 1977. Subsets of young adult patients with HL continue to relapse, even after stem cell transplantation, warranting new approaches. Against this background, we report a dramatic response in a young patient with advanced HL refractory to the standard treatment who responded to the combination of a pan-histone deacetylase inhibitor (vorinostat, suberoylanilide hydroxamic acid, SAHA) and mammalian target of rapamycin (mTOR) inhibitor therapy (sirolimus,rapamume). In-depth immunohistochemical and morphoproteomic analyses of this exceptional responder to targeted therapy have yielded potential insights into the biology of advanced HL. The PI3K/AKT/mTOR pathway is a commonly activated pathway in multiple tumor types including HL. The patient was treated using therapy based on mechanistic in vitro data demonstrating that combined histone deacetylase (HDAC) and mTOR inhibition act together on this pathway, resulting in inhibition of reciprocal feedback networks, leading to better anti-proliferative activity. The in vivo response signature from this patient's tissue sample sheds light on immune dysregulation in HL. We describe the response signature achieved from targeting immune dysregulation in addition to targeting the key oncogenic PI3K/AKT/mTOR pathway. We also expand on the role of rapamycin analogs in oncology. This study supports a role for an immune-type pathogenesis that is amenable to immune modulating targeted therapy in refractory HL. Significance: We report an exceptional responder to molecularly targeted and immune modulator therapy in advanced Hodgkin's lymphoma. The morphoproteomic/morphometric findings in this “unusual responder” patient's relapsed HL that correlate best, as a response

  6. Engineering of Hollow Mesoporous Silica Nanoparticles for Remarkably Enhanced Tumor Active Targeting Efficacy

    PubMed Central

    Chen, Feng; Hong, Hao; Shi, Sixiang; Goel, Shreya; Valdovinos, Hector F.; Hernandez, Reinier; Theuer, Charles P.; Barnhart, Todd E.; Cai, Weibo

    2014-01-01

    Hollow mesoporous silica nanoparticle (HMSN) has recently gained increasing interests due to their tremendous potential as an attractive nano-platform for cancer imaging and therapy. However, possibly due to the lack of efficient in vivo targeting strategy and well-developed surface engineering techniques, engineering of HMSN for in vivo active tumor targeting, quantitative tumor uptake assessment, multimodality imaging, biodistribution and enhanced drug delivery have not been achieved to date. Here, we report the in vivo tumor targeted positron emission tomography (PET)/near-infrared fluorescence (NIRF) dual-modality imaging and enhanced drug delivery of HMSN using a generally applicable surface engineering technique. Systematic in vitro and in vivo studies have been performed to investigate the stability, tumor targeting efficacy and specificity, biodistribution and drug delivery capability of well-functionalized HMSN nano-conjugates. The highest uptake of TRC105 (which binds to CD105 on tumor neovasculature) conjugated HMSN in the 4T1 murine breast cancer model was ~10%ID/g, 3 times higher than that of the non-targeted group, making surface engineered HMSN a highly attractive drug delivery nano-platform for future cancer theranostics. PMID:24875656

  7. Targeted antigen delivery and activation of dendritic cells in vivo: steps towards cost effective vaccines.

    PubMed

    Tacken, Paul J; Figdor, Carl G

    2011-02-01

    During the past decade, the immunotherapeutic potential of ex vivo generated professional antigen presenting dendritic cells (DCs) has been explored in the clinic. Albeit safe, clinical results have thus far been limited. A major disadvantage of current cell-based dendritic cell (DC) therapies, preventing universal implementation of this form of immunotherapy, is the requirement that vaccines need to be tailor made for each individual. Targeted delivery of antigens to DC surface receptors in vivo would circumvent this laborious and expensive ex vivo culturing steps involved with these cell-based therapies. In addition, the opportunity to target natural and often rare DC subsets in vivo might have advantages over loading more artificial ex vivo cultured DCs. Preclinical studies show targeting antigens to DCs effectively induces humoral responses, while cellular responses are induced provided a DC maturation or activation stimulus is co-administered. Here, we discuss strategies to target antigens to distinct DC subsets and to simultaneously employ adjuvants to activate these cells to induce immunity.

  8. MET/HGF pathway activation as a paradigm of resistance to targeted therapies

    PubMed Central

    Ko, Brian; He, Tianfang; Gadgeel, Shirish

    2017-01-01

    Resistance to targeted therapeutics is a key issue limiting the long-term utility of these medications in the management of molecularly selected subsets of cancer patients, including patients with non-small cell lung cancer harboring oncogenic alterations affecting EGFR, ALK and other genes. Bypass resistance mediated by activation of MET kinase has emerged as a frequent, validated and pivotal resistance mechanism in multiple types of cancers. Biochemical understanding is accumulating to explain the unique role of MET in such bypass pathways, providing alternate downstream activation opportunities and intricate interactions during epithelial-mesenchymal transitions. Multiple diagnostic testing platforms have become available for selecting appropriate patients for MET targeting in a variety of settings. Importantly, in light of the failures of several earlier clinical studies of MET targeting agents, a large array of recent and current MET-focused trials are incorporating stricter patient selection and more robust predictive biomarkers providing hope for validation of MET targeting as a clinically impactful strategy. PMID:28164089

  9. TRAF6 Activation in Multiple Myeloma: A Potential Therapeutic Target

    PubMed Central

    Liu, Hong; Tamashiro, Samantha; Baritaki, Stavroula; Penichet, Manuel; Yu, Youhua; Chen, Haiming; Berenson, James; Bonavida, Benjamin

    2013-01-01

    Multiple myeloma (MM) is an incurable B-lymphocyte malignancy. New therapeutic options have become available during the past several years; however nearly all patients acquire resistance to currently available therapeutic agents. Mechanisms contributing to the pathogenesis and chemoresistance of MM include genetic abnormalities, chromosomal translocations, gene mutations, the interaction between MM cells and the bone marrow microenvironment, and defects in the apoptotic signaling pathways. Survival signaling pathways associated with the pathogenesis of MM and bone marrow stromal cells play crucial roles in promoting growth, survival, adhesion, immortalization, angiogenesis, and drug resistance. The receptor activator of nuclear factor-kappa B/receptor activator of nuclear factor-kappa B ligand/tumor necrosis factor receptor-associated factor (RANK/RANKL-TRAF6) signal pathway mediates osteolytic bone lesions through the activation of the NF-κB and Janus kinase/signal transducer and activator of transcription (JNK) pathways in osteoclast precursor cells and thus contributes to the main clinical manifestations of bone disease. TRAF6 has also been identified as a ligase for Akt ubiquitination and membrane recruitment and its phosphorylation on growth factor stimulation. The inhibition of TRAF6 by silencing RNA or by decoy peptides decreases MM tumor cell proliferation and increases apoptosis as well as bone resorption. Some proteasome inhibitors and benzoxadiazole derivatives showed inhibitory effects on the activity and function of TRAF6. Overall, we propose that TRAF6 may be considered as a potential therapeutic target for the treatment of MM. PMID:22440007

  10. SECONDARY WASTE MANAGEMENT STRATEGY FOR EARLY LOW ACTIVITY WASTE TREATMENT

    SciTech Connect

    TW, CRAWFORD

    2008-07-17

    This study evaluates parameters relevant to River Protection Project secondary waste streams generated during Early Low Activity Waste operations and recommends a strategy for secondary waste management that considers groundwater impact, cost, and programmatic risk. The recommended strategy for managing River Protection Project secondary waste is focused on improvements in the Effiuent Treatment Facility. Baseline plans to build a Solidification Treatment Unit adjacent to Effluent Treatment Facility should be enhanced to improve solid waste performance and mitigate corrosion of tanks and piping supporting the Effiuent Treatment Facility evaporator. This approach provides a life-cycle benefit to solid waste performance and reduction of groundwater contaminants.

  11. Health Activism Targeting Corporations: A Critical Health Communication Perspective.

    PubMed

    Zoller, Heather M

    2017-02-01

    Health activists and health social movements have transformed medical treatment, promoted public health policies, and extended civil rights for people with illness and disability. This essay explores health activism that targets corporate-generated illness and risk in order to understand the unique communicative challenges involved in this area of contention. Arguing for greater critical engagement with policy, the article integrates policy research with social movements, subpolitics, and issue management literature. Drawing from activist discourse and multidisciplinary research, the article describes how a wide array of groups groups build visibility for corporate health effects, create the potential for networking and collaboration, and politicize health by attributing illness to corporate behaviors. The discussion articulates the implications of this activism for health communication theory, research, and practice.

  12. Precise Measurement of Drift Velocities in Active-Target Detectors

    NASA Astrophysics Data System (ADS)

    Jensen, Louis

    2016-09-01

    Nuclear experiments with radioactive beams are needed to improve our understanding of nuclei structure far from stability. Radioactive beams typically have low beam rates, but active-target detectors can compensate for these low beam rates. In active-target detectors that are also Time-Projection Chambers (TPC), ionized electrons drift through an electric fieldto a detection device to imagethe trajectory of charged-particle ionization tracks within the chamber's gas volume. The measurement of the ionized electrons' drift velocity is crucial for the accurate imaging of these tracks. In order to measure this drift velocity, we will use a UV laser and photo-sensitive foil in a the ND-Cubedetector we are developing, periodically releasingelectrons from the foil at a known timesand a known distance from the electron detector, thereby precisely measuring the drift velocity in situ. We have surveyed several materials to find a material that will work well with typical solid-state UV lasers on the market. We plan to determine the best material and thickness of the foil to maximize the number of photoelectrons. The precision that will be afforded by this measurement of the drift velocity will allow us to eliminate a source of systematic uncertainty.

  13. 78 FR 35612 - Agency Information Collection Activities; Comment Request; Targeted Teacher Shortage Areas...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-06-13

    ... Agency Information Collection Activities; Comment Request; Targeted Teacher Shortage Areas Nationwide... to this notice will be considered public records. Title of Collection: Targeted Teacher Shortage... Family Education Loan Programs (FFELP) regulations, which address the targeted teacher...

  14. Size controlled protein nanoemulsions for active targeting of folate receptor positive cells.

    PubMed

    Loureiro, Ana; Nogueira, Eugénia; Azoia, Nuno G; Sárria, Marisa P; Abreu, Ana S; Shimanovich, Ulyana; Rollett, Alexandra; Härmark, Johan; Hebert, Hans; Guebitz, Georg; Bernardes, Gonçalo J L; Preto, Ana; Gomes, Andreia C; Cavaco-Paulo, Artur

    2015-11-01

    Bovine serum albumin (BSA) nanoemulsions were produced by high pressure homogenization with a tri-block copolymer (Poloxamer 407), which presents a central hydrophobic chain of polyoxypropylene (PPO) and two identical lateral hydrophilic chains of polyethylene glycol (PEG). We observed a linear correlation between tri-block copolymer concentration and size - the use of 5mg/mL of Poloxamer 407 yields nanoemulsions smaller than 100nm. Molecular dynamics and fluorescent tagging of the tri-block copolymer highlight their mechanistic role on the size of emulsions. This novel method enables the fabrication of highly stable albumin emulsions in the nano-size range, highly desirable for controlled drug delivery. Folic Acid (FA)-tagged protein nanoemulsions were shown to promote specific folate receptor (FR)-mediated targeting in FR positive cells. The novel strategy presented here enables the construction of size controlled, functionalized protein-based nanoemulsions with excellent characteristics for active targeting in cancer therapy.

  15. Proteomics: a strategy to understand the novel targets in protein misfolding and cancer therapy.

    PubMed

    Nagaraj, Nagathihalli S; Singh, Om V; Merchant, Nipun B

    2010-08-01

    Proteins carry out important functions as they fold themselves. Protein misfolding occurs during different biochemical processes and may lead to the development of diseases such as cancer, which is characterized by genetic instability. The cancer microenvironment exposes malignant cells to a variety of stressful conditions that may further promote protein misfolding. Tumor development and progression often arises from mutations that interfere with the appropriate function of tumor-suppressor proteins and oncogenes. These may be due to alteration of catalytic activity of the protein, loss of binding sites for effector proteins or alterations of the native folded protein conformation. Src family kinases, p53, mTOR and C-terminus of HSC70 interacting protein (CHIPs) are some examples associated with protein misfolding and tumorigenesis. Molecular chaperones, such as heat-shock protein (HSP)70 and HSP90, assist protein folding and recognize target misfolded proteins for degradation. It is likely that this misfolding in cancer is linked by common principles, and may, therefore, present an exciting possibility to identify common targets for therapeutic intervention. Here we aim to review a number of examples that show how alterations in the folding of tumor-suppressor proteins or oncogenes lead to tumorigenesis. The possibility of targeting the targets to repair or degrade protein misfolding in cancer therapy is discussed.

  16. Novel strategies to target the ubiquitin proteasome system in multiple myeloma

    PubMed Central

    Lub, Susanne; Maes, Ken; Menu, Eline; De Bruyne, Elke; Vanderkerken, Karin; Van Valckenborgh, Els

    2016-01-01

    Multiple myeloma (MM) is a hematological malignancy characterized by the accumulation of plasma cells in the bone marrow (BM). The success of the proteasome inhibitor bortezomib in the treatment of MM highlights the importance of the ubiquitin proteasome system (UPS) in this particular cancer. Despite the prolonged survival of MM patients, a significant amount of patients relapse or become resistant to therapy. This underlines the importance of the development and investigation of novel targets to improve MM therapy. The UPS plays an important role in different cellular processes by targeted destruction of proteins. The ubiquitination process consists of enzymes that transfer ubiquitin to proteins targeting them for proteasomal degradation. An emerging and promising approach is to target more disease specific components of the UPS to reduce side effects and overcome resistance. In this review, we will focus on different components of the UPS such as the ubiquitin activating enzyme E1, the ubiquitin conjugating enzyme E2, the E3 ubiquitin ligases, the deubiquitinating enzymes (DUBs) and the proteasome. We will discuss their role in MM and the implications in drug discovery for the treatment of MM. PMID:26695547

  17. Targeting lymphocyte activation through the lymphotoxin and LIGHT pathways

    PubMed Central

    2008-01-01

    Summary Cytokines mediate key communication pathways essential for regulation of immune responses. Full activation of antigen-responding lymphocytes requires cooperating signals from the tumor necrosis factor (TNF)-related cytokines and their specific receptors. LIGHT, a lymphotoxin-β (LTβ)-related TNF family member, modulates T-cell activation through two receptors, the herpesvirus entry mediator (HVEM) and indirectly through the LT-β receptor. An unexpected finding revealed a non-canonical binding site on HVEM for the immunoglobulin superfamily member, B and T lymphocyte attenuator (BTLA), and an inhibitory signaling protein suppressing T-cell activation. Thus, HVEM can act as a molecular switch between proinflammatory and inhibitory signaling. The non-canonical HVEM-BTLA pathway also acts to counter LTβR signaling that promotes the proliferation of antigen-presenting dendritic cells (DCs) within lymphoid tissue microenvironments. These results indicate LTβ receptor and HVEM-BTLA pathways form an integrated signaling circuit. Targeting these cytokine pathways with specific antagonists (antibody or decoy receptor) can alter lymphocyte differentiation and activation. Alternately, agonists directed at their cell surface receptors can restore homeostasis and potentially reset immune and inflammatory processes, which may be useful in treating autoimmune and infectious diseases and cancer. PMID:18613837

  18. Permanent Genetic Access to Transiently Active Neurons via TRAP: Targeted Recombination in Active Populations

    PubMed Central

    Guenthner, Casey J.; Miyamichi, Kazunari; Yang, Helen H.; Heller, H. Craig; Luo, Liqun

    2013-01-01

    SUMMARY Targeting genetically encoded tools for neural circuit dissection to relevant cellular populations is a major challenge in neurobiology. We developed a new approach, Targeted Recombination in Active Populations (TRAP), to obtain genetic access to neurons that were activated by defined stimuli. This method utilizes mice in which the tamoxifen-dependent recombinase CreERT2 is expressed in an activity-dependent manner from the loci of the immediate early genes Arc and Fos. Active cells that express CreERT2 can undergo recombination only when tamoxifen is present, allowing genetic access to neurons that are active during a time window of less than 12 h. We show that TRAP can selectively provide access to neurons activated by specific somatosensory, visual, and auditory stimuli, and by experience in a novel environment. When combined with tools for labeling, tracing, recording, and manipulating neurons, TRAP offers a powerful new approach for understanding how the brain processes information and generates behavior. PMID:23764283

  19. Targeting VIP and PACAP receptor signalling: new therapeutic strategies in multiple sclerosis

    PubMed Central

    Tan, Yossan-Var; Waschek, James A

    2011-01-01

    MS (multiple sclerosis) is a chronic autoimmune and neurodegenerative pathology of the CNS (central nervous system) affecting approx. 2.5 million people worldwide. Current and emerging DMDs (disease-modifying drugs) predominantly target the immune system. These therapeutic agents slow progression and reduce severity at early stages of MS, but show little activity on the neurodegenerative component of the disease. As the latter determines permanent disability, there is a critical need to pursue alternative modalities. VIP (vasoactive intestinal peptide) and PACAP (pituitary adenylate cyclase-activating peptide) have potent anti-inflammatory and neuroprotective actions, and have shown significant activity in animal inflammatory disease models including the EAE (experimental autoimmune encephalomyelitis) MS model. Thus, their receptors have become candidate targets for inflammatory diseases. Here, we will discuss the immunomodulatory and neuroprotective actions of VIP and PACAP and their signalling pathways, and then extensively review the structure–activity relationship data and biophysical interaction studies of these peptides with their cognate receptors. PMID:21895607

  20. Review: Targeting trachoma: Strategies to reduce the leading infectious cause of blindness.

    PubMed

    Baneke, Alex

    2012-03-01

    The World Health Organisation (WHO) estimated that in 2002, 1.3 million people were blind due to trachoma, an eye infection caused by Chlamydia trachomatis. This review examines the evidence behind current strategies to reduce the global burden of trachoma. Trachoma disappeared from most western nations before the advent of antibiotics, probably due to improvements in water, sanitation and hygiene. The current effort to target trachoma, headed by the WHO and the Alliance for the Global Elimination of Trachoma by 2020, is called the SAFE (Surgery, Antibiotics, Facial cleanliness and Environmental improvement) strategy. Surgery for trachoma is more cost effective than extra-capsular cataract surgery and can reverse trichiasis (in-growing eyelashes), but needs to be repeated every few years. A single oral dose of azithromycin can eliminate trachoma infection, but cannot be used in infants under 6 months old, and needs to be given every few years in communities with a high prevalence of disease. Improved health education and facial hygiene has been linked to a lower incidence of trachoma, but the evidence is less clear than for surgery and antibiotics. Pit latrines and spraying with permethrin insecticide may reduce the spread of trachoma via eye-seeking flies.

  1. Targeting Nitric Oxide with Natural Derived Compounds as a Therapeutic Strategy in Vascular Diseases

    PubMed Central

    Forte, Maurizio; Damato, Antonio; Ambrosio, Mariateresa; Puca, Annibale A.; Sciarretta, Sebastiano; Frati, Giacomo; Vecchione, Carmine

    2016-01-01

    Within the family of endogenous gasotransmitters, nitric oxide (NO) is the smallest gaseous intercellular messenger involved in the modulation of several processes, such as blood flow and platelet aggregation control, essential to maintain vascular homeostasis. NO is produced by nitric oxide synthases (NOS) and its effects are mediated by cGMP-dependent or cGMP-independent mechanisms. Growing evidence suggests a crosstalk between the NO signaling and the occurrence of oxidative stress in the onset and progression of vascular diseases, such as hypertension, heart failure, ischemia, and stroke. For these reasons, NO is considered as an emerging molecular target for developing therapeutic strategies for cardio- and cerebrovascular pathologies. Several natural derived compounds, such as polyphenols, are now proposed as modulators of NO-mediated pathways. The aim of this review is to highlight the experimental evidence on the involvement of nitric oxide in vascular homeostasis focusing on the therapeutic potential of targeting NO with some natural compounds in patients with vascular diseases. PMID:27651855

  2. Targeting Nitric Oxide with Natural Derived Compounds as a Therapeutic Strategy in Vascular Diseases.

    PubMed

    Forte, Maurizio; Conti, Valeria; Damato, Antonio; Ambrosio, Mariateresa; Puca, Annibale A; Sciarretta, Sebastiano; Frati, Giacomo; Vecchione, Carmine; Carrizzo, Albino

    2016-01-01

    Within the family of endogenous gasotransmitters, nitric oxide (NO) is the smallest gaseous intercellular messenger involved in the modulation of several processes, such as blood flow and platelet aggregation control, essential to maintain vascular homeostasis. NO is produced by nitric oxide synthases (NOS) and its effects are mediated by cGMP-dependent or cGMP-independent mechanisms. Growing evidence suggests a crosstalk between the NO signaling and the occurrence of oxidative stress in the onset and progression of vascular diseases, such as hypertension, heart failure, ischemia, and stroke. For these reasons, NO is considered as an emerging molecular target for developing therapeutic strategies for cardio- and cerebrovascular pathologies. Several natural derived compounds, such as polyphenols, are now proposed as modulators of NO-mediated pathways. The aim of this review is to highlight the experimental evidence on the involvement of nitric oxide in vascular homeostasis focusing on the therapeutic potential of targeting NO with some natural compounds in patients with vascular diseases.

  3. Novel treatment strategies targeting alpha-synuclein in multiple system atrophy as a model of synucleinopathy

    PubMed Central

    Valera, Elvira; Compagnoni, Giacomo Monzio; Masliah, Eliezer

    2016-01-01

    Neurodegenerative disorders with alpha-synuclein (α-syn) accumulation (synucleinopathies) include Parkinson's disease, Parkinson's disease dementia, dementia with Lewy bodies and multiple system atrophy (MSA). Due to the involvement of toxic α-syn aggregates in the molecular origin of these disorders, developing effective therapies targeting α-syn is a priority as a disease-modifying alternative to current symptomatic treatments. Importantly, the clinical and pathological attributes of MSA make this disorder an excellent candidate as a synucleinopathy model for accelerated drug development. Recent therapeutic strategies targeting α-syn in in vivo and in vitro models of MSA, as well as in clinical trials, have been focused on the pathological mechanisms of α-syn synthesis, aggregation, clearance, and/or cell-to-cell propagation of its neurotoxic conformers. Here we summarize the most relevant approaches in this direction, with emphasis on their potential as general synucleinopathy modifiers, and enumerate research areas for potential improvement in MSA drug discovery. PMID:26924723

  4. Final Report for Bio-Inspired Approaches to Moving-Target Defense Strategies

    SciTech Connect

    Fink, Glenn A.; Oehmen, Christopher S.

    2012-09-01

    This report records the work and contributions of the NITRD-funded Bio-Inspired Approaches to Moving-Target Defense Strategies project performed by Pacific Northwest National Laboratory under the technical guidance of the National Security Agency’s R6 division. The project has incorporated a number of bio-inspired cyber defensive technologies within an elastic framework provided by the Digital Ants. This project has created the first scalable, real-world prototype of the Digital Ants Framework (DAF)[11] and integrated five technologies into this flexible, decentralized framework: (1) Ant-Based Cyber Defense (ABCD), (2) Behavioral Indicators, (3) Bioinformatic Clas- sification, (4) Moving-Target Reconfiguration, and (5) Ambient Collaboration. The DAF can be used operationally to decentralize many such data intensive applications that normally rely on collection of large amounts of data in a central repository. In this work, we have shown how these component applications may be decentralized and may perform analysis at the edge. Operationally, this will enable analytics to scale far beyond current limitations while not suffering from the bandwidth or computational limitations of centralized analysis. This effort has advanced the R6 Cyber Security research program to secure digital infrastructures by developing a dynamic means to adaptively defend complex cyber systems. We hope that this work will benefit both our client’s efforts in system behavior modeling and cyber security to the overall benefit of the nation.

  5. An efficient targeted nuclease strategy for high-resolution mapping of DNA binding sites

    PubMed Central

    Skene, Peter J; Henikoff, Steven

    2017-01-01

    We describe Cleavage Under Targets and Release Using Nuclease (CUT&RUN), a chromatin profiling strategy in which antibody-targeted controlled cleavage by micrococcal nuclease releases specific protein-DNA complexes into the supernatant for paired-end DNA sequencing. Unlike Chromatin Immunoprecipitation (ChIP), which fragments and solubilizes total chromatin, CUT&RUN is performed in situ, allowing for both quantitative high-resolution chromatin mapping and probing of the local chromatin environment. When applied to yeast and human nuclei, CUT&RUN yielded precise transcription factor profiles while avoiding crosslinking and solubilization issues. CUT&RUN is simple to perform and is inherently robust, with extremely low backgrounds requiring only ~1/10th the sequencing depth as ChIP, making CUT&RUN especially cost-effective for transcription factor and chromatin profiling. When used in conjunction with native ChIP-seq and applied to human CTCF, CUT&RUN mapped directional long range contact sites at high resolution. We conclude that in situ mapping of protein-DNA interactions by CUT&RUN is an attractive alternative to ChIP-seq. DOI: http://dx.doi.org/10.7554/eLife.21856.001 PMID:28079019

  6. Magnetic nanoparticles: a strategy to target the choroidal layer in the posterior segment of the eye

    PubMed Central

    Giannaccini, Martina; Pedicini, Lucia; De Matienzo, Guglielma; Chiellini, Federica; Dente, Luciana; Raffa, Vittoria

    2017-01-01

    Despite the higher rate of blindness due to population aging, minimally invasive and selective drug delivery to the eye still remains an open challenge, especially in the posterior segment. The retina, the retinal pigment epithelium (RPE) and the choroid are posterior segment cell layers, which may be affected by several diseases. In particular, damages to the choroid are associated with poor prognosis in the most severe pathologies. A drug delivery approach, able to target the choroid, is still missing. Recently, we demonstrated that intravitreally injected magnetic nanoparticles (MNP) are able to rapidly and persistently localise within the RPE in an autonomous manner. In this work we functionalised the MNP surface with the vascular endothelial growth factor, a bioactive molecule capable of transcytosis from the RPE towards more posterior layers. Such functionalisation successfully addressed the MNPs to the choroid, while MNP functionalised with a control polypeptide (poly-L-lysine) showed the same localisation pattern of the naked MNP particles. These data suggest that the combination of MNP with different bioactive molecules could represent a powerful strategy for cell-specific targeting of the eye posterior segment. PMID:28256525

  7. Development of an automated multiple-target mask CD disposition system to enable new sampling strategy

    NASA Astrophysics Data System (ADS)

    Ma, Jian; Farnsworth, Jeff; Bassist, Larry; Cui, Ying; Mammen, Bobby; Padmanaban, Ramaswamy; Nadamuni, Venkatesh; Kamath, Muralidhar; Buckmann, Ken; Neff, Julie; Freiberger, Phil

    2006-03-01

    Traditional mask critical dimension (CD) disposition systems with only one or two targets is being challenged by the new requirements from mask-users as the wafer process control becomes more complicated in the newer generation of technologies. Historically, the mask shop does not necessarily measure and disposition off the same kind of CD structures that wafer fabs do. Mask disposition specifications and structures come from the frame-design and the tapeout, while wafer-level CD dispositions are mainly based on the historical process window established per CD-skew experiments and EOL (end of line) yield. In the current high volume manufacturing environment, the mask CDs are mainly dispositioned off their mean-to-target (MTT) and uniformity (6sigma) on one or two types of pre-determined structures. The disposition specification is set to ensure the printed mask will meet the design requirements and to ensure minimum deviation from them. The CD data are also used to adjust the dose of the mask exposure tools to control CD MTT. As a result, the mask CD disposition automation system was built to allow only one or two kinds of targets at most. In contrast, wafer-fabs measure a fairly wide range of different structures to ensure their process is on target and in control. The number of such structures that are considered critical is increasing due the growing complexity of the technology. To fully comprehend the wafer-level requirements, it is highly desirable to align the mask CD sample site and disposition to be the same as that of the wafer-fabs, to measure the OPC (optical proximity correction) structures or equivalent whenever possible, and to establish the true correlation between mask CD measurements vs. wafer CD measurement. In this paper, the development of an automated multiple-target mask CD disposition system with the goal of enabling new sampling strategy is presented. The pros and cons of its implementation are discussed. The new system has been inserted in

  8. Cancer Stem Cells: The Potential Targets of Chinese Medicines and Their Active Compounds

    PubMed Central

    Hong, Ming; Tan, Hor Yue; Li, Sha; Cheung, Fan; Wang, Ning; Nagamatsu, Tadashi; Feng, Yibin

    2016-01-01

    The pivotal role of cancer stem cells (CSCs) in the initiation and progression of malignancies has been rigorously validated, and the specific methods for identifying and isolating the CSCs from the parental cancer population have also been rapidly developed in recent years. This review aims to provide an overview of recent research progress of Chinese medicines (CMs) and their active compounds in inhibiting tumor progression by targeting CSCs. A great deal of CMs and their active compounds, such as Antrodia camphorate, berberine, resveratrol, and curcumin have been shown to regress CSCs, in terms of reversing drug resistance, inducing cell death and inhibiting cell proliferation as well as metastasis. Furthermore, one of the active compounds in coptis, berbamine may inhibit tumor progression by modulating microRNAs to regulate CSCs. The underlying molecular mechanisms and related signaling pathways involved in these processes were also discussed and concluded in this paper. Overall, the use of CMs and their active compounds may be a promising therapeutic strategy to eradicate cancer by targeting CSCs. However, further studies are needed to clarify the potential of clinical application of CMs and their active compounds as complementary and alternative therapy in this field. PMID:27338343

  9. Targeting VE-PTP activates TIE2 and stabilizes the ocular vasculature

    PubMed Central

    Shen, Jikui; Frye, Maike; Lee, Bonnie L.; Reinardy, Jessica L.; McClung, Joseph M.; Ding, Kun; Kojima, Masashi; Xia, Huiming; Seidel, Christopher; Silva, Raquel Lima e; Dong, Aling; Hackett, Sean F.; Wang, Jiangxia; Howard, Brian W.; Vestweber, Dietmar; Kontos, Christopher D.; Peters, Kevin G.; Campochiaro, Peter A.

    2014-01-01

    Retinal and choroidal neovascularization (NV) and vascular leakage contribute to visual impairment in several common ocular diseases. The angiopoietin/TIE2 (ANG/TIE2) pathway maintains vascular integrity, and negative regulators of this pathway are potential therapeutic targets for these diseases. Here, we demonstrated that vascular endothelial-protein tyrosine phosphatase (VE-PTP), which negatively regulates TIE2 activation, is upregulated in hypoxic vascular endothelial cells, particularly in retinal NV. Intraocular injection of an anti–VE-PTP antibody previously shown to activate TIE2 suppressed ocular NV. Furthermore, a small-molecule inhibitor of VE-PTP catalytic activity (AKB-9778) activated TIE2, enhanced ANG1-induced TIE2 activation, and stimulated phosphorylation of signaling molecules in the TIE2 pathway, including AKT, eNOS, and ERK. In mouse models of neovascular age-related macular degeneration, AKB-9778 induced phosphorylation of TIE2 and strongly suppressed NV. Ischemia-induced retinal NV, which is relevant to diabetic retinopathy, was accentuated by the induction of ANG2 but inhibited by AKB-9778, even in the presence of high levels of ANG2. AKB-9778 also blocked VEGF-induced leakage from dermal and retinal vessels and prevented exudative retinal detachments in double-transgenic mice with high expression of VEGF in photoreceptors. These data support targeting VE-PTP to stabilize retinal and choroidal blood vessels and suggest that this strategy has potential for patients with a wide variety of retinal and choroidal vascular diseases PMID:25180601

  10. Inhibiting Drivers of Non-mutational Drug Tolerance Is a Salvage Strategy for Targeted Melanoma Therapy

    PubMed Central

    Smith, Michael P.; Brunton, Holly; Rowling, Emily J.; Ferguson, Jennifer; Arozarena, Imanol; Miskolczi, Zsofia; Lee, Jessica L.; Girotti, Maria R.; Marais, Richard; Levesque, Mitchell P.; Dummer, Reinhard; Frederick, Dennie T.; Flaherty, Keith T.; Cooper, Zachary A.; Wargo, Jennifer A.; Wellbrock, Claudia

    2016-01-01

    Summary Once melanomas have progressed with acquired resistance to mitogen-activated protein kinase (MAPK)-targeted therapy, mutational heterogeneity presents a major challenge. We therefore examined the therapy phase before acquired resistance had developed and discovered the melanoma survival oncogene MITF as a driver of an early non-mutational and reversible drug-tolerance state, which is induced by PAX3-mediated upregulation of MITF. A drug-repositioning screen identified the HIV1-protease inhibitor nelfinavir as potent suppressor of PAX3 and MITF expression. Nelfinavir profoundly sensitizes BRAF and NRAS mutant melanoma cells to MAPK-pathway inhibitors. Moreover, nelfinavir is effective in BRAF and NRAS mutant melanoma cells isolated from patients progressed on MAPK inhibitor (MAPKi) therapy and in BRAF/NRAS/PTEN mutant tumors. We demonstrate that inhibiting a driver of MAPKi-induced drug tolerance could improve current approaches of targeted melanoma therapy. PMID:26977879

  11. A viral strategy for targeting and manipulating interneurons across vertebrate species.

    PubMed

    Dimidschstein, Jordane; Chen, Qian; Tremblay, Robin; Rogers, Stephanie L; Saldi, Giuseppe-Antonio; Guo, Lihua; Xu, Qing; Liu, Runpeng; Lu, Congyi; Chu, Jianhua; Grimley, Joshua S; Krostag, Anne-Rachel; Kaykas, Ajamete; Avery, Michael C; Rashid, Mohammad S; Baek, Myungin; Jacob, Amanda L; Smith, Gordon B; Wilson, Daniel E; Kosche, Georg; Kruglikov, Illya; Rusielewicz, Tomasz; Kotak, Vibhakar C; Mowery, Todd M; Anderson, Stewart A; Callaway, Edward M; Dasen, Jeremy S; Fitzpatrick, David; Fossati, Valentina; Long, Michael A; Noggle, Scott; Reynolds, John H; Sanes, Dan H; Rudy, Bernardo; Feng, Guoping; Fishell, Gord

    2016-12-01

    A fundamental impediment to understanding the brain is the availability of inexpensive and robust methods for targeting and manipulating specific neuronal populations. The need to overcome this barrier is pressing because there are considerable anatomical, physiological, cognitive and behavioral differences between mice and higher mammalian species in which it is difficult to specifically target and manipulate genetically defined functional cell types. In particular, it is unclear the degree to which insights from mouse models can shed light on the neural mechanisms that mediate cognitive functions in higher species, including humans. Here we describe a novel recombinant adeno-associated virus that restricts gene expression to GABAergic interneurons within the telencephalon. We demonstrate that the viral expression is specific and robust, allowing for morphological visualization, activity monitoring and functional manipulation of interneurons in both mice and non-genetically tractable species, thus opening the possibility to study GABAergic function in virtually any vertebrate species.

  12. Target-classification approach applied to active UXO sites

    NASA Astrophysics Data System (ADS)

    Shubitidze, F.; Fernández, J. P.; Shamatava, Irma; Barrowes, B. E.; O'Neill, K.

    2013-06-01

    This study is designed to illustrate the discrimination performance at two UXO active sites (Oklahoma's Fort Sill and the Massachusetts Military Reservation) of a set of advanced electromagnetic induction (EMI) inversion/discrimination models which include the orthonormalized volume magnetic source (ONVMS), joint diagonalization (JD), and differential evolution (DE) approaches and whose power and flexibility greatly exceed those of the simple dipole model. The Fort Sill site is highly contaminated by a mix of the following types of munitions: 37-mm target practice tracers, 60-mm illumination mortars, 75-mm and 4.5'' projectiles, 3.5'', 2.36'', and LAAW rockets, antitank mine fuzes with and without hex nuts, practice MK2 and M67 grenades, 2.5'' ballistic windshields, M2A1-mines with/without bases, M19-14 time fuzes, and 40-mm practice grenades with/without cartridges. The site at the MMR site contains targets of yet different sizes. In this work we apply our models to EMI data collected using the MetalMapper (MM) and 2 × 2 TEMTADS sensors. The data for each anomaly are inverted to extract estimates of the extrinsic and intrinsic parameters associated with each buried target. (The latter include the total volume magnetic source or NVMS, which relates to size, shape, and material properties; the former includes location, depth, and orientation). The estimated intrinsic parameters are then used for classification performed via library matching and the use of statistical classification algorithms; this process yielded prioritized dig-lists that were submitted to the Institute for Defense Analyses (IDA) for independent scoring. The models' classification performance is illustrated and assessed based on these independent evaluations.

  13. Hyaluronic acid-coated liposomes for active targeting of gemcitabine.

    PubMed

    Arpicco, Silvia; Lerda, Carlotta; Dalla Pozza, Elisa; Costanzo, Chiara; Tsapis, Nicolas; Stella, Barbara; Donadelli, Massimo; Dando, Ilaria; Fattal, Elias; Cattel, Luigi; Palmieri, Marta

    2013-11-01

    The aim of this work was the preparation, characterization, and preliminary evaluation of the targeting ability toward pancreatic adenocarcinoma cells of liposomes containing the gemcitabine lipophilic prodrug [4-(N)-lauroyl-gemcitabine, C12GEM]. Hyaluronic acid (HA) was selected as targeting agent since it is biodegradable, biocompatible, and can be chemically modified and its cell surface receptor CD44 is overexpressed on various tumors. For this purpose, conjugates between a phospholipid, the 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine (DPPE), and HA of two different low molecular weights 4800 Da (12 disaccharidic units) and 12,000 Da (32 disaccharidic units), were prepared, characterized, and introduced in the liposomes during the preparation. Different liposomal formulations were prepared and their characteristics were analyzed: size, Z potential, and TEM analyses underline a difference in the HA-liposomes from the non-HA ones. In order to better understand the HA-liposome cellular localization and to evaluate their interaction with CD44 receptor, confocal microscopy studies were performed. The results demonstrate that HA facilitates the recognition of liposomes by MiaPaCa2 cells (CD44(+)) and that the uptake increases with increase in the polymer molecular weight. Finally, the cytotoxicity of the different preparations was evaluated and data show that incorporation of C12GEM increases their cytotoxic activity and that HA-liposomes inhibit cell growth more than plain liposomes. Altogether, the results demonstrate the specificity of C12GEM targeting toward CD44-overexpressing pancreatic adenocarcinoma cell line using HA as a ligand.

  14. A genomic strategy for the functional validation of colorectal cancer genes identifies potential therapeutic targets.

    PubMed

    Grade, Marian; Hummon, Amanda B; Camps, Jordi; Emons, Georg; Spitzner, Melanie; Gaedcke, Jochen; Hoermann, Patrick; Ebner, Reinhard; Becker, Heinz; Difilippantonio, Michael J; Ghadimi, B Michael; Beissbarth, Tim; Caplen, Natasha J; Ried, Thomas

    2011-03-01

    Genes that are highly overexpressed in tumor cells can be required for tumor cell survival and have the potential to be selective therapeutic targets. In an attempt to identify such targets, we combined a functional genomics and a systems biology approach to assess the consequences of RNAi-mediated silencing of overexpressed genes that were selected from 140 gene expression profiles from colorectal cancers (CRCs) and matched normal mucosa. In order to identify credible models for in-depth functional analysis, we first confirmed the overexpression of these genes in 25 different CRC cell lines. We then identified five candidate genes that profoundly reduced the viability of CRC cell lines when silenced with either siRNAs or short-hairpin RNAs (shRNAs), i.e., HMGA1, TACSTD2, RRM2, RPS2 and NOL5A. These genes were further studied by systematic analysis of comprehensive gene expression profiles generated following siRNA-mediated silencing. Exploration of these RNAi-specific gene expression signatures allowed the identification of the functional space in which the five genes operate and showed enrichment for cancer-specific signaling pathways, some known to be involved in CRC. By comparing the expression of the RNAi signature genes with their respective expression levels in an independent set of primary rectal carcinomas, we could recapitulate these defined RNAi signatures, therefore, establishing the biological relevance of our observations. This strategy identified the signaling pathways that are affected by the prominent oncogenes HMGA1 and TACSTD2, established a yet unknown link between RRM2 and PLK1 and identified RPS2 and NOL5A as promising potential therapeutic targets in CRC.

  15. Evolution of the heteroharmonic strategy for target-range computation in the echolocation of Mormoopidae

    PubMed Central

    Mora, Emanuel C.; Macías, Silvio; Hechavarría, Julio; Vater, Marianne; Kössl, Manfred

    2013-01-01

    Echolocating bats use the time elapsed from biosonar pulse emission to the arrival of echo (defined as echo-delay) to assess target-distance. Target-distance is represented in the brain by delay-tuned neurons that are classified as either “heteroharmonic” or “homoharmormic.” Heteroharmonic neurons respond more strongly to pulse-echo pairs in which the timing of the pulse is given by the fundamental biosonar harmonic while the timing of echoes is provided by one (or several) of the higher order harmonics. On the other hand, homoharmonic neurons are tuned to the echo delay between similar harmonics in the emitted pulse and echo. It is generally accepted that heteroharmonic computations are advantageous over homoharmonic computations; i.e., heteroharmonic neurons receive information from call and echo in different frequency-bands which helps to avoid jamming between pulse and echo signals. Heteroharmonic neurons have been found in two species of the family Mormoopidae (Pteronotus parnellii and Pteronotus quadridens) and in Rhinolophus rouxi. Recently, it was proposed that heteroharmonic target-range computations are a primitive feature of the genus Pteronotus that was preserved in the evolution of the genus. Here, we review recent findings on the evolution of echolocation in Mormoopidae, and try to link those findings to the evolution of the heteroharmonic computation strategy (HtHCS). We stress the hypothesis that the ability to perform heteroharmonic computations evolved separately from the ability of using long constant-frequency echolocation calls, high duty cycle echolocation, and Doppler Shift Compensation. Also, we present the idea that heteroharmonic computations might have been of advantage for categorizing prey size, hunting eared insects, and living in large conspecific colonies. We make five testable predictions that might help future investigations to clarify the evolution of the heteroharmonic echolocation in Mormoopidae and other families. PMID

  16. Targeted hepatitis B vaccination--a cost effective immunisation strategy for the UK?

    PubMed Central

    Williams, J R; Nokes, D J; Anderson, R M

    1996-01-01

    OBJECTIVE: To compare the potential cost effectiveness of vaccination against hepatitis B virus (HBV) targeted at genitourinary clinic (GU) attendees with that of universal infant vaccination. DESIGN: A mathematical model of sexual and perinatal transmission of HBV was used to compare the effectiveness among heterosexual and homosexual populations of programmes of mass infant vaccination and targeted immunisation of genitourinary medicine (GU) clinic attendees. Each was applied to 90% of the eligible population with differing assumptions about rates of compliance and seroconversion - problems of delivery (obtaining high compliance) was considered a significant drawback of targeted vaccination. Observed relationships between GU clinic attendance and sex partner change rates for heterosexuals and for homosexuals were used to define the rates of vaccination uptake within sexual activity risk groups. SETTING: England and Wales. RESULTS: Model results showed that for heterosexuals universal infant vaccination became more effective than clinic based vaccination only approximately 40 years after the start of the programme and that the predicted cost effectiveness of GU clinic vaccination was greater at all times. For homosexuals, clinic vaccination was always more effective over the time frame considered, but by 50 years if it were carried out without prior screening it had become appreciably less cost effective than a mass infant programme. With prior screening in GU clinics this cost effectiveness deficit was only marginal. CONCLUSIONS: Targeted vaccination might have a much greater potential than is realised at present, particularly if it were possible to improve compliance of clinic attendees. A fuller comparison between mass infant and targeted vaccination must await the specific inclusion in the model of other risk groups such as intravenous drug users. An important determinant of the relative merits of the two approaches is the relationship between rates of

  17. TARGETED LIPID BASED DRUG CONJUGATES: A NOVEL STRATEGY FOR DRUG DELIVERY

    PubMed Central

    Vadlapudi, Aswani Dutt; Vadlapatla, Ramya Krishna; Kwatra, Deep; Earla, Ravinder; Samanta, Swapan K.; Pal, Dhananjay; Mitra, Ashim K.

    2012-01-01

    A majority of studies involving prodrugs are directed to overcome low bioavailability of the parent drug. The aim of this study is to increase the bioavailability of acyclovir (ACV) by designing a novel prodrug delivery system which is more lipophilic, and at the same time site specific. In this study, a lipid raft has been conjugated to the parent drug molecule to impart lipophilicity. Simultaneously a targeting moiety that can be recognized by a specific transporter/receptor in the cell membrane has also been tethered to the other terminal of lipid raft. Targeted lipid prodrugs i.e., biotin-ricinoleicacid-acyclovir (B-R-ACV) and biotin-12hydroxystearicacid-acyclovir (B-12HS-ACV) were synthesized with ricinoleicacid and 12hydroxystearicacid as the lipophilic rafts and biotin as the targeting moiety. Biotin-ACV (B-ACV), ricinoleicacid-ACV (R-ACV) and 12hydroxystearicacid-ACV (12HS-ACV) were also synthesized to delineate the individual effects of the targeting and the lipid moieties. Cellular accumulation studies were performed in confluent MDCK-MDR1 and Caco-2 cells. The targeted lipid prodrugs B-R-ACV and B-12HS-ACV exhibited much higher cellular accumulation than B-ACV, R-ACV and 12HS-ACV in both cell lines. This result indicates that both the targeting and the lipid moiety act synergistically towards cellular uptake. The biotin conjugated prodrugs caused a decrease in the uptake of [3H] biotin suggesting the role of sodium dependent multivitamin transporter (SMVT) in uptake. The affinity of these targeted lipid prodrugs towards SMVT was studied in MDCK-MDR1 cells. Both the targeted lipid prodrugs B-R-ACV (20.25 ± 1.74 µM) and B-12HS-ACV (23.99 ± 3.20 µM) demonstrated higher affinity towards SMVT than B-ACV (30.90 ± 4.19 µM). Further, dose dependent studies revealed a concentration dependent inhibitory effect on [3H] biotin uptake in the presence of biotinylated prodrugs. Transepithelial transport studies showed lowering of [3H] biotin permeability in the

  18. Targeted lipid based drug conjugates: a novel strategy for drug delivery.

    PubMed

    Vadlapudi, Aswani Dutt; Vadlapatla, Ramya Krishna; Kwatra, Deep; Earla, Ravinder; Samanta, Swapan K; Pal, Dhananjay; Mitra, Ashim K

    2012-09-15

    A majority of studies involving prodrugs are directed to overcome low bioavailability of the parent drug. The aim of this study is to increase the bioavailability of acyclovir (ACV) by designing a novel prodrug delivery system which is more lipophilic, and at the same time site specific. In this study, a lipid raft has been conjugated to the parent drug molecule to impart lipophilicity. Simultaneously a targeting moiety that can be recognized by a specific transporter/receptor in the cell membrane has also been tethered to the other terminal of lipid raft. Targeted lipid prodrugs i.e., biotin-ricinoleicacid-acyclovir (B-R-ACV) and biotin-12hydroxystearicacid-acyclovir (B-12HS-ACV) were synthesized with ricinoleicacid and 12hydroxystearicacid as the lipophilic rafts and biotin as the targeting moiety. Biotin-ACV (B-ACV), ricinoleicacid-ACV (R-ACV) and 12hydroxystearicacid-ACV (12HS-ACV) were also synthesized to delineate the individual effects of the targeting and the lipid moieties. Cellular accumulation studies were performed in confluent MDCK-MDR1 and Caco-2 cells. The targeted lipid prodrugs B-R-ACV and B-12HS-ACV exhibited much higher cellular accumulation than B-ACV, R-ACV and 12HS-ACV in both cell lines. This result indicates that both the targeting and the lipid moiety act synergistically toward cellular uptake. The biotin conjugated prodrugs caused a decrease in the uptake of [(3)H] biotin suggesting the role of sodium dependent multivitamin transporter (SMVT) in uptake. The affinity of these targeted lipid prodrugs toward SMVT was studied in MDCK-MDR1 cells. Both the targeted lipid prodrugs B-R-ACV (20.25 ± 1.74 μM) and B-12HS-ACV (23.99 ± 3.20 μM) demonstrated higher affinity towards SMVT than B-ACV (30.90 ± 4.19 μM). Further, dose dependent studies revealed a concentration dependent inhibitory effect on [(3)H] biotin uptake in the presence of biotinylated prodrugs. Transepithelial transport studies showed lowering of [(3)H] biotin permeability in

  19. Combined target and post-run target strategy for a comprehensive analysis of pesticides in ambient air using liquid chromatography-Orbitrap high resolution mass spectrometry.

    PubMed

    Coscollà, Clara; León, Nuria; Pastor, Agustín; Yusà, Vicent

    2014-11-14

    A comprehensive strategy for the analysis of current airborne pesticides has been developed using liquid chromatography coupled to high resolution mass spectrometry. The methodology includes both quantitative target analysis and post-run target screening analysis. The quantitative method was validated after a previous statistical optimisation of the main factors governing the ion source ionization and a study of the single-stage Orbitrap fragmentation through the HCD cell. The quantitative method presented recoveries ranging from 73 to 116%, with precision (RSD) lower than 20%, for the 35 substances in the scope of the target method. The full-scan accurate mass data were acquired with a resolving power of 50000 FWHM (scan speed, 2 Hz), and alternating two acquisition events, ESI+ without fragmentation and ESI+ with fragmentation. The method-LOQ was 6.5 pg m(-3) for most of the target pesticides. For post-target screening a customized theoretical database, that included pesticides, metabolites and other substances such as emerging flame retardants was built up. For identification, accurate exact mass with less than 5 ppm, and some diagnostic ions including isotopes and/or fragments were used. The strategy was applied to ten samples collected in a rural area of Valencia (Spain). Four pesticides, namely carbendazim, metalaxyl, myclobutanil and terbuthylazine, were detected in concentrations from 16 pg m(-3) to 174 pg m(-3). Some pesticides and metabolites (endothal, fenfuram, terbuthylazine-2-OH), in addition to two flame retardants were tentatively identified in the post-run target screening analysis.

  20. Linking Objects to Actions: Encoding of Target Object and Grasping Strategy in Primate Ventral Premotor Cortex

    PubMed Central

    Franquemont, Lachlan; Black, Michael J.; Donoghue, John P.

    2015-01-01

    Neural activity in ventral premotor cortex (PMv) has been associated with the process of matching perceived objects with the motor commands needed to grasp them. It remains unclear how PMv networks can flexibly link percepts of objects affording multiple grasp options into a final desired hand action. Here, we use a relational encoding approach to track the functional state of PMv neuronal ensembles in macaque monkeys through the process of passive viewing, grip planning, and grasping movement execution. We used objects affording multiple possible grip strategies. The task included separate instructed delay periods for object presentation and grip instruction. This approach allowed us to distinguish responses elicited by the visual presentation of the objects from those associated with selecting a given motor plan for grasping. We show that PMv continuously incorporates information related to object shape and grip strategy as it becomes available, revealing a transition from a set of ensemble states initially most closely related to objects, to a new set of ensemble patterns reflecting unique object-grip combinations. These results suggest that PMv dynamically combines percepts, gradually navigating toward activity patterns associated with specific volitional actions, rather than directly mapping perceptual object properties onto categorical grip representations. Our results support the idea that PMv is part of a network that dynamically computes motor plans from perceptual information. SIGNIFICANCE STATEMENT The present work demonstrates that the activity of groups of neurons in primate ventral premotor cortex reflects information related to visually presented objects, as well as the motor strategy used to grasp them, linking individual objects to multiple possible grips. PMv could provide useful control signals for neuroprosthetic assistive devices designed to interact with objects in a flexible way. PMID:26224870

  1. Folate-conjugated β-cyclodextrin from click chemistry strategy and for tumor-targeted drug delivery.

    PubMed

    Zhang, Huaihong; Cai, Zhaosheng; Sun, Yu; Yu, Fei; Chen, Yaoqiang; Sun, Baiwang

    2012-09-01

    To enhance site-specific intracellular delivery against the folate receptor, a drug carrier was designed and synthesized by bioconjugation of folic acid (FA) to β-cyclodextrins (β-CD) through a poly(ethylene glycol) (PEG) spacer from "click chemistry" strategy. The resulted conjugates were confirmed by (1)H NMR and IR spectroscopy. Host-guest interactions between hydrophobic drug and β-CD are capable of entrapping a hydrophobic drug, like 5-Fluorouracil, to form drug-β-CD-PEG-FA nanoparticles (NPs) in aqueous solution. The morphology and size of β-CD-PEG-FA NPs were measured by transmission electron microscopy (TEM) and dynamic light scattering (DLS). The targeting ability of the β-CD-PEG-FA NPs was investigated against two kinds of cell lines (HeLa and A549), which have different amounts of folate receptors on their surface. Confocal image analysis revealed that β-CD-PEG-FA conjugate-assembled nanoparticles exhibited a greater extent of cellular uptake against HeLa cells than A549 cells. This suggests folate-receptor-mediated endocytosis can affect the cellular uptake efficiency of drug-loaded β-CD-PEG-FA NPs. The β-CD-PEG-FA conjugates that are presented may be promising active tumor-targeting carrier candidates via folate mediation.

  2. Strategies to Address Common Challenges When Teaching in an Active Learning Classroom

    ERIC Educational Resources Information Center

    Petersen, Christina I.; Gorman, Kristen S.

    2014-01-01

    This chapter provides practical strategies for addressing common challenges that arise for teachers in active learning classrooms. Our strategies come from instructors with experience teaching in these environments.

  3. Arenavirus nucleoprotein targets interferon regulatory factor-activating kinase IKKε.

    PubMed

    Pythoud, Christelle; Rodrigo, W W Shanaka I; Pasqual, Giulia; Rothenberger, Sylvia; Martínez-Sobrido, Luis; de la Torre, Juan Carlos; Kunz, Stefan

    2012-08-01

    Arenaviruses perturb innate antiviral defense by blocking induction of type I interferon (IFN) production. Accordingly, the arenavirus nucleoprotein (NP) was shown to block activation and nuclear translocation of interferon regulatory factor 3 (IRF3) in response to virus infection. Here, we sought to identify cellular factors involved in innate antiviral signaling targeted by arenavirus NP. Consistent with previous studies, infection with the prototypic arenavirus lymphocytic choriomeningitis virus (LCMV) prevented phosphorylation of IRF3 in response to infection with Sendai virus, a strong inducer of the retinoic acid-inducible gene I (RIG-I)/mitochondrial antiviral signaling (MAVS) pathway of innate antiviral signaling. Using a combination of coimmunoprecipitation and confocal microscopy, we found that LCMV NP associates with the IκB kinase (IKK)-related kinase IKKε but that, rather unexpectedly, LCMV NP did not bind to the closely related TANK-binding kinase 1 (TBK-1). The NP-IKKε interaction was highly conserved among arenaviruses from different clades. In LCMV-infected cells, IKKε colocalized with NP but not with MAVS located on the outer membrane of mitochondria. LCMV NP bound the kinase domain (KD) of IKKε (IKBKE) and blocked its autocatalytic activity and its ability to phosphorylate IRF3, without undergoing phosphorylation. Together, our data identify IKKε as a novel target of arenavirus NP. Engagement of NP seems to sequester IKKε in an inactive complex. Considering the important functions of IKKε in innate antiviral immunity and other cellular processes, the NP-IKKε interaction likely plays a crucial role in arenavirus-host interaction.

  4. Novel treatment strategies for smooth muscle disorders: Targeting Kv7 potassium channels.

    PubMed

    Haick, Jennifer M; Byron, Kenneth L

    2016-09-01

    Smooth muscle cells provide crucial contractile functions in visceral, vascular, and lung tissues. The contractile state of smooth muscle is largely determined by their electrical excitability, which is in turn influenced by the activity of potassium channels. The activity of potassium channels sustains smooth muscle cell membrane hyperpolarization, reducing cellular excitability and thereby promoting smooth muscle relaxation. Research over the past decade has indicated an important role for Kv7 (KCNQ) voltage-gated potassium channels in the regulation of the excitability of smooth muscle cells. Expression of multiple Kv7 channel subtypes has been demonstrated in smooth muscle cells from viscera (gastrointestinal, bladder, myometrial), from the systemic and pulmonary vasculature, and from the airways of the lung, from multiple species, including humans. A number of clinically used drugs, some of which were developed to target Kv7 channels in other tissues, have been found to exert robust effects on smooth muscle Kv7 channels. Functional studies have indicated that Kv7 channel activators and inhibitors have the ability to relax and contact smooth muscle preparations, respectively, suggesting a wide range of novel applications for the pharmacological tool set. This review summarizes recent findings regarding the physiological functions of Kv7 channels in smooth muscle, and highlights potential therapeutic applications based on pharmacological targeting of smooth muscle Kv7 channels throughout the body.

  5. Drugging PI3K in cancer: refining targets and therapeutic strategies

    PubMed Central

    Yap, Timothy A; Bjerke, Lynn; Clarke, Paul A; Workman, Paul

    2015-01-01

    The phosphatidylinositol-3 kinase (PI3K) pathway is one of the most frequently activated pathogenic signalling routes in human cancers, making it a rational and important target for innovative anticancer drug development and precision medicine. The three main classes of PI3K inhibitors currently in clinical testing comprise dual pan-Class I PI3K/mTOR inhibitors, pan-Class I PI3K inhibitors lacking significant mTOR activity and isoform-selective PI3K inhibitors. A major step forward in recent years is the progression of over 30 small molecule PI3K inhibitors into clinical trials and the first regulatory approval of the PI3Kδ inhibitor idelalisib for multiple B-cell malignancies. This review article focuses on the progress made in the discovery and development of novel PI3K inhibitors, with an emphasis on antitumour activity and tolerability profiles for agents that have entered clinical trials. We also discuss the key issues of drug resistance, patient selection approaches and rational targeted combinations. Finally, we envision the future development and use of PI3K inhibitors for the treatment of patients with a range of malignancies. PMID:26117819

  6. Active Learning Strategies for Phenotypic Profiling of High-Content Screens.

    PubMed

    Smith, Kevin; Horvath, Peter

    2014-06-01

    High-content screening is a powerful method to discover new drugs and carry out basic biological research. Increasingly, high-content screens have come to rely on supervised machine learning (SML) to perform automatic phenotypic classification as an essential step of the analysis. However, this comes at a cost, namely, the labeled examples required to train the predictive model. Classification performance increases with the number of labeled examples, and because labeling examples demands time from an expert, the training process represents a significant time investment. Active learning strategies attempt to overcome this bottleneck by presenting the most relevant examples to the annotator, thereby achieving high accuracy while minimizing the cost of obtaining labeled data. In this article, we investigate the impact of active learning on single-cell-based phenotype recognition, using data from three large-scale RNA interference high-content screens representing diverse phenotypic profiling problems. We consider several combinations of active learning strategies and popular SML methods. Our results show that active learning significantly reduces the time cost and can be used to reveal the same phenotypic targets identified using SML. We also identify combinations of active learning strategies and SML methods which perform better than others on the phenotypic profiling problems we studied.

  7. Saturated muscle activation contributes to compensatory reaching strategies following stroke

    PubMed Central

    McCrea, Patrick H; Eng, Janice J; Hodgson, Antony J

    2012-01-01

    The control and execution of movement could potentially be altered by the presence of stroke-induced weakness if muscles are incapable of generating sufficient power. The purpose of this study was to identify compensatory strategies during a forward (sagittal) reaching task for twenty persons with chronic stroke and ten healthy age-matched controls. We hypothesized that the paretic anterior deltoid would be maximally activated (i.e., saturated) during a reaching task and that task completion would require activation of additional muscles, resulting in compensatory movements out of the sagittal plane. For reaching movements by control subjects, joint motion remained largely in the sagittal plane and hand trajectories were smooth and direct. Movement characteristics of the non-paretic arm of stroke subjects were similar to control subjects except for small increases in the abduction angle and the percentage that anterior deltoid was activated. In contrast, reaching movements of the paretic arm of stroke subjects were characterized by increased activation of all muscles, especially the lateral deltoid, in addition to the anterior deltoid, with resulting shoulder abduction power and segmented and indirect hand motion. For the paretic arm of stroke subjects, muscle and kinetic compensations increased with impairment severity and weaker muscles were used at a higher percentage of their available muscle activity. These results suggest that the inability to generate sufficient force with the typical agonists involved during a forward reaching task may necessitate compensatory muscle recruitment strategies to complete the task. PMID:16014786

  8. Saturated muscle activation contributes to compensatory reaching strategies after stroke.

    PubMed

    McCrea, Patrick H; Eng, Janice J; Hodgson, Antony J

    2005-11-01

    The control and execution of movement could potentially be altered by the presence of stroke-induced weakness if muscles are incapable of generating sufficient power. The purpose of this study was to identify compensatory strategies during a forward (sagittal) reaching task for 20 persons with chronic stroke and 10 healthy age-matched controls. We hypothesized that the paretic anterior deltoid would be maximally activated (i.e., saturated) during a reaching task and that task completion would require activation of additional muscles, resulting in compensatory movements out of the sagittal plane. For reaching movements by control subjects, joint motion remained largely in the sagittal plane and hand trajectories were smooth and direct. Movement characteristics of the nonparetic arm of stroke subjects were similar to control subjects except for small increases in the abduction angle and the percentage that anterior deltoid was activated. In contrast, reaching movements of the paretic arm of stroke subjects were characterized by increased activation of all muscles, especially the lateral deltoid, in addition to the anterior deltoid, with resulting shoulder abduction power and segmented and indirect hand motion. For the paretic arm of stroke subjects, muscle and kinetic compensations increased with impairment severity and weaker muscles were used at a higher percentage of their available muscle activity. These results suggest that the inability to generate sufficient force with the typical agonists involved during a forward reaching task may necessitate compensatory muscle recruitment strategies to complete the task.

  9. Evaluating Transcription Factor Activity Changes by Scoring Unexplained Target Genes in Expression Data

    PubMed Central

    Berchtold, Evi; Csaba, Gergely; Zimmer, Ralf

    2016-01-01

    Several methods predict activity changes of transcription factors (TFs) from a given regulatory network and measured expression data. But available gene regulatory networks are incomplete and contain many condition-dependent regulations that are not relevant for the specific expression measurement. It is not known which combination of active TFs is needed to cause a change in the expression of a target gene. A method to systematically evaluate the inferred activity changes is missing. We present such an evaluation strategy that indicates for how many target genes the observed expression changes can be explained by a given set of active TFs. To overcome the problem that the exact combination of active TFs needed to activate a gene is typically not known, we assume a gene to be explained if there exists any combination for which the predicted active TFs can possibly explain the observed change of the gene. We introduce the i-score (inconsistency score), which quantifies how many genes could not be explained by the set of activity changes of TFs. We observe that, even for these minimal requirements, published methods yield many unexplained target genes, i.e. large i-scores. This holds for all methods and all expression datasets we evaluated. We provide new optimization methods to calculate the best possible (minimal) i-score given the network and measured expression data. The evaluation of this optimized i-score on a large data compendium yields many unexplained target genes for almost every case. This indicates that currently available regulatory networks are still far from being complete. Both the presented Act-SAT and Act-A* methods produce optimal sets of TF activity changes, which can be used to investigate the difficult interplay of expression and network data. A web server and a command line tool to calculate our i-score and to find the active TFs associated with the minimal i-score is available from https://services.bio.ifi.lmu.de/i-score. PMID:27723775

  10. Tumor therapeutics by design: targeting and activation of death receptors.

    PubMed

    Wajant, Harald; Gerspach, Jeannette; Pfizenmaier, Klaus

    2005-02-01

    Due to their strong apoptosis-inducing capacity, the death receptor ligands CD95L, TNF and TRAIL have been widely viewed as potential cancer therapeutics. While clinical data with CD95L and TRAIL are not yet available, TNF is a registered drug, albeit only for loco-regional application in a limited number of indications. The TNF experience has told us that specific delivery and restricted action is a major challenge in the development of multifunctional, pleiotropically acting cytokines into effective cancer therapeutics. Thus, gene-therapeutic approaches and new cytokine variants have been designed over the last 10 years with the aim of increasing anti-tumoral activity and reducing systemic side effects. Here, we present our current view of the therapeutic potential of the death receptor ligands TNF, CD95L and TRAIL and of the progress made towards improving their efficacy by tumor targeting, use of gene therapy and genetic engineering. Results generated with newly designed fusion proteins suggest that enhanced tumor-directed activity and prevention of undesirable actions of death receptor ligands is possible, thereby opening up a useful therapeutic window for all of the death receptor ligands, including CD95L.

  11. Nutritional strategies of physically active subjects with muscle dysmorphia

    PubMed Central

    2013-01-01

    Background The aim of this study was to identify dietary strategies for physically active individuals with muscle dysmorphia based on a systematic literature review. Method References were included if the study population consisted of adults over 18 years old who were physically active in fitness centers. We identified reports through an electronic search ofScielo, Lilacs and Medline using the following keywords: muscle dysmorphia, vigorexia, distorted body image, and exercise. We found eight articles in Scielo, 17 in Medline and 12 in Lilacs. Among the total number of 37 articles, only 17 were eligible for inclusion in this review. Results The results indicated that the feeding strategies used by physically active individuals with muscle dysmorphia did not include planning or the supervision of a nutritionist. Diet included high protein and low fat foods and the ingestion of dietary and ergogenic supplements to reduce weight. Conclusion Physically active subjects with muscle dysmorphia could benefit from the help of nutritional professionals to evaluate energy estimation, guide the diet and its distribution in macronutrient and consider the principle of nutrition to functional recovery of the digestive process, promote liver detoxification, balance and guide to organic adequate intake of supplemental nutrients and other substances. PMID:23706013

  12. Targeting neuronal nitric oxide synthase as a valuable strategy for the therapy of neurological disorders

    PubMed Central

    Maccallini, Cristina; Amoroso, Rosa

    2016-01-01

    The management of neurological disorders have huge and increasing human and economic costs. Despite this, there is a scarcity of effective therapeutics, and there is an extreme urgency for new and real treatments. In this short review we analyze some promising advancements in the search of new bioactive molecules targeting neuronal nitric oxide synthase (nNOS), an enzyme deputed to the biosynthesis of nitric oxide (NO). In different conditions of neuronal damages, this molecule is overproduced, contributing to the pathogenesis and progression of neuronal diseases. Two main approaches to modulate nNOS are discussed: a first one consisting in the direct inhibition of the enzyme by means of small organic molecules, which can be also active against other different targets involved in such diseases. A second section is dedicated to molecules able to prevent the formation of the ternary complex N-methyl-D-aspartate (NMDA)-type glutamate receptors, postsynaptic density-95 (PSD95) protein-nNOS, which is necessary to activate the latter for the biosynthesis of NO. PMID:28123402

  13. Optimized nonclinical safety assessment strategies supporting clinical development of therapeutic monoclonal antibodies targeting inflammatory diseases.

    PubMed

    Brennan, Frank R; Cauvin, Annick; Tibbitts, Jay; Wolfreys, Alison

    2014-05-01

    An increasing number of immunomodulatory monoclonal antibodies (mAbs) and IgG Fc fusion proteins are either approved or in early-to-late stage clinical trials for the treatment of chronic inflammatory conditions, autoimmune diseases and organ transplant rejection. The exquisite specificity of mAbs, in combination with their multi-functional properties, high potency, long half-life (permitting intermittent dosing and prolonged pharamcological effects), and general lack of off-target toxicity makes them ideal therapeutics. Dosing with mAbs for these severe and debilitating but often non life-threatening diseases is usually prolonged, for several months or years, and not only affects adults, including sensitive populations such as woman of child-bearing potential (WoCBP) and the elderly, but also children. Immunosuppression is usually a therapeutic goal of these mAbs and when administered to patients whose treatment program often involves other immunosuppressive therapies, there is an inherent risk for frank immunosuppression and reduced host defence which when prolonged increases the risk of infection and cancer. In addition when mAbs interact with the immune system they can induce other adverse immune-mediated drug reactions such as infusion reactions, cytokine release syndrome, anaphylaxis, immune-complex-mediated pathology and autoimmunity. An overview of the nonclinical safety assessment and risk mitigation strategies utilized to characterize these immunomodulatory mAbs and Fc fusion proteins to support first-in human (FIH) studies and futher clinical development in inflammatory disease indications is provided. Specific emphasis is placed on the design of studies to qualify animal species for toxicology studies, early studies to investigate safety and define PK/PD relationships, FIH-enabling and chronic toxicology studies, immunotoxicity, developmental, reproductive and juvenile toxicity studies and studies to determine the potential for immunosuppression and

  14. p53 activated by AND gate genetic circuit under radiation and hypoxia for targeted cancer gene therapy

    PubMed Central

    Ding, Miao; Li, Rong; He, Rong; Wang, Xingyong; Yi, Qijian; Wang, Weidong

    2015-01-01

    Radio-activated gene therapy has been developed as a novel therapeutic strategy against cancer; however, expression of therapeutic gene in peritumoral tissues will result in unacceptable toxicity to normal cells. To restrict gene expression in targeted tumor mass, we used hypoxia and radiation tolerance features of tumor cells to develop a synthetic AND gate genetic circuit through connecting radiation sensitivity promoter cArG6, heat shock response elements SNF1, HSF1 and HSE4 with retroviral vector plxsn. Their construction and dynamic activity process were identified through downstream enhanced green fluorescent protein and wtp53 expression in non-small cell lung cancer A549 cells and in a nude mice model. The result showed that AND gate genetic circuit could be activated by lower required radiation dose (6 Gy) and after activated, AND gate could induce significant apoptosis effects and growth inhibition of cancer cells in vitro and in vivo. The radiation- and hypoxia-activated AND gate genetic circuit, which could lead to more powerful target tumoricidal activity represented a promising strategy for both targeted and effective gene therapy of human lung adenocarcinoma and low dose activation character of the AND gate genetic circuit implied that this model could be further exploited to decrease side-effects of clinical radiation therapy. PMID:26177264

  15. p53 activated by AND gate genetic circuit under radiation and hypoxia for targeted cancer gene therapy.

    PubMed

    Ding, Miao; Li, Rong; He, Rong; Wang, Xingyong; Yi, Qijian; Wang, Weidong

    2015-09-01

    Radio-activated gene therapy has been developed as a novel therapeutic strategy against cancer; however, expression of therapeutic gene in peritumoral tissues will result in unacceptable toxicity to normal cells. To restrict gene expression in targeted tumor mass, we used hypoxia and radiation tolerance features of tumor cells to develop a synthetic AND gate genetic circuit through connecting radiation sensitivity promoter cArG6 , heat shock response elements SNF1, HSF1 and HSE4 with retroviral vector plxsn. Their construction and dynamic activity process were identified through downstream enhanced green fluorescent protein and wtp53 expression in non-small cell lung cancer A549 cells and in a nude mice model. The result showed that AND gate genetic circuit could be activated by lower required radiation dose (6 Gy) and after activated, AND gate could induce significant apoptosis effects and growth inhibition of cancer cells in vitro and in vivo. The radiation- and hypoxia-activated AND gate genetic circuit, which could lead to more powerful target tumoricidal activity represented a promising strategy for both targeted and effective gene therapy of human lung adenocarcinoma and low dose activation character of the AND gate genetic circuit implied that this model could be further exploited to decrease side-effects of clinical radiation therapy.

  16. TRIC: an automated alignment strategy for reproducible protein quantification in targeted proteomics

    PubMed Central

    Röst, Hannes L.; Liu, Yansheng; D’Agostino, Giuseppe; Zanella, Matteo; Navarro, Pedro; Rosenberger, George; Collins, Ben C.; Gillet, Ludovic; Testa, Giuseppe; Malmström, Lars; Aebersold, Ruedi

    2016-01-01

    Large scale, quantitative proteomic studies have become essential for the analysis of clinical cohorts, large perturbation experiments and systems biology studies. While next-generation mass spectrometric techniques such as SWATH-MS have substantially increased throughput and reproducibility, ensuring consistent quantification of thousands of peptide analytes across multiple LC-MS/MS runs remains a challenging and laborious manual process. To produce highly consistent and quantitatively accurate proteomics data matrices in an automated fashion, we have developed the TRIC software which utilizes fragment ion data to perform cross-run alignment, consistent peak-picking and quantification for high throughput targeted proteomics. TRIC uses a graph-based alignment strategy based on non-linear retention time correction to integrate peak elution information from all LC-MS/MS runs acquired in a study. When compared to state-of-the-art SWATH-MS data analysis, the algorithm was able to reduce the identification error by more than 3-fold at constant recall, while correcting for highly non-linear chromatographic effects. On a pulsed-SILAC experiment performed on human induced pluripotent stem (iPS) cells, TRIC was able to automatically align and quantify thousands of light and heavy isotopic peak groups and substantially increased the quantitative completeness and biological information in the data, providing insights into protein dynamics of iPS cells. Overall, this study demonstrates the importance of consistent quantification in highly challenging experimental setups, and proposes an algorithm to automate this task, constituting the last missing piece in a pipeline for automated analysis of massively parallel targeted proteomics datasets. PMID:27479329

  17. Cellular Delivery and Photochemical Activation of Antisense Agents through a Nucleobase Caging Strategy

    PubMed Central

    Govan, Jeane M.; Uprety, Rajendra; Thomas, Meryl; Lusic, Hrvoje; Lively, Mark O.; Deiters, Alexander

    2013-01-01

    Antisense oligonucleotides are powerful tools to regulate gene expression in cells and model organisms. However, a transfection or microinjection is needed for efficient delivery of the antisense agent. We report the conjugation of multiple HIV TAT peptides to a hairpin-protected antisense agent through a light-cleavable nucleobase caging group. This conjugation allows for the facile delivery of the antisense agent without a transfection reagent and photochemical activation offers precise control over gene expression. The developed approach is highly modular, as demonstrated by the conjugation of folic acid to the caged antisense agent. This enabled targeted cell delivery through cell-surface folate receptors followed by photochemical triggering of antisense activity. Importantly, the presented strategy delivers native oligonucleotides after light-activation, devoid of any delivery functionalities or modifications that could otherwise impair their antisense activity. PMID:23915424

  18. Targeting Enhancer of Zeste Homolog 2 as a promising strategy for cancer treatment

    PubMed Central

    Marchesi, Irene; Bagella, Luigi

    2016-01-01

    Polycomb group proteins represent a global silencing system involved in development regulation. In specific, they regulate the transition from proliferation to differentiation, contributing to stem-cell maintenance and inhibiting an inappropriate activation of differentiation programs. Enhancer of Zeste Homolog 2 (EZH2) is the catalytic subunit of Polycomb repressive complex 2, which induces transcriptional inhibition through the tri-methylation of histone H3, an epigenetic change associated with gene silencing. EZH2 expression is high in precursor cells while its level decreases in differentiated cells. EZH2 is upregulated in various cancers with high levels associated with metastatic cancer and poor prognosis. Indeed, aberrant expression of EZH2 causes the inhibition of several tumor suppressors and differentiation genes, resulting in an uncontrolled proliferation and tumor formation. This editorial explores the role of Polycomb repressive complex 2 in cancer, focusing in particular on EZH2. The canonical function of EZH2 in gene silencing, the non-canonical activities as the methylation of other proteins and the role in gene transcriptional activation, were summarized. Moreover, mutations of EZH2, responsible for an increased methyltransferase activity in cancer, were recapitulated. Finally, various drugs able to inhibit EZH2 with different mechanism were described, specifically underscoring the effects in several cancers, in order to clarify the role of EZH2 and understand if EZH2 blockade could be a new strategy for developing specific therapies or a way to increase sensitivity of cancer cells to standard therapies. PMID:27081636

  19. Lessons from Nature: Sources and Strategies for Developing AMPK Activators for Cancer Chemotherapeutics.

    PubMed

    Arkwright, Richard T; Deshmukh, Rahul; Adapa, Nikhil; Stevens, Ryan; Zonder, Emily; Zhang, Zhongyu; Farshi, Pershang; Ahmed, Reda Saber Ibrahim; El-Banna, Hossny Awad; Chan, Tak-Hang; Dou, Q Ping

    2015-01-01

    Adenosine Monophosphate-Activated Protein Kinase or AMPK is a highly-conserved master-regulator of numerous cellular processes, including: Maintaining cellular-energy homeostasis, modulation of cytoskeletaldynamics, directing cell growth-rates and influencing cell-death pathways. AMPK has recently emerged as a promising molecular target in cancer therapy. In fact, AMPK deficiencies have been shown to enhance cell growth and proliferation, which is consistent with enhancement of tumorigenesis by AMPK-loss. Conversely, activation of AMPK is associated with tumor growth suppression via inhibition of the Mammalian Target of Rapamycin Complex-1 (mTORC1) or the mTOR signal pathway. The scientific communities' recognition that AMPK-activating compounds possess an anti-neoplastic effect has contributed to a rush of discoveries and developments in AMPK-activating compounds as potential anticancer-drugs. One such example is the class of compounds known as Biguanides, which include Metformin and Phenformin. The current review will showcase natural compounds and their derivatives that activate the AMPK-complex and signaling pathway. In addition, the biology and history of AMPK-signaling and AMPK-activating compounds will be overviewed, their anticancer-roles and mechanisms-of-actions will be discussed, and potential strategies for the development of novel, selective AMPK-activators with enhanced efficacy and reduced toxicity will be proposed.

  20. A Field Trial of Alternative Targeted Screening Strategies for Chagas Disease in Arequipa, Peru

    PubMed Central

    Hunter, Gabrielle C.; Borrini-Mayorí, Katty; Ancca Juárez, Jenny; Castillo Neyra, Ricardo; Verastegui, Manuela R.; Malaga Chavez, Fernando S.; Cornejo del Carpio, Juan Geny; Córdova Benzaquen, Eleazar; Náquira, César; Gilman, Robert H.; Bern, Caryn; Levy, Michael Z.

    2012-01-01

    Background Chagas disease is endemic in the rural areas of southern Peru and a growing urban problem in the regional capital of Arequipa, population ∼860,000. It is unclear how to implement cost-effective screening programs across a large urban and periurban environment. Methods We compared four alternative screening strategies in 18 periurban communities, testing individuals in houses with 1) infected vectors; 2) high vector densities; 3) low vector densities; and 4) no vectors. Vector data were obtained from routine Ministry of Health insecticide application campaigns. We performed ring case detection (radius of 15 m) around seropositive individuals, and collected data on costs of implementation for each strategy. Results Infection was detected in 21 of 923 (2.28%) participants. Cases had lived more time on average in rural places than non-cases (7.20 years versus 3.31 years, respectively). Significant risk factors on univariate logistic regression for infection were age (OR 1.02; p = 0.041), time lived in a rural location (OR 1.04; p = 0.022), and time lived in an infested area (OR 1.04; p = 0.008). No multivariate model with these variables fit the data better than a simple model including only the time lived in an area with triatomine bugs. There was no significant difference in prevalence across the screening strategies; however a self-assessment of disease risk may have biased participation, inflating prevalence among residents of houses where no infestation was detected. Testing houses with infected-vectors was least expensive. Ring case detection yielded four secondary cases in only one community, possibly due to vector-borne transmission in this community, apparently absent in the others. Conclusions Targeted screening for urban Chagas disease is promising in areas with ongoing vector-borne transmission; however, these pockets of epidemic transmission remain difficult to detect a priori. The flexibility to adapt to the epidemiology that

  1. Antitumor activity of a folate receptor-targeted immunoglobulin G-doxorubicin conjugate

    PubMed Central

    Yang, Tan; Xu, Ling; Li, Bin; Li, Weijie; Ma, Xiang; Fan, Lingling; Lee, Robert J; Xu, Chuanrui; Xiang, Guangya

    2017-01-01

    Development of antibody-drug conjugates (ADCs) is a promising therapeutic strategy for cancer therapy. In this study, folate was conjugated via a polyethyleneglycol (PEG) linker to immunoglobulin G (IgG), which was linked to doxorubicin (DOX), to form a novel ADC folate-PEG-IgG-DOX (FA-PEG-IgG-DOX). The FA-PEG-IgG-DOX showed high targeting efficiency in HeLa and KB cells and significantly improved the uptake and retention of DOX compared with IgG-DOX about 10-fold. Subsequently, FA-PEG-IgG-DOX was shown to have at least 8 times higher antitumor activity than IgG-DOX both in HeLa and KB cells and also induced more apoptosis in those cells than IgG-DOX. Moreover, FA-PEG-IgG-DOX had a 2 times longer circulating time than FA-IgG-DOX, but did not increase the DOX distribution in mouse hearts. Importantly, FA-PEG-IgG-DOX treatment significantly inhibited tumor growth in xenograft mice. Together, our results indicate that FA-PEG-IgG is an effective ADC carrier for delivery of chemotherapeutic agents and that conjugating tumor targeting ligands to antibodies is a promising strategy for producing ADC drugs.

  2. Novel Molecular Strategies and Targets for Opioid Drug Discovery for the Treatment of Chronic Pain

    PubMed Central

    Olson, Keith M.; Lei, Wei; Keresztes, Attila; LaVigne, Justin; Streicher, John M.

    2017-01-01

    Opioid drugs like morphine and fentanyl are the gold standard for treating moderate to severe acute and chronic pain. However, opioid drug use can be limited by serious side effects, including constipation, tolerance, respiratory suppression, and addiction. For more than 100 years, we have tried to develop opioids that decrease or eliminate these liabilities, with little success. Recent advances in understanding opioid receptor signal transduction have suggested new possibilities to activate the opioid receptors to cause analgesia, while reducing or eliminating unwanted side effects. These new approaches include designing functionally selective ligands, which activate desired signaling cascades while avoiding signaling cascades that are thought to provoke side effects. It may also be possible to directly modulate downstream signaling through the use of selective activators and inhibitors. Separate from downstream signal transduction, it has also been found that when the opioid system is stimulated, various negative feedback systems are upregulated to compensate, which can drive side effects. This has led to the development of multi-functional molecules that simultaneously activate the opioid receptor while blocking various negative feedback receptor systems including cholecystokinin and neurokinin-1. Other novel approaches include targeting heterodimers of the opioid and other receptor systems which may drive side effects, and making endogenous opioid peptides druggable, which may also reduce opioid mediated side effects. Taken together, these advances in our molecular understanding provide a path forward to break the barrier in producing an opioid with reduced or eliminated side effects, especially addiction, which may provide relief for millions of patients. PMID:28356897

  3. Targeting the kynurenine pathway-related alterations in Alzheimer's disease: a future therapeutic strategy.

    PubMed

    Plangár, Imola; Zádori, Dénes; Klivényi, Péter; Toldi, József; Vécsei, László

    2011-01-01

    Alzheimer's disease (AD) is a chronic neurodegenerative disorder associated with dementia as a main feature. Despite decades of thorough research in the field of AD, the pathomechanism is still not fully understood. The development of novel experimental models can help us in the discovery of both genetic and non-genetic components of disease pathogenesis. As currently available therapies in AD can provide merely moderate or only temporary symptomatic relief, there is a great demand for the development of new drugs with higher therapeutic potential. Some of the candidates would be those targeting the kynurenine pathway, the neuroactive metabolites of which are surely involved in both neurodegeneration and neuroprotection, mainly in relation with glutamate excitotoxicity and oxidative stress. Both analogs of the neuroprotective kynurenic acid and small molecule enzyme inhibitors preventing the formation of neurotoxic compounds may have potential therapeutic significance. However, there is a great need for new strategies to improve efficacy, transport across the blood-brain barrier and bioavailability, naturally with simultaneous minimization of the adverse side-effects.

  4. HDAC4 Reduction: A Novel Therapeutic Strategy to Target Cytoplasmic Huntingtin and Ameliorate Neurodegeneration

    PubMed Central

    Mielcarek, Michal; Landles, Christian; Weiss, Andreas; Bradaia, Amyaouch; Seredenina, Tamara; Inuabasi, Linda; Osborne, Georgina F.; Wadel, Kristian; Touller, Chrystelle; Butler, Rachel; Robertson, Janette; Franklin, Sophie A.; Smith, Donna L.; Park, Larry; Marks, Paul A.; Wanker, Erich E.; Olson, Eric N.; Luthi-Carter, Ruth; van der Putten, Herman; Beaumont, Vahri; Bates, Gillian P.

    2013-01-01

    Histone deacetylase (HDAC) 4 is a transcriptional repressor that contains a glutamine-rich domain. We hypothesised that it may be involved in the molecular pathogenesis of Huntington's disease (HD), a protein-folding neurodegenerative disorder caused by an aggregation-prone polyglutamine expansion in the huntingtin protein. We found that HDAC4 associates with huntingtin in a polyglutamine-length-dependent manner and co-localises with cytoplasmic inclusions. We show that HDAC4 reduction delayed cytoplasmic aggregate formation, restored Bdnf transcript levels, and rescued neuronal and cortico-striatal synaptic function in HD mouse models. This was accompanied by an improvement in motor coordination, neurological phenotypes, and increased lifespan. Surprisingly, HDAC4 reduction had no effect on global transcriptional dysfunction and did not modulate nuclear huntingtin aggregation. Our results define a crucial role for the cytoplasmic aggregation process in the molecular pathology of HD. HDAC4 reduction presents a novel strategy for targeting huntingtin aggregation, which may be amenable to small-molecule therapeutics. PMID:24302884

  5. Targeted Removal of Bioavailable Metal as a Detoxification Strategy for Carbon Nanotubes

    PubMed Central

    Liu, Xinyuan; Guo, Lin; Morris, Daniel; Kane, Agnes B.; Hurt, Robert H.

    2008-01-01

    There is substantial evidence for toxicity and/or carcinogenicity upon inhalation of pure transition metals in fine particulate form. Carbon nanotube catalyst residues may trigger similar metal-mediated toxicity, but only if the metal is bioavailable and not fully encapsulated within fluid-protective carbon shells. Recent studies have documented the presence of bioavailable iron and nickel in a variety of commercial as-produced and vendor “purified” nanotubes, and the present article examines techniques to avoid or remove this bioavailable metal. First, data are presented on the mechanisms potentially responsible for free metal in “purified” samples, including kinetic limitations during metal dissolution, the re-deposition or adsorption of metal on nanotube outer surfaces, and carbon shell damage during last-step oxidation or one-pot purification. Optimized acid treatment protocols are presented for targeting the free metal, considering the effects of acid strength, composition, time, and conditions for post-treatment water washing. Finally, after optimized acid treatment, it is shown that the remaining, non-bioavailable (encapsulated) metal persists in a stable and biologically unavailable form up to two months in an in vitro biopersistence assay, suggesting that simple removal of bioavailable (free) metal is a promising strategy for reducing nanotube health risks. PMID:19255622

  6. Combined strategies of apomorphine diester prodrugs and nanostructured lipid carriers for efficient brain targeting

    NASA Astrophysics Data System (ADS)

    Liu, Kuo-Sheng; Wen, Chih-Jen; Yen, Tzu-Chen; Sung, K. C.; Ku, Ming-Chuan; Wang, Jhi-Joung; Fang, Jia-You

    2012-03-01

    Our aim is to develop nanostructured lipid carriers (NLCs) for loading the apomorphine diester prodrugs, diacetyl apomorphine (DAA) and diisobutyryl apomorphine (DIA), into the brain. NLCs were prepared using sesame oil/cetyl palmitate as the lipid matrices. Experiments were performed with the objective of evaluating the physicochemical characteristics, drug release, safety and brain-targeting efficacy of the NLCs. The size of regular NLCs (N-NLCs) was 214 nm. The addition of Forestall (FE) and polyethylene glycol (PEG) to the NLCs (P-NLCs) increased the particle diameter to 250 nm. The zeta potentials of N-NLCs and P-NLCs were respectively shown to be - 21 and 48 mV. Diester prodrugs were more lipophilic and more chemically stable than the parent apomorphine. The hydrolysis study indicated that the prodrugs underwent bioconversion in plasma and brain extract, with DAA exhibiting faster degradation than DIA. Sustained release was achieved through the synergistic effect of integrating strategies of prodrugs and NLCs, with the longer carbon chain showing the slower release (DIA < DAA). None of the NLCs tested here exhibited a toxicity problem according to the examination of neutrophil lactate dehydrogenase (LDH) release and hemolysis. Results of a bioimaging study in mice showed that P-NLCs largely accumulated in the brain. The distribution duration of the fluorescent dye in the brain region was also prolonged by the nanocarriers.

  7. Anticancer strategies based on the metabolic profile of tumor cells: therapeutic targeting of the Warburg effect

    PubMed Central

    Chen, Xi-sha; Li, Lan-ya; Guan, Yi-di; Yang, Jin-ming; Cheng, Yan

    2016-01-01

    Tumor cells rely mainly on glycolysis for energy production even in the presence of sufficient oxygen, a phenomenon termed the Warburg effect, which is the most outstanding characteristic of energy metabolism in cancer cells. This metabolic adaptation is believed to be critical for tumor cell growth and proliferation, and a number of onco-proteins and tumor suppressors, including the PI3K/Akt/mTOR signaling pathway, Myc, hypoxia-inducible factor and p53, are involved in the regulation of this metabolic adaptation. Moreover, glycolytic cancer cells are often invasive and impervious to therapeutic intervention. Thus, altered energy metabolism is now appreciated as a hallmark of cancer and a promising target for cancer treatment. A better understanding of the biology and the regulatory mechanisms of aerobic glycolysis has the potential to facilitate the development of glycolysis-based therapeutic interventions for cancer. In addition, glycolysis inhibition combined with DNA damaging drugs or chemotherapeutic agents may be effective anticancer strategies through weakening cell damage repair capacity and enhancing drug cytotoxicity. PMID:27374491

  8. Innovative Strategy on Hydrogen Evolution Reaction Utilizing Activated Liquid Water

    PubMed Central

    Hwang, Bing-Joe; Chen, Hsiao-Chien; Mai, Fu-Der; Tsai, Hui-Yen; Yang, Chih-Ping; Rick, John; Liu, Yu-Chuan

    2015-01-01

    Splitting water for hydrogen production using light, or electrical energy, is the most developed ‘green technique’. For increasing efficiency in hydrogen production, currently, the most exciting and thriving strategies are focused on efficient and inexpensive catalysts. Here, we report an innovative idea for efficient hydrogen evolution reaction (HER) utilizing plasmon-activated liquid water with reduced hydrogen-bonded structure by hot electron transfer. This strategy is effective for all HERs in acidic, basic and neutral systems, photocatalytic system with a g-C3N4 (graphite carbon nitride) electrode, as well as in an inert system with an ITO (indium tin oxide) electrode. Compared to deionized water, the efficiency of HER increases by 48% based on activated water ex situ on a Pt electrode. Increase in energy efficiency from activated water is 18% at a specific current yield of −20 mA in situ on a nanoscale-granulated Au electrode. Moreover, the onset potential of −0.023 V vs RHE was very close to the thermodynamic potential of the HER (0 V). The measured current density at the corresponding overpotential for HER in an acidic system was higher than any data previously reported in the literature. This approach establishes a new vista in clean green energy production. PMID:26541371

  9. Innovative Strategy on Hydrogen Evolution Reaction Utilizing Activated Liquid Water

    NASA Astrophysics Data System (ADS)

    Hwang, Bing-Joe; Chen, Hsiao-Chien; Mai, Fu-Der; Tsai, Hui-Yen; Yang, Chih-Ping; Rick, John; Liu, Yu-Chuan

    2015-11-01

    Splitting water for hydrogen production using light, or electrical energy, is the most developed ‘green technique’. For increasing efficiency in hydrogen production, currently, the most exciting and thriving strategies are focused on efficient and inexpensive catalysts. Here, we report an innovative idea for efficient hydrogen evolution reaction (HER) utilizing plasmon-activated liquid water with reduced hydrogen-bonded structure by hot electron transfer. This strategy is effective for all HERs in acidic, basic and neutral systems, photocatalytic system with a g-C3N4 (graphite carbon nitride) electrode, as well as in an inert system with an ITO (indium tin oxide) electrode. Compared to deionized water, the efficiency of HER increases by 48% based on activated water ex situ on a Pt electrode. Increase in energy efficiency from activated water is 18% at a specific current yield of -20 mA in situ on a nanoscale-granulated Au electrode. Moreover, the onset potential of -0.023 V vs RHE was very close to the thermodynamic potential of the HER (0 V). The measured current density at the corresponding overpotential for HER in an acidic system was higher than any data previously reported in the literature. This approach establishes a new vista in clean green energy production.

  10. Comparison of active, passive and magnetic targeting to tumors of multifunctional paclitaxel/SPIO-loaded nanoparticles for tumor imaging and therapy.

    PubMed

    Schleich, Nathalie; Po, Chrystelle; Jacobs, Damien; Ucakar, Bernard; Gallez, Bernard; Danhier, Fabienne; Préat, Véronique

    2014-11-28

    Multifunctional nanoparticles combining therapy and imaging have the potential to improve cancer treatment by allowing personalized therapy. Herein, we aimed to compare in vivo different strategies in terms of targeting capabilities: (1) passive targeting via the EPR effect, (2) active targeting of αvβ3 integrin via RGD grafting, (3) magnetic targeting via a magnet placed on the tumor and (4) the combination of magnetic targeting and active targeting of αvβ3 integrin. For a translational approach, PLGA-based nanoparticles loaded with paclitaxel and superparamagnetic iron oxides were used. Electron Spin Resonance spectroscopy and Magnetic Resonance Imaging (MRI) were used to both quantify and visualize the accumulation of multifunctional nanoparticles into the tumors. We demonstrate that compared to untargeted or single targeted nanoparticles, the combination of both active strategy and magnetic targeting drastically enhanced (i) nanoparticle accumulation into the tumor tissue with an 8-fold increase compared to passive targeting (1.12% and 0.135% of the injected dose, respectively), (ii) contrast in MRI (imaging purpose) and (iii) anti-cancer efficacy with a median survival time of 22 days compared to 13 for the passive targeting (therapeutic purpose). Double targeting of nanoparticles to tumors by different mechanisms could be a promising translational approach for the management of therapeutic treatment and personalized therapy.

  11. Bi-objective optimization of a multiple-target active debris removal mission

    NASA Astrophysics Data System (ADS)

    Bérend, Nicolas; Olive, Xavier

    2016-05-01

    The increasing number of space debris in Low-Earth Orbit (LEO) raises the question of future Active Debris Removal (ADR) operations. Typical ADR scenarios rely on an Orbital Transfer Vehicle (OTV) using one of the two following disposal strategies: the first one consists in attaching a deorbiting kit, such as a solid rocket booster, to the debris after rendezvous; with the second one, the OTV captures the debris and moves it to a low-perigee disposal orbit. For multiple-target ADR scenarios, the design of such a mission is very complex, as it involves two optimization levels: one for the space debris sequence, and a second one for the "elementary" orbit transfer strategy from a released debris to the next one in the sequence. This problem can be seen as a Time-Dependant Traveling Salesman Problem (TDTSP) with two objective functions to minimize: the total mission duration and the total propellant consumption. In order to efficiently solve this problem, ONERA has designed, under CNES contract, TOPAS (Tool for Optimal Planning of ADR Sequence), a tool that implements a Branch & Bound method developed in previous work together with a dedicated algorithm for optimizing the "elementary" orbit transfer. A single run of this tool yields an estimation of the Pareto front of the problem, which exhibits the trade-off between mission duration and propellant consumption. We first detail our solution to cope with the combinatorial explosion of complex ADR scenarios with 10 debris. The key point of this approach is to define the orbit transfer strategy through a small set of parameters, allowing an acceptable compromise between the quality of the optimum solution and the calculation cost. Then we present optimization results obtained for various 10 debris removal scenarios involving a 15-ton OTV, using either the deorbiting kit or the disposal orbit strategy. We show that the advantage of one strategy upon the other depends on the propellant margin, the maximum duration allowed

  12. Proatherogenic macrophage activities are targeted by the flavonoid quercetin.

    PubMed

    Lara-Guzman, Oscar J; Tabares-Guevara, Jorge H; Leon-Varela, Yudy M; Álvarez, Rafael M; Roldan, Miguel; Sierra, Jelver A; Londoño-Londoño, Julian A; Ramirez-Pineda, Jose R

    2012-11-01

    Many studies have demonstrated that the flavonoid quercetin protects against cardiovascular disease (CVD) and related risk factors. Atherosclerosis, the underlying cause of CVD, is also attenuated by oral quercetin administration in animal models. Although macrophages are key players during fatty streak formation and plaque progression and aggravation, little is known about the effects of quercetin on atherogenic macrophages. Here, we report that primary bone marrow-derived macrophages internalized less oxidized low-density lipoprotein (oxLDL) and accumulated less intracellular cholesterol in the presence of quercetin. This reduction of foam cell formation correlated with reduced surface expression of the oxLDL receptor CD36. Quercetin also targeted the lipopolysaccharide-dependent, oxLDL-independent pathway of lipid droplet formation in macrophages. In oxLDL-stimulated macrophages, quercetin inhibited reactive oxygen species production and interleukin (IL)-6 secretion. In a system that evaluated cholesterol crystal-induced IL-1β secretion via nucleotide-binding domain and leucine-rich repeat containing protein 3 inflammasome activation, quercetin also exhibited an inhibitory effect. Dyslipidemic apolipoprotein E-deficient mice chronically treated with intraperitoneal quercetin injections had smaller atheromatous lesions, reduced lipid deposition, and less macrophage and T cell inflammatory infiltrate in the aortic roots than vehicle-treated animals. Serum levels of total cholesterol and the lipid peroxidation product malondialdehyde were also reduced in these mice. Our results demonstrate that quercetin interferes with both key proatherogenic activities of macrophages, namely foam cell formation and pro-oxidant/proinflammatory responses, and these effects may explain the atheroprotective properties of this common flavonoid.

  13. Target of rapamycin activation predicts lifespan in fruit flies

    PubMed Central

    Scialò, Filippo; Sriram, Ashwin; Naudí, Alba; Ayala, Victoria; Jové, Mariona; Pamplona, Reinald; Sanz, Alberto

    2015-01-01

    Aging and age-related diseases are one of the most important health issues that the world will confront during the 21st century. Only by understanding the proximal causes will we be able to find treatments to reduce or delay the onset of degenerative diseases associated with aging. Currently, the prevalent paradigm in the field is the accumulation of damage. However, a new theory that proposes an alternative explanation is gaining momentum. The hyperfunction theory proposes that aging is not a consequence of a wear and tear process, but a result of the continuation of developmental programs during adulthood. Here we use Drosophila melanogaster, where evidence supporting both paradigms has been reported, to identify which parameters that have been previously related with lifespan best predict the rate of aging in wild type flies cultured at different temperatures. We find that mitochondrial function and mitochondrial reactive oxygen species (mtROS) generation correlates with metabolic rate, but not with the rate of aging. Importantly, we find that activation of nutrient sensing pathways (i.e. insulin-PI3K/Target of rapamycin (Tor) pathway) correlates with lifespan, but not with metabolic rate. Our results, dissociate metabolic rate and lifespan in wild type flies and instead link nutrient sensing signaling with longevity as predicted by the hyperfunction theory. PMID:26259964

  14. An active electron polarized scintillating GSO target for neutrino physics

    NASA Astrophysics Data System (ADS)

    Baiboussinov, B.; Braggio, C.; Cardini, A.; Carugno, G.; Congiu, F.; Gain, S.; Galeazzi, G.; Lai, A.; Lehman, A.; Mocci, P.; Mura, A.; Quochi, F.; Saba, M.; Saitta, B.; Sartori, G.

    2012-12-01

    The feasibility of an electron-polarized, active target to be used as detector in neutrino scattering experiments, suggested by several theoretical papers, has been investigated. We report on the properties of the paramagnetic crystal Gd2SiO5 (GSO), in which 7.7% of the total number of electrons present can be polarized by lowering the temperature and applying an intense external magnetic field. The material magnetic susceptibility has been measured down to cryogenic temperatures showing that for H=5 T and T=4 K about 80% of the maximum allowed magnetization can be attained. Also the spectral and time response of the crystal have been characterized and the scintillation process has been studied using a photomultiplier to measure the response to gamma rays irradiation and cosmic rays operating the GSO crystal at 13.5 K. An avalanche photodiode (APD) readout of the scintillation signal from the GSO crystal has also been performed, since the magnetic field-independent response of this device allows it to be placed close to the crystal in the cryogenic environment.

  15. Hepatitis B control in the World Health Organization's Western Pacific Region: targets, strategies, status.

    PubMed

    Hennessey, Karen; Mendoza-Aldana, Jorge; Bayutas, Benjamin; Lorenzo-Mariano, Kayla Mae; Diorditsa, Sergey

    2013-12-27

    WHO's Western Pacific Region has the highest rates of hepatitis B virus (HBV) infection in the world; most countries have >8% prevalence of HBV chronic infection in their adult population. In 2005, Member States of the Region adopted a resolution to reduce chronic hepatitis B infection prevalence to less than 2% among children by 2012 as an interim milestone toward a regional goal of less than 1% prevalence. Country commitments to hepatitis B control and successes represent a remarkable public health achievement by preventing over 1 million chronic infections and 300,000 HBV-related deaths per birth cohort. Reported here is a review of the process and strategies for translating this public health initiative into practice including such activities as setting up an Expert Resource Panel, developing implementation guidelines, focusing on facility births while supporting efforts to reach home births, providing guidance for conducting seroprevalence surveys, and establishing a verification process.

  16. Natural killer cell immunosenescence in acute myeloid leukaemia patients: new targets for immunotherapeutic strategies?

    PubMed

    Sanchez-Correa, Beatriz; Campos, Carmen; Pera, Alejandra; Bergua, Juan M; Arcos, Maria Jose; Bañas, Helena; Casado, Javier G; Morgado, Sara; Duran, Esther; Solana, Rafael; Tarazona, Raquel

    2016-04-01

    Several age-associated changes in natural killer (NK) cell phenotype have been reported that contribute to the defective NK cell response observed in elderly patients. A remodelling of the NK cell compartment occurs in the elderly with a reduction in the output of immature CD56(bright) cells and an accumulation of highly differentiated CD56(dim) NK cells. Acute myeloid leukaemia (AML) is generally a disease of older adults. NK cells in AML patients show diminished expression of several activating receptors that contribute to impaired NK cell function and, in consequence, to AML blast escape from NK cell immunosurveillance. In AML patients, phenotypic changes in NK cells have been correlated with disease progression and survival. NK cell-based immunotherapy has emerged as a possibility for the treatment of AML patients. The understanding of age-associated alterations in NK cells is therefore necessary to define adequate therapeutic strategies in older AML patients.

  17. An in silico strategy identified the target gene candidates regulated by dehydration responsive element binding proteins (DREBs) in Arabidopsis genome.

    PubMed

    Wang, Shichen; Yang, Shuo; Yin, Yuejia; Guo, Xiaosen; Wang, Shan; Hao, Dongyun

    2009-01-01

    Identification of downstream target genes of stress-relating transcription factors (TFs) is desirable in understanding cellular responses to various environmental stimuli. However, this has long been a difficult work for both experimental and computational practices. In this research, we presented a novel computational strategy which combined the analysis of the transcription factor binding site (TFBS) contexts and machine learning approach. Using this strategy, we conducted a genome-wide investigation into novel direct target genes of dehydration responsive element binding proteins (DREBs), the members of AP2-EREBPs transcription factor super family which is reported to be responsive to various abiotic stresses in Arabidopsis. The genome-wide searching yielded in total 474 target gene candidates. With reference to the microarray data for abiotic stresses-inducible gene expression profile, 268 target gene candidates out of the total 474 genes predicted, were induced during the 24-h exposure to abiotic stresses. This takes about 57% of total predicted targets. Furthermore, GO annotations revealed that these target genes are likely involved in protein amino acid phosphorylation, protein binding and Endomembrane sorting system. The results suggested that the predicted target gene candidates were adequate to meet the essential biological principle of stress-resistance in plants.

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

    PubMed Central

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

    2012-01-01

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

  19. A targeted door-to-door strategy for sleeping sickness detection in low-prevalence settings in Côte d’Ivoire

    PubMed Central

    Koffi, Mathurin; N’Djetchi, Martial; Ilboudo, Hamidou; Kaba, Dramane; Coulibaly, Bamoro; N’Gouan, Emmanuel; Kouakou, Lingué; Bucheton, Bruno; Solano, Philippe; Courtin, Fabrice; Ehrhardt, Stephan; Jamonneau, Vincent

    2016-01-01

    Significant efforts to control human African trypanosomiasis (HAT) over the three past decades have resulted in drastic reductions of disease prevalence in Côte d’Ivoire. In this context, the costly and labor-intensive active mass screening strategy is no longer efficient. In addition to a more cost-effective passive surveillance system being implemented in this low-prevalence context, our aim was to develop an alternative targeted active screening strategy. In 2012, we carried out a targeted door-to-door (TDD) survey focused on the immediate vicinities of former HAT patients detected in the HAT focus of Bonon and compared the results to those obtained during classical active mass screening (AMS) surveys conducted from 2000 to 2012 in the same area. The TDD that provides a friendlier environment, inviting inhabitants to participate and gain awareness of the disease, detected significantly more HAT cases than the AMS. These results suggest that the TDD is an efficient and useful strategy in low-prevalence settings where very localized transmission cycles may persist and, in combination with passive surveillance, could help in eliminating HAT. PMID:27849517

  20. Children's Age-Related Speed--Accuracy Strategies in Intercepting Moving Targets in Two Dimensions

    ERIC Educational Resources Information Center

    Rothenberg-Cunningham, Alek; Newell, Karl M.

    2013-01-01

    Purpose: This study investigated the age-related speed--accuracy strategies of children, adolescents, and adults in performing a rapid striking task that allowed the self-selection of the interception position in a virtual, two-dimensional environment. Method: The moving target had curvilinear trajectories that were determined by combinations of…

  1. A PCR-free fluorescence strategy for detecting telomerase activity via double amplification strategy.

    PubMed

    Zhang, Xiafei; Cheng, Rui; Shi, Zhilu; Jin, Yan

    2016-01-15

    As a universal tumor biomarker, research on the activity and inhibition of telomerase is of great importance for cancer diagnosis and therapy. Although the telomeric repeat amplification protocol (TRAP) has served as a powerful assay for detecting telomerase activity, its application has been significantly limited by amplification related errors and time-consuming procedure. To address the limitations of PCR-based protocol, a dual amplification fluorescence assay was developed for PCR-free detecting telomerase activity. Briefly, we designed an arch-structure DNA probe to specifically control strand displacement reaction and subsequent enzyme-aided amplification. Telomerase substrate (TS) primer was extended by telomerase to form long elongation products which contain several TTAGGG repeat units. So, one elongation product can release more than one trigger DNA (t-DNA) via strand displacement reaction to realize first amplification. Subsequently, t-DNA specifically opened molecular beacon (MB) to restore the fluorescence of MB. Meanwhile, t-DNA was recycled by the aid of nicking endonuclease to continuously open more and more MBs, leading to a second amplification. Owing to the double amplification strategy, the proposed method allowed the measurement of telomerase activity in crude cell extracts equivalent to 5 HeLa cells and 10 CCRF-CEM cells without PCR amplification. Besides, the influence of telomere-binding ligands on the telomerase activity demonstrated that the proposed method holds the potential to evaluate the inhibition efficiency of telomerase inhibitors.

  2. Active control strategy on a catenary-pantograph validated model

    NASA Astrophysics Data System (ADS)

    Sanchez-Rebollo, C.; Jimenez-Octavio, J. R.; Carnicero, A.

    2013-04-01

    Dynamic simulation methods have become essential in the design process and control of the catenary-pantograph system, overall since high-speed trains and interoperability criteria are getting very trendy. This paper presents an original hardware-in-the-loop (HIL) strategy aimed at integrating a multicriteria active control within the catenary-pantograph dynamic interaction. The relevance of HIL control systems applied in the frame of the pantograph is undoubtedly increasing due to the recent and more demanding requirements for high-speed railway systems. Since the loss of contact between the catenary and the pantograph leads to arcing and electrical wear, and too high contact forces cause mechanical wear of both the catenary wires and the strips of the pantograph, not only prescribed but also economic and performance criteria ratify such a relevance. Different configurations of the proportional-integral-derivative (PID) controller are proposed and applied to two different plant systems. Since this paper is mainly focused on the control strategy, both plant systems are simulation models though the methodology is suitable for a laboratory bench. The strategy of control involves a multicriteria optimisation of the contact force and the consumption of the energy supplied by the control force, a genetic algorithm has been applied for this purpose. Thus, the PID controller is fitted according to these conflicting objectives and tested within a nonlinear lumped model and a nonlinear finite element model, being the last one validated against the European Standard EN 50318. Finally, certain tests have been accomplished in order to analyse the robustness of the control strategy. Particularly, the relevance or the plant simulation, the running speed and the instrumentation time delay are studied in this paper.

  3. Target-depth estimation in active sonar: Cramer-Rao bounds for a bilinear sound-speed profile.

    PubMed

    Mours, Alexis; Ioana, Cornel; Mars, Jérôme I; Josso, Nicolas F; Doisy, Yves

    2016-09-01

    This paper develops a localization method to estimate the depth of a target in the context of active sonar, at long ranges. The target depth is tactical information for both strategy and classification purposes. The Cramer-Rao lower bounds for the target position as range and depth are derived for a bilinear profile. The influence of sonar parameters on the standard deviations of the target range and depth are studied. A localization method based on ray back-propagation with a probabilistic approach is then investigated. Monte-Carlo simulations applied to a summer Mediterranean sound-speed profile are performed to evaluate the efficiency of the estimator. This method is finally validated on data in an experimental tank.

  4. Targeting the TLR4 signaling pathway by polyphenols: A novel therapeutic strategy for neuroinflammation.

    PubMed

    Rahimifard, Mahban; Maqbool, Faheem; Moeini-Nodeh, Shermineh; Niaz, Kamal; Abdollahi, Mohammad; Braidy, Nady; Nabavi, Seyed Mohammad; Nabavi, Seyed Fazel

    2017-02-21

    A wide array of cell signaling mediators and their interactions play vital roles in neuroinflammation associated with ischemia, brain trauma, developmental disorders and age-related neurodegeneration. Along with neurons, microglia and astrocytes are also affected by the inflammatory cascade by releasing pro-inflammatory cytokines, chemokines and reactive oxygen species. The release of pro-inflammatory mediators in response to neural dysfunction may be helpful, neutral or even deleterious to normal cellular survival. Moreover, the important role of NF-κB factors in the central nervous system (CNS) through toll-like receptor (TLR) activation has been well established. This review demonstrates recent findings regarding therapeutic aspects of polyphenolic compounds for the treatment of neuroinflammation, with the aim of regulating TLR4. Polyphenols including flavonoids, phenolic acids, phenolic alcohols, stilbenes and lignans, can target TLR4 signaling pathways in multiple ways. Toll interacting protein expression could be modulated by epigallocatechin-3-gallate. Resveratrol may also exert neuroprotective effects via the TLR4/NF-κB/STAT signaling cascade. Its role in activation of cascade via interfering with TLR4 oligomerization upon receptor stimulation has also been reported. Curcumin, another polyphenol, can suppress overexpression of inflammatory mediators via inhibiting the TLR4-MAPK/NF-κB pathway. It can also reduce neuronal apoptosis via a mechanism concerning the TLR4/MyD88/NF-κB signaling pathway in microglia/macrophages. Despite a symphony of in vivo and in vitro studies, many molecular and pharmacological aspects of neuroinflammation remain unclear. It is proposed that natural compounds targeting TLR4 may serve as important pharmacophores for the development of potent drugs for the treatment of neurological disorders.

  5. Targeting CD44 with nanoparticles in head and neck squamous cell carcinoma: A novel therapeutic strategy against cancer stem cells

    NASA Astrophysics Data System (ADS)

    Thapa, Ranjeeta

    Head and neck squamous cell carcinoma (HNSCC) is the sixth most common type of cancer worldwide and is associated with significant morbidity and mortality. Advances in multi-modality treatments have only minimally improved survival rates in the past several years. Recent attention has been focused on the hypothesis that cancer stem cells (CSCs) may be responsible for the failure of current treatments. In HNSCC, a CSC population is contained within the cell fraction that expresses high levels of CD44. CD44 is a cell surface glycoprotein and was the first CSC marker to be described in solid malignancies. in this study, hyaluronan conjugated, dextran-coated super paramagnetic iron-oxide nanoparticles (HA-DESPIONs) were used to target the CD44 population in CD44-overexpressed HNSCC cell lines for treatment by establishing the interaction of HA-DESPIONs with radiation and hyperthermia therapy. The first part of this dissertation studied the cytotoxic, radiosensitizing, and hyperthermic properties of the HA-DESPIONs using cell proliferation and clonogenic survival assays. Cells were grown, plated, treated with HA-DESPIONs, irradiated/exposed to local hyperthermia, and then analyzed for apoptosis. HA-DESPIONs proved to be relatively non-toxic and nonradiosensitizing. However, temperature-dependent cell survival reduction upon incubation with HA-DESPIONs was observed with evidence of apoptotic cell death. These results supported further development of an alternating magnetic field (AMF) approach to activate the HADESPIONs attached to CSCs. In the second part of the dissertation, an AMF generator was constructed and its heat generating effect was tested via kinetic and dose-dependent bulk heating experiments by exposing magnetic nanoparticles to AMF. For elimination of the CD44 population, cells were treated with HA-DESPIONs/DESPIONs, exposed to AMF, and processed for flow cytometrybased apoptosis analysis. Magnetic nanoparticles caused concentration-dependent bulk heating

  6. New Strategies in Engineering T-Cell Receptor Gene-Modified T Cells to More Effectively Target Malignancies

    PubMed Central

    Schmitt, Thomas M.; Stromnes, Ingunn M.; Chapuis, Aude G.; Greenberg, Philip D.

    2016-01-01

    The immune system, and T cells in particular, have the ability to target and destroy malignant cells. However, anti-tumor immune responses induced from the endogenous T cell repertoire are often insufficient for the eradication of established tumors, as illustrated by the failure of cancer vaccination strategies or checkpoint blockade for most tumors. Genetic modification of T cells to express a defined T cell receptor (TCR) can provide the means to rapidly generate large numbers of tumor-reactive T cells capable of targeting tumor cells in vivo. However, cell-intrinsic factors as well as immunosuppressive factors in the tumor microenvironment can limit the function of such gene-modified T cells. New strategies currently being developed are refining and enhancing this approach, resulting in cellular therapies that more effectively target tumors and that are less susceptible to tumor immune-evasion. PMID:26463711

  7. New Strategies in Engineering T-cell Receptor Gene-Modified T cells to More Effectively Target Malignancies.

    PubMed

    Schmitt, Thomas M; Stromnes, Ingunn M; Chapuis, Aude G; Greenberg, Philip D

    2015-12-01

    The immune system, T cells in particular, have the ability to target and destroy malignant cells. However, antitumor immune responses induced from the endogenous T-cell repertoire are often insufficient for the eradication of established tumors, as illustrated by the failure of cancer vaccination strategies or checkpoint blockade for most tumors. Genetic modification of T cells to express a defined T-cell receptor (TCR) can provide the means to rapidly generate large numbers of tumor-reactive T cells capable of targeting tumor cells in vivo. However, cell-intrinsic factors as well as immunosuppressive factors in the tumor microenvironment can limit the function of such gene-modified T cells. New strategies currently being developed are refining and enhancing this approach, resulting in cellular therapies that more effectively target tumors and that are less susceptible to tumor immune evasion.

  8. Efficient strategy for the molecular diagnosis of intellectual disability using targeted high-throughput sequencing

    PubMed Central

    Redin, Claire; Gérard, Bénédicte; Lauer, Julia; Herenger, Yvan; Muller, Jean; Quartier, Angélique; Masurel-Paulet, Alice; Willems, Marjolaine; Lesca, Gaétan; El-Chehadeh, Salima; Le Gras, Stéphanie; Vicaire, Serge; Philipps, Muriel; Dumas, Michaël; Geoffroy, Véronique; Feger, Claire; Haumesser, Nicolas; Alembik, Yves; Barth, Magalie; Bonneau, Dominique; Colin, Estelle; Dollfus, Hélène; Doray, Bérénice; Delrue, Marie-Ange; Drouin-Garraud, Valérie; Flori, Elisabeth; Fradin, Mélanie; Francannet, Christine; Goldenberg, Alice; Lumbroso, Serge; Mathieu-Dramard, Michèle; Martin-Coignard, Dominique; Lacombe, Didier; Morin, Gilles; Polge, Anne; Sukno, Sylvie; Thauvin-Robinet, Christel; Thevenon, Julien; Doco-Fenzy, Martine; Genevieve, David; Sarda, Pierre; Edery, Patrick; Isidor, Bertrand; Jost, Bernard; Olivier-Faivre, Laurence; Mandel, Jean-Louis; Piton, Amélie

    2014-01-01

    Background Intellectual disability (ID) is characterised by an extreme genetic heterogeneity. Several hundred genes have been associated to monogenic forms of ID, considerably complicating molecular diagnostics. Trio-exome sequencing was recently proposed as a diagnostic approach, yet remains costly for a general implementation. Methods We report the alternative strategy of targeted high-throughput sequencing of 217 genes in which mutations had been reported in patients with ID or autism as the major clinical concern. We analysed 106 patients with ID of unknown aetiology following array-CGH analysis and other genetic investigations. Ninety per cent of these patients were males, and 75% sporadic cases. Results We identified 26 causative mutations: 16 in X-linked genes (ATRX, CUL4B, DMD, FMR1, HCFC1, IL1RAPL1, IQSEC2, KDM5C, MAOA, MECP2, SLC9A6, SLC16A2, PHF8) and 10 de novo in autosomal-dominant genes (DYRK1A, GRIN1, MED13L, TCF4, RAI1, SHANK3, SLC2A1, SYNGAP1). We also detected four possibly causative mutations (eg, in NLGN3) requiring further investigations. We present detailed reasoning for assigning causality for each mutation, and associated patients’ clinical information. Some genes were hit more than once in our cohort, suggesting they correspond to more frequent ID-associated conditions (KDM5C, MECP2, DYRK1A, TCF4). We highlight some unexpected genotype to phenotype correlations, with causative mutations being identified in genes associated to defined syndromes in patients deviating from the classic phenotype (DMD, TCF4, MECP2). We also bring additional supportive (HCFC1, MED13L) or unsupportive (SHROOM4, SRPX2) evidences for the implication of previous candidate genes or mutations in cognitive disorders. Conclusions With a diagnostic yield of 25% targeted sequencing appears relevant as a first intention test for the diagnosis of ID, but importantly will also contribute to a better understanding regarding the specific contribution of the many genes

  9. Optimal strategies for virtual screening of induced-fit and flexible target in the 2015 D3R Grand Challenge

    NASA Astrophysics Data System (ADS)

    Ye, Zhaofeng; Baumgartner, Matthew P.; Wingert, Bentley M.; Camacho, Carlos J.

    2016-09-01

    Induced fit or protein flexibility can make a given structure less useful for docking and/or scoring. The 2015 Drug Design Data Resource (D3R) Grand Challenge provided a unique opportunity to prospectively test optimal strategies for virtual screening in these type of targets: heat shock protein 90 (HSP90), a protein with multiple ligand-induced binding modes; and mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4), a kinase with a large flexible pocket. Using previously known co-crystal structures, we tested predictions from methods that keep the receptor structure fixed and used (a) multiple receptor/ligand co-crystals as binding templates for minimization or docking ("close"), (b) methods that align or dock to a single receptor ("cross"), and (c) a hybrid approach that chose from multiple bound ligands as initial templates for minimization to a single receptor ("min-cross"). Pose prediction using our "close" models resulted in average ligand RMSDs of 0.32 and 1.6 Å for HSP90 and MAP4K4, respectively, the most accurate models of the community-wide challenge. On the other hand, affinity ranking using our "cross" methods performed well overall despite the fact that a fixed receptor cannot model ligand-induced structural changes,. In addition, "close" methods that leverage the co-crystals of the different binding modes of HSP90 also predicted the best affinity ranking. Our studies suggest that analysis of changes on the receptor structure upon ligand binding can help select an optimal virtual screening strategy.

  10. Optimal strategies for virtual screening of induced-fit and flexible target in the 2015 D3R Grand Challenge.

    PubMed

    Ye, Zhaofeng; Baumgartner, Matthew P; Wingert, Bentley M; Camacho, Carlos J

    2016-09-01

    Induced fit or protein flexibility can make a given structure less useful for docking and/or scoring. The 2015 Drug Design Data Resource (D3R) Grand Challenge provided a unique opportunity to prospectively test optimal strategies for virtual screening in these type of targets: heat shock protein 90 (HSP90), a protein with multiple ligand-induced binding modes; and mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4), a kinase with a large flexible pocket. Using previously known co-crystal structures, we tested predictions from methods that keep the receptor structure fixed and used (a) multiple receptor/ligand co-crystals as binding templates for minimization or docking ("close"), (b) methods that align or dock to a single receptor ("cross"), and (c) a hybrid approach that chose from multiple bound ligands as initial templates for minimization to a single receptor ("min-cross"). Pose prediction using our "close" models resulted in average ligand RMSDs of 0.32 and 1.6 Å for HSP90 and MAP4K4, respectively, the most accurate models of the community-wide challenge. On the other hand, affinity ranking using our "cross" methods performed well overall despite the fact that a fixed receptor cannot model ligand-induced structural changes,. In addition, "close" methods that leverage the co-crystals of the different binding modes of HSP90 also predicted the best affinity ranking. Our studies suggest that analysis of changes on the receptor structure upon ligand binding can help select an optimal virtual screening strategy.

  11. Targeting the pro-angiogenic forms of VEGF or inhibiting their expression as anti-cancer strategies.

    PubMed

    Guyot, Mélanie; Hilmi, Caroline; Ambrosetti, Damien; Merlano, Marco; Lo Nigro, Cristiana; Durivault, Jérôme; Grépin, Renaud; Pagès, Gilles

    2017-02-07

    Tumor growth relies on oxygen and blood supply depending on neo-vascularization. This process is mediated by the Vascular Endothelial Growth Factor (VEGF) in many tumors. This paradigm has led to the development of specific therapeutic approaches targeting VEGF or its receptors. Despite their promising effects, these strategies have not improved overall survival of patients suffering from different cancers compared to standard therapies. We hypothesized that the existence of anti-angiogenic forms of VEGF VEGFxxxb which are still present in many tumors limit the therapeutic effects of the anti-VEGF antibodies bevacizumab/Avastin (BVZ). To test this hypothesis, we generated renal cell carcinoma cells (RCC) expressing VEGF165b. The incidence of tumors xenografts generated in nude mice and their growth were inferior to those obtained with control cells. Whereas BVZ had no effect on control tumors, it slowed-down the growth of tumor generated with VEGF165b expressing cells. A prophylactic immunization against the domain discriminating VEGF from VEGFxxxb isoforms inhibited the growth of tumor generated with two different syngenic tumor cell lines (melanoma (B16 cells) and RCC (RENCA cells)). Purified immunoglobulins from immunized mice also slowed-down tumor growth of human RCC xenografts in nude mice, producing a potent effect compared to BVZ in this model. Furthermore, down-regulating the serine-arginine-rich splicing factor 1 (SRSF1) or masking SRSF1 binding sites by 2'O-Methyl RNA resulted in the increase of the VEGFxxxb/VEGF ratio. Therefore, a vaccine approach, specific antibodies against pro-angiogenic forms of VEGF, or increasing the VEGFxxxb/VEGF ratio may represent new prophylactic or pro-active anti-cancer strategies.

  12. Effective virtual screening strategy toward covalent ligands: identification of novel NEDD8-activating enzyme inhibitors.

    PubMed

    Zhang, Shengping; Tan, Jiani; Lai, Zhonghui; Li, Ying; Pang, Junxia; Xiao, Jianhu; Huang, Zhangjian; Zhang, Yihua; Ji, Hui; Lai, Yisheng

    2014-06-23

    The NEDD8-activating enzyme (NAE) is an emerging target for cancer therapy, which regulates the degradation and turnover of a variety of cancer-related proteins by activating the cullin-RING E3 ubiquitin ligases. Among a limited number of known NAE inhibitors, the covalent inhibitors have demonstrated the most potent efficacy through their covalently linked adducts with NEDD8. Inspired by this unique mechanism, in this study, a novel combined strategy of virtual screening (VS) was adopted with the aim to identify diverse covalent inhibitors of NAE. To be specific, a docking-enabled pharmacophore model was first built from the possible active conformations of chosen covalent inhibitors. Meanwhile, a dynamic structure-based phamacophore was also established based on the snapshots derived from molecular dynamic simulation. Subsequent screening of a focused ZINC database using these pharmacophore models combined with covalent docking discovered three novel active compounds. Among them, compound LZ3 exhibited the most potent NAE inhibitory activity with an IC50 value of 1.06 ± 0.18 μM. Furthermore, a cell-based washout experiment proved the proposed covalent binding mechanism for compound LZ3, which confirmed the successful application of our combined VS strategy, indicating it may provide a viable solution to systematically discover novel covalent ligands.

  13. Inner ear cell therapy targeting hereditary deafness by activation of stem cell homing factors.

    PubMed

    Kamiya, Kazusaku

    2015-01-01

    Congenital deafness affects about 1 in 1000 children and more than half of them have a genetic background such as Connexin26 (CX26) gene mutation. Inner ear cell therapy for sensorineural hearing loss has been expected to be an effective therapy for hereditary deafness. Previously, we developed a novel strategy for inner ear cell therapy using bone marrow mesenchymal stem cells as a supplement for cochlear fibrocytes functioning for cochlear ion transport. For cell therapy targeting hereditary deafness, a more effective cell delivery system to induce the stem cells into cochlear tissue is required, because gene mutations affect all cochlear cells cochlear cells expressing genes such as GJB2 encoding CX26. Stem cell homing is one of the crucial mechanisms to be activated for efficient cell delivery to the cochlear tissue. In our study, monocyte chemotactic protein-1, stromal cell-derived factor-1 and their receptors were found to be a key regulator for stem cell recruitment to the cochlear tissue. Thus, the activation of stem cell homing may be an efficient strategy for hearing recovery in hereditary deafness.

  14. Permanent genetic access to transiently active neurons via TRAP: targeted recombination in active populations.

    PubMed

    Guenthner, Casey J; Miyamichi, Kazunari; Yang, Helen H; Heller, H Craig; Luo, Liqun

    2013-06-05

    Targeting genetically encoded tools for neural circuit dissection to relevant cellular populations is a major challenge in neurobiology. We developed an approach, targeted recombination in active populations (TRAP), to obtain genetic access to neurons that were activated by defined stimuli. This method utilizes mice in which the tamoxifen-dependent recombinase CreER(T2) is expressed in an activity-dependent manner from the loci of the immediate early genes Arc and Fos. Active cells that express CreER(T2) can only undergo recombination when tamoxifen is present, allowing genetic access to neurons that are active during a time window of less than 12 hr. We show that TRAP can provide selective access to neurons activated by specific somatosensory, visual, and auditory stimuli and by experience in a novel environment. When combined with tools for labeling, tracing, recording, and manipulating neurons, TRAP offers a powerful approach for understanding how the brain processes information and generates behavior.

  15. Apoptosis as anticancer mechanism: function and dysfunction of its modulators and targeted therapeutic strategies

    PubMed Central

    Pistritto, Giuseppa; Trisciuoglio, Daniela; Ceci, Claudia; Garufi, Alessia; D'Orazi, Gabriella

    2016-01-01

    Apoptosis is a form of programmed cell death that results in the orderly and efficient removal of damaged cells, such as those resulting from DNA damage or during development. Apoptosis can be triggered by signals from within the cell, such as genotoxic stress, or by extrinsic signals, such as the binding of ligands to cell surface death receptors. Deregulation in apoptotic cell death machinery is an hallmark of cancer. Apoptosis alteration is responsible not only for tumor development and progression but also for tumor resistance to therapies. Most anticancer drugs currently used in clinical oncology exploit the intact apoptotic signaling pathways to trigger cancer cell death. Thus, defects in the death pathways may result in drug resistance so limiting the efficacy of therapies. Therefore, a better understanding of the apoptotic cell death signaling pathways may improve the efficacy of cancer therapy and bypass resistance. This review will highlight the role of the fundamental regulators of apoptosis and how their deregulation, including activation of anti-apoptotic factors (i.e., Bcl-2, Bcl-xL, etc) or inactivation of pro-apoptotic factors (i.e., p53 pathway) ends up in cancer cell resistance to therapies. In addition, therapeutic strategies aimed at modulating apoptotic activity are briefly discussed. PMID:27019364

  16. A novel Trojan-horse targeting strategy to reduce the non-specific uptake of nanocarriers by non-cancerous cells.

    PubMed

    Shen, Zheyu; Wu, Hao; Yang, Sugeun; Ma, Xuehua; Li, Zihou; Tan, Mingqian; Wu, Aiguo

    2015-11-01

    One big challenge with active targeting of nanocarriers is non-specific binding between targeting molecules and non-target moieties expressed on non-cancerous cells, which leads to non-specific uptake of nanocarriers by non-cancerous cells. Here, we propose a novel Trojan-horse targeting strategy to hide or expose the targeting molecules of nanocarriers on-demand. The non-specific uptake by non-cancerous cells can be reduced because the targeting molecules are hidden in hydrophilic polymers. The nanocarriers are still actively targetable to cancer cells because the targeting molecules can be exposed on-demand at tumor regions. Typically, Fe3O4 nanocrystals (FN) as magnetic resonance imaging (MRI) contrast agents were encapsulated into albumin nanoparticles (AN), and then folic acid (FA) and pH-sensitive polymers (PP) were grafted onto the surface of AN-FN to construct PP-FA-AN-FN nanoparticles. Fourier transform infrared spectroscopy (FT-IR), dynamic light scattering (DLS), transmission electron microscope (TEM) and gel permeation chromatography (GPC) results confirm successful construction of PP-FA-AN-FN. According to difference of nanoparticle-cellular uptake between pH 7.4 and 5.5, the weight ratio of conjugated PP to nanoparticle FA-AN-FN (i.e. graft density) and the molecular weight of PP (i.e. graft length) are optimized to be 1.32 and 5.7 kDa, respectively. In vitro studies confirm that the PP can hide ligand FA to prevent it from binding to cells with FRα at pH 7.4 and shrink to expose FA at pH 5.5. In vivo studies demonstrate that our Trojan-horse targeting strategy can reduce the non-specific uptake of the PP-FA-AN-FN by non-cancerous cells. Therefore, our PP-FA-AN-FN might be used as an accurately targeted MRI contrast agent.

  17. Targeting the proteolytic processing of the viral glycoprotein precursor is a promising novel antiviral strategy against arenaviruses.

    PubMed

    Rojek, Jillian M; Pasqual, Giulia; Sanchez, Ana B; Nguyen, Ngoc-Thao; de la Torre, Juan-Carlos; Kunz, Stefan

    2010-01-01

    A crucial step in the arenavirus life cycle is the biosynthesis of the viral envelope glycoprotein (GP) responsible for virus attachment and entry. Processing of the GP precursor (GPC) by the cellular proprotein convertase site 1 protease (S1P), also known as subtilisin-kexin-isozyme 1 (SKI-1), is crucial for cell-to-cell propagation of infection and production of infectious virus. Here, we sought to evaluate arenavirus GPC processing by S1P as a target for antiviral therapy using a recently developed peptide-based S1P inhibitor, decanoyl (dec)-RRLL-chloromethylketone (CMK), and the prototypic arenavirus lymphocytic choriomeningitis virus (LCMV). To control for off-target effects of dec-RRLL-CMK, we employed arenavirus reverse genetics to introduce a furin recognition site into the GPC of LCMV. The rescued mutant virus grew to normal titers, and the processing of its GPC critically depended on cellular furin, but not S1P. Treatment with the S1P inhibitor dec-RRLL-CMK resulted in specific blocking of viral spread and virus production of LCMV. Combination of the protease inhibitor with ribavirin, currently used clinically for treatment of human arenavirus infections, resulted in additive drug effects. In cells deficient in S1P, the furin-dependent LCMV variant established persistent infection, whereas wild-type LCMV underwent extinction without the emergence of S1P-independent escape variants. Together, the potent antiviral activity of an inhibitor of S1P-dependent GPC cleavage, the additive antiviral effect with ribavirin, and the low probability of emergence of S1P-independent viral escape variants make S1P-mediated GPC processing by peptide-derived inhibitors a promising strategy for the development of novel antiarenaviral drugs.

  18. Emerging gene editing strategies for Duchenne muscular dystrophy targeting stem cells

    PubMed Central

    Bertoni, Carmen

    2014-01-01

    The progressive loss of muscle mass characteristic of many muscular dystrophies impairs the efficacy of most of the gene and molecular therapies currently being pursued for the treatment of those disorders. It is becoming increasingly evident that a therapeutic application, to be effective, needs to target not only mature myofibers, but also muscle progenitors cells or muscle stem cells able to form new muscle tissue and to restore myofibers lost as the result of the diseases or during normal homeostasis so as to guarantee effective and lost lasting effects. Correction of the genetic defect using oligodeoxynucleotides (ODNs) or engineered nucleases holds great potential for the treatment of many of the musculoskeletal disorders. The encouraging results obtained by studying in vitro systems and model organisms have set the groundwork for what is likely to become an emerging field in the area of molecular and regenerative medicine. Furthermore, the ability to isolate and expand from patients various types of muscle progenitor cells capable of committing to the myogenic lineage provides the opportunity to establish cell lines that can be used for transplantation following ex vivo manipulation and expansion. The purpose of this article is to provide a perspective on approaches aimed at correcting the genetic defect using gene editing strategies and currently under development for the treatment of Duchenne muscular dystrophy (DMD), the most sever of the neuromuscular disorders. Emphasis will be placed on describing the potential of using the patient own stem cell as source of transplantation and the challenges that gene editing technologies face in the field of regenerative biology. PMID:24795643

  19. Replication Study: BET bromodomain inhibition as a therapeutic strategy to target c-Myc

    PubMed Central

    Aird, Fraser; Kandela, Irawati; Mantis, Christine

    2017-01-01

    In 2015, as part of the Reproducibility Project: Cancer Biology, we published a Registered Report (Kandela et al., 2015) that described how we intended to replicate selected experiments from the paper "BET bromodomain inhibition as a therapeutic strategy to target c-Myc" (Delmore et al., 2011). Here we report the results of those experiments. We found that treatment of human multiple myeloma (MM) cells with the small-molecular inhibitor of BET bromodomains, (+)-JQ1, selectively downregulated MYC transcription, which is similar to what was reported in the original study (Figure 3B; Delmore et al., 2011). Efficacy of (+)-JQ1 was evaluated in an orthotopically xenografted model of MM. Overall survival was increased in (+)-JQ1 treated mice compared to vehicle control, similar to the original study (Figure 7E; Delmore et al., 2011). Tumor burden, as determined by bioluminescence, was decreased in (+)-JQ1 treated mice compared to vehicle control; however, while the effect was in the same direction as the original study (Figure 7C-D; Delmore et al., 2011), it was not statistically significant. The opportunity to detect a statistically significant difference was limited though, due to the higher rate of early death in the control group, and increased overall survival in (+)-JQ1 treated mice before the pre-specified tumor burden analysis endpoint. Additionally, we evaluated the (−)-JQ1 enantiomer that is structurally incapable of inhibiting BET bromodomains, which resulted in a minimal impact on MYC transcription, but did not result in a statistically significant difference in tumor burden or survival distributions compared to treatment with (+)-JQ1. Finally, we report meta-analyses for each result. DOI: http://dx.doi.org/10.7554/eLife.21253.001 PMID:28100400

  20. Targeting Reductions in Sitting Time to Increase Physical Activity and Improve Health.

    PubMed

    Keadle, Sarah K; Conroy, David E; Buman, Matthew P; Dunstan, David W; Matthews, Charles E

    2017-03-08

    New evidence suggests that reductions in sedentary behavior may increase physical activity and improve health. These findings point to new behavioral targets for intervention and new ways to think about intervening to increase overall physical activity in the population. This report provides a knowledge update reflecting the rapid accumulation of new evidence related to sedentary behavior and health among adults. Recent observational studies suggest that leveraging the time-inverse relationship between sedentary and active behaviors by replacing sitting with standing, light or moderate-intensity activity can have important health benefits, particularly among less active adults. Clinical studies are providing evidence of the probable physiologic mechanisms underlying these associations, as well as insights into the cardiometabolic impact of breaking up and reducing sedentary behavior. In contrast to the well-established behavioral theories that guide the development and dissemination of evidence-based interventions to increase moderate-vigorous intensity physical activity (MVPA), much less is known about how to reduce sedentary time in order to increase daily activities. It has become clear that the environmental, social and individual level-determinants for sedentary time are distinct from those linked to the adoption and maintenance of MVPA. As a result, novel intervention strategies that focus on sitting and lower intensity activities by leveraging the surrounding environment (e.g., workplace, school, home) as well as individual-level cues and habits of sedentary behavior are being tested to increase the potency of interventions designed to increase overall physical activity. Herein we summarize the solutions-oriented research across the behavioral research framework, with a focus on highlighting areas of synergy across disciplines and identifying gaps for future research.

  1. A snapshot of physical activity programs targeting Aboriginal and Torres Strait Islander people in Australia.

    PubMed

    Macniven, Rona; Elwell, Michelle; Ride, Kathy; Bauman, Adrian; Richards, Justin

    2017-01-19

    Issue addressed: Participation in physical activity programs can be an effective strategy to reduce chronic disease risk factors and improve broader social outcomes. Health and social outcomes are worse among Aboriginal and Torres Strait Islanders than non-Indigenous Australians, who represent an important group for culturally specific programs. The extent of current practice in physical activity programs is largely unknown. This study identifies such programs targeting this population group and describes their characteristics.Methods: Bibliographic and Internet searches and snowball sampling identified eligible programs operating between 2012 and 2015 in Australia (phase 1). Program coordinators were contacted to verify sourced information (phase 2). Descriptive characteristics were documented for each program.Results: A total of 110 programs were identified across urban, rural and remote locations within all states and territories. Only 11 programs were located through bibliographic sources; the remainder through Internet searches. The programs aimed to influence physical activity for health or broader social outcomes. Sixty five took place in community settings and most involved multiple sectors such as sport, health and education. Almost all were free for participants and involved Indigenous stakeholders. The majority received Government funding and had commenced within the last decade. More than 20 programs reached over 1000 people each; 14 reached 0-100 participants. Most included process or impact evaluation indicators, typically reflecting their aims.Conclusion: This snapshot provides a comprehensive description of current physical activity program provision for Aboriginal and Torres Strait Islander people across Australia. The majority of programs were only identified through the grey literature. Many programs collect evaluation data, yet this is underrepresented in academic literature.So what?: Capturing current practice can inform future efforts to

  2. Targeting pyrimidine pathway of Plasmodium knowlesi: new strategies towards identification of novel antimalarial chemotherapeutic agents.

    PubMed

    Rashmi, Mayank; Yadav, Manoj Kumar; Swati, D

    2017-03-15

    Plasmodium knowlesi has been recently recognized as a human malarial parasite, particularly in the region of south-east Asia. The effective prevention and treatment of this disease is increasingly bound to fail due to the emergence of drug resistance. Hence, design of new drugs against known targets is gaining importance. Pyrimidine pathway is a crucial metabolic pathway in P. knowlesi, and the enzymes involved are also unique in terms of their structure and function as compared to its human counterpart. Thus targeting Dihydroorotase, an enzyme involved in the pyrimidine pathway, provides a promising route for novel drug development. The 3D structure of P. knowlesi Dihydroorotase is not available. The structural homologues of the enzyme are not available in the database, so a threading approach is used to predict the structure. The steric clashes of the predicted model are removed by running a MD simulation of 20 ns. Then the resulting structure is validated by using Ramachandran plot and G-factor analysis. The active sites are predicted and they show interactions with His13, His15, Asp256, Lys97, His134 and His169 for two Zn atoms, and Arg17, Asn42, Thr43, Pro100, His260 and Lys271 for the Dihydroorotate. Interactions between the ligand and binding pocket residues are extracted to create a structure-based pharmacophore model of the docked complex. A four point based pharmacophore model, with four H-bond acceptors and one negative carboxyl ion, was used as a 3D query for screening against 2,664,779 standard lead compounds, obtained from freely available ZINC database. Top 15 compounds with higher pharmacophore-fit score were considered for further study. Among these, only four compounds show desired drug-like properties, and follow the Lipinski's rule of five. Two compounds (ZINC22066495, ZINC20136046) that are negatively charged are found to be more suitable for interaction with positively charged active site of enzyme. Molecular dynamics simulation is used to

  3. Triennial Growth Symposium: a review of science leading to host-targeted antibody strategies for preventing growth depression due to microbial colonization.

    PubMed

    Cook, M E

    2011-07-01

    In this review, the science used to develop host-targeted therapies for improving animal growth and feed efficiency is presented. In contrast to targeting the microbiota of the host, endogenous host proteins are targeted to regulate an overactive inflammatory response in the host. Activation of the immune/inflammatory systems of an animal is costly in terms of growth and feed efficiency. For example, reduced rates of BW gain and poorer feed efficiency in vaccinated animals compared with nonvaccinated animals have been well documented. Also, the growth rate and feed efficiency of animals colonized by microorganisms is only 80 to 90% of their germ-free counterparts. Further evidence of a cost associated with immune activation is that strategies that enhance the immune capability of an animal can reduce animal growth and feed efficiency. Research now indicates that the growth-promoting effects of antibiotics are indirect, and more likely the result of reduced immune activation due to decreased microbial exposure. Studies of mechanisms by which immune/inflammatory activation reduces animal growth and feed efficiency have shown that cytokines of the acute inflammatory response (i.e., IL-1 and tumor necrosis factor α) are key triggers for host muscle wasting. Cytokine-induced muscle wasting is linked to PG signaling pathways, and it has been proposed that regulation of the PG signaling pathways provide host targets for preventing an overreactive or unwarranted inflammatory event. Intestinal secretory phospholipase A(2) (sPLA(2)) has been found to be a useful and accessible (i.e., found in the intestinal lumen) host target for the regulation of an overreactive inflammatory response to conventional environments. This review presents the science and strategy for the regulation of intestinal sPLA(2) using orally administered egg yolk antibody against the enzyme. Clinically healthy animals fed egg antibodies to sPLA(2) had improved growth and feed efficiency. Literature

  4. Biomarkers of oxidative stress and cataract. Novel drug delivery therapeutic strategies targeting telomere reduction and the expression of telomerase activity in the lens epithelial cells with N-acetylcarnosine lubricant eye drops: anti-cataract which helps to prevent and treat cataracts in the eyes of dogs and other animals.

    PubMed

    Babizhayev, Mark A; Yegorov, Yegor E

    2014-01-01

    Cataracts in small animals are shown to be at least partially caused by oxidative damage to lens epithelial cells (LECs) and the internal lens; biomarkers of oxidative stress in the lens are considered as general biomarkers for life expectancy in the canine and other animals. Telomeres lengths and expressed telomerase activity in canine LECs may serve as important monitors of oxidative damage in normal LECs with documented higher levels of telomerase activity in cataractous LECs during cells' lifespan. Loss of functional telomere length below a critical threshold in LECs of canines during the effect of UV and chronic oxidative stress or metabolic failure, can activate programs leading to LEC senescence or death. Telomerase is induced in LECs of canines at critical stages of cataractogenesis initiation and exposure to oxidative stress through the involvement of catalytically active prooxidant transition metal (iron) ions. This work documents that transition metal ions (such as, ferrous ions- catalytic oxidants) might induce premature senescence in LECs of canines, telomere shortening with increased telomerase activity as adaptive response to UV light, oxidative and metabolic stresses. The therapeutic treatment with 1% N-acetylcarnosine (NAC) prodrug delivery is beneficial for prevention and dissolution of ripe cataracts in canines. This biological activity is based on the findings of ferroxidase activity pertinent to the dipeptide carnosine released ophthalmically from NAC prodrug of L-carnosine, stabilizing properties of carnosine on biological membranes based on the ability of the imidazole-containing dipeptides to interact with lipid peroxidation products and reactive oxygen species (ROS), to prevent membrane damage and delute the associated with membrane fragements protein aggregates. The advent of therapeutic treatment of cataracts in canines with N-acetylcarnosine lubricant eye drops through targeting the prevention of loss of functional telomere length below

  5. Target Assembly to Check Boresight Alignment of Active Sensors

    NASA Technical Reports Server (NTRS)

    Ramos-Izquierdo, Luis; Scott, V. Stanley; Riris, Haris; Cavanaugh, John; Liiva, Peter; Rodriguez, Michael

    2011-01-01

    A compact and portable target assembly (Fig. 1) has been developed to measure the boresite alignment of LRO's Lunar Orbiter Laser Altimeter (LOLA) instrument at the spacecraft level. The concept for this target assembly has evolved over many years with earlier versions used to test the Mars Observer Laser Altimeter (MOLA), the Geoscience Laser Altimeter System (GLAS), and the Mercury Laser Altimeter (MLA) space-based instruments.

  6. A Two-Step Strategy to Enhance Activity of Low Potency Peptides

    PubMed Central

    Krishnaji, Subrahmanian Tarakkad; Krishnamurthy, Vijay M.; Lin, Wei-En; Fortin, Jean-Philippe; Kumar, Krishna; Kopin, Alan S.

    2014-01-01

    Novel strategies are needed to expedite the generation and optimization of peptide probes targeting G protein-coupled receptors (GPCRs). We have previously shown that membrane tethered ligands (MTLs), recombinant proteins comprised of a membrane anchor, an extracellular linker, and a peptide ligand can be used to identify targeted receptor modulators. Although MTLs provide a useful tool to identify and/or modify functionally active peptides, a major limitation of this strategy is the reliance on recombinant protein expression. We now report the generation and pharmacological characterization of prototype peptide-linker-lipid conjugates, synthetic membrane anchored ligands (SMALs), which are designed as mimics of corresponding MTLs. In this study, we systematically compare the activity of selected peptides as MTLs versus SMALs. As prototypes, we focused on the precursor proteins of mature Substance P (SubP) and Cholecystokinin 4 (CCK4), specifically non-amidated SubP (SubP-COOH) and glycine extended CCK4 (CCK4-Gly-COOH). As low affinity soluble peptides these ligands each presented a challenging test case for assessment of MTL/SMAL technology. For each ligand, MTLs and corresponding SMALs showed agonist activity and comparable subtype selectivity. In addition, our results illustrate that membrane anchoring increases ligand potency. Furthermore, both MTL and SMAL induced signaling can be blocked by specific non-peptide antagonists suggesting that the anchored constructs may be orthosteric agonists. In conclusion, MTLs offer a streamlined approach for identifying low activity peptides which can be readily converted to higher potency SMALs. The ability to recapitulate MTL activity with SMALs extends the utility of anchored peptides as probes of GPCR function. PMID:25391026

  7. Ionizing Radiation Activates AMP-Activated Kinase (AMPK): A Target for Radiosensitization of Human Cancer Cells

    SciTech Connect

    Sanli, Toran; Rashid, Ayesha; Liu Caiqiong

    2010-09-01

    Purpose: Adenosine monophosphate (AMP)-activated kinase (AMPK) is a molecular energy sensor regulated by the tumor suppressor LKB1. Starvation and growth factors activate AMPK through the DNA damage sensor ataxia-telangiectasia mutated (ATM). We explored the regulation of AMPK by ionizing radiation (IR) and its role as a target for radiosensitization of human cancer cells. Methods and Materials: Lung, prostate, and breast cancer cells were treated with IR (2-8 Gy) after incubation with either ATM or AMPK inhibitors or the AMPK activator metformin. Then, cells were subjected to either lysis and immunoblotting, immunofluorescence microscopy, clonogenic survival assays, or cell cycle analysis. Results: IR induced a robust phosphorylation and activation of AMPK in all tumor cells, independent of LKB1. IR activated AMPK first in the nucleus, and this extended later into cytoplasm. The ATM inhibitor KU-55933 blocked IR activation of AMPK. AMPK inhibition with Compound C or anti-AMPK {alpha} subunit small interfering RNA (siRNA) blocked IR induction of the cell cycle regulators p53 and p21{sup waf/cip} as well as the IR-induced G2/M arrest. Compound C caused resistance to IR, increasing the surviving fraction after 2 Gy, but the anti-diabetic drug metformin enhanced IR activation of AMPK and lowered the surviving fraction after 2 Gy further. Conclusions: We provide evidence that IR activates AMPK in human cancer cells in an LKB1-independent manner, leading to induction of p21{sup waf/cip} and regulation of the cell cycle and survival. AMPK appears to (1) participate in an ATM-AMPK-p21{sup waf/cip} pathway, (2) be involved in regulation of the IR-induced G2/M checkpoint, and (3) may be targeted by metformin to enhance IR responses.

  8. Selective killing of cancer cells by β-lapachone: Direct checkpoint activation as a strategy against cancer

    PubMed Central

    Li, Youzhi; Sun, Xiangao; LaMont, J. Thomas; Pardee, Arthur B.; Li, Chiang J.

    2003-01-01

    Most chemotherapeutic drugs kill cancer cells by indirectly activating checkpoint-mediated apoptosis after creating nonselective damage to DNA or microtubules, which accounts for their toxicity toward normal cells. We seek to target cancer cells by directly activating checkpoint regulators without creating such damage. Here, we show that β-lapachone selectively induces apoptosis in cancer cells without causing the death of nontransformed cells in culture. This unusual selectivity against cancer cells is preceded by activation of S-phase checkpoint and selective induction of E2F1, a regulator of checkpoint-mediated apoptosis. This study suggests direct checkpoint activation as a strategy against cancer. PMID:12598645

  9. More than just finding color: strategy in global visual search is shaped by learned target probabilities.

    PubMed

    Williams, Carrick C; Pollatsek, Alexander; Cave, Kyle R; Stroud, Michael J

    2009-06-01

    In 2 experiments, eye movements were examined during searches in which elements were grouped into four 9-item clusters. The target (a red or blue T) was known in advance, and each cluster contained different numbers of target-color elements. Rather than color composition of a cluster invariantly guiding the order of search though clusters, the use of color was determined by the probability that the target would appear in a cluster of a certain color type: When the target was equally likely to be in any cluster containing the target color, fixations were directed to those clusters approximately equally, but when targets were more likely to appear in clusters with more target-color items, those clusters were likely to be fixated sooner. (The target probabilities guided search without explicit instruction.) Once fixated, the time spent within a cluster depended on the number of target-color elements, consistent with a search of only those elements. Thus, between-cluster search was influenced by global target probabilities signaled by amount of color or color ratios, whereas within-cluster search was directly driven by presence of the target color.

  10. Targeting glutaminolysis has antileukemic activity in acute myeloid leukemia and synergizes with BCL-2 inhibition.

    PubMed

    Jacque, Nathalie; Ronchetti, Anne Marie; Larrue, Clément; Meunier, Godelieve; Birsen, Rudy; Willems, Lise; Saland, Estelle; Decroocq, Justine; Maciel, Thiago Trovati; Lambert, Mireille; Poulain, Laury; Hospital, Marie Anne; Sujobert, Pierre; Joseph, Laure; Chapuis, Nicolas; Lacombe, Catherine; Moura, Ivan Cruz; Demo, Susan; Sarry, Jean Emmanuel; Recher, Christian; Mayeux, Patrick; Tamburini, Jérôme; Bouscary, Didier

    2015-09-10

    Cancer cells require glutamine to adapt to increased biosynthetic activity. The limiting step in intracellular glutamine catabolism involves its conversion to glutamate by glutaminase (GA). Different GA isoforms are encoded by the genes GLS1 and GLS2 in humans. Herein, we show that glutamine levels control mitochondrial oxidative phosphorylation (OXPHOS) in acute myeloid leukemia (AML) cells. Glutaminase C (GAC) is the GA isoform that is most abundantly expressed in AML. Both knockdown of GLS1 expression and pharmacologic GLS1 inhibition by the drug CB-839 can reduce OXPHOS, leading to leukemic cell proliferation arrest and apoptosis without causing cytotoxic activity against normal human CD34(+) progenitors. Strikingly, GLS1 knockdown dramatically inhibited AML development in NSG mice. The antileukemic activity of CB-839 was abrogated by both the expression of a hyperactive GAC(K320A) allele and the addition of the tricarboxyclic acid cycle product α-ketoglutarate, indicating the critical function of GLS1 in AML cell survival. Finally, glutaminolysis inhibition activated mitochondrial apoptosis and synergistically sensitized leukemic cells to priming with the BCL-2 inhibitor ABT-199. These findings show that targeting glutamine addiction via GLS1 inhibition offers a potential novel therapeutic strategy for AML.

  11. Neutrophil activity in chronic venous leg ulcers—A target for therapy?

    PubMed Central

    McDaniel, Jodi C.; Roy, Sashwati; Wilgus, Traci A.

    2013-01-01

    Chronic venous leg ulcers (CVLUs) affect approximately 600,000 people annually in the United States and accrue yearly treatment costs of US$2.5–5 billion. As the population ages, demands on health care resources for CVLU treatments are predicted to drastically increase because the incidence of CVLUs is highest in those ≥65 years of age. Furthermore, regardless of current standards of care, healing complications and high recurrence rates prevail. Thus, it is critical that factors leading to or exacerbating CVLUs be discerned and more effective, adjuvant, evidence-based treatment strategies be utilized. Previous studies have suggested that CVLUs’ pathogenesis is related to the prolonged presence of high numbers of activated neutrophils secreting proteases in the wound bed that destroy growth factors, receptors, and the extracellular matrix that are essential for healing. These events are believed to contribute to a chronically inflamed wound that fails to heal. Therefore, the purpose of this project was to review studies from the past 15 years (1996–2011) that characterized neutrophil activity in the microenvironment of human CVLUs for new evidence that could explicate the proposed relationship between excessive, sustained neutrophil activity and CVLUs. We also appraised the strength of evidence for current and potential therapeutics that target excessive neutrophil activity. PMID:23551462

  12. Comparison of Active and Electrostimulated Recovery Strategies After Fatiguing Exercise

    PubMed Central

    Vanderthommen, Marc; Makrof, Souleyma; Demoulin, Christophe

    2010-01-01

    The purpose of this study was to compare an electrostimulated to an active recovery strategy after a submaximal isometric fatiguing exercise. Nineteen healthy men completed three sessions (separated by at least 4 weeks) which included a knee extensors provocation exercise consisting of 3 sets of 25 isometric contractions. Contraction intensity level was fixed respectively at 60%, 55% and 50% of previously determined maximal voluntary contraction for the first, second and third sets. This provocation exercise was followed by either an active (AR) recovery (25 min pedaling on a cycle ergometer), an electrostimulated (ESR) recovery (25-min continuous and non-tetanic (5 Hz) stimulation of the quadriceps) or a strictly passive recovery (PR). Peak torques of knee extensors and subjective perception of muscle pain (VAS, 0-10) were evaluated before (pre-ex), immediately after the provocation exercise (post-ex), after the recovery period (post-rec), as well as 75 minutes (1h15) and one day (24h) after the exercise bout. Time course of peak torque was similar among the different recovery modes: ~ 75% of initial values at post-ex, ~ 90% at post-rec and at 1h15. At 24h, peak torque reached a level close to baseline values (PR: 99.1 ± 10.7%, AR: 105.3 ± 12.2%, ESR: 104.4 ± 10.5%). VAS muscle pain scores decreased rapidly between post-ex and post-rec (p < 0.001); there were no significant differences between the three recovery modes (p = 0.64). In conclusion, following a submaximal isometric knee extension exercise, neither electrostimulated nor active recovery strategies significantly improved the time course of muscle function recovery. Key points Three sets of submaximal isometric contractions at 60%, 55% and 50% of MVC induced an early fatigue without DOMS but did not lead to exhaustion. In comparison with passive recovery, active and electrostimulated recovery did not lead to significantly higher MVC torques 24h after the exercise bout. No significant differences were

  13. Relationship between behavioural coping strategies and acceptance in patients with fibromyalgia syndrome: Elucidating targets of interventions

    PubMed Central

    2011-01-01

    Background Previous research has found that acceptance of pain is more successful than cognitive coping variables for predicting adjustment to pain. This research has a limitation because measures of cognitive coping rely on observations and reports of thoughts or attempts to change thoughts rather than on overt behaviours. The purpose of the present study, therefore, is to compare the influence of acceptance measures and the influence of different behavioural coping strategies on the adjustment to chronic pain. Methods A sample of 167 individuals diagnosed with fibromyalgia syndrome completed the Chronic Pain Coping Inventory (CPCI) and the Chronic Pain Acceptance Questionnaire (CPAQ). Results Correlational analyses indicated that the acceptance variables were more related to distress and functioning than were behavioural coping variables. The average magnitudes of the coefficients for activity engagement and pain willingness (both subscales of pain acceptance) across the measures of distress and functioning were r = 0.42 and 0.25, respectively, meanwhile the average magnitude of the correlation between coping and functioning was r = 0.17. Regression analyses examined the independent, relative contributions of coping and acceptance to adjustment indicators and demonstrated that acceptance accounted for more variance than did coping variables. The variance contributed by acceptance scores ranged from 4.0 to 40%. The variance contributed by the coping variables ranged from 0 to 9%. Conclusions This study extends the findings of previous work in enhancing the adoption of acceptance-based interventions for maintaining accurate functioning in fibromyalgia patients. PMID:21714918

  14. Analysis of Operating Strategies Using Different Target Designs For 238Pu Production

    SciTech Connect

    Thomas, Tomcy; Sherman, Steven R; Sawhney, Dr. Rapinder

    2017-01-01

    An engineering effort is underway to re-establish capability to produce 238Pu oxide at the kilogram scale in the United States. A multi-step batch process is being developed to produce this important material. Recently, a portion of this process was studied using discrete-event simulation tools to determine whether the conceptual process might achieve its yearly production goal. The study showed the conceptual process can meet the yearly production goal under some circumstances, but process improvements would be needed to ensure greater likelihood of success. This study extends the work performed previously by examining the effects of changing the reactor target design on the yearly process output. Two new reactor target configurations are considered an aluminum-clad reactor target containing 50% greater 237Np oxide content than the original target, and a zirconium alloy-clad target using no aluminum. The results indicate that use of the new aluminum-clad target configuration may allow the process to achieve the same yearly production goal in less time using fewer targets. If the zirconium alloy-clad target is used, then even fewer targets would be needed to reach the production goal, but some process changes would be required to handle the zirconium cladding. The number of days needed to process a target batch to completion, and the steady state 238Pu oxide production rate, for each configuration are compared to the results from the initial simulation study.

  15. Colocalization recognition-activated cascade signal amplification strategy for ultrasensitive detection of transcription factors.

    PubMed

    Zhu, Desong; Wang, Lei; Xu, Xiaowen; Jiang, Wei

    2017-03-15

    Transcription factors (TFs) bind to specific double-stranded DNA (dsDNA) sequences in the regulatory regions of genes to regulate the process of gene transcription. Their expression levels sensitively reflect cell developmental situation and disease state. TFs have become potential diagnostic markers and therapeutic targets of cancers and some other diseases. Hence, high sensitive detection of TFs is of vital importance for early diagnosis of diseases and drugs development. The traditional exonucleases-assisted signal amplification methods suffered from the false positives caused by incomplete digestion of excess recognition probes. Herein, based on a new recognition way-colocalization recognition (CR)-activated dual signal amplification, an ultrasensitive fluorescent detection strategy for TFs was developed. TFs-induced the colocalization of three split recognition components resulted in noticeable increases of local effective concentrations and hybridization of three split components, which activated the subsequent cascade signal amplification including strand displacement amplification (SDA) and exponential rolling circle amplification (ERCA). This strategy eliminated the false positive influence and achieved ultra-high sensitivity towards the purified NF-κB p50 with detection limit of 2.0×10(-13)M. Moreover, NF-κB p50 can be detected in as low as 0.21ngμL(-1) HeLa cell nuclear extracts. In addition, this proposed strategy could be used for the screening of NF-κB p50 activity inhibitors and potential anti-NF-κB p50 drugs. Finally, our proposed strategy offered a potential method for reliable detection of TFs in medical diagnosis and treatment research of cancers and other related diseases.

  16. Identification of orthologous target pairs with shared active compounds and comparison of organism-specific activity patterns.

    PubMed

    Dimova, Dilyana; Stumpfe, Dagmar; Bajorath, Jürgen

    2015-11-01

    A systematic search for active small molecules shared by orthologous targets was carried out, leading to the identification of 803 compound-based orthologous target pairs covering a total of 938 orthologues, 358 unique targets and 98 organisms. Many orthologous target pairs were found to have substantial compound coverage, enabling the introduction of an orthologous target pairs classification including 'organism cliffs' and 'potency-retaining' pairs. A total of 158 orthologous target pairs involving human orthologues were identified, which were typically associated with drug discovery-relevant targets, organism combinations and compound data. Orthologous target pairs with human orthologues included 83 potency-retaining orthologous target pairs covering a variety of targets and organisms. On the basis of these orthologous target pairs, the compound search was further extended and 1149 potent compounds were identified that only had reported activities for non-human orthologues of 48 therapeutic targets, but not their human counterparts, hence providing a large pool of candidate compounds for further evaluation. The complete set of orthologous target pairs identified in our analysis, the orthologous target pairs classification including associated data and all candidate compounds are made freely available.

  17. Divergent Synthesis of Aeruginosins Based on a C(sp(3))-H Activation Strategy.

    PubMed

    Dailler, David; Danoun, Grégory; Ourri, Benjamin; Baudoin, Olivier

    2015-06-22

    A general and scalable access to the aeruginosin family of marine natural products, exhibiting potent inhibitory activity against serine proteases, is reported. This was enabled by the strategic use of two recently implemented Pd-catalyzed C(sp(3))-H activation reactions. The first method allowed us to obtain the common 2-carboxy-6-hydroxyoctahydroindole (Choi) core of the target molecules on a large scale, whereas the second method provided a rapid and divergent access to various hydroxyphenyllactic (Hpla) subunits, including halogenated ones. This unique strategy, together with an optimization of the fragment coupling sequence allowed the synthesis of four aeruginosins, that is, 98A-C and 298A from the chiral pool. Among them, aeruginosin 298A was synthesized on an unprecedentedly large scale. In addition, halogenated aeruginosins 98A and 98C were synthesized for the first time, thanks to a fine-tuning of the final hydrogenation step.

  18. Transfer of Mediational Strategies in Children: The Role of Activity and Awareness During Strategy Acquisition

    ERIC Educational Resources Information Center

    Borkowski, John G.; And Others

    1976-01-01

    The ability of nursery school and first-grade children to learn and transfer a mediational strategy utilizing prepositional relationships between paired-associate objects was investigated under several strategy training conditions. (Author/JMB)

  19. Colon-targeted cell-permeable NFκB inhibitory peptide is orally active against experimental colitis.

    PubMed

    Hong, Sungchae; Yum, Soohwan; Yoo, Hyun-Jung; Kang, Sookjin; Yoon, Jeong-Hyun; Min, Dosik; Kim, Young Mi; Jung, Yunjin

    2012-05-07

    For the purpose of development of orally active peptide therapeutics targeting NFκB for treatment of inflammatory bowel disease (IBD), two major barriers in oral delivery of therapeutic peptides, metabolic lability and tissue impermeability, were circumvented by introduction of a colon-targeted delivery system and cell permeable peptides (CPP) to NFκB inhibitory peptides (NIP). Suppression of NFκB activation was compared following treatment with various CPP conjugated NIPs (CPP-NIP). The most potent CPP-NIP was loaded in a capsule coated with a colon specific polymer, which was administered orally to colitic rats. The anti-inflammatory activity of the colon-targeted CPP-NIP was evaluated by measuring inflammatory indices in the inflamed colonic tissue. For confirmation of the local action of the CPP-NIP, the same experiment was done after rectal administration. Tissue permeability of the CPP-NIP was examined microscopically and spectrophotometrically using FITC-labeled CPP-NIP (CPP-NIP-FITC). NEMO binding domain peptide (NBD, TALDWSWLQTE) fused with a cell permeable peptide CTP (YGRRARRRARR), CTP-NBD, was most potent in inhibiting NFκB activity in cells. Colon-targeted CTP-NBD, but not colon-targeted NBD and CTP-NBD in an enteric capsule, ameliorated the colonic injury, which was in parallel with decrease in MPO activity and the levels of inflammatory mediators. Intracolonic treatment with CTP-NBD alleviated rat colitis and improved all the inflammatory indicators. CTP-NBD-FITC was detected at much greater level in the inflamed tissue than was NBD-FITC. Taken together, introduction of cell permeability and colon targetability to NIP may be a feasible strategy for an orally active peptide therapy for treatment of IBD.

  20. GSK621 Targets Glioma Cells via Activating AMP-Activated Protein Kinase Signalings

    PubMed Central

    Jiang, Hong; Liu, Wei; Zhan, Shi-Kun; Pan, Yi-Xin; Bian, Liu-Guan; Sun, Bomin; Sun, Qing-Fang; Pan, Si-Jian

    2016-01-01

    Here, we studied the anti-glioma cell activity by a novel AMP-activated protein kinase (AMPK) activator GSK621. We showed that GSK621 was cytotoxic to human glioma cells (U87MG and U251MG lines), possibly via provoking caspase-dependent apoptotic cell death. Its cytotoxicity was alleviated by caspase inhibitors. GSK621 activated AMPK to inhibit mammalian target of rapamycin (mTOR) and downregulate Tetraspanin 8 (Tspan8) in glioma cells. AMPK inhibition, through shRNA knockdown of AMPKα or introduction of a dominant negative (T172A) AMPKα, almost reversed GSK621-induced AMPK activation, mTOR inhibition and Tspan8 degradation. Consequently, GSK621’s cytotoxicity in glioma cells was also significantly attenuated by AMPKα knockdown or mutation. Further studies showed that GSK621, at a relatively low concentration, significantly potentiated temozolomide (TMZ)’s sensitivity and lethality against glioma cells. We summarized that GSK621 inhibits human glioma cells possibly via activating AMPK signaling. This novel AMPK activator could be a novel and promising anti-glioma cell agent. PMID:27532105

  1. Health insurance expansions for working families: a comparison of targeting strategies.

    PubMed

    Ferry, Danielle H; Garrett, Bowen; Glled, Sherry; Greenman, Emily K; Nichols, Len M

    2002-01-01

    We compare three eligibility criteria for targeting health insurance expansions in working families: poverty, hourly wages, and employment in a small firm. Making pairwise comparisons among these, we find that targeting by poverty is the most effective and efficient. A poverty-based method is also the most effective way to target those lacking access to employer-sponsored insurance and those with low take-up of such coverage. When we examine the effectiveness of targeting by family type, we find that marital status and number of workers in the family make little difference once we control for the presence of children and for poverty level.

  2. A Group Contingency Plus Self-Management Intervention Targeting At-Risk Secondary Students' Class-Work and Active Engagement.

    PubMed

    Trevino-Maack, Sylvia I; Kamps, Debra; Wills, Howard

    2015-01-01

    The purpose of the present study is to show that an independent group contingency (GC) combined with self-management strategies and randomized-reinforcer components can increase the amount of written work and active classroom responding in high school students. Three remedial reading classes and a total of 15 students participated in this study. Students used self-management strategies during independent reading time to increase the amount of writing in their reading logs. They used self-monitoring strategies to record whether or not they performed expected behaviors in class. A token economy using points and tickets was included in the GC to provide positive reinforcement for target responses. The results were analyzed through visual inspection of graphs and effect size computations and showed that the intervention increased the total amount of written words in the students' reading logs and overall classroom and individual student academic engagement.

  3. Screening strategies for active tuberculosis: focus on cost-effectiveness

    PubMed Central

    Dobler, Claudia Caroline

    2016-01-01

    In recent years, there has been renewed interest in screening for active tuberculosis (TB), also called active case-finding (ACF), as a possible means to achieve control of the global TB epidemic. ACF aims to increase the detection of TB, in order to diagnose and treat patients with TB earlier than if they had been diagnosed and treated only at the time when they sought health care because of symptoms. This will reduce or avoid secondary transmission of TB to other people, with the long-term goal of reducing the incidence of TB. Here, the history of screening for active TB, current screening practices, and the role of TB-diagnostic tools are summarized and the literature on cost-effectiveness of screening for active TB reviewed. Cost-effectiveness analyses indicate that community-wide ACF can be cost-effective in settings with a high incidence of TB. ACF among close TB contacts is cost-effective in settings with a low as well as a high incidence of TB. The evidence for cost-effectiveness of screening among HIV-infected persons is not as strong as for TB contacts, but the reviewed studies suggest that the intervention can be cost-effective depending on the background prevalence of TB and test volume. None of the cost-effectiveness analyses were informed by data from randomized controlled trials. As the results of randomized controlled trials evaluating different ACF strategies will become available in future, we will hopefully gain a better understanding of the role that ACF can play in achieving global TB control. PMID:27418848

  4. Small-Nucleic-Acid-Based Therapeutic Strategy Targeting the Transcription Factors Regulating the Vascular Inflammation, Remodeling and Fibrosis in Atherosclerosis

    PubMed Central

    Youn, Sung Won; Park, Kwan-Kyu

    2015-01-01

    Atherosclerosis arises when injury to the arterial wall induces an inflammatory cascade that is sustained by a complex network of cytokines, together with accumulation of lipids and fibrous material. Inflammatory cascades involve leukocyte adherence and chemotaxis, which are coordinated by the local secretion of adhesion molecules, chemotactic factors, and cytokines. Transcription factors are critical to the integration of the various steps of the cascade response to mediators of vascular injury, and are induced in a stimulus-dependent and cell-type-specific manner. Several small-nucleic-acid-based therapeutic strategies have recently been developed to target transcription factors: antisense oligodeoxynucleotides, RNA interference, microRNA, and decoy oligodeoxynucleotides. The aim of this review was to provide an overview of these particular targeted therapeutic strategies, toward regulation of the vascular inflammation, remodeling and fibrosis associated with atherosclerosis. PMID:26006249

  5. Mutation testing for directing upfront targeted therapy and post-progression combination therapy strategies in lung adenocarcinoma

    PubMed Central

    Salgia, Ravi

    2016-01-01

    ABSTRACT Introduction: Advances in the biology of non-small-cell lung cancer, especially adenocarcinoma, reveal multiple molecular subtypes driving oncogenesis. Accordingly, individualized targeted therapeutics are based on mutational diagnostics. Areas covered: Advances in strategies and techniques for individualized treatment, particularly of adenocarcinoma, are described through literature review. Approved therapies are established for some molecular subsets, with new driver mutations emerging that represent increasing proportions of patients. Actionable mutations are de novo oncogenic drivers or acquired resistance mediators, and mutational profiling is important for directing therapy. Patients should be monitored for emerging actionable resistance mutations. Liquid biopsy and associated multiplex diagnostics will be important means to monitor patients during treatment. Expert commentary: Outcomes with targeted agents may be improved by integrating mutation screens during treatment to optimize subsequent therapy. In order for this to be translated into impactful patient benefit, appropriate platforms and strategies need to be optimized and then implemented universally. PMID:27139190

  6. Immunization of stromal cell targeting fibroblast activation protein providing immunotherapy to breast cancer mouse model.

    PubMed

    Meng, Mingyao; Wang, Wenju; Yan, Jun; Tan, Jing; Liao, Liwei; Shi, Jianlin; Wei, Chuanyu; Xie, Yanhua; Jin, Xingfang; Yang, Li; Jin, Qing; Zhu, Huirong; Tan, Weiwei; Yang, Fang; Hou, Zongliu

    2016-08-01

    Unlike heterogeneous tumor cells, cancer-associated fibroblasts (CAF) are genetically more stable which serve as a reliable target for tumor immunotherapy. Fibroblast activation protein (FAP) which is restrictively expressed in tumor cells and CAF in vivo and plays a prominent role in tumor initiation, progression, and metastasis can function as a tumor rejection antigen. In the current study, we have constructed artificial FAP(+) stromal cells which mimicked the FAP(+) CAF in vivo. We immunized a breast cancer mouse model with FAP(+) stromal cells to perform immunotherapy against FAP(+) cells in the tumor microenvironment. By forced expression of FAP, we have obtained FAP(+) stromal cells whose phenotype was CD11b(+)/CD34(+)/Sca-1(+)/FSP-1(+)/MHC class I(+). Interestingly, proliferation capacity of the fibroblasts was significantly enhanced by FAP. In the breast cancer-bearing mouse model, vaccination with FAP(+) stromal cells has significantly inhibited the growth of allograft tumor and reduced lung metastasis indeed. Depletion of T cell assays has suggested that both CD4(+) and CD8(+) T cells were involved in the tumor cytotoxic immune response. Furthermore, tumor tissue from FAP-immunized mice revealed that targeting FAP(+) CAF has induced apoptosis and decreased collagen type I and CD31 expression in the tumor microenvironment. These results implicated that immunization with FAP(+) stromal cells led to the disruption of the tumor microenvironment. Our study may provide a novel strategy for immunotherapy of a broad range of cancer.

  7. Soay rams target reproductive activity towards promiscuous females' optimal insemination period.

    PubMed

    Preston, B T; Stevenson, I R; Wilson, K

    2003-10-07

    Female promiscuity is thought to have resulted in the evolution of male behaviours that confer advantages in the sperm competition that ensues. In mammalian species, males can gain a post-copulatory advantage in this sperm 'raffle' by inseminating females at the optimal time relative to ovulation, leading to the prediction that males should preferentially associate and copulate with females at these times. To the best of our knowledge, we provide the first high-resolution test of this prediction using feral Soay sheep, which have a mating system characterized by male competition for access to highly promiscuous females. We find that competitive males time their mate guarding (and hence copulations) to occur close to the optimal insemination period (OIP), when females are also increasingly likely to 'cooperate' with copulation attempts. Subordinate males practice an alternative mating tactic, where they break the integrity of the consort pair and force copulations on females. The timing of these forced copulations is also targeted towards the OIP. We thus provide quantitative evidence that female promiscuity has resulted in the evolution of reproductive strategies in which males 'load' the sperm raffle by targeting their mating activity towards female OIPs, when the probability of sperm-competition success is at its greatest.

  8. Targeting the INCENP IN-box-Aurora B interaction to inhibit CPC activity in vivo.

    PubMed

    Gohard, Florence H; St-Cyr, Daniel J; Tyers, Mike; Earnshaw, William C

    2014-11-01

    The chromosome passenger complex (CPC) is an essential regulator of mitosis and cytokinesis. The CPC consists of Aurora B kinase, inner centromere protein (INCENP), and the targeting subunits survivin and borealin/Dasra B. INCENP is a scaffolding subunit for the CPC and activates Aurora B via its conserved IN-box domain. We show that overexpression of soluble IN-box in HeLa cells affects endogenous CPC localization and produces a significant increase in multinucleated and micronucleated cells consistent with CPC loss of function. The dominant-negative effect of soluble IN-box expression depends on residues corresponding to hINCENP W845 and/or F881, suggesting that these are essential for Aurora B binding in vivo. We then screened a targeted library of small (five to nine residues long) circular peptide (CP) IN-box fragments generated using split intein circular ligation of proteins and peptides (SICLOPPS) methodology. We identified a number of CPs that caused modest but reproducible increases in rates of multinucleated and micronucleated cells. Our results provide proof of concept that inhibition of the Aurora B-IN-box interaction is a viable strategy for interfering with CPC function in vivo.

  9. Photochemical internalisation, a minimally invasive strategy for light-controlled endosomal escape of cancer stem cell-targeting therapeutics.

    PubMed

    Selbo, Pål Kristian; Bostad, Monica; Olsen, Cathrine Elisabeth; Edwards, Victoria Tudor; Høgset, Anders; Weyergang, Anette; Berg, Kristian

    2015-08-01

    Despite progress in radio-, chemo- and photodynamic-therapy (PDT) of cancer, treatment resistance still remains a major problem for patients with aggressive tumours. Cancer stem cells (CSCs) or tumour-initiating cells are intrinsically and notoriously resistant to conventional cancer therapies and are proposed to be responsible for the recurrence of tumours after therapy. According to the CSC hypothesis, it is imperative to develop novel anticancer agents or therapeutic strategies that take into account the biology and role of CSCs. The present review outlines our recent study on photochemical internalisation (PCI) using the clinically relevant photosensitiser TPCS2a/Amphinex® as a rational, non-invasive strategy for the light-controlled endosomal escape of CSC-targeting drugs. PCI is an intracellular drug delivery method based on light-induced ROS-generation and a subsequent membrane-disruption of endocytic vesicles, leading to cytosolic release of the entrapped drugs of interest. In different proof-of-concept studies we have demonstrated that PCI of CSC-directed immunotoxins targeting CD133, CD44, CSPG4 and EpCAM is a highly specific and effective strategy for killing cancer cells and CSCs. CSCs overexpressing CD133 are PDT-resistant; however, this is circumvented by PCI of CD133-targeting immunotoxins. In view of the fact that TPCS2a is not a substrate of the efflux pumps ABCG2 and P-glycoprotein (ABCB1), the PCI-method is a promising anti-CSC therapeutic strategy. Due to a laser-controlled exposure, PCI of CSC-targeting drugs will be confined exclusively to the tumour tissue, suggesting that this drug delivery method has the potential to spare distant normal stem cells.

  10. Design Strategies for Redox Active Metalloenzymes: Applications in Hydrogen Production.

    PubMed

    Alcala-Torano, R; Sommer, D J; Bahrami Dizicheh, Z; Ghirlanda, G

    2016-01-01

    The last decades have seen an increased interest in finding alternative means to produce renewable fuels in order to satisfy the growing energy demands and to minimize environmental impact. Nature can serve as an inspiration for development of these methodologies, as enzymes are able to carry out a wide variety of redox processes at high efficiency, employing a wide array of earth-abundant transition metals to do so. While it is well recognized that the protein environment plays an important role in tuning the properties of the different metal centers, the structure/function relationships between amino acids and catalytic centers are not well resolved. One specific approach to study the role of proteins in both electron and proton transfer is the biomimetic design of redox active peptides, binding organometallic clusters in well-understood protein environments. Here we discuss different strategies for the design of peptides incorporating redox active FeS clusters, [FeFe]-hydrogenase organometallic mimics, and porphyrin centers into different peptide and protein environments in order to understand natural redox enzymes.

  11. [Flipped classroom as a strategy to enhance active learning].

    PubMed

    Wakabayashi, Noriyuki

    2015-03-01

    This paper reviews the introduction of a flipped class for fourth grade dentistry students, and analyzes the characteristics of the learning method. In fiscal 2013 and 2014, a series of ten three-hour units for removable partial prosthodontics were completed with the flipped class method; a lecture video of approximately 60 minutes was made by the teacher (author) and uploaded to the university's e-learning website one week before each class. Students were instructed to prepare for the class by watching the streaming video on their PC, tablet, or smartphone. In the flipped class, students were not given a lecture, but were asked to solve short questions displayed on screen, to make a short presentation about a part of the video lecture, and to discuss a critical question related to the main subject of the day. An additional team-based learning (TBL) session with individual and group answers was implemented. The average individual scores were considerably higher in the last two years, when the flipped method was implemented, than in the three previous years when conventional lectures were used. The following learning concepts were discussed: the role of the flipped method as an active learning strategy, the efficacy of lecture videos and short questions, students' participation in the class discussion, present-day value of the method, cooperation with TBL, the significance of active learning in relation with the students' learning ability, and the potential increase in the preparation time and workload for students.

  12. Effective, Active Learning Strategies for the Oceanography Classroom

    NASA Astrophysics Data System (ADS)

    Dmochowski, J. E.; Marinov, I.

    2014-12-01

    A decline in enrollment in STEM fields at the university level has prompted extensive research on alternative ways of teaching and learning science. Inquiry-based learning as well as the related "flipped" or "active" lectures, and similar teaching methods and philosophies have been proposed as more effective ways to disseminate knowledge in science classes than the traditional lecture. We will provide a synopsis of our experiences in implementing some of these practices into our Introductory Oceanography, Global Climate Change, and Ocean Atmosphere Dynamics undergraduate courses at the University of Pennsylvania, with both smaller and larger enrollments. By implementing tools such as at-home modules; computer labs; incorporation of current research; pre- and post-lecture quizzes; reflective, qualitative writing assignments; peer review; and a variety of in-class learning strategies, we aim to increase the science literacy of the student population and help students gain a more comprehensive knowledge of the topic, enhance their critical thinking skills, and correct misconceptions. While implementing these teaching techniques with college students is not without complications, we argue that a blended class that flexibly and creatively accounts for class size and science level improves the learning experience and the acquired knowledge. We will present examples of student assignments and activities as well as describe the lessons we have learned, and propose ideas for moving forward to best utilize innovative teaching tools in order to increase science literacy in oceanography and other climate-related courses.

  13. Targeting the hypoxic fraction of tumours using hypoxia-activated prodrugs.

    PubMed

    Phillips, Roger M

    2016-03-01

    The presence of a microenvironment within most tumours containing regions of low oxygen tension or hypoxia has profound biological and therapeutic implications. Tumour hypoxia is known to promote the development of an aggressive phenotype, resistance to both chemotherapy and radiotherapy and is strongly associated with poor clinical outcome. Paradoxically, it is recognised as a high-priority target and one of the therapeutic strategies designed to eradicate hypoxic cells in tumours is a group of compounds known collectively as hypoxia-activated prodrugs (HAPs) or bioreductive drugs. These drugs are inactive prodrugs that require enzymatic activation (typically by 1 or 2 electron oxidoreductases) to generate cytotoxic species with selectivity for hypoxic cells being determined by (1) the ability of oxygen to either reverse or inhibit the activation process and (2) the presence of elevated expression of oxidoreductases in tumours. The concepts underpinning HAP development were established over 40 years ago and have been refined over the years to produce a new generation of HAPs that are under preclinical and clinical development. The purpose of this article is to describe current progress in the development of HAPs focusing on the mechanisms of action, preclinical properties and clinical progress of leading examples.

  14. From Drug Screening to Target Deconvolution: a Target-Based Drug Discovery Pipeline Using Leishmania Casein Kinase 1 Isoform 2 To Identify Compounds with Antileishmanial Activity

    PubMed Central

    Durieu, Emilie; Prina, Eric; Leclercq, Olivier; Oumata, Nassima; Gaboriaud-Kolar, Nicolas; Vougogiannopoulou, Konstantina; Aulner, Nathalie; Defontaine, Audrey; No, Joo Hwan; Ruchaud, Sandrine; Skaltsounis, Alexios-Leandros; Galons, Hervé; Späth, Gerald F.; Meijer, Laurent

    2016-01-01

    Existing therapies for leishmaniases present significant limitations, such as toxic side effects, and are rendered inefficient by parasite resistance. It is of utmost importance to develop novel drugs targeting Leishmania that take these two limitations into consideration. We thus chose a target-based approach using an exoprotein kinase, Leishmania casein kinase 1.2 (LmCK1.2) that was recently shown to be essential for intracellular parasite survival and infectivity. We developed a four-step pipeline to identify novel selective antileishmanial compounds. In step 1, we screened 5,018 compounds from kinase-biased libraries with Leishmania and mammalian CK1 in order to identify hit compounds and assess their specificity. For step 2, we selected 88 compounds among those with the lowest 50% inhibitory concentration to test their biological activity on host-free parasites using a resazurin reduction assay and on intramacrophagic amastigotes using a high content phenotypic assay. Only 75 compounds showed antileishmanial activity and were retained for step 3 to evaluate their toxicity against mouse macrophages and human cell lines. The four compounds that displayed a selectivity index above 10 were then assessed for their affinity to LmCK1.2 using a target deconvolution strategy in step 4. Finally, we retained two compounds, PP2 and compound 42, for which LmCK1.2 seems to be the primary target. Using this four-step pipeline, we identify from several thousand molecules, two lead compounds with a selective antileishmanial activity. PMID:26902771

  15. More than Just Finding Color: Strategy in Global Visual Search Is Shaped by Learned Target Probabilities

    ERIC Educational Resources Information Center

    Williams, Carrick C.; Pollatsek, Alexander; Cave, Kyle R.; Stroud, Michael J.

    2009-01-01

    In 2 experiments, eye movements were examined during searches in which elements were grouped into four 9-item clusters. The target (a red or blue "T") was known in advance, and each cluster contained different numbers of target-color elements. Rather than color composition of a cluster invariantly guiding the order of search though…

  16. Sphaeropsidin A shows promising activity against drug-resistant cancer cells by targeting regulatory volume increase

    PubMed Central

    Mathieu, Véronique; Chantôme, Aurélie; Lefranc, Florence; Cimmino, Alessio; Miklos, Walter; Paulitschke, Verena; Mohr, Thomas; Maddau, Lucia; Kornienko, Alexander; Berger, Walter; Vandier, Christophe; Evidente, Antonio; Delpire, Eric; Kiss, Robert

    2016-01-01

    Despite the recent advances in the treatment of tumors with intrinsic chemotherapy resistance, such as melanoma and renal cancers, their prognosis remains poor and new chemical agents with promising activity against these cancers are urgently needed. Sphaeropsidin A, a fungal metabolite whose anticancer potential had previously received little attention, was isolated from Diplodia cupressi and found to display specific anticancer activity in vitro against melanoma and kidney cancer subpanels in the National Cancer Institute (NCI) 60-cell line screen. The NCI data revealed a mean LC50 of ca. 10 μM and a cellular sensitivity profile that did not match that of any other agent in the 765,000 compound database. Subsequent mechanistic studies in melanoma and other multidrug-resistant in vitro cancer models showed that sphaeropsidin A can overcome apoptosis as well as multidrug resistance by inducing a marked and rapid cellular shrinkage related to the loss of intracellular Cl− and the decreased HCO3− concentration in the culture supernatant. These changes in ion homeostasis and the absence of effects on the plasma membrane potential were attributed to the sphaeropsidin A-induced impairment of regulatory volume increase (RVI). Preliminary results also indicate that depending on the type of cancer, the sphaeropsidin A effects on RVI could be related to Na–K–2Cl electroneutral cotransporter or Cl−/HCO3− anion exchanger(s) targeting. This study underscores the modulation of ion-transporter activity as a promising therapeutic strategy to combat drug-resistant cancers and identifies the fungal metabolite, sphaeropsidin A, as a lead to develop anticancer agents targeting RVI in cancer cells. PMID:25868554

  17. Household-based cash transfer targeting strategies in Zimbabwe: are we reaching the most vulnerable children?

    PubMed

    Robertson, Laura; Mushati, Phyllis; Eaton, Jeffrey W; Sherr, Lorraine; Makoni, Jeremiah C; Skovdal, Morten; Crea, Tom; Mavise, Gideon; Dumba, Lovemore; Schumacher, Christina; Munyati, Shungu; Nyamukapa, Constance; Gregson, Simon

    2012-12-01

    Census data, collected in July 2009, from 27,672 children were used to compare the effectiveness, coverage and efficacy of three household-based methods for targeting cash transfers to vulnerable children in eastern Zimbabwe: targeting the poorest households using a wealth index; targeting HIV-affected households using socio-demographic information (households caring for orphans, chronically-ill or disabled members; child-headed households); and targeting labour-constrained households using dependency ratios. All three methods failed to identify large numbers of children with poor social and educational outcomes. The wealth index approach was the most efficient at reaching children with poor outcomes whilst socio-demographic targeting reached more vulnerable children but was less efficient.

  18. Targeting of the activation-induced cytosine deaminase is strongly influenced by the sequence and structure of the targeted DNA.

    PubMed

    Shen, Hong Ming; Ratnam, Sarayu; Storb, Ursula

    2005-12-01

    Activation-induced deaminase (AID) initiates immunoglobulin somatic hypermutation (SHM). Since in vitro AID was shown to deaminate cytosines on single-stranded DNA or the nontranscribed strand, it remained a puzzle how in vivo AID targets both DNA strands equally. Here we investigate the roles of transcription and DNA sequence in cytosine deamination. Strikingly different results are found with different substrates. Depending on the target sequence, the transcribed DNA strand is targeted as well as or better than the nontranscribed strand. The preferential targeting is not related to the frequency of AID hot spots. Comparison of cytosine deamination by AID and bisulfite shows different targeting patterns suggesting that AID may locally unwind the DNA. We conclude that somatic hypermutation on both DNA strands is the natural outcome of AID action on a transcribed gene; furthermore, the DNA sequence or structure and topology play major roles in targeting AID in vitro and in vivo. On the other hand, the lack of mutations in the first approximately 100 nucleotides and beyond about 1 to 2 kb from the promoter of immunoglobulin genes during SHM must be due to special conditions of transcription and chromatin in vivo.

  19. Folate-targeted docetaxel-lipid-based-nanosuspensions for active-targeted cancer therapy

    PubMed Central

    Wang, Lili; Li, Min; Zhang, Na

    2012-01-01

    The purpose of this study was to develop two novel drug delivery systems based on biodegradable docetaxel-lipid-based-nanosuspensions. The first one was poly(ethylene glycol)- modified docetaxel-lipid-based-nanosuspensions (pLNS). It was developed to increase the cycle time of the drug within the body and enhance the accumulation of the drug at the tumor site. The second one was targeted docetaxel-lipid-based-nanosuspensions (tLNS) using folate as the target ligand. The tLNS could target the tumor cells that overexpressed folate receptor (FR). The morphology, particle size, and zeta potential of pLNS and tLNS were characterized, respectively. The in vitro cytotoxicity evaluation of Duopafei®, pLNS, and tLNS were performed in human hepatocellular liver carcinoma HepG2 (FR−) and B16 (FR+) cells, respectively. The in vivo antitumor efficacy and pharmacokinetics, as well as the drug tissue distribution, were evaluated in Kunming mice bearing B16 cells. The particle size of pLNS was 204.2 ± 6.18 nm and tLNS had a mean particle size of 220.6 ± 9.54 nm. Cytotoxicity of tLNS against B16 (FR+) cell lines was superior to pLNS (P < 0.05), while there was no significant difference in the half maximum inhibitory concentration values for HepG2 (FR−) cells between pLNS and tLNS. The results of the in vivo antitumor efficacy evaluation showed that tLNS exhibited higher antitumor efficacy by reducing tumor volume (P < 0.01) compared with Duopafei and pLNS, respectively. The results of the in vivo biodistribution study indicate that the better antitumor efficacy of tLNS was attributed to the increased accumulation of the drug in the tumor. PMID:22802688

  20. Targeting of a common receptor shared by CXCL8 and N-Ac-PGP as a therapeutic strategy to alleviate chronic neutrophilic lung diseases.

    PubMed

    Snelgrove, Robert J

    2011-09-30

    Persistent neutrophilia is implicated in the pathology of several chronic lung diseases and consequently targeting the signals that drive the recruitment of these cells offers a plausible therapeutic strategy. The tripeptide Pro-Gly-Pro (PGP) is a neutrophil chemoattractant derived from extracellular matrix collagen and implicated in diseases such as COPD and cystic fibrosis. It was anticipated that PGP exerts its chemoatactic activity by mimicking key sequences found within classical neutrophil chemokines, such as CXCL8, and binding their receptors, CXCR1/2. Recently, however, the role of CXCR1/2 as the receptors for PGP has been questioned. In this issue of European Journal of Pharmacology, three studies address this controversy and demonstrate CXCR1/2 to be a common receptor for CXCL8 and PGP. Accordingly, these studies demonstrate the therapeutic potential of targeting this shared receptor to simultaneously alleviate neutrophilic inflammation driven by multiple neutrophil chemoattractants.

  1. Selective Activation of Neuronal Targets With Sinusoidal Electric Stimulation

    PubMed Central

    Freeman, Daniel K.; Eddington, Donald K.; Rizzo, Joseph F.

    2010-01-01

    Electric stimulation of the CNS is being evaluated as a treatment modality for a variety of neurological, psychiatric, and sensory disorders. Despite considerable success in some applications, existing stimulation techniques offer little control over which cell types or neuronal substructures are activated by stimulation. The ability to more precisely control neuronal activation would likely improve the clinical outcomes associated with these applications. Here, we show that specific frequencies of sinusoidal stimulation can be used to preferentially activate certain retinal cell types: photoreceptors are activated at 5 Hz, bipolar cells at 25 Hz, and ganglion cells at 100 Hz. In addition, low-frequency stimulation (≤25 Hz) did not activate passing axons but still elicited robust synaptically mediated responses in ganglion cells; therefore, elicited neural activity is confined to within a focal region around the stimulating electrode. Our results suggest that sinusoidal stimulation provides significantly improved control over elicited neural activity relative to conventional pulsatile stimulation. PMID:20810683

  2. Targeting the schizophrenia genome: a fast track strategy from GWAS to clinic

    PubMed Central

    Lencz, T; Malhotra, A K

    2015-01-01

    The Psychiatric Genomics Consortium–Schizophrenia Workgroup (PGC–SCZ) has recently published a genomewide association study (GWAS) identifying >100 genetic loci, encompassing a total of 341 protein-coding genes, attaining genomewide significance for susceptibility to schizophrenia. Given the extremely long time (12–15 years) and expense (>$1 billion) associated with the development of novel drug targets, repurposing of drugs with known and validated targets may be the most expeditious path toward deriving clinical utility from these GWAS findings. In the present study, we examined all genes within loci implicated by the PGC–SCZ GWAS against databases of targets of both approved and registered pharmaceutical compounds. We identified 20 potential schizophrenia susceptibility genes that encode proteins that are the targets of approved drugs. Of these, we prioritized genes/targets that are of clear neuropsychiatric interest and that are also sole members of the linkage disequilibrium block surrounding a PGC–SCZ GWAS hit. In addition to DRD2, 5 genes meet these criteria: CACNA1C, CACNB2, CACNA1I, GRIN2A and HCN1. An additional 20 genes coding for proteins that are the targets of drugs in registered clinical trials, but without approved indications, were also identified. Although considerable work is still required to fully explicate the biological implications of the PGC–SCZ GWAS results, pathways related to these known, druggable targets may represent a promising starting point. PMID:25869805

  3. Activation of AMP-activated kinase as a strategy for managing autosomal dominant polycystic kidney disease.

    PubMed

    McCarty, Mark F; Barroso-Aranda, Jorge; Contreras, Francisco

    2009-12-01

    There is evidence that overactivity of both mammalian target of rapamycin (mTOR) and cystic fibrosis transmembrane conductance regulator (CFTR) contributes importantly to the progressive expansion of renal cysts in autosomal dominant polycystic kidney disease (ADPKD). Recent research has established that AMP-activated kinase (AMPK) can suppress the activity of each of these proteins. Clinical AMPK activators such as metformin and berberine may thus have potential in the clinical management of ADPKD. The traditional use of berberine in diarrhea associated with bacterial infections may reflect, in part, the inhibitory impact of AMPK on chloride extrusion by small intestinal enterocytes.

  4. Aptamers: Active Targeting Ligands for Cancer Diagnosis and Therapy

    PubMed Central

    Wu, Xu; Chen, Jiao; Wu, Min; Zhao, Julia Xiaojun

    2015-01-01

    Aptamers, including DNA, RNA and peptide aptamers, are a group of promising recognition units that can specifically bind to target molecules and cells. Due to their excellent specificity and high affinity to targets, aptamers have attracted great attention in various fields in which selective recognition units are required. They have been used in biosensing, drug delivery, disease diagnosis and therapy (especially for cancer treatment). In this review, we summarized recent applications of DNA and RNA aptamers in cancer theranostics. The specific binding ability of aptamers to cancer-related markers and cancer cells ensured their high performance for early diagnosis of cancer. Meanwhile, the efficient targeting ability of aptamers to cancer cells and tissues provided a promising way to deliver imaging agents and drugs for cancer imaging and therapy. Furthermore, with the development of nanoscience and nanotechnology, the conjugation of aptamers with functional nanomaterials paved an exciting way for the fabrication of theranostic agents for different types of cancers, which might be a powerful tool for cancer treatment. PMID:25699094

  5. Aptamers: active targeting ligands for cancer diagnosis and therapy.

    PubMed

    Wu, Xu; Chen, Jiao; Wu, Min; Zhao, Julia Xiaojun

    2015-01-01

    Aptamers, including DNA, RNA and peptide aptamers, are a group of promising recognition units that can specifically bind to target molecules and cells. Due to their excellent specificity and high affinity to targets, aptamers have attracted great attention in various fields in which selective recognition units are required. They have been used in biosensing, drug delivery, disease diagnosis and therapy (especially for cancer treatment). In this review, we summarized recent applications of DNA and RNA aptamers in cancer theranostics. The specific binding ability of aptamers to cancer-related markers and cancer cells ensured their high performance for early diagnosis of cancer. Meanwhile, the efficient targeting ability of aptamers to cancer cells and tissues provided a promising way to deliver imaging agents and drugs for cancer imaging and therapy. Furthermore, with the development of nanoscience and nanotechnology, the conjugation of aptamers with functional nanomaterials paved an exciting way for the fabrication of theranostic agents for different types of cancers, which might be a powerful tool for cancer treatment.

  6. The insect excretory system as a target for novel pest control strategies.

    PubMed

    Ruiz-Sanchez, Esau; O'Donnell, Michael J

    2015-10-01

    The insect excretory system plays essential roles in osmoregulation, ionoregulation and toxin elimination. Understanding the mechanisms of fluid and ion transport by the epithelial cells of the excretory system provides a foundation for development of novel pest management strategies. In the present review, we focus on two such strategies: first, impairment of osmoregulation by manipulation of diuretic or antidiuretic signaling pathways and second, interference with toxin elimination by inhibition of toxin transport systems.

  7. Targeting drug sensitivity predictors: New potential strategies to improve pharmacotherapy of human brain disorders.

    PubMed

    Kalueff, Allan V; Stewart, Adam Michael; Nguyen, Michael; Song, Cai; Gottesman, Irving I

    2015-12-03

    One of the main challenges in medicine is the lack of efficient drug therapies for common human disorders. For example, although depressed patients receive powerful antidepressants, many often remain resistant to psychopharmacotherapy. The growing recognition of complex interplay between the drug targets and the predictors of drug sensitivity requires an improved understanding of these two key aspects of drug action and their potentially shared molecular networks. Here, we apply the concept of endophenotypes and their interplay to drug action and sensitivity. Based on these analyses, we postulate that novel drugs may be developed by targeting specific molecular pathways that integrate drug targets with drug sensitivity predictors.

  8. Proteolysis-Targeting Chimeras: Induced Protein Degradation as a Therapeutic Strategy.

    PubMed

    Ottis, Philipp; Crews, Craig M

    2017-03-20

    Until recently, the only ways to reduce specific protein signaling were to either knock down the target by RNAi or to interfere with the signaling by inhibiting an enzyme or receptor within the signal transduction cascade. Herein, we review an emerging class of small molecule pharmacological agents, called PROTACs, that present a novel approach to specifically target proteins and their respective signaling pathways. These heterobifunctional molecules utilize endogenous cellular quality control machinery by recruiting it to target proteins in order to induce their degradation.

  9. Targeting the kinase activities of ATR and ATM exhibits antitumoral activity in mouse models of MLL-rearranged AML.

    PubMed

    Morgado-Palacin, Isabel; Day, Amanda; Murga, Matilde; Lafarga, Vanesa; Anton, Marta Elena; Tubbs, Anthony; Chen, Hua-Tang; Ergan, Aysegul; Anderson, Rhonda; Bhandoola, Avinash; Pike, Kurt G; Barlaam, Bernard; Cadogan, Elaine; Wang, Xi; Pierce, Andrew J; Hubbard, Chad; Armstrong, Scott A; Nussenzweig, André; Fernandez-Capetillo, Oscar

    2016-09-13

    Among the various subtypes of acute myeloid leukemia (AML), those with chromosomal rearrangements of the MLL oncogene (AML-MLL) have a poor prognosis. AML-MLL tumor cells are resistant to current genotoxic therapies because of an attenuated response by p53, a protein that induces cell cycle arrest and apoptosis in response to DNA damage. In addition to chemicals that damage DNA, efforts have focused on targeting DNA repair enzymes as a general chemotherapeutic approach to cancer treatment. Here, we found that inhibition of the kinase ATR, which is the primary sensor of DNA replication stress, induced chromosomal breakage and death of mouse AML(MLL) cells (with an MLL-ENL fusion and a constitutively active N-RAS independently of p53. Moreover, ATR inhibition as a single agent exhibited antitumoral activity, both reducing tumor burden after establishment and preventing tumors from growing, in an immunocompetent allograft mouse model of AML(MLL) and in xenografts of a human AML-MLL cell line. We also found that inhibition of ATM, a kinase that senses DNA double-strand breaks, also promoted the survival of the AML(MLL) mice. Collectively, these data indicated that ATR or ATM inhibition represent potential therapeutic strategies for the treatment of AML, especially MLL-driven leukemias.

  10. Recently diagnosed rheumatoid arthritis patients benefit from a treat-to-target strategy: results from the DREAM registry.

    PubMed

    Steunebrink, Laura M M; Vonkeman, Harald E; ten Klooster, Peter M; Hoekstra, Monique; van Riel, Piet L C M; van de Laar, Mart A F J

    2016-03-01

    Despite considerable evidence on the efficacy and safety of early aggressive treat-to-target (T2T) strategies in early rheumatoid arthritis (RA), a proportion of patients still fail to reach remission. The goal of this study is to examine remission rates and predictors of remission in a real life T2T cohort of consecutive patients with a recent diagnosis of RA. Baseline demographics, clinical, laboratory and patient-reported variables and 1-year follow-up disease activity data were used from patients with early RA included in the DREAM remission induction cohort II study. Survival analyses and simple and multivariable logistic regression analyses were used to examine remission rates and significant predictors of achieving remission. A total of 137 recently diagnosed consecutive RA patients were available for this study. During the first year after inclusion, DAS28 remission was achieved at least once in 77.2 % of the patients and the median time to first remission was 17 weeks. None of the examined baseline variables were robustly associated with achieving remission within 1 year and in the multivariable analysis only lower ESR (p = 0.005) remained significantly associated with achieving fast remission within 17 weeks. During the first year of their disease a high proportion of recently diagnosed RA patient achieved remission, with only a small percentage of patients needing bDMARD therapy. Combined with the absence of baseline predictors of remission, this suggests that clinicians in daily clinical practice may focus on DAS28 scores only, without needing to take other patients characteristics into account.

  11. Comparison of active and passive sampling strategies for the monitoring of pesticide contamination in streams

    NASA Astrophysics Data System (ADS)

    Assoumani, Azziz; Margoum, Christelle; Guillemain, Céline; Coquery, Marina

    2014-05-01

    constants (Rs). Each constant links the mass of the a target contaminant accumulated in the sampler to its concentration in water. At the end of the field application, the Rs are used to calculate the TWA concentration of each target contaminant with the final mass of the contaminants accumulated in the sampler. Stir Bar Sorptive Extraction (SBSE) is a solvent free sample preparation technique dedicated to the analysis of moderately hydrophobic to hydrophobic compounds in liquid and gas samples. It is composed of a magnet enclosed in a glass tube coated with a thick film of polydimethysiloxane (PDMS). We recently developed the in situ application of SBSE as a passive sampling technique (herein named "Passive SBSE") for the monitoring of agricultural pesticides. The aim of this study is to perform the calibration of the passive SBSE in the laboratory, and to apply and compare this technique to active sampling strategies for the monitoring of 16 relatively hydrophobic to hydrophobic pesticides in streams, during 2 1-month sampling campaigns. Time-weighted averaged concentrations of the target pesticides obtained from passive SBSE were compared to the target pesticide concentrations of grab samples, and time-related and flow-dependent samples of the streams. Results showed passive SBSE as an efficient alternative to conventional active sampling strategies.

  12. Zinc-finger Nucleases as a Novel Therapeutic Strategy for Targeting Hepatitis B Virus DNAs

    PubMed Central

    Cradick, Thomas J; Keck, Kathy; Bradshaw, Shannon; Jamieson, Andrew C; McCaffrey, Anton P

    2010-01-01

    Hepatitis B virus (HBV) chronically infects 350–400 million people worldwide and causes >1 million deaths yearly. Current therapies prevent new viral genome formation, but do not target pre-existing viral genomic DNA, thus curing only ~1/2 of patients. We targeted HBV DNA for cleavage using zinc-finger nucleases (ZFNs), which cleave as dimers. Co-transfection of our ZFN pair with a target plasmid containing the HBV genome resulted in specific cleavage. After 3 days in culture, 26% of the target remained linear, whereas ~10% was cleaved and misjoined tail-to-tail. Notably, ZFN treatment decreased levels of the hepatitis C virus pregenomic RNA by 29%. A portion of cleaved plasmids are repaired in cells, often with deletions and insertions. To track misrepair, we introduced an XbaI restriction site in the spacer between the ZFN sites. Targeted cleavage and misrepair destroys the XbaI site. After 3 days in culture, ~6% of plasmids were XbaI-resistant. Thirteen of 16 clones sequenced contained frameshift mutations that would lead to truncations of the viral core protein. These results demonstrate, for the first time, the possibility of targeting episomal viral DNA genomes using ZFNs. PMID:20160705

  13. Missing the target: including perspectives of women with overweight and obesity to inform stigma‐reduction strategies

    PubMed Central

    Himmelstein, M. S.; Gorin, A. A.; Suh, Y. J.

    2017-01-01

    Summary Objective Pervasive weight stigma and discrimination have led to ongoing calls for efforts to reduce this bias. Despite increasing research on stigma‐reduction strategies, perspectives of individuals who have experienced weight stigma have rarely been included to inform this research. The present study conducted a systematic examination of women with high body weight to assess their perspectives about a broad range of strategies to reduce weight‐based stigma. Methods Women with overweight or obesity (N = 461) completed an online survey in which they evaluated the importance, feasibility and potential impact of 35 stigma‐reduction strategies in diverse settings. Participants (91.5% who reported experiencing weight stigma) also completed self‐report measures assessing experienced and internalized weight stigma. Results Most participants assigned high importance to all stigma‐reduction strategies, with school‐based and healthcare approaches accruing the highest ratings. Adding weight stigma to existing anti‐harassment workplace training was rated as the most impactful and feasible strategy. The family environment was viewed as an important intervention target, regardless of participants' experienced or internalized stigma. Conclusion These findings underscore the importance of including people with stigmatized identities in stigma‐reduction research; their insights provide a necessary and valuable contribution that can inform ways to reduce weight‐based inequities and prioritize such efforts. PMID:28392929

  14. Integrin Targeting and Toxicological Assessment of Peptide-Conjugated Liposome Delivery Systems to Activated Endothelial Cells.

    PubMed

    Kermanizadeh, Ali; Villadsen, Klaus; Østrem, Ragnhild G; Jensen, Knud J; Møller, Peter; Loft, Steffen

    2017-04-01

    Utilization of functionalized liposomes as the means of targeted delivery of therapeutics may enhance specific transport of biologically active drugs to target tissues, while avoiding or reducing undesired side effects. In the present investigation, peptide-conjugated cationic liposomes were constructed with the aim of targeting integrins (i.e. vitronectin and/or fibronectin receptors) on activated endothelial cells. The peptide-conjugated liposomes induced only cytotoxicity at the highest concentration in non-activated or activated endothelial cells, as well as in co-culture of endothelial cells and macrophages. There was unaltered secretion of cytokines after exposure of peptide-conjugated liposomes to endothelial cells, indicating that the materials were not inflammogenic. Liposomes with a peptide targeting the fibronectin receptor (integrin α5β1) were more effective in targeting of activated endothelial cells, as compared to a liposome with a peptide that targeted both the fibronectin and vitronectin receptors, as well as liposomes with a control peptide. The liposome targeted to the fibronectin receptor also displayed uptake in endothelial cells in co-culture with activated macrophages. Therefore, this study demonstrates the feasibility of constructing a peptide-conjugated cationic liposome, which displays targeting to activated endothelial cells at concentrations that are not cytotoxic or inflammogenic to the cells.

  15. A new disaster victim identification management strategy targeting "near identification-threshold" cases: Experiences from the Boxing Day tsunami.

    PubMed

    Wright, Kirsty; Mundorff, Amy; Chaseling, Janet; Forrest, Alexander; Maguire, Christopher; Crane, Denis I

    2015-05-01

    The international disaster victim identification (DVI) response to the Boxing Day tsunami, led by the Royal Thai Police in Phuket, Thailand, was one of the largest and most complex in DVI history. Referred to as the Thai Tsunami Victim Identification operation, the group comprised a multi-national, multi-agency, and multi-disciplinary team. The traditional DVI approach proved successful in identifying a large number of victims quickly. However, the team struggled to identify certain victims due to incomplete or poor quality ante-mortem and post-mortem data. In response to these challenges, a new 'near-threshold' DVI management strategy was implemented to target presumptive identifications and improve operational efficiency. The strategy was implemented by the DNA Team, therefore DNA kinship matches that just failed to reach the reporting threshold of 99.9% were prioritized, however the same approach could be taken by targeting, for example, cases with partial fingerprint matches. The presumptive DNA identifications were progressively filtered through the Investigation, Dental and Fingerprint Teams to add additional information necessary to either strengthen or conclusively exclude the identification. Over a five-month period 111 victims from ten countries were identified using this targeted approach. The new identifications comprised 87 adults, 24 children and included 97 Thai locals. New data from the Fingerprint Team established nearly 60% of the total near-threshold identifications and the combined DNA/Physical method was responsible for over 30%. Implementing the new strategy, targeting near-threshold cases, had positive management implications. The process initiated additional ante-mortem information collections, and established a much-needed, distinct "end-point" for unresolved cases.

  16. Identifying New Drug Targets for Potent Phospholipase D Inhibitors: Combining Sequence Alignment, Molecular Docking, and Enzyme Activity/Binding Assays.

    PubMed

    Djakpa, Helene; Kulkarni, Aditya; Barrows-Murphy, Scheneque; Miller, Greg; Zhou, Weihong; Cho, Hyejin; Török, Béla; Stieglitz, Kimberly

    2016-05-01

    Phospholipase D enzymes cleave phospholipid substrates generating choline and phosphatidic acid. Phospholipase D from Streptomyces chromofuscus is a non-HKD (histidine, lysine, and aspartic acid) phospholipase D as the enzyme is more similar to members of the diverse family of metallo-phosphodiesterase/phosphatase enzymes than phospholipase D enzymes with active site HKD repeats. A highly efficient library of phospholipase D inhibitors based on 1,3-disubstituted-4-amino-pyrazolopyrimidine core structure was utilized to evaluate the inhibition of purified S. chromofuscus phospholipase D. The molecules exhibited inhibition of phospholipase D activity (IC50 ) in the nanomolar range with monomeric substrate diC4 PC and micromolar range with phospholipid micelles and vesicles. Binding studies with vesicle substrate and phospholipase D strongly indicate that these inhibitors directly block enzyme vesicle binding. Following these compelling results as a starting point, sequence searches and alignments with S. chromofuscus phospholipase D have identified potential new drug targets. Using AutoDock, inhibitors were docked into the enzymes selected from sequence searches and alignments (when 3D co-ordinates were available) and results analyzed to develop next-generation inhibitors for new targets. In vitro enzyme activity assays with several human phosphatases demonstrated that the predictive protocol was accurate. The strategy of combining sequence comparison, docking, and high-throughput screening assays has helped to identify new drug targets and provided some insight into how to make potential inhibitors more specific to desired targets.

  17. Modelling the consequences of targeted selective treatment strategies on performance and emergence of anthelmintic resistance amongst grazing calves.

    PubMed

    Berk, Zoe; Laurenson, Yan C S M; Forbes, Andrew B; Kyriazakis, Ilias

    2016-12-01

    The development of anthelmintic resistance by helminths can be slowed by maintaining refugia on pasture or in untreated hosts. Targeted selective treatments (TST) may achieve this through the treatment only of individuals that would benefit most from anthelmintic, according to certain criteria. However TST consequences on cattle are uncertain, mainly due to difficulties of comparison between alternative strategies. We developed a mathematical model to compare: 1) the most 'beneficial' indicator for treatment selection and 2) the method of selection of calves exposed to Ostertagia ostertagi, i.e. treating a fixed percentage of the population with the lowest (or highest) indicator values versus treating individuals who exceed (or are below) a given indicator threshold. The indicators evaluated were average daily gain (ADG), faecal egg counts (FEC), plasma pepsinogen, combined FEC and plasma pepsinogen, versus random selection of individuals. Treatment success was assessed in terms of benefit per R (BPR), the ratio of average benefit in weight gain to change in frequency of resistance alleles R (relative to an untreated population). The optimal indicator in terms of BPR for fixed percentages of calves treated was plasma pepsinogen and the worst ADG; in the latter case treatment was applied to some individuals who were not in need of treatment. The reverse was found when calves were treated according to threshold criteria, with ADG being the best target indicator for treatment. This was also the most beneficial strategy overall, with a significantly higher BPR value than any other strategy, but its degree of success depended on the chosen threshold of the indicator. The study shows strong support for TST, with all strategies showing improvements on calves treated selectively, compared with whole-herd treatment at 3, 8, 13 weeks post-turnout. The developed model appeared capable of assessing the consequences of other TST strategies on calf populations.

  18. Comparing demographic, health status and psychosocial strategies of audience segmentation to promote physical activity.

    PubMed

    Boslaugh, Sarah E; Kreuter, Matthew W; Nicholson, Robert A; Naleid, Kimberly

    2005-08-01

    The goal of audience segmentation is to identify population subgroups that are homogeneous with respect to certain variables associated with a given outcome or behavior. When such groups are identified and understood, targeted intervention strategies can be developed to address their unique characteristics and needs. This study compares the results of audience segmentation for physical activity that is based on either demographic, health status or psychosocial variables alone, or a combination of all three types of variables. Participants were 1090 African-American and White adults from two public health centers in St Louis, MO. Using a classification-tree algorithm to form homogeneous groups, analyses showed that more segments with greater variability in physical activity were created using psychosocial versus health status or demographic variables and that a combination of the three outperformed any individual set of variables. Simple segmentation strategies such as those relying on demographic variables alone provided little improvement over no segmentation at all. Audience segmentation appears to yield more homogeneous subgroups when psychosocial and health status factors are combined with demographic variables.

  19. An Active-Learning Strategies Primer for Achieving Ability-Based Educational Outcomes

    PubMed Central

    Gleason, Brenda L.; Peeters, Michael J.; Resman-Targoff, Beth H.; Karr, Samantha; McBane, Sarah; Kelley, Kristi; Thomas, Tyan

    2011-01-01

    Active learning is an important component of pharmacy education. By engaging students in the learning process, they are better able to apply the knowledge they gain. This paper describes evidence supporting the use of active-learning strategies in pharmacy education and also offers strategies for implementing active learning in pharmacy curricula in the classroom and during pharmacy practice experiences. PMID:22171114

  20. Structure-based DNA-targeting strategies with small molecule ligands for drug discovery.

    PubMed

    Sheng, Jia; Gan, Jianhua; Huang, Zhen

    2013-09-01

    Nucleic acids are the molecular targets of many clinical anticancer drugs. However, compared with proteins, nucleic acids have traditionally attracted much less attention as drug targets in structure-based drug design, partially because limited structural information of nucleic acids complexed with potential drugs is available. Over the past several years, enormous progresses in nucleic acid crystallization, heavy-atom derivatization, phasing, and structural biology have been made. Many complicated nucleic acid structures have been determined, providing new insights into the molecular functions and interactions of nucleic acids, especially DNAs complexed with small molecule ligands. Thus, opportunities have been created to further discover nucleic acid-targeting drugs for disease treatments. This review focuses on the structure studies of DNAs complexed with small molecule ligands for discovering lead compounds, drug candidates, and/or therapeutics.

  1. Structure-Based DNA-Targeting Strategies with Small Molecule Ligands for Drug Discovery

    PubMed Central

    Sheng, Jia; Gan, Jianhua; Huang, Zhen

    2014-01-01

    Nucleic acids are the molecular targets of many clinical anticancer drugs. However, compared with proteins, nucleic acids have traditionally attracted much less attention as drug targets in structure-based drug design, partially because limited structural information of nucleic acids complexed with potential drugs is available. Over the past several years, enormous progresses in nucleic acid crystallization, heavy-atom derivatization, phasing, and structural biology have been made. Many complicated nucleic acid structures have been determined, providing new insights into the molecular functions and interactions of nucleic acids, especially DNAs complexed with small molecule ligands. Thus, opportunities have been created to further discover nucleic acid-targeting drugs for disease treatments. This review focuses on the structure studies of DNAs complexed with small molecule ligands for discovering lead compounds, drug candidates, and/or therapeutics. PMID:23633219

  2. Pharmacological targeting of PI3K isoforms as a therapeutic strategy in chronic lymphocytic leukaemia

    PubMed Central

    Blunt, Matthew D.; Steele, Andrew J.

    2015-01-01

    PI3Kδ inhibitors such as idelalisib are providing improved therapeutic options for the treatment of chronic lymphocytic leukaemia (CLL). However under certain conditions, inhibition of a single PI3K isoform can be compensated by the other PI3K isoforms, therefore PI3K inhibitors which target multiple PI3K isoforms may provide greater efficacy. The development of compounds targeting multiple PI3K isoforms (α, β, δ, and γ) in CLL cells, in vitro, resulted in sustained inhibition of BCR signalling but with enhanced cytotoxicity and the potential for improve clinical responses. This review summarises the progress of PI3K inhibitor development and describes the rationale and potential for targeting multiple PI3K isoforms. PMID:26500849

  3. Novel approaches in anti-angiogenic treatment targeting endothelial F-actin: a new anti-angiogenic strategy?

    PubMed

    Thoenes, Lilja; Günther, Michael

    2008-12-01

    As a functional blood supply is crucial for growth of solid tumors, the development of anticancer agents to inhibit the formation of new tumor blood vessels is an area of extensive research. Endothelial cell motility driven by the dynamics of the cytoskeleton is a key feature of angiogenesis. Agents that preferentially target endothelial tubulin are well established, and inhibition of the endothelial actin dynamics appears to be another promising anti-angiogenic strategy. Remodeling of the actin cytoskeleton is regulated by several pathways involving a large number of signaling proteins. Therefore, therapeutic strategies for the modulation of actin dynamics include agents that target the actin cytoskeleton directly, as well as inhibitors of actin binding proteins and regulators in upstream pathways. This review provides an overview of the regulation of the actin cytoskeleton and proteins that could potentially be targeted by therapeutic agents. In addition, an outline of promising agents, which includes recombinant proteins, endogenous effectors and treatment regimes that exert anti-angiogenic effects partly mediated by affecting endothelial actin dynamics is provided.

  4. Intestinal inflammation targets cancer-inducing activity of the microbiota

    PubMed Central

    Arthur, Janelle C.; Perez-Chanona, Ernesto; Mühlbauer, Marcus; Tomkovich, Sarah; Uronis, Joshua M.; Fan, Ting-Jia; Campbell, Barry J.; Abujamel, Turki; Dogan, Belgin; Rogers, Arlin B.; Rhodes, Jonathan M.; Stintzi, Alain; Simpson, Kenneth W.; Hansen, Jonathan J.; Keku, Temitope O.; Fodor, Anthony A.; Jobin, Christian

    2013-01-01

    Inflammation alters host physiology to promote cancer, as seen in colitis-associated colorectal cancer (CRC). Here we identify the intestinal microbiota as a target of inflammation that impacts the progression of CRC. High-throughput sequencing revealed that inflammation modifies gut microbial composition in colitis-susceptible interleukin-10-deficient (Il10−/−) mice. Monocolonization with the commensal Escherichia coli NC101 promoted invasive carcinoma in azoxymethane (AOM)-treated Il10−/− mice. Deletion of the polyketide synthase (pks) genotoxic island from E. coli NC101 decreased tumor multiplicity and invasion in AOM/Il10−/− mice, without altering intestinal inflammation. Mucosa-associated pks+ E. coli were found in a significantly high percentage of inflammatory bowel disease (IBD) and CRC patients. This suggests that in mice, colitis can promote tumorigenesis by altering microbial composition and inducing the expansion of microorganisms with genotoxic capabilities. PMID:22903521

  5. Nanobody conjugated PLGA nanoparticles for active targeting of African Trypanosomiasis.

    PubMed

    Arias, José L; Unciti-Broceta, Juan D; Maceira, José; Del Castillo, Teresa; Hernández-Quero, José; Magez, Stefan; Soriano, Miguel; García-Salcedo, José A

    2015-01-10

    Targeted delivery of therapeutics is an alternative approach for the selective treatment of infectious diseases. The surface of African trypanosomes, the causative agents of African trypanosomiasis, is covered by a surface coat consisting of a single variant surface glycoprotein, termed VSG. This coat is recycled by endocytosis at a very high speed, making the trypanosome surface an excellent target for the delivery of trypanocidal drugs. Here, we report the design of a drug nanocarrier based on poly ethylen glycol (PEG) covalently attached (PEGylated) to poly(D,L-lactide-co-glycolide acid) (PLGA) to generate PEGylated PLGA nanoparticles. This nanocarrier was coupled to a single domain heavy chain antibody fragment (nanobody) that specifically recognizes the surface of the protozoan pathogen Trypanosoma brucei. Nanoparticles were loaded with pentamidine, the first-line drug for T. b. gambiense acute infection. An in vitro effectiveness assay showed a 7-fold decrease in the half-inhibitory concentration (IC50) of the formulation relative to free drug. Furthermore, in vivo therapy using a murine model of African trypanosomiasis demonstrated that the formulation cured all infected mice at a 10-fold lower dose than the minimal full curative dose of free pentamidine and 60% of mice at a 100-fold lower dose. This nanocarrier has been designed with components approved for use in humans and loaded with a drug that is currently in use to treat the disease. Moreover, this flexible nanobody-based system can be adapted to load any compound, opening a range of new potential therapies with application to other diseases.

  6. Comparison of Irradiation and Wolbachia Based Approaches for Sterile-Male Strategies Targeting Aedes albopictus

    PubMed Central

    Atyame, Célestine M.; Labbé, Pierrick; Lebon, Cyrille; Weill, Mylène; Moretti, Riccardo; Marini, Francesca; Gouagna, Louis Clément; Calvitti, Maurizio; Tortosa, Pablo

    2016-01-01

    The global expansion of Aedes albopictus together with the absence of vaccines for most of the arboviruses transmitted by this mosquito has stimulated the development of sterile-male strategies aiming at controlling disease transmission through the suppression of natural vector populations. In this context, two environmentally friendly control strategies, namely the Sterile Insect Technique (SIT) and the Wolbachia-based Incompatible Insect Technique (IIT) are currently being developed in several laboratories worldwide. So far however, there is a lack of comparative assessment of these strategies under the same controlled conditions. Here, we compared the mating capacities, i.e. insemination capacity, sterilization capacity and mating competitiveness of irradiated (35 Gy) and incompatible Ae. albopictus males at different ages and ratios under laboratory controlled conditions. Our data show that there was no significant difference in insemination capacity of irradiated and incompatible males, both male types showing lower capacities than untreated males at 1 day but recovering full capacity within 5 days following emergence. Regarding mating competitiveness trials, a global observed trend is that incompatible males tend to induce a lower hatching rate than irradiated males in cage controlled confrontations. More specifically, incompatible males were found more competitive than irradiated males in 5:1 ratio regardless of age, while irradiated males were only found more competitive than incompatible males in the 1:1 ratio at 10 days old. Overall, under the tested conditions, IIT seemed to be slightly more effective than SIT. However, considering that a single strategy will likely not be adapted to all environments, our data stimulates the need for comparative assessments of distinct strategies in up-scaled conditions in order to identify the most suitable and safe sterilizing technology to be implemented in a specific environmental setting and to identify the

  7. Comparison of Irradiation and Wolbachia Based Approaches for Sterile-Male Strategies Targeting Aedes albopictus.

    PubMed

    Atyame, Célestine M; Labbé, Pierrick; Lebon, Cyrille; Weill, Mylène; Moretti, Riccardo; Marini, Francesca; Gouagna, Louis Clément; Calvitti, Maurizio; Tortosa, Pablo

    2016-01-01

    The global expansion of Aedes albopictus together with the absence of vaccines for most of the arboviruses transmitted by this mosquito has stimulated the development of sterile-male strategies aiming at controlling disease transmission through the suppression of natural vector populations. In this context, two environmentally friendly control strategies, namely the Sterile Insect Technique (SIT) and the Wolbachia-based Incompatible Insect Technique (IIT) are currently being developed in several laboratories worldwide. So far however, there is a lack of comparative assessment of these strategies under the same controlled conditions. Here, we compared the mating capacities, i.e. insemination capacity, sterilization capacity and mating competitiveness of irradiated (35 Gy) and incompatible Ae. albopictus males at different ages and ratios under laboratory controlled conditions. Our data show that there was no significant difference in insemination capacity of irradiated and incompatible males, both male types showing lower capacities than untreated males at 1 day but recovering full capacity within 5 days following emergence. Regarding mating competitiveness trials, a global observed trend is that incompatible males tend to induce a lower hatching rate than irradiated males in cage controlled confrontations. More specifically, incompatible males were found more competitive than irradiated males in 5:1 ratio regardless of age, while irradiated males were only found more competitive than incompatible males in the 1:1 ratio at 10 days old. Overall, under the tested conditions, IIT seemed to be slightly more effective than SIT. However, considering that a single strategy will likely not be adapted to all environments, our data stimulates the need for comparative assessments of distinct strategies in up-scaled conditions in order to identify the most suitable and safe sterilizing technology to be implemented in a specific environmental setting and to identify the

  8. Develop a novel target-basis of anti-virulence strategy for controlling HLB

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The goal of this CRB-funded research project is to develop target-based anti-virulence therapeutics for Huanglongbing (HLB). Since the first report of citrus HLB in Florida in 2005, the disease is now looming large in Texas and California. In Florida, citrus growers are encountering severe decline o...

  9. Nuclease-aided target recycling signal amplification strategy for ochratoxin A monitoring.

    PubMed

    Lv, Lei; Li, Donghao; Cui, Chengbi; Zhao, Yangyang; Guo, Zhijun

    2017-01-15

    Ochratoxin A (OTA), a toxin produced by Aspergillus ochraceus and Penicillium verrucosum, is one of the most abundant food-contaminating mycotoxins worldwide. OTA mainly exerts nephrotoxicity, immunotoxicity, mutagenicity, carcinogenicity, teratogenicity, and neurotoxicity. This paper describes a simple and sensitive aptamer/single-walled carbon nanohorn (SWCNH)-based assay for OTA detection. SWCNHs can protect DNA from DNase I cleavage. However, aptamers can be detached from the surface of SWCNHs through specific target binding, exposing them to enzymatic cleavage and releases the target for a new cycle. Cycling of targets leads to significant signal amplification and low limit of detection (LOD), resulting in a nearly 20-fold reduction in LOD for OTA assay compared with non-target recycling under the same experimental parameters. This technique responded specifically to OTA without interference from other analogues (Ochratoxin B, Ochratoxin C, warfarin, and N-acetyl-l-phenylalanine). Moreover, the application of this technique in real sample has been verified using red wine samples spiked with a series of OTA concentrations. This aptasensor offers a great practical importance in food safety and can be widely extended for detection of other toxins by replacing the sequence of the recognition aptamer.

  10. Comparison of Item Targeting Strategies for Pass/Fail Computer Adaptive Tests.

    ERIC Educational Resources Information Center

    Bergstrom, Betty A.; Gershon, Richard

    The most useful method of item selection for making pass-fail decisions with a Computerized Adaptive Test (CAT) was studied. Medical technology students (n=86) took a computer adaptive test in which items were targeted to the ability of the examinee. The adaptive algorithm that selected items and estimated person measures used the Rasch model and…

  11. Leaders as combat fighter pilots. Research project targets leaders who support money-losing business strategies.

    PubMed

    Mitlyng, J W; Francis, D M; Wenzel, F J

    2001-01-01

    When strategic plans go awry and begin losing money, the smart thing to do is change course. But some leaders get so involved with the plan, they fail to navigate properly and fly right into the target. The organization can lose millions. Examine why this happens and what you can do to prevent it from happening in your organization.

  12. A New Strategy to Reduce Influenza Escape: Detecting Therapeutic Targets Constituted of Invariance Groups.

    PubMed

    Lao, Julie; Vanet, Anne

    2017-03-02

    The pathogenicity of the different flu species is a real public health problem worldwide. To combat this scourge, we established a method to detect drug targets, reducing the possibility of escape. Besides being able to attach a drug candidate, these targets should have the main characteristic of being part of an essential viral function. The invariance groups that are sets of residues bearing an essential function can be detected genetically. They consist of invariant and synthetic lethal residues (interdependent residues not varying or slightly varying when together). We analyzed an alignment of more than 10,000 hemagglutinin sequences of influenza to detect six invariance groups, close in space, and on the protein surface. In parallel we identified five potential pockets on the surface of hemagglutinin. By combining these results, three potential binding sites were determined that are composed of invariance groups located respectively in the vestigial esterase domain, in the bottom of the stem and in the fusion area. The latter target is constituted of residues involved in the spring-loaded mechanism, an essential step in the fusion process. We propose a model describing how this potential target could block the reorganization of the hemagglutinin HA2 secondary structure and prevent viral entry into the host cell.

  13. The Relationship between Retailers' Targeting and E-Commerce Strategies: An Empirical Analysis.

    ERIC Educational Resources Information Center

    Doherty, Neil F.; Ellis-Chadwick, Fiona E.

    2003-01-01

    This survey of senior marketing executives in the United Kingdom's largest retail organizations investigated the extent to which the adoption of e-commerce is influenced by the socio-demographic characteristics of their target customers. Results demonstrate that organizations are most likely to adopt the Internet if their typical customer is male,…

  14. New therapeutic strategies targeting D1-type dopamine receptors for neuropsychiatric disease

    PubMed Central

    Kim, Young-Cho; Alberico, Stephanie L.; Emmons, Eric; Narayanan, Nandakumar S.

    2017-01-01

    The neurotransmitter dopamine acts via two major classes of receptors, D1-type and D2-type. D1 receptors are highly expressed in the striatum and can also be found in the cerebral cortex. Here we review the role of D1 dopamine signaling in two major domains: L-DOPA-induced dyskinesias in Parkinson’s disease and cognition in neuropsychiatric disorders. While there are many drugs targeting D2-type receptors, there are no drugs that specifically target D1 receptors. It has been difficult to use selective D1-receptor agonists for clinical applications due to issues with bioavailability, binding affinity, pharmacological kinetics, and side effects. We propose potential therapies that selectively modulate D1 dopamine signaling by targeting second messengers downstream of D1 receptors, allosteric modulators, or by making targeted modifications to D1-receptor machinery. The development of therapies specific to D1-receptor signaling could be a new frontier in the treatment of neurological and psychiatric disorders. PMID:28280503

  15. A New Strategy to Reduce Influenza Escape: Detecting Therapeutic Targets Constituted of Invariance Groups

    PubMed Central

    Lao, Julie; Vanet, Anne

    2017-01-01

    The pathogenicity of the different flu species is a real public health problem worldwide. To combat this scourge, we established a method to detect drug targets, reducing the possibility of escape. Besides being able to attach a drug candidate, these targets should have the main characteristic of being part of an essential viral function. The invariance groups that are sets of residues bearing an essential function can be detected genetically. They consist of invariant and synthetic lethal residues (interdependent residues not varying or slightly varying when together). We analyzed an alignment of more than 10,000 hemagglutinin sequences of influenza to detect six invariance groups, close in space, and on the protein surface. In parallel we identified five potential pockets on the surface of hemagglutinin. By combining these results, three potential binding sites were determined that are composed of invariance groups located respectively in the vestigial esterase domain, in the bottom of the stem and in the fusion area. The latter target is constituted of residues involved in the spring-loaded mechanism, an essential step in the fusion process. We propose a model describing how this potential target could block the reorganization of the hemagglutinin HA2 secondary structure and prevent viral entry into the host cell. PMID:28257108

  16. A Time to Kill: When is Leadership Targeting an Effective Counterterrorism Strategy

    DTIC Science & Technology

    2007-12-01

    55 B. PHASE 2 ASSESSMENT ................................57 VI. PHASE III: FROM KURDISTAN TO DEATH: THE ZARQAWI...ORGANIZATION IN IRAQ; ..................................61 A. KURDISTAN TO DEATH ................................61 1. Inspirational...Cronin cites several cases of successful leadership targeting, including Peru’s Shining Path, the Kurdistan Workers Party, the Real Irish Republican

  17. An enzymatically activated fluorescence probe for targeted tumor imaging

    PubMed Central

    Kamiya, Mako; Kobayashi, Hisataka; Hama, Yukihiro; Koyama, Yoshinori; Bernardo, Marcelino; Nagano, Tetsuo; Choyke, Peter L.; Urano, Yasuteru

    2008-01-01

    β-Galactosidase is a widely used reporter enzyme, but although several substrates are available for in vitro detection, its application for in vivo optical imaging remains a challenge. To obtain a probe suitable for in vivo use, we modified our previously developed activatable fluorescence probe, TG-βGal (J. Am. Chem. Soc., 2005, 127, 4888-4894), on the basis of photochemical and photophysical experiments. The new probe, AM-TG-βGal, provides a dramatic fluorescence enhancement upon reaction with β-galactosidase, and further hydrolysis of the ester moiety by ubiquitous intracellular esterases affords a hydrophilic product that is well retained within the cells without loss of fluorescence. We used a mouse tumor model to assess the practical utility of AM-TG-βGal, after confirming that tumors in the model could be labeled with avidin-β-galactosidase conjugate. This conjugate was administered to the mice in vivo, followed by AM-TG-βGal, and subsequent ex vivo fluorescence imaging clearly visualized intraperitoneal tumors as small as 200 μm. This strategy has potential clinical application, for example in video-assisted laparoscopic tumor resection. PMID:17352471

  18. Iron biofortification in the 21st century: setting realistic targets, overcoming obstacles, and new strategies for healthy nutrition.

    PubMed

    Vasconcelos, Marta W; Gruissem, Wilhelm; Bhullar, Navreet K

    2016-10-22

    Plant-based foods offer a wide range of nutrients that are essential for human and animal health. Among these nutrients, iron stands out as one of the most important micronutrients. Increasing the iron content in many staple and non-staple plant foods continues to be a goal of many scientists around the world. However, the success of such initiatives has sometimes fallen short of their expected targets. In this review we highlight the most recent and promising results that have contributed to increasing the iron content in different crops. We also discuss methods that to date have been used to reach iron biofortification goals and new strategies that we believe are most promising for crop biofortification in the future. Plant anatomical, physiological and metabolic hurdles still need to be tackled for making progress on further increasing currently reached levels of micronutrient improvements. New strategies need to take into account growing environmental challenges that may constrain biofortification efforts.

  19. Systematic mining of analog series with related core structures in multi-target activity space.

    PubMed

    Gupta-Ostermann, Disha; Hu, Ye; Bajorath, Jürgen

    2013-08-01

    We have aimed to systematically extract analog series with related core structures from multi-target activity space to explore target promiscuity of closely related analogous. Therefore, a previously introduced SAR matrix structure was adapted and further extended for large-scale data mining. These matrices organize analog series with related yet distinct core structures in a consistent manner. High-confidence compound activity data yielded more than 2,300 non-redundant matrices capturing 5,821 analog series that included 4,288 series with multi-target and 735 series with multi-family activities. Many matrices captured more than three analog series with activity against more than five targets. The matrices revealed a variety of promiscuity patterns. Compound series matrices also contain virtual compounds, which provide suggestions for compound design focusing on desired activity profiles.

  20. A new antibiotic with potent activity targets MscL

    PubMed Central

    Iscla, Irene; Wray, Robin; Blount, Paul; Larkins-Ford, Jonah; Conery, Annie L; Ausubel, Frederick M; Ramu, Soumya; Kavanagh, Angela; Huang, Johnny X; Blaskovich, Mark A; Cooper, Matthew A; Obregon-Henao, Andres; Orme, Ian; Tjandra, Edwin S; Stroeher, Uwe H; Brown, Melissa H; Macardle, Cindy; van Holst, Nick; Ling Tong, Chee; Slattery, Ashley D; Gibson, Christopher T; Raston, Colin L; Boulos, Ramiz A

    2015-01-01

    The growing problem of antibiotic-resistant bacteria is a major threat to human health. Paradoxically, new antibiotic discovery is declining, with most of the recently approved antibiotics corresponding to new uses for old antibiotics or structurally similar derivatives of known antibiotics. We used an in silico approach to design a new class of nontoxic antimicrobials for the bacteria-specific mechanosensitive ion channel of large conductance, MscL. One antimicrobial of this class, compound 10, is effective against methicillin-resistant Staphylococcus aureus with no cytotoxicity in human cell lines at the therapeutic concentrations. As predicted from in silico modeling, we show that the mechanism of action of compound 10 is at least partly dependent on interactions with MscL. Moreover we show that compound 10 cured a methicillin-resistant S. aureus infection in the model nematode Caenorhabditis elegans. Our work shows that compound 10, and other drugs that target MscL, are potentially important therapeutics against antibiotic-resistant bacterial infections. PMID:25649856

  1. Activation of lexical and syntactic target language properties in translation.

    PubMed

    Ruiz, C; Paredes, N; Macizo, P; Bajo, M T

    2008-07-01

    Is reading for translation equal to reading in monolingual contexts? Horizontal/parallel theories of translation propose that normal reading and reading for translation differ because the translator engages in partial reformulation while reading for translating the source text. In contrast, vertical/serial theories assume that the translators first extract the meaning of the message, and only then they proceed to reformulate it. In two experiments, we manipulated lexical and syntactic properties of the target language (TL) while translators read for repetition or for translation. On-line sentence comprehension was affected by the lexical frequency of words in the TL (Experiment 1) and the syntactic congruency between the source language (SL) and TL sentences (Experiment 2). However, the influence of lexical and syntactic TL properties was restricted to the reading for translation task. According to our results, the horizontal view of translation includes code-to-code links between the SL and TL involving at least the lexical and syntactic level of processing.

  2. A new antibiotic with potent activity targets MscL.

    PubMed

    Iscla, Irene; Wray, Robin; Blount, Paul; Larkins-Ford, Jonah; Conery, Annie L; Ausubel, Frederick M; Ramu, Soumya; Kavanagh, Angela; Huang, Johnny X; Blaskovich, Mark A; Cooper, Matthew A; Obregon-Henao, Andres; Orme, Ian; Tjandra, Edwin S; Stroeher, Uwe H; Brown, Melissa H; Macardle, Cindy; van Holst, Nick; Ling Tong, Chee; Slattery, Ashley D; Gibson, Christopher T; Raston, Colin L; Boulos, Ramiz A

    2015-07-01

    The growing problem of antibiotic-resistant bacteria is a major threat to human health. Paradoxically, new antibiotic discovery is declining, with most of the recently approved antibiotics corresponding to new uses for old antibiotics or structurally similar derivatives of known antibiotics. We used an in silico approach to design a new class of nontoxic antimicrobials for the bacteria-specific mechanosensitive ion channel of large conductance, MscL. One antimicrobial of this class, compound 10, is effective against methicillin-resistant Staphylococcus aureus with no cytotoxicity in human cell lines at the therapeutic concentrations. As predicted from in silico modeling, we show that the mechanism of action of compound 10 is at least partly dependent on interactions with MscL. Moreover we show that compound 10 cured a methicillin-resistant S. aureus infection in the model nematode Caenorhabditis elegans. Our work shows that compound 10, and other drugs that target MscL, are potentially important therapeutics against antibiotic-resistant bacterial infections.

  3. Analysis of Residential System Strategies Targeting Least-Cost Solutions Leading to Net Zero Energy Homes: Preprint

    SciTech Connect

    Anderson, R.; Christensen, C.; Horowitz, S.

    2006-04-01

    The U. S. Department of Energy's Building America residential systems research project uses an analysis-based system research approach to identify research priorities, identify technology gaps and opportunities, establish a consistent basis to track research progress, and identify system solutions that are most likely to succeed as the initial targets for residential system research projects. This report describes the analysis approach used by the program to determine the most cost-effective pathways to achieve whole-house energy-savings goals. This report also provides an overview of design/technology strategies leading to net zero energy buildings as the basis for analysis of future residential system performance.

  4. A computational strategy to select optimized protein targets for drug development toward the control of cancer diseases.

    PubMed

    Carels, Nicolas; Tilli, Tatiana; Tuszynski, Jack A

    2015-01-01

    In this report, we describe a strategy for the optimized selection of protein targets suitable for drug development against neoplastic diseases taking the particular case of breast cancer as an example. We combined human interactome and transcriptome data from malignant and control cell lines because highly connected proteins that are up-regulated in malignant cell lines are expected to be suitable protein targets for chemotherapy with a lower rate of undesirable side effects. We normalized transcriptome data and applied a statistic treatment to objectively extract the sub-networks of down- and up-regulated genes whose proteins effectively interact. We chose the most connected ones that act as protein hubs, most being in the signaling network. We show that the protein targets effectively identified by the combination of protein connectivity and differential expression are known as suitable targets for the successful chemotherapy of breast cancer. Interestingly, we found additional proteins, not generally targeted by drug treatments, which might justify the extension of existing formulation by addition of inhibitors designed against these proteins with the consequence of improving therapeutic outcomes. The molecular alterations observed in breast cancer cell lines represent either driver events and/or driver pathways that are necessary for breast cancer development or progression. However, it is clear that signaling mechanisms of the luminal A, B and triple negative subtypes are different. Furthermore, the up- and down-regulated networks predicted subtype-specific drug targets and possible compensation circuits between up- and down-regulated genes. We believe these results may have significant clinical implications in the personalized treatment of cancer patients allowing an objective approach to the recycling of the arsenal of available drugs to the specific case of each breast cancer given their distinct qualitative and quantitative molecular traits.

  5. Pathophysiological response to hypoxia - from the molecular mechanisms of malady to drug discovery:hypoxia-inducible factor-1 (HIF-1)-active cells as a target for cancer therapy.

    PubMed

    Kizaka-Kondoh, Shinae; Kuchimaru, Takahiro; Kadonosono, Tetsuya

    2011-01-01

    The microenvironment of solid tumors is characterized by low pO(2) that is well below physiological levels. Intratumoral hypoxia is a major factor contributing to cancer progression and is exacerbated as a result of oxygen consumption by rapidly proliferating tumor cells near blood vessels, poor lymphatic drainage resulting in high interstitial pressure, and irregular blood supply through immature tumor vasculature. Hypoxia-inducible factor-1 (HIF-1) is the main transcription factor that regulates cellular responses to hypoxia. Cellular changes induced by HIF-1 are extremely important targets for cancer therapy. Therefore, targeting strategies to counteract HIF-1-active cells are essential for cancer therapy. In this study, we introduce a novel strategy for targeting HIF-1-active cells.

  6. Classroom Activities: Simple Strategies to Incorporate Student-Centered Activities within Undergraduate Science Lectures.

    PubMed

    Lom, Barbara

    2012-01-01

    The traditional science lecture, where an instructor delivers a carefully crafted monolog to a large audience of students who passively receive the information, has been a popular mode of instruction for centuries. Recent evidence on the science of teaching and learning indicates that learner-centered, active teaching strategies can be more effective learning tools than traditional lectures. Yet most colleges and universities retain lectures as their central instructional method. This article highlights several simple collaborative teaching techniques that can be readily deployed within traditional lecture frameworks to promote active learning. Specifically, this article briefly introduces the techniques of: reader's theatre, think-pair-share, roundtable, jigsaw, in-class quizzes, and minute papers. Each technique is broadly applicable well beyond neuroscience courses and easily modifiable to serve an instructor's specific pedagogical goals. The benefits of each technique are described along with specific examples of how each technique might be deployed within a traditional lecture to create more active learning experiences.

  7. Using the “target constituent removal combined with bioactivity assay” strategy to investigate the optimum arecoline content in charred areca nut

    PubMed Central

    Peng, Wei; Liu, Yu-Jie; Hu, Mei-Bian; Yan, Dan; Gao, Yong-Xiang; Wu, Chun-Jie

    2017-01-01

    Charred areca nut (CAN) is used to treat dyspepsia and abdominal distension in children. However, reports revealed that arecoline, the most important active constituent of CAN, possesses potential toxicities. This study was designed to investigate the optimum arecoline content in CAN, using the “target constituent removal combined with bioactivity assay” strategy. Based on PTLC method, we prepared CAN lacking all arecoline (WAC-100R) and a series of different ratios of arecoline-removed CAN samples (WAC-Rx). MTT and acute toxicity assays indicated that decreasing content by 50% decreased CAN toxicity significantly. Animal results revealed arecoline contents over 50% could guarantee the beneficial effects of CAN on gastrointestinal tract. Additionally, decreasing arecoline content in CAN by 50% decreased its pro-apoptotic effects significantly. Furthermore, decreasing 50% arecoline content in CAN down-regulated the expressions of Cleaved-Caspase-3, c-jun, c-fos, COX-2, PGE2, and IL-1α. Thus, our results revealed that CAN with 50% arecoline content (WAC-50R) has similar beneficial effects on the gastrointestinal tract to CAN, whereas its toxicity was decreased significantly. Collectively, our study suggested that the strategy of “target constituent removal combined with bioactivity assay” is a promising method to identify the optimum arecoline content in CAN, which is approximately 0.12%. PMID:28054652

  8. Evolving systemic targeted therapy strategies in uveal melanoma and implications for ophthalmic management: a review.

    PubMed

    Goh, Amanda Yl; Layton, Christopher J

    2016-08-01

    Uveal melanoma (UM) is the most common primary ocular tumour in adults. Despite good local control of the primary tumour with current methods, survival after the development of metastasis has remained poor over the last 30 years. After cutaneous melanoma, UM is the most common type of melanoma, and an ongoing debate exists regarding whether these conditions should be considered separate entities, particularly in the context of targeted therapy, where many of the initial trials for patients with metatatic cutaneous melanoma excluded metastatic UM. This paper will review the recent and ongoing investigations designed to validate systemic targeted therapy and immunotherapy in patients with metastatic UM and suggests ways in which these developments may affect management of UM by ophthalmologists in the near future.

  9. Iontophoresis of minoxidil sulphate loaded microparticles, a strategy for follicular drug targeting?

    PubMed

    Gelfuso, Guilherme M; Barros, M Angélica de Oliveira; Delgado-Charro, M Begoña; Guy, Richard H; Lopez, Renata F V

    2015-10-01

    The feasibility of targeting drugs to hair follicles by a combination of microencapsulation and iontophoresis has been evaluated. Minoxidil sulphate (MXS), which is used in the treatment of alopecia, was selected as a relevant drug with respect to follicular penetration. The skin permeation and disposition of MXS encapsulated in chitosan microparticles (MXS-MP) was evaluated in vitro after passive and iontophoretic delivery. Uptake of MXS was quantified at different exposure times in the stratum corneum (SC) and hair follicles. Microencapsulation resulted in increased (6-fold) drug accumulation in the hair follicles relative to delivery from a simple MXS solution. Application of iontophoresis enhanced follicular delivery for both the solution and the microparticle formulations. It appears, therefore, that microencapsulation and iontophoresis can act synergistically to enhance topical drug targeting to hair follicles.

  10. A Cell-targeted Photodynamic Nanomedicine Strategy for Head & Neck Cancers

    PubMed Central

    Master, Alyssa; Malamas, Anthony; Solanki, Rachna; Clausen, Dana M.; Eiseman, Julie L.; Gupta, Anirban Sen

    2013-01-01

    Photodynamic Therapy (PDT) holds great promise for the treatment of head and neck (H&N) carcinomas where repeated loco-regional therapy often becomes necessary due to the highly aggressive and recurrent nature of the cancers. While interstitial light delivery technologies are being refined for PDT of H&N and other cancers, a parallel clinically relevant research area is the formulation of photosensitizers in nanovehicles that allow systemic administration yet preferential enhanced uptake in the tumor. This approach can render dual-selectivity of PDT, by harnessing both the drug and the light delivery within the tumor. To this end, we report on a cell-targeted nanomedicine approach for the photosensitizer silicon phthalocyanine-4 (Pc 4), by packaging it within polymeric micelles that are surface-decorated with GE11-peptides to promote enhanced cell-selective binding and receptor-mediated internalization in EGFR-overexpressing H&N cancer cells. Using fluorescence spectroscopy and confocal microscopy, we demonstrate in vitro that the EGFR-targeted Pc 4-nanoformulation undergoes faster and higher uptake in EGFR-overexpressing H&N SCC-15 cells. We further demonstrate that this enhanced Pc 4 uptake results in significant cell-killing and drastically reduced post-PDT clonogenicity. Building on this in vitro data, we demonstrate that the EGFR-targeted Pc 4-nanoformulation results in significant intra-tumoral drug uptake and subsequent enhanced PDT response, in vivo, in SCC-15 xenografts in mice. Altogether our results show significant promise towards a cell-targeted photodynamic nanomedicine for effective treatment of H&N carcinomas. PMID:23531079

  11. A cell-targeted photodynamic nanomedicine strategy for head and neck cancers.

    PubMed

    Master, Alyssa; Malamas, Anthony; Solanki, Rachna; Clausen, Dana M; Eiseman, Julie L; Sen Gupta, Anirban

    2013-05-06

    Photodynamic therapy (PDT) holds great promise for the treatment of head and neck (H&N) carcinomas where repeated loco-regional therapy often becomes necessary due to the highly aggressive and recurrent nature of the cancers. While interstitial light delivery technologies are being refined for PDT of H&N and other cancers, a parallel clinically relevant research area is the formulation of photosensitizers in nanovehicles that allow systemic administration yet preferential enhanced uptake in the tumor. This approach can render dual-selectivity of PDT, by harnessing both the drug and the light delivery within the tumor. To this end, we report on a cell-targeted nanomedicine approach for the photosensitizer silicon phthalocyanine-4 (Pc 4), by packaging it within polymeric micelles that are surface-decorated with GE11-peptides to promote enhanced cell-selective binding and receptor-mediated internalization in EGFR-overexpressing H&N cancer cells. Using fluorescence spectroscopy and confocal microscopy, we demonstrate in vitro that the EGFR-targeted Pc 4-nanoformulation undergoes faster and higher uptake in EGFR-overexpressing H&N SCC-15 cells. We further demonstrate that this enhanced Pc 4 uptake results in significant cell-killing and drastically reduced post-PDT clonogenicity. Building on this in vitro data, we demonstrate that the EGFR-targeted Pc 4-nanoformulation results in significant intratumoral drug uptake and subsequent enhanced PDT response, in vivo, in SCC-15 xenografts in mice. Altogether our results show significant promise toward a cell-targeted photodynamic nanomedicine for effective treatment of H&N carcinomas.

  12. Genetic and chemical knockdown: a complementary strategy for evaluating an anti-infective target

    PubMed Central

    Ramachandran, Vasanthi; Singh, Ragini; Yang, Xiaoyu; Tunduguru, Ragadeepthi; Mohapatra, Subrat; Khandelwal, Swati; Patel, Sanjana; Datta, Santanu

    2013-01-01

    The equity of a drug target is principally evaluated by its genetic vulnerability with tools ranging from antisense- and microRNA-driven knockdowns to induced expression of the target protein. In order to upgrade the process of antibacterial target identification and discern its most effective type of inhibition, an in silico toolbox that evaluates its genetic and chemical vulnerability leading either to stasis or cidal outcome was constructed and validated. By precise simulation and careful experimentation using enolpyruvyl shikimate-3-phosphate synthase and its specific inhibitor glyphosate, it was shown that genetic knockdown is distinct from chemical knockdown. It was also observed that depending on the particular mechanism of inhibition, viz competitive, uncompetitive, and noncompetitive, the antimicrobial potency of an inhibitor could be orders of magnitude different. Susceptibility of Escherichia coli to glyphosate and the lack of it in Mycobacterium tuberculosis could be predicted by the in silico platform. Finally, as predicted and simulated in the in silico platform, the translation of growth inhibition to a cidal effect was able to be demonstrated experimentally by altering the carbon source from sorbitol to glucose. PMID:23413046

  13. NAIMA: target amplification strategy allowing quantitative on-chip detection of GMOs.

    PubMed

    Morisset, Dany; Dobnik, David; Hamels, Sandrine; Zel, Jana; Gruden, Kristina

    2008-10-01

    We have developed a novel multiplex quantitative DNA-based target amplification method suitable for sensitive, specific and quantitative detection on microarray. This new method named NASBA Implemented Microarray Analysis (NAIMA) was applied to GMO detection in food and feed, but its application can be extended to all fields of biology requiring simultaneous detection of low copy number DNA targets. In a first step, the use of tailed primers allows the multiplex synthesis of template DNAs in a primer extension reaction. A second step of the procedure consists of transcription-based amplification using universal primers. The cRNA product is further on directly ligated to fluorescent dyes labelled 3DNA dendrimers allowing signal amplification and hybridized without further purification on an oligonucleotide probe-based microarray for multiplex detection. Two triplex systems have been applied to test maize samples containing several transgenic lines, and NAIMA has shown to be sensitive down to two target copies and to provide quantitative data on the transgenic contents in a range of 0.1-25%. Performances of NAIMA are comparable to singleplex quantitative real-time PCR. In addition, NAIMA amplification is faster since 20 min are sufficient to achieve full amplification.

  14. Targeted therapeutics in SLE: emerging strategies to modulate the interferon pathway

    PubMed Central

    Oon, Shereen; Wilson, Nicholas J; Wicks, Ian

    2016-01-01

    Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease characterized by impaired immune tolerance, resulting in the generation of pathogenic autoantibodies and immune complexes. Although autoreactive B lymphocytes have been the first targets for biologic therapies in SLE, the importance of the innate immune system, and in particular, pathways involved in interferon (IFN) signaling, has emerged. There are now data supporting a central role for a plasmacytoid dendritic cell-derived type I IFN pathway in SLE, with a number of biologic therapeutics and small-molecule inhibitors undergoing clinical trials. Monoclonal antibodies targeting IFN-α have completed phase II clinical trials, and an antibody against the type I IFN receptor is entering a phase III trial. However, other IFNs, such as IFN gamma, and the more recently discovered type III IFNs, are also emerging as targets in SLE; and blockade of upstream components of the IFN signaling pathway may enable inhibition of more than one IFN subtype. In this review, we discuss the current understanding of IFNs in SLE, focusing on emerging therapies. PMID:27350879

  15. NRF2 Activation as Target to Implement Therapeutic Treatments

    NASA Astrophysics Data System (ADS)

    Bocci, Velio; Valacchi, Giuseppe

    2015-02-01

    A chronic increase of oxidative stress is typical of serious pathologies such as myocardial infarction, stroke, chronic limb ischemia, chronic obstructive pulmonary disease (COPD), type II-diabetes, age-related macular degeneration leads to an epic increase of morbidity and mortality in all countries of the world. The initial inflammation followed by an excessive release of reactive oxygen species (ROS) implies a diffused cellular injury that needs to be corrected by an inducible expression of the innate detoxifying and antioxidant system. The transcription factor Nrf2, when properly activated, is able to restore a redox homeostasis and possibly improve human health.

  16. Nrf2 activation as target to implement therapeutic treatments

    PubMed Central

    Bocci, Velio; Valacchi, Giuseppe

    2015-01-01

    A chronic increase of oxidative stress is typical of serious pathologies such as myocardial infarction, stroke, chronic limb ischemia, chronic obstructive pulmonary disease (COPD), type II-diabetes, age-related macular degeneration leads to an epic increase of morbidity and mortality in all countries of the world. The initial inflammation followed by an excessive release of reactive oxygen species (ROS) implies a diffused cellular injury that needs to be corrected by an inducible expression of the innate detoxifying and antioxidant system. The transcription factor Nrf2, when properly activated, is able to restore a redox homeostasis and possibly improve human health. PMID:25699252

  17. Targeting of phage particles towards endothelial cells by antibodies selected through a multi-parameter selection strategy

    PubMed Central

    Mandrup, Ole A.; Lykkemark, Simon; Kristensen, Peter

    2017-01-01

    One of the hallmarks of cancer is sustained angiogenesis. Here, normal endothelial cells are activated, and their formation of new blood vessels leads to continued tumour growth. An improved patient condition is often observed when angiogenesis is prevented or normalized through targeting of these genomically stable endothelial cells. However, intracellular targets constitute a challenge in therapy, as the agents modulating these targets have to be delivered and internalized specifically to the endothelial cells. Selection of antibodies binding specifically to certain cell types is well established. It is nonetheless a challenge to ensure that the binding of antibodies to the target cell will mediate internalization. Previously selection of such antibodies has been performed targeting cancer cell lines; most often using either monovalent display or polyvalent display. In this article, we describe selections that isolate internalizing antibodies by sequential combining monovalent and polyvalent display using two types of helper phages, one which increases display valence and one which reduces background. One of the selected antibodies was found to mediate internalization into human endothelial cells, although our results confirms that the single stranded nature of the DNA packaged into phage particles may limit applications aimed at targeting nucleic acids in mammalian cells. PMID:28186116

  18. Targeting poly(ADP-ribose) polymerase activity for cancer therapy

    PubMed Central

    Mégnin-Chanet, Frédérique; Bollet, Marc A.

    2010-01-01

    Poly(ADP-ribosyl)ation is a ubiquitous protein modification found in mammalian cells that modulates many cellular responses, including DNA repair. The poly(ADP-ribose) polymerase (PARP) family catalyze the formation and addition onto proteins of negatively charged ADP-ribose polymers synthesized from NAD+. The absence of PARP-1 and PARP-2, both of which are activated by DNA damage, results in hypersensitivity to ionizing radiation and alkylating agents. PARP inhibitors that compete with NAD+ at the enzyme’s activity site are effective chemo- and radiopotentiation agents and, in BRCA-deficient tumors, can be used as single-agent therapies acting through the principle of synthetic lethality. Through extensive drug-development programs, third-generation inhibitors have now entered clinical trials and are showing great promise. However, both PARP-1 and PARP-2 are not only involved in DNA repair but also in transcription regulation, chromatin modification, and cellular homeostasis. The impact on these processes of PARP inhibition on long-term therapeutic responses needs to be investigated. PMID:20725763

  19. Didymin: an orally active citrus flavonoid for targeting neuroblastoma.

    PubMed

    Singhal, Sharad S; Singhal, Sulabh; Singhal, Preeti; Singhal, Jyotsana; Horne, David; Awasthi, Sanjay

    2017-02-08

    Neuroblastoma, a rapidly growing yet treatment responsive cancer, is the third most common cancer of children and the most common solid tumor in infants. Unfortunately, neuroblastoma that has lost p53 function often has a highly treatment-resistant phenotype leading to tragic outcomes. In the context of neuroblastoma, the functions of p53 and MYCN (which is amplified in ~25% of neuroblastomas) are integrally linked because they are mutually transcriptionally regulated, and because they together regulate the catalytic activity of RNA polymerases. Didymin is a citrus-derived natural compound that kills p53 wild-type as well as drug-resistant p53-mutant neuroblastoma cells in culture. In addition, orally administered didymin causes regression of neuroblastoma xenografts in mouse models, without toxicity to non-malignant cells, neural tissues, or neural stem cells. RKIP is a Raf-inhibitory protein that regulates MYCN activation, is transcriptionally upregulated by didymin, and appears to play a key role in the anti-neuroblastoma actions of didymin. In this review, we discuss how didymin overcomes drug-resistance in p53-mutant neuroblastoma through RKIP-mediated inhibition of MYCN and its effects on GRK2, PKCs, Let-7 micro-RNA, and clathrin-dependent endocytosis by Raf-dependent and -independent mechanisms. In addition, we will discuss studies supporting potential clinical impact and translation of didymin as a low cost, safe, and effective oral agent that could change the current treatment paradigm for refractory neuroblastoma.

  20. Strategies for novel therapeutic approaches targeting cytokines and signaling pathways of osteoclasto- and osteoblastogenesis in the fight against immune-mediated bone and joint diseases.

    PubMed

    Sipos, W; Pietschmann, P; Rauner, M

    2008-01-01

    For many bone and joint diseases in humans, including postmenopausal osteoporosis, rheumatoid arthritis, and ankylosing spondylitis, an immune-mediated etiology has either been proven or is considered as a co-factor in pathogenesis. The identification of the receptor activator of nuclear factor kappaB (RANK)/RANK ligand (RANKL)/osteoprotegerin (OPG)-interplay and the in-depth characterization of the signaling pathways induced upon RANK activation, including molecules such as TNF receptor-associated factor 6 (TRAF6), nuclear factor-kappaB (NF-kappaB), and signal transducer and activator of T cells (STAT)-3, now promise to give the opportunity to target osteoclastogenesis specifically. Additionally, many byways influencing osteoclastogenesis have been elucidated, thus giving rise to additional therapeutic approaches. These are based mainly upon the effects of diverse cytokines on osteoclast differentiation with interleukin (IL)-17 and interferone (IFN)-gamma being most prominent at the moment. The same applies for the recently established signaling pathways in osteoblastogenesis, which have attracted much attention in the recent years. In this respect, much attention has been attributed towards bone morphogenetic proteins (BMPs) and the Wnt signaling cascade. In this review, an overview on the key molecules, which (could) serve as promising targets for novel therapeutic interventions with the aim of enhancing osteoblast formation or suppressing osteoclast development, is given. Further on, antibody-based therapeutical schemes as well as methodologically novel, albeit predominantly theoretical at the moment, strategies in the fight against immune-mediated osteopathologies are discussed.

  1. Active search strategies and the SETI protocols - Is there a conflict?

    NASA Astrophysics Data System (ADS)

    Lemarchand, Guillermo A.; Tarter, Donald E.

    1993-10-01

    The widely approved Declaration of Principles Concerning Activities following the Detection of Extraterrestrial Intelligence and the Proposed Protocol for Sending of Communications to Extraterrestrial Intelligence are examined with respect to how they apply to active as opposed to passive search strategies by radio astronomers. This article maintains that the existing protocols do not and should not impede active search strategies. An active search strategy based on the transmission of an interstellar terrestrial message using the synchronization of the SN 1987A hyperboloid is described. A brief discussion is made concerning the social 'pros' and 'cons' of an active search for humanity.

  2. New Advances in Nanotechnology-Based Diagnosis and Therapeutics for Breast Cancer: An Assessment of Active-Targeting Inorganic Nanoplatforms.

    PubMed

    Falagan-Lotsch, Priscila; Grzincic, Elissa M; Murphy, Catherine J

    2017-01-18

    Breast cancer is a major cause of suffering and mortality among women. Limitations in the current diagnostic methods and treatment approaches have led to new strategies to positively impact the survival rates and quality of life of breast cancer patients. Nanotechnology offers a real possibility of mitigating breast cancer mortality by early-stage cancer detection and more precise diagnosis as well as more effective treatments with minimal side effects. The current nanoplatforms approved for breast cancer therapeutics are based on passive tumor targeting using organic nanoparticles and have not provided the expected significant improvements in the clinic. In this review, we present the emerging approaches in breast cancer nanomedicine based on active targeting using versatile inorganic nanoplatforms with biomedical relevance, such as gold, silica, and iron oxide nanoparticles, as well as their efficacy in breast cancer imaging, drug and gene delivery, thermal therapy, combinational therapy, and theranostics in preclinical studies. The main challenges for clinical translation and perspectives are discussed.

  3. Lab-scale experimental strategy for determining micropollutant partition coefficient and biodegradation constants in activated sludge.

    PubMed

    Pomiès, M; Choubert, J M; Wisniewski, C; Miège, C; Budzinski, H; Coquery, M

    2015-03-01

    The nitrifying/denitrifying activated sludge process removes several micropollutants from wastewater by sorption onto sludge and/or biodegradation. The objective of this paper is to propose and evaluate a lab-scale experimental strategy for the determination of partition coefficient and biodegradation constant for micropollutant with an objective of modelling their removal. Four pharmaceutical compounds (ibuprofen, atenolol, diclofenac and fluoxetine) covering a wide hydrophobicity range (log Kow from 0.16 to 4.51) were chosen. Dissolved and particulate concentrations were monitored for 4 days, inside two reactors working under aerobic and anoxic conditions, and under different substrate feed conditions (biodegradable carbon and nitrogen). We determined the mechanisms responsible for the removal of the target compounds: (i) ibuprofen was biodegraded, mainly under aerobic conditions by cometabolism with biodegradable carbon, whereas anoxic conditions suppressed biodegradation; (ii) atenolol was biodegraded under both aerobic and anoxic conditions (with a higher biodegradation rate under aerobic conditions), and cometabolism with biodegradable carbon was the main mechanism; (iii) diclofenac and fluoxetine were removed by sorption only. Finally, the abilities of our strategy were evaluated by testing the suitability of the parameters for simulating effluent concentrations and removal efficiency at a full-scale plant.

  4. The neurotensin gene is a downstream target for Ras activation.

    PubMed Central

    Evers, B M; Zhou, Z; Celano, P; Li, J

    1995-01-01

    Ras regulates novel patterns of gene expression and the differentiation of various eukaryotic cell types. Stable transfection of Ha-ras into the human colon cancer line CaCo2 results in the morphologic differentiation to a small bowel phenotype. The purpose of our study was to determine whether the Ras regulatory pathway plays a role in the expression of the neurotensin gene (NT/N), a terminally differentiated endocrine product specifically localized in the gastrointestinal tract to the adult small bowel. We found that CaCo2-ras cells, but not parental CaCo2, express high levels of the human NT/N gene and, moreover, that this increase in gene expression is regulated at the level of transcription. Transfection experiments using NT/N-CAT mutation constructs identify the proximal 200 bp of NT/N flanking sequence as sufficient for maximal Ras-mediated NT/N reporter gene induction. Furthermore, a proximal AP-1/CRE motif is crucial for this Ras-mediated NT/N activation. Wild-type Ha-ras induces NT/N gene expression, albeit at lower levels than activated Ras; a dominant-negative Raf blocks this NT/N induction, suggesting that Raf lies down-stream of Ras in this pathway. In addition, postconfluent cultures of CaCo2 cells, which are differentiated to a small bowel phenotype, express the NT/N gene by 6 d after reaching confluency; this increase of NT/N expression is associated with concomitant increases of cellular p21ras protein. We conclude that Ras (both wild-type and activated) enhances expression of the NT/N gene in the gut-derived CaCo2 cell line, suggesting an important role for the Ras signaling pathway in NT/N gene transcription. Our results underscore the possibility that tissue-specific genes (such as NT/N) expressed in distinct subpopulations of the gut may be subject to Ras regulation. Finally, we speculate that the NT/N gene and the CaCo2 and CaCo2-ras cell systems will provide unique models to further define the cellular mechanisms leading to mammalian

  5. Decoding Target Distance and Saccade Amplitude from Population Activity in the Macaque Lateral Intraparietal Area (LIP)

    PubMed Central

    Bremmer, Frank; Kaminiarz, Andre; Klingenhoefer, Steffen; Churan, Jan

    2016-01-01

    Primates perform saccadic eye movements in order to bring the image of an interesting target onto the fovea. Compared to stationary targets, saccades toward moving targets are computationally more demanding since the oculomotor system must use speed and direction information about the target as well as knowledge about its own processing latency to program an adequate, predictive saccade vector. In monkeys, different brain regions have been implicated in the control of voluntary saccades, among them the lateral intraparietal area (LIP). Here we asked, if activity in area LIP reflects the distance between fovea and saccade target, or the amplitude of an upcoming saccade, or both. We recorded single unit activity in area LIP of two macaque monkeys. First, we determined for each neuron its preferred saccade direction. Then, monkeys performed visually guided saccades along the preferred direction toward either stationary or moving targets in pseudo-randomized order. LIP population activity allowed to decode both, the distance between fovea and saccade target as well as the size of an upcoming saccade. Previous work has shown comparable results for saccade direction (Graf and Andersen, 2014a,b). Hence, LIP population activity allows to predict any two-dimensional saccade vector. Functional equivalents of macaque area LIP have been identified in humans. Accordingly, our results provide further support for the concept of activity from area LIP as neural basis for the control of an oculomotor brain-machine interface. PMID:27630547

  6. Targeting Midbodies in Ovarian Cancer Stem Cells as a Therapeutic Strategy

    DTIC Science & Technology

    2013-10-01

    markers (CD133+, CD44+, CD117+). (Dyall et al., 2010; Ponnusamy et al., 2008). In both strategies, putative CSCs were fixed, spun onto coverslips...and stained for MBs using two different and effective MB markers , MKLP1 (Fig. 1) and MgcRacGAP. There was near complete (98.8+/- 0.3%) concordance...in MB staining using these markers . In both CSC preparations MBs were found to be significantly higher in the CSC fraction (Fig. 2, SP). We are

  7. Targeting executioner procaspase-3 with the procaspase-activating compound B-PAC-1 induces apoptosis in multiple myeloma cells.

    PubMed

    Zaman, Shadia; Wang, Rui; Gandhi, Varsha

    2015-11-01

    Multiple myeloma (MM) is a plasma cell neoplasm that has a low apoptotic index. We investigated a new class of small molecules that target the terminal apoptosis pathway, called procaspase activating compounds (PACs), in myeloma cells. PAC agents (PAC-1 and B-PAC-1) convert executioner procaspases (procaspase 3, 6, and 7) to active caspases 3, 6, and 7, which cleave target substrates to induce cellular apoptosis cascade. We hypothesized that targeting this terminal step could overcome survival and drug-resistance signals in myeloma cells and induce programmed cell death. Myeloma cells expressed executioner caspases. Additionally, our studies demonstrated that B-PAC-1 is cytotoxic to chemotherapy-resistant or sensitive myeloma cell lines (n = 7) and primary patient cells (n = 11). Exogenous zinc abrogated B-PAC-1-induced cell demise. Apoptosis induced by B-PAC-1 treatment was similar in the presence or absence of growth-promoting cytokines such as interleukin 6 and hepatocyte growth factor. Presence or absence of antiapoptotic proteins such as BCL-2, BCL-XL, or MCL-1 did not impact B-PAC-1-mediated programmed cell death. Collectively, our data demonstrate the proapoptotic effect of B-PAC-1 in MM and suggest that activating terminal executioner procaspases 3, 6, and 7 bypasses survival and drug-resistance signals in myeloma cells. This novel strategy has the potential to become an effective antimyeloma therapy.

  8. Multi-Target-Directed Ligands and other Therapeutic Strategies in the Search of a Real Solution for Alzheimer's Disease

    PubMed Central

    Agis-Torres, Angel; Sölhuber, Monica; Fernandez, Maria; Sanchez-Montero, J.M.

    2014-01-01

    The lack of an adequate therapy for Alzheimer's Disease (AD) contributes greatly to the continuous growing amount of papers and reviews, reflecting the important efforts made by scientists in this field. It is well known that AD is the most common cause of dementia, and up-to-date there is no prevention therapy and no cure for the disease, which contrasts with the enormous efforts put on the task. On the other hand many aspects of AD are currently debated or even unknown. This review offers a view of the current state of knowledge about AD which includes more relevant findings and processes that take part in the disease; it also shows more relevant past, present and future research on therapeutic drugs taking into account the new paradigm “Multi-Target-Directed Ligands” (MTDLs). In our opinion, this paradigm will lead from now on the research toward the discovery of better therapeutic solutions, not only in the case of AD but also in other complex diseases. This review highlights the strategies followed by now, and focuses other emerging targets that should be taken into account for the future development of new MTDLs. Thus, the path followed in this review goes from the pathology and the processes involved in AD to the strategies to consider in on-going and future researches. PMID:24533013

  9. Strategies to Increase After-School Program Staff Skills to Promote Healthy Eating and Physical Activity.

    PubMed

    Weaver, R Glenn; Beets, Michael W; Beighle, Aaron; Webster, Collin; Huberty, Jennifer; Moore, Justin B

    2016-01-01

    Standards targeting children's healthy eating and physical activity (HEPA) in after-school programs call for staff to display or refrain from HEPA-promoting or -discouraging behaviors that are linked to children's HEPA. This study evaluated strategies to align staff behaviors with HEPA Standards. Staff at four after-school programs serving approximately 500 children participated in professional development training from January 2012 to May 2013. Site leaders also attended workshops and received technical suppo