Monoenergetic ion acceleration and Rayleigh-Taylor instability of the composite target irradiated by the laser pulse

NASA Astrophysics Data System (ADS)

Khudik, Vladimir; Yi, S. Austin; Shvets, Gennady

2012-10-01

Acceleration of ions in the two-specie composite target irradiated by a circularly polarized laser pulse is studied analytically and via particle-in-cell (PIC) simulations. A self-consistent analytical model of the composite target is developed. In this model, target parameters are stationary in the center of mass of the system: heavy and light ions are completely separated from each other and form two layers, while electrons are bouncing in the potential well formed by the laser ponderomotive and electrostatic potentials. They are distributed in the direction of acceleration by the Boltzmann law and over velocities by the Maxwell-Juttner law. The laser pulse interacts directly only with electrons in a thin sheath layer, and these electrons transfer the laser pressure to the target ions. In the fluid approximation it is shown, the composite target is still susceptible to the Rayleigh-Taylor instability [1]. Using PIC simulations we found the growth rate of initially seeded perturbations as a function of their wavenumber for different composite target parameters and compare it with analytical results. Useful scaling laws between this rate and laser pulse pressure and target parameters are discussed.[4pt] [1] T.P. Yu, A. Pukhov, G. Shvets, M. Chen, T. H. Ratliff, S. A. Yi, and V. Khudik, Phys. Plasmas, 18, 043110 (2011).

Bladder sensory physiology: neuroactive compounds and receptors, sensory transducers, and target-derived growth factors as targets to improve function

PubMed Central

Gonzalez, Eric J.; Merrill, Liana

2014-01-01

Urinary bladder dysfunction presents a major problem in the clinical management of patients suffering from pathological conditions and neurological injuries or disorders. Currently, the etiology underlying altered visceral sensations from the urinary bladder that accompany the chronic pain syndrome, bladder pain syndrome (BPS)/interstitial cystitis (IC), is not known. Bladder irritation and inflammation are histopathological features that may underlie BPS/IC that can change the properties of lower urinary tract sensory pathways (e.g., peripheral and central sensitization, neurochemical plasticity) and contribute to exaggerated responses of peripheral bladder sensory pathways. Among the potential mediators of peripheral nociceptor sensitization and urinary bladder dysfunction are neuroactive compounds (e.g., purinergic and neuropeptide and receptor pathways), sensory transducers (e.g., transient receptor potential channels) and target-derived growth factors (e.g., nerve growth factor). We review studies related to the organization of the afferent limb of the micturition reflex and discuss neuroplasticity in an animal model of urinary bladder inflammation to increase the understanding of functional bladder disorders and to identify potential novel targets for development of therapeutic interventions. Given the heterogeneity of BPS/IC and the lack of consistent treatment benefits, it is unlikely that a single treatment directed at a single target in micturition reflex pathways will have a mass benefit. Thus, the identification of multiple targets is a prudent approach, and use of cocktail treatments directed at multiple targets should be considered. PMID:24760999

Discovery potential for directional dark matter detection with nuclear emulsions

NASA Astrophysics Data System (ADS)

Guler, A. M.; NEWSdm Collaboration

2017-06-01

Direct Dark Matter searches are nowadays one of the most exciting research topics. Several Experimental efforts are concentrated on the development, construction, and operation of detectors looking for the scattering of target nuclei with Weakly Interactive Massive Particles (WIMPs). In this field a new frontier can be opened by directional detectors able to reconstruct the direction of the WIMP-recoiled nucleus thus allowing to extend dark matter searches beyond the neutrino floor. Exploiting directionality would also give a proof of the galactic origin of dark matter making it possible to have a clear and unambiguous signal to background separation. The angular distribution of WIPM-scattered nuclei is indeed expected to be peaked in the direction of the motion of the Solar System in the Galaxy, i.e. toward the Cygnus constellation, while the background distribution is expected to be isotropic. Current directional experiments are based on the use of gas TPC whose sensitivity is limited by the small achievable detector mass. In this paper we show the potentiality in terms of exclusion limit of a directional experiment based on the use of a solid target made by newly developed nuclear emulsions and read-out systems reaching sub-micrometric resolution.

Initial study of Schroedinger eigenmaps for spectral target detection

NASA Astrophysics Data System (ADS)

Dorado-Munoz, Leidy P.; Messinger, David W.

2016-08-01

Spectral target detection refers to the process of searching for a specific material with a known spectrum over a large area containing materials with different spectral signatures. Traditional target detection methods in hyperspectral imagery (HSI) require assuming the data fit some statistical or geometric models and based on the model, to estimate parameters for defining a hypothesis test, where one class (i.e., target class) is chosen over the other classes (i.e., background class). Nonlinear manifold learning methods such as Laplacian eigenmaps (LE) have extensively shown their potential use in HSI processing, specifically in classification or segmentation. Recently, Schroedinger eigenmaps (SE), which is built upon LE, has been introduced as a semisupervised classification method. In SE, the former Laplacian operator is replaced by the Schroedinger operator. The Schroedinger operator includes by definition, a potential term V that steers the transformation in certain directions improving the separability between classes. In this regard, we propose a methodology for target detection that is not based on the traditional schemes and that does not need the estimation of statistical or geometric parameters. This method is based on SE, where the potential term V is taken into consideration to include the prior knowledge about the target class and use it to steer the transformation in directions where the target location in the new space is known and the separability between target and background is augmented. An initial study of how SE can be used in a target detection scheme for HSI is shown here. In-scene pixel and spectral signature detection approaches are presented. The HSI data used comprise various target panels for testing simultaneous detection of multiple objects with different complexities.

Spatial decoupling of targets and flashing stimuli for visual brain-computer interfaces

NASA Astrophysics Data System (ADS)

Waytowich, Nicholas R.; Krusienski, Dean J.

2015-06-01

Objective. Recently, paradigms using code-modulated visual evoked potentials (c-VEPs) have proven to achieve among the highest information transfer rates for noninvasive brain-computer interfaces (BCIs). One issue with current c-VEP paradigms, and visual-evoked paradigms in general, is that they require direct foveal fixation of the flashing stimuli. These interfaces are often visually unpleasant and can be irritating and fatiguing to the user, thus adversely impacting practical performance. In this study, a novel c-VEP BCI paradigm is presented that attempts to perform spatial decoupling of the targets and flashing stimuli using two distinct concepts: spatial separation and boundary positioning. Approach. For the paradigm, the flashing stimuli form a ring that encompasses the intended non-flashing targets, which are spatially separated from the stimuli. The user fixates on the desired target, which is classified using the changes to the EEG induced by the flashing stimuli located in the non-foveal visual field. Additionally, a subset of targets is also positioned at or near the stimulus boundaries, which decouples targets from direct association with a single stimulus. This allows a greater number of target locations for a fixed number of flashing stimuli. Main results. Results from 11 subjects showed practical classification accuracies for the non-foveal condition, with comparable performance to the direct-foveal condition for longer observation lengths. Online results from 5 subjects confirmed the offline results with an average accuracy across subjects of 95.6% for a 4-target condition. The offline analysis also indicated that targets positioned at or near the boundaries of two stimuli could be classified with the same accuracy as traditional superimposed (non-boundary) targets. Significance. The implications of this research are that c-VEPs can be detected and accurately classified to achieve comparable BCI performance without requiring potentially irritating direct foveation of flashing stimuli. Furthermore, this study shows that it is possible to increase the number of targets beyond the number of stimuli without degrading performance. Given the superior information transfer rate of c-VEP paradigms, these results can lead to the development of more practical and ergonomic BCIs.

Small mitochondria-targeting molecules as anti-cancer agents

PubMed Central

Wang, Feng; Ogasawara, Marcia A.; Huang, Peng

2009-01-01

Alterations in mitochondrial structure and functions have long been observed in cancer cells. Targeting mitochondria as a cancer therapeutic strategy has gained momentum in the recent years. The signaling pathways that govern mitochondrial function, apoptosis and molecules that affect mitochondrial integrity and cell viability have been important topics of the recent review in the literature. In this article, we first briefly summarize the rationale and biological basis for developing mitochondrial-targeted compounds as potential anticancer agents, and then provide key examples of small molecules that either directly impact mitochondria or functionally affect the metabolic alterations in cancer cells with mitochondrial dysfunction. The main focus is on the small molecular weight compounds with potential applications in cancer treatment. We also summarize information on the drug developmental stages of the key mitochondria-targeted compounds and their clinical trial status. The advantages and potential shortcomings of targeting the mitochondria for cancer treatment are also discussed. PMID:19995573

Aptamers as tools for target prioritization and lead identification.

PubMed

Burgstaller, Petra; Girod, Anne; Blind, Michael

2002-12-15

The increasing number of potential drug target candidates has driven the development of novel technologies designed to identify functionally important targets and enhance the subsequent lead discovery process. Highly specific synthetic nucleic acid ligands--also known as aptamers--offer a new exciting route in the drug discovery process by linking target validation directly with HTS. Recently, aptamers have proven to be valuable tools for modulating the function of endogenous cellular proteins in their natural environment. A set of technologies has been developed to use these sophisticated ligands for the validation of potential drug targets in disease models. Moreover, aptamers that are specific antagonists of protein function can act as substitute interaction partners in HTS assays to facilitate the identification of small-molecule lead compounds.

TALE-mediated epigenetic suppression of CDKN2A increases replication in human fibroblasts.

PubMed

Bernstein, Diana L; Le Lay, John E; Ruano, Elena G; Kaestner, Klaus H

2015-05-01

Current strategies to alter disease-associated epigenetic modifications target ubiquitously expressed epigenetic regulators. This approach does not allow specific genes to be controlled in specific cell types; therefore, tools to selectively target epigenetic modifications in the desired cell type and strategies to more efficiently correct aberrant gene expression in disease are needed. Here, we have developed a method for directing DNA methylation to specific gene loci by conjugating catalytic domains of DNA methyltransferases (DNMTs) to engineered transcription activator-like effectors (TALEs). We demonstrated that these TALE-DNMTs direct DNA methylation specifically to the targeted gene locus in human cells. Further, we determined that minimizing direct nucleotide sequence repeats within the TALE moiety permits efficient lentivirus transduction, allowing easy targeting of primary cell types. Finally, we demonstrated that directed DNA methylation with a TALE-DNMT targeting the CDKN2A locus, which encodes the cyclin-dependent kinase inhibitor p16, decreased CDKN2A expression and increased replication of primary human fibroblasts, as intended. Moreover, overexpression of p16 in these cells reversed the proliferative phenotype, demonstrating the specificity of our epigenetic targeting. Together, our results demonstrate that TALE-DNMTs can selectively target specific genes and suggest that this strategy has potential application for the development of locus-specific epigenetic therapeutics.

TALE-mediated epigenetic suppression of CDKN2A increases replication in human fibroblasts

PubMed Central

Bernstein, Diana L.; Le Lay, John E.; Ruano, Elena G.; Kaestner, Klaus H.

2015-01-01

Current strategies to alter disease-associated epigenetic modifications target ubiquitously expressed epigenetic regulators. This approach does not allow specific genes to be controlled in specific cell types; therefore, tools to selectively target epigenetic modifications in the desired cell type and strategies to more efficiently correct aberrant gene expression in disease are needed. Here, we have developed a method for directing DNA methylation to specific gene loci by conjugating catalytic domains of DNA methyltransferases (DNMTs) to engineered transcription activator–like effectors (TALEs). We demonstrated that these TALE-DNMTs direct DNA methylation specifically to the targeted gene locus in human cells. Further, we determined that minimizing direct nucleotide sequence repeats within the TALE moiety permits efficient lentivirus transduction, allowing easy targeting of primary cell types. Finally, we demonstrated that directed DNA methylation with a TALE-DNMT targeting the CDKN2A locus, which encodes the cyclin-dependent kinase inhibitor p16, decreased CDKN2A expression and increased replication of primary human fibroblasts, as intended. Moreover, overexpression of p16 in these cells reversed the proliferative phenotype, demonstrating the specificity of our epigenetic targeting. Together, our results demonstrate that TALE-DNMTs can selectively target specific genes and suggest that this strategy has potential application for the development of locus-specific epigenetic therapeutics. PMID:25866970

Integrative FourD omics approach profiles the target network of the carbon storage regulatory system

PubMed Central

Sowa, Steven W.; Gelderman, Grant; Leistra, Abigail N.; Buvanendiran, Aishwarya; Lipp, Sarah; Pitaktong, Areen; Vakulskas, Christopher A.; Romeo, Tony; Baldea, Michael

2017-01-01

Abstract Multi-target regulators represent a largely untapped area for metabolic engineering and anti-bacterial development. These regulators are complex to characterize because they often act at multiple levels, affecting proteins, transcripts and metabolites. Therefore, single omics experiments cannot profile their underlying targets and mechanisms. In this work, we used an Integrative FourD omics approach (INFO) that consists of collecting and analyzing systems data throughout multiple time points, using multiple genetic backgrounds, and multiple omics approaches (transcriptomics, proteomics and high throughput sequencing crosslinking immunoprecipitation) to evaluate simultaneous changes in gene expression after imposing an environmental stress that accentuates the regulatory features of a network. Using this approach, we profiled the targets and potential regulatory mechanisms of a global regulatory system, the well-studied carbon storage regulatory (Csr) system of Escherichia coli, which is widespread among bacteria. Using 126 sets of proteomics and transcriptomics data, we identified 136 potential direct CsrA targets, including 50 novel ones, categorized their behaviors into distinct regulatory patterns, and performed in vivo fluorescence-based follow up experiments. The results of this work validate 17 novel mRNAs as authentic direct CsrA targets and demonstrate a generalizable strategy to integrate multiple lines of omics data to identify a core pool of regulator targets. PMID:28126921

Cytokines and cytokine networks target neurons to modulate long-term potentiation.

PubMed

Prieto, G Aleph; Cotman, Carl W

2017-04-01

Cytokines play crucial roles in the communication between brain cells including neurons and glia, as well as in the brain-periphery interactions. In the brain, cytokines modulate long-term potentiation (LTP), a cellular correlate of memory. Whether cytokines regulate LTP by direct effects on neurons or by indirect mechanisms mediated by non-neuronal cells is poorly understood. Elucidating neuron-specific effects of cytokines has been challenging because most brain cells express cytokine receptors. Moreover, cytokines commonly increase the expression of multiple cytokines in their target cells, thus increasing the complexity of brain cytokine networks even after single-cytokine challenges. Here, we review evidence on both direct and indirect-mediated modulation of LTP by cytokines. We also describe novel approaches based on neuron- and synaptosome-enriched systems to identify cytokines able to directly modulate LTP, by targeting neurons and synapses. These approaches can test multiple samples in parallel, thus allowing the study of multiple cytokines simultaneously. Hence, a cytokine networks perspective coupled with neuron-specific analysis may contribute to delineation of maps of the modulation of LTP by cytokines. Copyright © 2017 Elsevier Ltd. All rights reserved.

Cytokines and cytokine networks target neurons to modulate long-term potentiation

PubMed Central

Prieto, G. Aleph; Cotman, Carl W.

2017-01-01

Cytokines play crucial roles in the communication between brain cells including neurons and glia, as well as in the brain-periphery interactions. In the brain, cytokines modulate long-term potentiation (LTP), a cellular correlate of memory. Whether cytokines regulate LTP by direct effects on neurons or by indirect mechanisms mediated by non-neuronal cells is poorly understood. Elucidating neuron-specific effects of cytokines has been challenging because most brain cells express cytokine receptors. Moreover, cytokines commonly increase the expression of multiple cytokines in their target cells, thus increasing the complexity of brain cytokine networks even after single-cytokine challenges. Here, we review evidence on both direct and indirect-mediated modulation of LTP by cytokines. We also describe novel approaches based on neuron- and synaptosome-enriched systems to identify cytokines able to directly modulate LTP, by targeting neurons and synapses. These approaches can test multiple samples in parallel, thus allowing the study of multiple cytokines simultaneously. Hence, a cytokine networks perspective coupled with neuron-specific analysis may contribute to delineation of maps of the modulation of LTP by cytokines. PMID:28377062

Yeast as a potential vehicle for neglected tropical disease drug discovery.

PubMed

Denny, P W; Steel, P G

2015-01-01

High-throughput screening (HTS) efforts for neglected tropical disease (NTD) drug discovery have recently received increased attention because several initiatives have begun to attempt to reduce the deficit in new and clinically acceptable therapies for this spectrum of infectious diseases. HTS primarily uses two basic approaches, cell-based and in vitro target-directed screening. Both of these approaches have problems; for example, cell-based screening does not reveal the target or targets that are hit, whereas in vitro methodologies lack a cellular context. Furthermore, both can be technically challenging, expensive, and difficult to miniaturize for ultra-HTS [(u)HTS]. The application of yeast-based systems may overcome some of these problems and offer a cost-effective platform for target-directed screening within a eukaryotic cell context. Here, we review the advantages and limitations of the technologies that may be used in yeast cell-based, target-directed screening protocols, and we discuss how these are beginning to be used in NTD drug discovery. © 2014 Society for Laboratory Automation and Screening.

Non-Maxwellian electron distributions by direct laser acceleration in near-critical plasmas

NASA Astrophysics Data System (ADS)

Toncian, T.; Wang, C.; Arefiev, A.; McCary, E.; Meadows, A.; Blakeney, J.; Chester, C.; Roycroft, R.; Fu, H.; Yan, X. Q.; Schreiber, J.; Pomerantz, I.; Quevedo, H.; Dyer, G.; Gaul, E.; Ditmire, T.; Hegelich, B. M.

2015-11-01

The irradiation of few nm thick targets by a finite-contrast high-intensity short-pulse laser results in a strong pre-expansion of these targets at the arrival time of the main pulse. The targets will decompress to near and lower than critical electron densities plasmas extending over lengths of few micrometers. The laser-matter interaction of the main pulse with such a highly localized but inhomogeneous the target leads to the generation of a channel and further self focussing of the laser beam. As measured in a experiment conducted with the GHOST laser system at UT Austin, 2D PIC simulations predict Direct Laser Acceleration of non-Maxwellian electron distribution in the laser propagation direction for such targets. The hereby high density electron bunches have potential applications as injector beams for a further wakefield acceleration stage. This work was supported by NNSA cooperative agreement DE-NA0002008, the DARPA's PULSE program (12-63-PULSE-FP014) and the AFOSR (FA9550-14-1-0045).

Direct-drive inertial confinement fusion research at the Laboratory for Laser Energetics: charting the path to thermonuclear ignition

NASA Astrophysics Data System (ADS)

McCrory, R. L.; Regan, S. P.; Loucks, S. J.; Meyerhofer, D. D.; Skupsky, S.; Betti, R.; Boehly, T. R.; Craxton, R. S.; Collins, T. J. B.; Delettrez, J. A.; Edgell, D.; Epstein, R.; Fletcher, K. A.; Freeman, C.; Frenje, J. A.; Glebov, V. Yu.; Goncharov, V. N.; Harding, D. R.; Igumenshchev, I. V.; Keck, R. L.; Kilkenny, J. D.; Knauer, J. P.; Li, C. K.; Marciante, J.; Marozas, J. A.; Marshall, F. J.; Maximov, A. V.; McKenty, P. W.; Myatt, J.; Padalino, S.; Petrasso, R. D.; Radha, P. B.; Sangster, T. C.; Séguin, F. H.; Seka, W.; Smalyuk, V. A.; Soures, J. M.; Stoeckl, C.; Yaakobi, B.; Zuegel, J. D.

2005-10-01

Significant theoretical and experimental progress continues to be made at the University of Rochester's Laboratory for Laser Energetics (LLE), charting the path to direct-drive inertial confinement fusion (ICF) ignition. Direct drive offers the potential for higher-gain implosions than x-ray drive and is a leading candidate for an inertial fusion energy power plant. LLE's direct-drive ICF ignition target designs for the National Ignition Facility (NIF) are based on hot-spot ignition. A cryogenic target with a spherical DT-ice layer, within or without a foam matrix, enclosed by a thin plastic shell, will be directly irradiated with ~1.5 MJ of laser energy. Cryogenic and plastic/foam (surrogate-cryogenic) targets that are hydrodynamically scaled from these ignition target designs are imploded on the 60-beam, 30 kJ, UV OMEGA laser system to validate the key target physics issues, including energy coupling, hydrodynamic instabilities and implosion symmetry. Prospects for direct-drive ignition on the NIF are extremely favourable, even while it is in its x-ray-drive irradiation configuration, with the development of the polar-direct-drive concept. A high-energy petawatt capability is being constructed at LLE next to the existing 60-beam OMEGA compression facility. This OMEGA EP (extended performance) laser will add two short-pulse, 2.6 kJ beams to the OMEGA laser system to backlight direct-drive ICF implosions and study fast-ignition physics with focused intensities up to 6 × 1020 W cm-2.

miR-182 targets CHL1 and controls tumor growth and invasion in papillary thyroid carcinoma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhu, Hongling; Fang, Jin; Zhang, Jichen

2014-07-18

Highlights: • miR-182 and CHL1 expression patterns are negatively correlated. • CHL1 is a direct target of miR-182 in PTC cells. • miR-182 suppression inhibits PTC cell growth and invasion. • CHL1 is involved in miR-182-mediated cell behavior. - Abstract: In this study, we investigated the role and underlying mechanism of action of miR-182 in papillary thyroid carcinoma (PTC). Bioinformatics analysis revealed close homolog of LI (CHL1) as a potential target of miR-182. Upregulation of miR-182 was significantly correlated with CHL1 downregulation in human PTC tissues and cell lines. miR-182 suppressed the expression of CHL1 mRNA through direct targeting ofmore » the 3′-untranslated region (3′-UTR). Downregulation of miR-182 suppressed growth and invasion of PTC cells. Silencing of CHL1 counteracted the effects of miR-182 suppression, while its overexpression mimicked these effects. Our data collectively indicate that miR-182 in PTC promotes cell proliferation and invasion through direct suppression of CHL1, supporting the potential utility of miR-182 inhibition as a novel therapeutic strategy against PTC.« less

CRISPR-mediated targeting of HER2 inhibits cell proliferation through a dominant negative mutation.

PubMed

Wang, Huajing; Sun, William

2017-01-28

With the discovery of the CRISPR/Cas9 technology, genome editing could be performed in a rapid, precise and effective manner. Its potential applications in functional interrogation of cancer-causing genes and cancer therapy have been extensively explored. In this study, we demonstrated the use of the CRISPR/Cas9 system to directly target the oncogene HER2. Directing Cas9 to exons of the HER2 gene inhibited cell growth in breast cancer cell lines that harbor amplification of the HER2 locus. The inhibitory effect was potentiated with the addition of PARP inhibitors. Unexpectedly, CRISPR-induced mutations did not significantly affect the level of HER2 protein expression. Instead, CRISPR targeting appeared to exert its effect through a dominant negative mutation. This HER2 mutant interfered with the MAPK/ERK axis of HER2 downstream signaling. Our work provides a novel mechanism underlying the anti-cancer effects of HER2-targeting by CRISPR/Cas9, which is distinct from the clinical drug Herceptin. In addition, it opens up the possibility that incomplete CRISPR targeting of certain oncogenes could still have therapeutic value by generation of dominant negative mutants. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Fragment-Based Screening of a Natural Product Library against 62 Potential Malaria Drug Targets Employing Native Mass Spectrometry

PubMed Central

2018-01-01

Natural products are well known for their biological relevance, high degree of three-dimensionality, and access to areas of largely unexplored chemical space. To shape our understanding of the interaction between natural products and protein targets in the postgenomic era, we have used native mass spectrometry to investigate 62 potential protein targets for malaria using a natural-product-based fragment library. We reveal here 96 low-molecular-weight natural products identified as binding partners of 32 of the putative malarial targets. Seventy-nine (79) fragments have direct growth inhibition on Plasmodium falciparum at concentrations that are promising for the development of fragment hits against these protein targets. This adds a fragment library to the published HTS active libraries in the public domain. PMID:29436819

Fragment-Based Screening of a Natural Product Library against 62 Potential Malaria Drug Targets Employing Native Mass Spectrometry.

PubMed

Vu, Hoan; Pedro, Liliana; Mak, Tin; McCormick, Brendan; Rowley, Jessica; Liu, Miaomiao; Di Capua, Angela; Williams-Noonan, Billy; Pham, Ngoc B; Pouwer, Rebecca; Nguyen, Bao; Andrews, Katherine T; Skinner-Adams, Tina; Kim, Jessica; Hol, Wim G J; Hui, Raymond; Crowther, Gregory J; Van Voorhis, Wesley C; Quinn, Ronald J

2018-04-13

Natural products are well known for their biological relevance, high degree of three-dimensionality, and access to areas of largely unexplored chemical space. To shape our understanding of the interaction between natural products and protein targets in the postgenomic era, we have used native mass spectrometry to investigate 62 potential protein targets for malaria using a natural-product-based fragment library. We reveal here 96 low-molecular-weight natural products identified as binding partners of 32 of the putative malarial targets. Seventy-nine (79) fragments have direct growth inhibition on Plasmodium falciparum at concentrations that are promising for the development of fragment hits against these protein targets. This adds a fragment library to the published HTS active libraries in the public domain.

Discovery of direct inhibitors of Keap1-Nrf2 protein-protein interaction as potential therapeutic and preventive agents.

PubMed

Abed, Dhulfiqar Ali; Goldstein, Melanie; Albanyan, Haifa; Jin, Huijuan; Hu, Longqin

2015-07-01

The Keap1-Nrf2-ARE pathway is an important antioxidant defense mechanism that protects cells from oxidative stress and the Keap1-Nrf2 protein-protein interaction (PPI) has become an important drug target to upregulate the expression of ARE-controlled cytoprotective oxidative stress response enzymes in the development of therapeutic and preventive agents for a number of diseases and conditions. However, most known Nrf2 activators/ARE inducers are indirect inhibitors of Keap1-Nrf2 PPI and they are electrophilic species that act by modifying the sulfhydryl groups of Keap1׳s cysteine residues. The electrophilicity of these indirect inhibitors may cause "off-target" side effects by reacting with cysteine residues of other important cellular proteins. Efforts have recently been focused on the development of direct inhibitors of Keap1-Nrf2 PPI. This article reviews these recent research efforts including the development of high throughput screening assays, the discovery of peptide and small molecule direct inhibitors, and the biophysical characterization of the binding of these inhibitors to the target Keap1 Kelch domain protein. These non-covalent direct inhibitors of Keap1-Nrf2 PPI could potentially be developed into effective therapeutic or preventive agents for a variety of diseases and conditions.

Novel role of apatinib as a multi-target RTK inhibitor in the direct suppression of hepatocellular carcinoma cells.

PubMed

Li, Xiaojin; Xu, Anjian; Li, Huihui; Zhang, Bei; Cao, Bangwei; Huang, Jian

2018-05-01

Although apatinib has been demonstrated with potential antitumor activity in multiple solid tumors, the underlying mechanism of apatinib for the treatment of hepatocellular carcinoma (HCC) remains unclear. In the present study, we explored if there are any direct suppression effects of apatinib on HCC cells and its relevant targets. We investigated the effect of apatinib on viability of five HCC cell lines and an intrahepatic cholangiocarcinoma cell line, and colony formation, apoptosis and migration of representative HCC cells in vitro; and HCC progression in a xenograft mouse model. Using a phospho-receptor tyrosine kinase pathway array with 49 different tyrosine kinases, we screened and verified the tyrosine kinase targets involved in apatinib response. Apatinib treatment significantly inhibited HCC cell viability, proliferation, colony formation, and migration, and enhanced cell apoptosis in a concentration-dependent manner (p < 0.05). Furthermore, apatinib showed a favorable anti-tumor growth effect (71% of inhibition ratio, p < 0.05) in an established human HCC xenograft mice model with good safety. RTK pathway arrays and western blots analysis demonstrated that apatinib significantly downregulated the phosphorylation levels of several tyrosine kinase receptors, particularly PDGFR-α and IGF-IR, and inhibited Akt phosphorylation. These data suggest that the apatinib may have a direct anti-HCC effect as a direct multi-target RTK inhibitor of HCC cells and a promising potentiality in HCC clinical therapies. Copyright © 2018 Elsevier B.V. All rights reserved.

Early Career Academic Mentoring Using Twitter: The Case of #ECRchat

ERIC Educational Resources Information Center

Ferguson, Hazel; Wheat, Katherine L.

2015-01-01

Early career academics around the world frequently see themselves as being in need of targeted career support to navigate the years directly following PhD graduation. The growth of discussion groups on Twitter that target these users raises questions about their potential usefulness to address career development support needs. This paper reflects…

Recombinant Buckwheat Trypsin Inhibitor Induces Mitophagy by Directly Targeting Mitochondria and Causes Mitochondrial Dysfunction in Hep G2 Cells.

PubMed

Wang, Zhuanhua; Li, Shanshan; Ren, Rong; Li, Jiao; Cui, Xiaodong

2015-09-09

Mitochondria are essential targets for cancer chemotherapy and other disease treatments. Recombinant buckwheat trypsin inhibitor (rBTI), a member of the potato type I proteinase inhibitor family, was derived from tartary buckwheat extracts. Our results showed that rBTI directly targeted mitochondria and induced mitochondrial fragmentation and mitophagy. This occurs through enhanced depolarization of the mitochondrial membrane potential, increasing reactive oxygen species (ROS) generation associated with the rise of the superoxide dismutase and catalase activity and glutathione peroxidase (GSH) content, and changes in the GSH/oxidized glutathione ratio. Mild and transient ROS induced by rBTI were shown to be important signaling molecules required to induce Hep G2 mitophagy to remove dysfunctional mitochondria. Furthermore, rBTI could directly induce mitochondrial fragmentation. It was also noted that rBTI highly increased colocalization of mitochondria in treated cells compared to nontreated cells. Tom 20, a subunit of the translocase of the mitochondrial outer membrane complex responsible for recognizing mitochondrial presequences, may be the direct target of rBTI.

A new prospect in cancer therapy: targeting cancer stem cells to eradicate cancer.

PubMed

Chen, Li-Sha; Wang, An-Xin; Dong, Bing; Pu, Ke-Feng; Yuan, Li-Hua; Zhu, Yi-Min

2012-12-01

According to the cancer stem cell theory, cancers can be initiated by cancer stem cells. This makes cancer stem cells prime targets for therapeutic intervention. Eradicating cancer stem cells by efficient targeting agents may have the potential to cure cancer. In this review, we summarize recent breakthroughs that have improved our understanding of cancer stem cells, and we discuss the therapeutic strategy of targeting cancer stem cells, a promising future direction for cancer stem cell research.

Integrative FourD omics approach profiles the target network of the carbon storage regulatory system.

PubMed

Sowa, Steven W; Gelderman, Grant; Leistra, Abigail N; Buvanendiran, Aishwarya; Lipp, Sarah; Pitaktong, Areen; Vakulskas, Christopher A; Romeo, Tony; Baldea, Michael; Contreras, Lydia M

2017-02-28

Multi-target regulators represent a largely untapped area for metabolic engineering and anti-bacterial development. These regulators are complex to characterize because they often act at multiple levels, affecting proteins, transcripts and metabolites. Therefore, single omics experiments cannot profile their underlying targets and mechanisms. In this work, we used an Integrative FourD omics approach (INFO) that consists of collecting and analyzing systems data throughout multiple time points, using multiple genetic backgrounds, and multiple omics approaches (transcriptomics, proteomics and high throughput sequencing crosslinking immunoprecipitation) to evaluate simultaneous changes in gene expression after imposing an environmental stress that accentuates the regulatory features of a network. Using this approach, we profiled the targets and potential regulatory mechanisms of a global regulatory system, the well-studied carbon storage regulatory (Csr) system of Escherichia coli, which is widespread among bacteria. Using 126 sets of proteomics and transcriptomics data, we identified 136 potential direct CsrA targets, including 50 novel ones, categorized their behaviors into distinct regulatory patterns, and performed in vivo fluorescence-based follow up experiments. The results of this work validate 17 novel mRNAs as authentic direct CsrA targets and demonstrate a generalizable strategy to integrate multiple lines of omics data to identify a core pool of regulator targets. © The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.

Prioritizing therapeutic targets using patient-derived xenograft models

PubMed Central

Lodhia, K.A; Hadley, A; Haluska, P; Scott, C.L

2015-01-01

Effective systemic treatment of cancer relies on the delivery of agents with optimal therapeutic potential. The molecular age of medicine has provided genomic tools that can identify a large number of potential therapeutic targets in individual patients, heralding the promise of personalized treatment. However, determining which potential targets actually drive tumor growth and should be prioritized for therapy is challenging. Indeed, reliable molecular matches of target and therapeutic agent have been stringently validated in the clinic for only a small number of targets. Patient-derived xenografts (PDX) are tumor models developed in immunocompromised mice using tumor procured directly from the patient. As patient surrogates, PDX models represent a powerful tool for addressing individualized therapy. Challenges include humanizing the immune system of PDX models and ensuring high quality molecular annotation, in order to maximise insights for the clinic. Importantly, PDX can be sampled repeatedly and in parallel, to reveal clonal evolution, which may predict mechanisms of drug resistance and inform therapeutic strategy design. PMID:25783201

Improved Lysosomal Trafficking Can Modulate the Potency of Antibody Drug Conjugates.

PubMed

DeVay, Rachel M; Delaria, Kathy; Zhu, Guoyun; Holz, Charles; Foletti, Davide; Sutton, Janette; Bolton, Gary; Dushin, Russell; Bee, Christine; Pons, Jaume; Rajpal, Arvind; Liang, Hong; Shelton, David; Liu, Shu-Hui; Strop, Pavel

2017-04-19

Antibody drug conjugates (ADCs) provide an efficacious and relatively safe means by which chemotherapeutic agents can be specifically targeted to cancer cells. In addition to the selection of antibody targets, ADCs offer a modular design that allows selection of ADC characteristics through the choice of linker chemistries, toxins, and conjugation sites. Many studies have indicated that release of toxins bound to antibodies via noncleavable linker chemistries relies on the internalization and intracellular trafficking of the ADC. While this can make noncleavable ADCs more stable in the serum, it can also result in lower efficacy when their respective targets are not internalized efficiently or are recycled back to the cell surface following internalization. Here, we show that a lysosomally targeted ADC against the protein APLP2 mediates cell killing, both in vitro and in vivo, more effectively than an ADC against Trop2, a protein with less efficient lysosomal targeting. We also engineered a bispecific ADC with one arm targeting HER2 for the purpose of directing the ADC to tumors, and the other arm targeting APLP2, whose purpose is to direct the ADC to lysosomes for toxin release. This proof-of-concept bispecific ADC demonstrates that this technology can be used to shift the intracellular trafficking of a constitutively recycled target by directing one arm of the antibody against a lysosomally delivered protein. Our data also show limitations of this approach and potential future directions for development.

Specific c-Jun target genes in malignant melanoma.

PubMed

Schummer, Patrick; Kuphal, Silke; Vardimon, Lily; Bosserhoff, Anja K; Kappelmann, Melanie

2016-05-03

A fundamental event in the development and progression of malignant melanoma is the de-regulation of cancer-relevant transcription factors. We recently showed that c-Jun is a main regulator of melanoma progression and, thus, is the most important member of the AP-1 transcription factor family in this disease. Surprisingly, no cancer-related specific c-Jun target genes in melanoma were described in the literature, so far. Therefore, we focused on pre-existing ChIP-Seq data (Encyclopedia of DNA Elements) of 3 different non-melanoma cell lines to screen direct c-Jun target genes. Here, a specific c-Jun antibody to immunoprecipitate the associated promoter DNA was used. Consequently, we identified 44 direct c-Jun targets and a detailed analysis of 6 selected genes confirmed their deregulation in malignant melanoma. The identified genes were differentially regulated comparing 4 melanoma cell lines and normal human melanocytes and we confirmed their c-Jun dependency. Direct interaction between c-Jun and the promoter/enhancer regions of the identified genes was confirmed by us via ChIP experiments. Interestingly, we revealed that the direct regulation of target gene expression via c-Jun can be independent of the existence of the classical AP-1 (5´-TGA(C/G)TCA-3´) consensus sequence allowing for the subsequent down- or up-regulation of the expression of these cancer-relevant genes. In summary, the results of this study indicate that c-Jun plays a crucial role in the development and progression of malignant melanoma via direct regulation of cancer-relevant target genes and that inhibition of direct c-Jun targets through inhibition of c-Jun is a potential novel therapeutic option for treatment of malignant melanoma.

Optimized programming algorithm for cylindrical and directional deep brain stimulation electrodes.

PubMed

Anderson, Daria Nesterovich; Osting, Braxton; Vorwerk, Johannes; Dorval, Alan D; Butson, Christopher R

2018-04-01

Deep brain stimulation (DBS) is a growing treatment option for movement and psychiatric disorders. As DBS technology moves toward directional leads with increased numbers of smaller electrode contacts, trial-and-error methods of manual DBS programming are becoming too time-consuming for clinical feasibility. We propose an algorithm to automate DBS programming in near real-time for a wide range of DBS lead designs. Magnetic resonance imaging and diffusion tensor imaging are used to build finite element models that include anisotropic conductivity. The algorithm maximizes activation of target tissue and utilizes the Hessian matrix of the electric potential to approximate activation of neurons in all directions. We demonstrate our algorithm's ability in an example programming case that targets the subthalamic nucleus (STN) for the treatment of Parkinson's disease for three lead designs: the Medtronic 3389 (four cylindrical contacts), the direct STNAcute (two cylindrical contacts, six directional contacts), and the Medtronic-Sapiens lead (40 directional contacts). The optimization algorithm returns patient-specific contact configurations in near real-time-less than 10 s for even the most complex leads. When the lead was placed centrally in the target STN, the directional leads were able to activate over 50% of the region, whereas the Medtronic 3389 could activate only 40%. When the lead was placed 2 mm lateral to the target, the directional leads performed as well as they did in the central position, but the Medtronic 3389 activated only 2.9% of the STN. This DBS programming algorithm can be applied to cylindrical electrodes as well as novel directional leads that are too complex with modern technology to be manually programmed. This algorithm may reduce clinical programming time and encourage the use of directional leads, since they activate a larger volume of the target area than cylindrical electrodes in central and off-target lead placements.

Activity-based proteome profiling of potential cellular targets of Orlistat--an FDA-approved drug with anti-tumor activities.

PubMed

Yang, Peng-Yu; Liu, Kai; Ngai, Mun Hong; Lear, Martin J; Wenk, Markus R; Yao, Shao Q

2010-01-20

Orlistat, or tetrahydrolipstatin (THL), is an FDA-approved antiobesity drug with potential antitumor activities. Cellular off-targets and potential side effects of Orlistat in cancer therapies, however, have not been extensively explored thus far. In this study, we report the total of synthesis of THL-like protein-reactive probes, in which extremely conservative modifications (i.e., an alkyne handle) were introduced in the parental THL structure to maintain the native biological properties of Orlistat, while providing the necessary functionality for target identification via the bio-orthogonal click chemistry. With these natural productlike, cell-permeable probes, we were able to demonstrate, for the first time, this chemical proteomic approach is suitable for the identification of previously unknown cellular targets of Orlistat. In addition to the expected fatty acid synthase (FAS), we identified a total of eight new targets, some of which were further validated by experiments including Western blotting, recombinant protein expression, and site-directed mutagenesis. Our findings have important implications in the consideration of Orlistat as a potential anticancer drug at its early stages of development for cancer therapy. Our strategy should be broadly useful for off-target identification against quite a number of existing drugs and/or candidates, which are also covalent modifiers of their biological targets.

Target-directed Dynamic Combinatorial Chemistry: A Study on Potentials and Pitfalls as Exemplified on a Bacterial Target.

PubMed

Frei, Priska; Pang, Lijuan; Silbermann, Marleen; Eriş, Deniz; Mühlethaler, Tobias; Schwardt, Oliver; Ernst, Beat

2017-08-25

Target-directed dynamic combinatorial chemistry (DCC) is an emerging technique for the efficient identification of inhibitors of pharmacologically relevant targets. In this contribution, we present an application for a bacterial target, the lectin FimH, a crucial virulence factor of uropathogenic E. coli being the main cause of urinary tract infections. A small dynamic library of acylhydrazones was formed from aldehydes and hydrazides and equilibrated at neutral pH in presence of aniline as nucleophilic catalyst. The major success factors turned out to be an accordingly adjusted ratio of scaffolds and fragments, an adequate sample preparation prior to HPLC analysis, and the data processing. Only then did the ranking of the dynamic library constituents correlate well with affinity data. Furthermore, as a support of DCC applications especially to larger libraries, a new protocol for improved hit identification was established. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Safe Handling of Oral Antineoplastic Medications: Focus on Targeted Therapeutics in the Home Setting

PubMed Central

Cass, Yaakov; Connor, Thomas H.; Tabachnik, Alexander

2017-01-01

Introduction With the growing number of oral targeted therapies being approved for use in cancer therapy, the potential for long-term administration of these drugs to cancer patients is expanding. The use of these drugs in the home setting has the potential to expose family members and caregivers to them either through direct contact with the drugs or indirectly by exposure to the parent compounds and/or their active metabolites in contaminated patient's waste. Methods A systematic literature review was performed and the known adverse health effect of 32 oral targeted therapeutics is summarized. In particular, the carcinogenicity, genotoxicity, and embryo-foetal toxicity, along with the route of excretion were evaluated. Results Carcinogenicity testing has not been performed on most of the oral targeted therapeutics and the genotoxicity data are mixed. However, the majority of these drugs exhibit adverse reproductive effects, some of which are severe. Currently available data does not permit the possibility of a health hazard from inappropriate handling of drugs and contaminated patients waste to be ignored, especially in a long-term home setting. Further research is needed to understand these issues. Conclusions With the expanding use of targeted therapies in the home setting, family members and caregivers, especially those of reproductive risk age, are, potentially at risk. Overall basic education and related precautions should be taken to protect family members and caregivers from indirect or direct exposure from these drugs. Further investigations and discussion on this subject is warranted. PMID:27009803

Demodex as a Delivery Vector for Topical Targeted Medications in the Skin for Early Melanoma and Non-Melanoma Skin Cancer.

PubMed

Strobel, Stephen L

2017-09-01

The potential utilization of Demodex mites as delivery vectors for cytotoxic medications directed to early skin cancer is proposed. Potential benefits, proof of concept, and limitations are discussed. © 2017 by the Association of Clinical Scientists, Inc.

Automated Detection of Repetitive Motor Behaviors as an Outcome Measurement in Intellectual and Developmental Disabilities

ERIC Educational Resources Information Center

Gilchrist, Kristin H.; Hegarty-Craver, Meghan; Christian, Robert B.; Grego, Sonia; Kies, Ashley C.; Wheeler, Anne C.

2018-01-01

Repetitive sensory motor behaviors are a direct target for clinical treatment and a potential treatment endpoint for individuals with intellectual or developmental disabilities. By removing the burden associated with video annotation or direct observation, automated detection of stereotypy would allow for longer term monitoring in ecologic…

Early visuomotor representations revealed from evoked local field potentials in motor and premotor cortical areas.

PubMed

O'Leary, John G; Hatsopoulos, Nicholas G

2006-09-01

Local field potentials (LFPs) recorded from primary motor cortex (MI) have been shown to be tuned to the direction of visually guided reaching movements, but MI LFPs have not been shown to be tuned to the direction of an upcoming movement during the delay period that precedes movement in an instructed-delay reaching task. Also, LFPs in dorsal premotor cortex (PMd) have not been investigated in this context. We therefore recorded LFPs from MI and PMd of monkeys (Macaca mulatta) and investigated whether these LFPs were tuned to the direction of the upcoming movement during the delay period. In three frequency bands we identified LFP activity that was phase-locked to the onset of the instruction stimulus that specified the direction of the upcoming reach. The amplitude of this activity was often tuned to target direction with tuning widths that varied across different electrodes and frequency bands. Single-trial decoding of LFPs demonstrated that prediction of target direction from this activity was possible well before the actual movement is initiated. Decoding performance was significantly better in the slowest-frequency band compared with that in the other two higher-frequency bands. Although these results demonstrate that task-related information is available in the local field potentials, correlations among these signals recorded from a densely packed array of electrodes suggests that adequate decoding performance for neural prosthesis applications may be limited as the number of simultaneous electrode recordings is increased.

Kohn-Sham potentials from electron densities using a matrix representation within finite atomic orbital basis sets

NASA Astrophysics Data System (ADS)

Zhang, Xing; Carter, Emily A.

2018-01-01

We revisit the static response function-based Kohn-Sham (KS) inversion procedure for determining the KS effective potential that corresponds to a given target electron density within finite atomic orbital basis sets. Instead of expanding the potential in an auxiliary basis set, we directly update the potential in its matrix representation. Through numerical examples, we show that the reconstructed density rapidly converges to the target density. Preliminary results are presented to illustrate the possibility of obtaining a local potential in real space from the optimized potential in its matrix representation. We have further applied this matrix-based KS inversion approach to density functional embedding theory. A proof-of-concept study of a solvated proton transfer reaction demonstrates the method's promise.

MicroRNA-510 promotes cell and tumor growth by targeting peroxiredoxin1 in breast cancer

PubMed Central

2013-01-01

Introduction MicroRNAs are small non-coding RNAs that are involved in the post-transcriptional negative regulation of mRNAs. MicroRNA 510 (miR-510) was initially shown to have a potential oncogenic role in breast cancer by the observation of its elevated levels in human breast tumor samples when compared to matched non-tumor samples. Few targets have been identified for miR-510. However, as microRNAs function through the negative regulation of their direct targets, the identification of those targets is critical for the understanding of their functional role in breast cancer. Methods Breast cancer cell lines were transfected with pre-miR-510 or antisense miR-510 and western blotting and quantitative real time PCR were performed. Functional assays performed included cell growth, migration, invasion, colony formation, cytotoxicity and in vivo tumor growth. We performed a PCR assay to identify novel direct targets of miR-510. The study focused on peroxiredoxin 1 (PRDX1) as it was identified through our screen and was bioinformatically predicted to contain a miR-510 seed site in its 3' untranslated region (3'UTR). Luciferase reporter assays and site-directed mutagenesis were performed to confirm PRDX1 as a direct target. The Student's two-sided, paired t-test was used and a P-value less than 0.05 was considered significant. Results We show that miR-510 overexpression in non-transformed and breast cancer cells can increase their cell growth, migration, invasion and colony formation in vitro. We also observed increased tumor growth when miR-510 was overexpressed in vivo. We identified PRDX1 through a novel PCR screen and confirmed it as a direct target using luciferase reporter assays. The reintroduction of PRDX1 into breast cancer cell lines without its regulatory 3'UTR confirmed that miR-510 was mediating its migratory phenotype at least in part through the negative regulation of PRDX1. Furthermore, the PI3K/Akt pathway was identified as a positive regulator of miR-510 both in vitro and in vivo. Conclusions In this study, we provide evidence to support a role for miR-510 as a novel oncomir. We show that miR-510 directly binds to the 3'UTR of PRDX1 and blocks its protein expression, thereby suppressing migration of human breast cancer cells. Taken together, these data support a pivotal role for miR-510 in breast cancer progression and suggest it as a potential therapeutic target in breast cancer patients. PMID:23971998

MicroRNA-510 promotes cell and tumor growth by targeting peroxiredoxin1 in breast cancer.

PubMed

Guo, Qi J; Mills, Jamie N; Bandurraga, Savannah G; Nogueira, Lourdes M; Mason, Natalie J; Camp, E Ramsay; Larue, Amanda C; Turner, David P; Findlay, Victoria J

2013-01-01

MicroRNAs are small non-coding RNAs that are involved in the post-transcriptional negative regulation of mRNAs. MicroRNA 510 (miR-510) was initially shown to have a potential oncogenic role in breast cancer by the observation of its elevated levels in human breast tumor samples when compared to matched non-tumor samples. Few targets have been identified for miR-510. However, as microRNAs function through the negative regulation of their direct targets, the identification of those targets is critical for the understanding of their functional role in breast cancer. Breast cancer cell lines were transfected with pre-miR-510 or antisense miR-510 and western blotting and quantitative real time PCR were performed. Functional assays performed included cell growth, migration, invasion, colony formation, cytotoxicity and in vivo tumor growth. We performed a PCR assay to identify novel direct targets of miR-510. The study focused on peroxiredoxin 1 (PRDX1) as it was identified through our screen and was bioinformatically predicted to contain a miR-510 seed site in its 3' untranslated region (3'UTR). Luciferase reporter assays and site-directed mutagenesis were performed to confirm PRDX1 as a direct target. The Student's two-sided, paired t-test was used and a P-value less than 0.05 was considered significant. We show that miR-510 overexpression in non-transformed and breast cancer cells can increase their cell growth, migration, invasion and colony formation in vitro. We also observed increased tumor growth when miR-510 was overexpressed in vivo. We identified PRDX1 through a novel PCR screen and confirmed it as a direct target using luciferase reporter assays. The reintroduction of PRDX1 into breast cancer cell lines without its regulatory 3'UTR confirmed that miR-510 was mediating its migratory phenotype at least in part through the negative regulation of PRDX1. Furthermore, the PI3K/Akt pathway was identified as a positive regulator of miR-510 both in vitro and in vivo. In this study, we provide evidence to support a role for miR-510 as a novel oncomir. We show that miR-510 directly binds to the 3'UTR of PRDX1 and blocks its protein expression, thereby suppressing migration of human breast cancer cells. Taken together, these data support a pivotal role for miR-510 in breast cancer progression and suggest it as a potential therapeutic target in breast cancer patients.

Recent advances in botulinum neurotoxin inhibitor development.

PubMed

Kiris, Erkan; Burnett, James C; Kane, Christopher D; Bavari, Sina

2014-01-01

Botulinum neurotoxins (BoNTs) are endopeptidases that target motor neurons and block acetylcholine neurotransmitter release. This action results in the muscle paralysis that defines the disease botulism. To date, there are no FDA-approved therapeutics to treat BoNT-mediated paralysis after intoxication of the motor neuron. Importantly, the rationale for pursuing treatments to counter these toxins is driven by their potential misuse. Current drug discovery efforts have mainly focused on small molecules, peptides, and peptidomimetics that can directly and competitively inhibit BoNT light chain proteolytic activity. Although this is a rational approach, direct inhibition of the Zn(2+) metalloprotease activity has been elusive as demonstrated by the dearth of candidates undergoing clinical evaluation. Therefore, broadening the scope of viable targets beyond that of active site protease inhibitors represents an additional strategy that could move the field closer to the clinic. Here we review the rationale, and discuss the outcomes of earlier approaches and highlight potential new targets for BoNT inhibition. These include BoNT uptake and processing inhibitors, enzymatic inhibitors, and modulators of neuronal processes associated with toxin clearance, neurotransmitter potentiation, and other pathways geared towards neuronal recovery and repair.

Drug-targeting methodologies with applications: A review

PubMed Central

Kleinstreuer, Clement; Feng, Yu; Childress, Emily

2014-01-01

Targeted drug delivery to solid tumors is a very active research area, focusing mainly on improved drug formulation and associated best delivery methods/devices. Drug-targeting has the potential to greatly improve drug-delivery efficacy, reduce side effects, and lower the treatment costs. However, the vast majority of drug-targeting studies assume that the drug-particles are already at the target site or at least in its direct vicinity. In this review, drug-delivery methodologies, drug types and drug-delivery devices are discussed with examples in two major application areas: (1) inhaled drug-aerosol delivery into human lung-airways; and (2) intravascular drug-delivery for solid tumor targeting. The major problem addressed is how to deliver efficiently the drug-particles from the entry/infusion point to the target site. So far, most experimental results are based on animal studies. Concerning pulmonary drug delivery, the focus is on the pros and cons of three inhaler types, i.e., pressurized metered dose inhaler, dry powder inhaler and nebulizer, in addition to drug-aerosol formulations. Computational fluid-particle dynamics techniques and the underlying methodology for a smart inhaler system are discussed as well. Concerning intravascular drug-delivery for solid tumor targeting, passive and active targeting are reviewed as well as direct drug-targeting, using optimal delivery of radioactive microspheres to liver tumors as an example. The review concludes with suggestions for future work, considereing both pulmonary drug targeting and direct drug delivery to solid tumors in the vascular system. PMID:25516850

ATR architecture for multisensor fusion

NASA Astrophysics Data System (ADS)

Hamilton, Mark K.; Kipp, Teresa A.

1996-06-01

The work of the U.S. Army Research Laboratory (ARL) in the area of algorithms for the identification of static military targets in single-frame electro-optical (EO) imagery has demonstrated great potential in platform-based automatic target identification (ATI). In this case, the term identification is used to mean being able to tell the difference between two military vehicles -- e.g., the M60 from the T72. ARL's work includes not only single-sensor forward-looking infrared (FLIR) ATI algorithms, but also multi-sensor ATI algorithms. We briefly discuss ARL's hybrid model-based/data-learning strategy for ATI, which represents a significant step forward in ATI algorithm design. For example, in the case of single sensor FLIR it allows the human algorithm designer to build directly into the algorithm knowledge that can be adequately modeled at this time, such as the target geometry which directly translates into the target silhouette in the FLIR realm. In addition, it allows structure that is not currently well understood (i.e., adequately modeled) to be incorporated through automated data-learning algorithms, which in a FLIR directly translates into an internal thermal target structure signature. This paper shows the direct applicability of this strategy to both the single-sensor FLIR as well as the multi-sensor FLIR and laser radar.

Novel high throughput pooled shRNA screening identifies NQO1 as a potential drug target for host directed therapy for tuberculosis

PubMed Central

Li, Qing; Karim, Ahmad F.; Ding, Xuedong; Das, Biswajit; Dobrowolski, Curtis; Gibson, Richard M.; Quiñones-Mateu, Miguel E.; Karn, Jonathan; Rojas, Roxana E.

2016-01-01

Chemical regulation of macrophage function is one key strategy for developing host-directed adjuvant therapies for tuberculosis (TB). A critical step to develop these therapies is the identification and characterization of specific macrophage molecules and pathways with a high potential to serve as drug targets. Using a barcoded lentivirus-based pooled short-hairpin RNA (shRNA) library combined with next generation sequencing, we identified 205 silenced host genes highly enriched in mycobacteria-resistant macrophages. Twenty-one of these “hits” belonged to the oxidoreductase functional category. NAD(P)H:quinone oxidoreductase 1 (NQO1) was the top oxidoreductase “hit”. NQO1 expression was increased after mycobacterial infection, and NQO1 knockdown increased macrophage differentiation, NF-κB activation, and the secretion of pro-inflammatory cytokines TNF-α and IL-1β in response to infection. This suggests that mycobacteria hijacks NQO1 to down-regulate pro-inflammatory and anti-bacterial functions. The competitive inhibitor of NQO1 dicoumarol synergized with rifampin to promote intracellular killing of mycobacteria. Thus, NQO1 is a new host target in mycobacterial infection that could potentially be exploited to increase antibiotic efficacy in vivo. Our findings also suggest that pooled shRNA libraries could be valuable tools for genome-wide screening in the search for novel druggable host targets for adjunctive TB therapies. PMID:27297123

Mapping Proteome-Wide Interactions of Reactive Chemicals Using Chemoproteomic Platforms

PubMed Central

Counihan, Jessica L.; Ford, Breanna; Nomura, Daniel K.

2015-01-01

A large number of pharmaceuticals, endogenous metabolites, and environmental chemicals act through covalent mechanisms with protein targets. Yet, their specific interactions with the proteome still remain poorly defined for most of these reactive chemicals. Deciphering direct protein targets of reactive small-molecules is critical in understanding their biological action, off-target effects, potential toxicological liabilities, and development of safer and more selective agents. Chemoproteomic technologies have arisen as a powerful strategy that enable the assessment of proteome-wide interactions of these irreversible agents directly in complex biological systems. We review here several chemoproteomic strategies that have facilitated our understanding of specific protein interactions of irreversibly-acting pharmaceuticals, endogenous metabolites, and environmental electrophiles to reveal novel pharmacological, biological, and toxicological mechanisms. PMID:26647369

Human portable preconcentrator system

DOEpatents

Linker, Kevin L.; Brusseau, Charles A.; Hannum, David W.; Puissant, James G.; Varley, Nathan R.

2003-08-12

A preconcentrator system and apparatus suited to human portable use wherein sample potentially containing a target chemical substance is drawn into a chamber and through a pervious screen. The screen is adapted to capture target chemicals and then, upon heating, to release those chemicals into the chamber. Chemicals captured and then released in this fashion are then carried to a portable chemical detection device such as a portable ion mobility spectrometer. In the preferred embodiment, the means for drawing sample into the chamber comprises a reversible fan which, when operated in reverse direction, creates a backpressure that facilitates evolution of captured target chemicals into the chamber when the screen is heated. The screen can be positioned directly in front of the detector prior to heating to improve detection capability.

Circulating and disseminated tumor cells: diagnostic tools and therapeutic targets in motion

PubMed Central

Lin, Peter P.; Gires, Olivier

2017-01-01

Enumeration of circulating tumor cells (CTCs) in peripheral blood with the gold standard CellSearchTM has proven prognostic value for tumor recurrence and progression of metastatic disease. Therefore, the further molecular characterization of isolated CTCs might have clinical relevance as liquid biopsy for therapeutic decision-making and to monitor disease progression. The direct analysis of systemic cancer appears particularly important in view of the known disparity in expression of therapeutic targets as well as epithelial-to-mesenchymal transition (EMT)-based heterogeneity between primary and systemic tumor cells, which all substantially complicate monitoring and therapeutic targeting at present. Since CTCs are the potential precursor cells of metastasis, their in-depth molecular profiling should also provide a useful resource for target discovery. The present review will discuss the use of systemically spread cancer cells as liquid biopsy and focus on potential target antigens. PMID:27683128

[Unconscious Acoustical Stimuli Effects on Event-related Potentials in Humans].

PubMed

Kopeikina, E A; Choroshich, V V; Aleksandrov, A Y; Ivanova, V Y

2015-01-01

Unconscious perception essentially affects human behavior. The main results in this area obtained in experiments with visual stimuli. However, the acoustical stimuli play not less important role in behavior. The main idea of this paper is the electroencephalographic investigation of unconscious acoustical stimulation effects on electro-physiological activity of the brain. For this purpose, the event-related potentials were acquired under unconscious stimulus priming paradigm. The one syllable, three letter length, Russian words and pseudo-words with single letter substitution were used as primes and targets. As a result, we find out that repetition and alternative priming similarly affects the event-related potential's component with 200 ms latency after target application in frontal parietal and temporal areas. Under alternative priming the direction of potential amplitude modification nearby 400 ms was altered for word and semi-word targets. Alternative priming reliably increase ERP's amplitude in 400 ms locality with pseudo-word targets and decrease it under word targets. Taking into account, that all participants were unable to distinguish the applied prime stimuli, we can assume that the event-related potential changes evoked by unconscious perception of acoustical stimuli. The ERP amplitude dynamics revealed in current investigation demonstrate the opportunity of subliminal acoustical stimuli to modulate the electrical activity evoked by verbal acoustical stimulation.

Identification of potential target genes of ROR-alpha in THP1 and HUVEC cell lines.

PubMed

Gulec, Cagri; Coban, Neslihan; Ozsait-Selcuk, Bilge; Sirma-Ekmekci, Sema; Yildirim, Ozlem; Erginel-Unaltuna, Nihan

2017-04-01

ROR-alpha is a nuclear receptor, activity of which can be modulated by natural or synthetic ligands. Due to its possible involvement in, and potential therapeutic target for atherosclerosis, we aimed to identify ROR-alpha target genes in monocytic and endothelial cell lines. We performed chromatin immunoprecipitation (ChIP) followed by tiling array (ChIP-on-chip) for ROR-alpha in monocytic cell line THP1 and endothelial cell line HUVEC. Following bioinformatic analysis of the array data, we tested four candidate genes in terms of dependence of their expression level on ligand-mediated ROR-alpha activity, and two of them in terms of promoter occupancy by ROR-alpha. Bioinformatic analyses of ChIP-on-chip data suggested that ROR-alpha binds to genomic regions near the transcription start site (TSS) of more than 3000 genes in THP1 and HUVEC. Potential ROR-alpha target genes in both cell types seem to be involved mainly in membrane receptor activity, signal transduction and ion transport. While SPP1 and IKBKA were shown to be direct target genes of ROR-alpha in THP1 monocytes, inflammation related gene HMOX1 and heat shock protein gene HSPA8 were shown to be potential target genes of ROR-alpha. Our results suggest that ROR-alpha may regulate signaling receptor activity, and transmembrane transport activity through its potential target genes. ROR-alpha seems also to play role in cellular sensitivity to environmental substances like arsenite and chloroprene. Although, the expression analyses have shown that synthetic ROR-alpha ligands can modulate some of potential ROR-alpha target genes, functional significance of ligand-dependent modulation of gene expression needs to be confirmed with further analyses. Copyright © 2017 Elsevier Inc. All rights reserved.

Host-Directed Therapeutics as a Novel Approach for Tuberculosis Treatment.

PubMed

Kim, Ye-Ram; Yang, Chul-Su

2017-09-28

Despite significant efforts to improve the treatment of tuberculosis (TB), it remains a prevalent infectious disease worldwide owing to the limitations of current TB therapeutic regimens. Recent work on novel TB treatment strategies has suggested that directly targeting host factors may be beneficial for TB treatment. Such strategies, termed host-directed therapeutics (HDTs), focus on host-pathogen interactions. HDTs may be more effective than the currently approved TB drugs, which are limited by the long durations of treatment needed and the emergence of drug-resistant strains. Targets of HDTs include host factors such as cytokines, immune checkpoints, immune cell functions, and essential enzyme activities. This review article discusses examples of potentially promising HDTs and introduces novel approaches for their development.

Understanding approach and avoidance in verbal descriptions of everyday actions: An ERP study.

PubMed

Marrero, Hipólito; Urrutia, Mabel; Beltrán, David; Gámez, Elena; Díaz, José M

2017-06-01

Understanding verbal descriptions of everyday actions could involve the neural representation of action direction (avoidance and approach) toward persons and things. We recorded the electrophysiological activity of participants while they were reading approach/avoidance action sentences that were directed toward a target: a thing/a person (i.e., "Petra accepted/rejected Ramón in her group"/ "Petra accepted/rejected the receipt of the bank"). We measured brain potentials time locked to the target word. In the case of things, we found a N400-like component with right frontal distribution modulated by approach/avoidance action. This component was more negative in avoidance than in approach sentences. In the case of persons, a later negative event-related potential (545-750 ms) with left frontal distribution was sensitive to verb direction, showing more negative amplitude for approach than avoidance actions. In addition, more negativity in approach-person sentences was associated with fear avoidance trait, whereas less negativity in avoidance-person sentences was associated with a greater approach trait. Our results support that verbal descriptions of approach/avoidance actions are encoded differently depending on whether the target is a thing or a person. Implications of these results for a social, emotional and motivational understanding of action language are discussed.

SU-F-T-345: Quasi-Dead Beams: Clinical Relevance and Implications for Automatic Planning

DOE Office of Scientific and Technical Information (OSTI.GOV)

Price, R; Veltchev, I; Lin, T

Purpose: Beam direction selection for fixed-beam IMRT planning is typically a manual process. Severe dose-volume limits on critical structures in the thorax often result in atypical selection of beam directions as compared to other body sites. This work demonstrates the potential consequences as well as clinical relevance. Methods: 21 thoracic cases treated with 5–7 beam directions, 6 cases including non-coplanar arrangements, with fractional doses of 150–411cGy were analyzed. Endpoints included per-beam modulation scaling factor (MSF), variation from equal weighting, and delivery QA passing rate. Results: During analysis of patient-specific delivery QA a sub-standard passing rate was found for a singlemore » 5-field plan (90.48% of pixels evaluated passing 3% dose, 3mm DTA). During investigation it was found that a single beam demonstrated a MSF of 34.7 and contributed only 2.7% to the mean dose of the target. In addition, the variation from equal weighting for this beam was 17.3% absolute resulting in another beam with a MSF of 4.6 contributing 41.9% to the mean dose to the target; a variation of 21.9% from equal weighting. The average MSF for the remaining 20 cases was 4.0 (SD 1.8) with an average absolute deviation of 2.8% from equal weighting (SD 3.1%). Conclusion: Optimization in commercial treatment planning systems typically results in relatively equally weighted beams. Extreme variation from this can result in excessively high MSFs (very small segments) and potential decreases in agreement between planned and delivered dose distributions. In addition, the resultant beam may contribute minimal dose to the target (quasi-dead beam); a byproduct being increased treatment time and associated localization uncertainties. Potential ramifications exist for automatic planning algorithms should they allow for user-defined beam directions. Additionally, these quasi-dead beams may be embedded in the libraries for model-based systems potentially resulting in inefficient and less accurate deliveries.« less

Evaluation of interatomic potentials for rainbow scattering under axial channeling at KCl(0 0 1) surface by three-dimensional computer simulations based on binary collision approximation

NASA Astrophysics Data System (ADS)

Takeuchi, Wataru

2017-05-01

The rainbow angles corresponding to prominent peaks in the angular distributions of scattered projectiles with small angle, attributed to rainbow scattering (RS), under axial surface channeling conditions are strongly influenced by the interatomic potentials between projectiles and target atoms. The dependence of rainbow angles on normal energy of projectile energy to the target surface, being experimentally obtained by Specht et al. for RS of He, N, Ne and Ar atoms under <1 0 0> and <1 1 0> axial channeling conditions at a KCl(0 0 1) surface with projectile energies of 1-60 keV, was evaluated by the three-dimensional computer simulations using the ACOCT code based on the binary collision approximation with interatomic pair potentials. Good agreement between the ACOCT results using the ZBL pair potential and the individual pair potentials calculated from Hartree-Fock (HF) wave functions and the experimental ones was found for RS of He, N and Ne atoms from the atomic rows along <1 0 0> direction. For <1 1 0> direction, the ACOCT results employing the Moliere pair potential with adjustable screening length of O'Connor-Biersack (OB) formula, the ZBL pair potential and the individual HF pair potentials except for Ar → KCl using the OB pair potential are nearly in agreement with the experimental ones.

Microscopic Examination of Cold Spray Cermet Sn+In2O3 Coatings for Sputtering Target Materials

PubMed Central

Baszczuk, A.; Rutkowska-Gorczyca, M.; Jasiorski, M.; Małachowska, A.; Posadowski, W.; Znamirowski, Z.

2017-01-01

Low-pressure cold spraying is a newly developed technology with high application potential. The aim of this study was to investigate potential application of this technique for producing a new type of transparent conductive oxide films target. Cold spraying technique allows the manufacture of target directly on the backing plate; therefore the proposed sputtering target has a form of Sn+In2O3 coating sprayed onto copper substrate. The microstructure and properties of the feedstock powder prepared using three various methods as well as the deposited ones by low-pressure cold spraying coatings were evaluated, compared, and analysed. Produced cermet Sn+In2O3 targets were employed in first magnetron sputtering process to deposit preliminary, thin, transparent conducting oxide films onto the glass substrates. The resistivity of obtained preliminary films was measured and allows believing that fabrication of TCO (transparent conducting oxide) films using targets produced by cold spraying is possible in the future, after optimization of the deposition conditions. PMID:29109810

Microscopic Examination of Cold Spray Cermet Sn+In2O3 Coatings for Sputtering Target Materials.

PubMed

Winnicki, M; Baszczuk, A; Rutkowska-Gorczyca, M; Jasiorski, M; Małachowska, A; Posadowski, W; Znamirowski, Z; Ambroziak, A

2017-01-01

Low-pressure cold spraying is a newly developed technology with high application potential. The aim of this study was to investigate potential application of this technique for producing a new type of transparent conductive oxide films target. Cold spraying technique allows the manufacture of target directly on the backing plate; therefore the proposed sputtering target has a form of Sn+In 2 O 3 coating sprayed onto copper substrate. The microstructure and properties of the feedstock powder prepared using three various methods as well as the deposited ones by low-pressure cold spraying coatings were evaluated, compared, and analysed. Produced cermet Sn+In 2 O 3 targets were employed in first magnetron sputtering process to deposit preliminary, thin, transparent conducting oxide films onto the glass substrates. The resistivity of obtained preliminary films was measured and allows believing that fabrication of TCO (transparent conducting oxide) films using targets produced by cold spraying is possible in the future, after optimization of the deposition conditions.

Multimodal Encoding of Goal-Directed Actions in Monkey Ventral Premotor Grasping Neurons.

PubMed

Bruni, Stefania; Giorgetti, Valentina; Fogassi, Leonardo; Bonini, Luca

2017-01-01

Visuo-motor neurons of the ventral premotor area F5 encode "pragmatic" representations of object in terms of the potential motor acts (e.g., precision grip) afforded by it. Likewise, objects with identical pragmatic features (e.g., small spheres) but different behavioral value (e.g., edible or inedible) convey different "semantic" information and thus afford different goal-directed behaviors (e.g., grasp-to-eat or grasp-to-place). However, whether F5 neurons can extract distinct behavioral affordances from objects with similar pragmatic features is unknown. We recorded 134 F5 visuo-motor neurons in 2 macaques during a contextually cued go/no-go task in which the monkey grasped, or refrained from grasping, a previously presented edible or inedible target to eat it or placing it, respectively. Sixty-nine visuo-motor neurons showed motor selectivity for the target (35 food and 34 object), and about half of them (N = 35) exhibited congruent visual preference. Interestingly, when the monkey grasped in complete darkness and could identify the target only based on haptic feedback, visuo-motor neurons lost their precontact selectivity, but most of them (80%) showed it again 60 ms after hand-target contact. These findings suggest that F5 neurons possess a multimodal access to semantic information on objects, which are transformed into motor representations of the potential goal-directed actions afforded by them. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Optimal directed searches for continuous gravitational waves

NASA Astrophysics Data System (ADS)

Ming, Jing; Krishnan, Badri; Papa, Maria Alessandra; Aulbert, Carsten; Fehrmann, Henning

2016-03-01

Wide parameter space searches for long-lived continuous gravitational wave signals are computationally limited. It is therefore critically important that the available computational resources are used rationally. In this paper we consider directed searches, i.e., targets for which the sky position is known accurately but the frequency and spin-down parameters are completely unknown. Given a list of such potential astrophysical targets, we therefore need to prioritize. On which target(s) should we spend scarce computing resources? What parameter space region in frequency and spin-down should we search through? Finally, what is the optimal search setup that we should use? In this paper we present a general framework that allows us to solve all three of these problems. This framework is based on maximizing the probability of making a detection subject to a constraint on the maximum available computational cost. We illustrate the method for a simplified problem.

Properties of Protein Drug Target Classes

PubMed Central

Bull, Simon C.; Doig, Andrew J.

2015-01-01

Accurate identification of drug targets is a crucial part of any drug development program. We mined the human proteome to discover properties of proteins that may be important in determining their suitability for pharmaceutical modulation. Data was gathered concerning each protein’s sequence, post-translational modifications, secondary structure, germline variants, expression profile and drug target status. The data was then analysed to determine features for which the target and non-target proteins had significantly different values. This analysis was repeated for subsets of the proteome consisting of all G-protein coupled receptors, ion channels, kinases and proteases, as well as proteins that are implicated in cancer. Machine learning was used to quantify the proteins in each dataset in terms of their potential to serve as a drug target. This was accomplished by first inducing a random forest that could distinguish between its targets and non-targets, and then using the random forest to quantify the drug target likeness of the non-targets. The properties that can best differentiate targets from non-targets were primarily those that are directly related to a protein’s sequence (e.g. secondary structure). Germline variants, expression levels and interactions between proteins had minimal discriminative power. Overall, the best indicators of drug target likeness were found to be the proteins’ hydrophobicities, in vivo half-lives, propensity for being membrane bound and the fraction of non-polar amino acids in their sequences. In terms of predicting potential targets, datasets of proteases, ion channels and cancer proteins were able to induce random forests that were highly capable of distinguishing between targets and non-targets. The non-target proteins predicted to be targets by these random forests comprise the set of the most suitable potential future drug targets, and should therefore be prioritised when building a drug development programme. PMID:25822509

Acute myeloid leukemia targets for bispecific antibodies

PubMed Central

Hoseini, S S; Cheung, N K

2017-01-01

Despite substantial gains in our understanding of the genomics of acute myelogenous leukemia (AML), patient survival remains unsatisfactory especially among the older age group. T cell-based therapy of lymphoblastic leukemia is rapidly advancing; however, its application in AML is still lagging behind. Bispecific antibodies can redirect polyclonal effector cells to engage chosen targets on leukemia blasts. When the effector cells are natural-killer cells, both antibody-dependent and antibody-independent mechanisms could be exploited. When the effectors are T cells, direct tumor cytotoxicity can be engaged followed by a potential vaccination effect. In this review, we summarize the AML-associated tumor targets and the bispecific antibodies that have been studied. The potentials and limitations of each of these systems will be discussed. PMID:28157217

Pharmacology of Antisense Drugs.

PubMed

Bennett, C Frank; Baker, Brenda F; Pham, Nguyen; Swayze, Eric; Geary, Richard S

2017-01-06

Recent studies have led to a greater appreciation of the diverse roles RNAs play in maintaining normal cellular function and how they contribute to disease pathology, broadening the number of potential therapeutic targets. Antisense oligonucleotides are the most direct means to target RNA in a selective manner and have become an established platform technology for drug discovery. There are multiple molecular mechanisms by which antisense oligonucleotides can be used to modulate RNAs in cells, including promoting the degradation of the targeted RNA or modulating RNA function without degradation. Antisense drugs utilizing various antisense mechanisms are demonstrating therapeutic potential for the treatment of a broad variety of diseases. This review focuses on some of the advances that have taken place in translating antisense technology from the bench to the clinic.

The Potential of Automated Corrective Feedback to Remediate Cohesion Problems in Advanced Students' Writing

ERIC Educational Resources Information Center

Strobl, Carola

2017-01-01

This study explores the potential of a feedback environment using simple string-based pattern matching technology for the provision of automated corrective feedback on cohesion problems. Thirty-eight high-frequent problems, including non-target like use of connectives and co-references were addressed providing both direct and indirect feedback.…

miR-130b targets NKD2 and regulates the Wnt signaling to promote proliferation and inhibit apoptosis in osteosarcoma cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Li, Zhi; Li, Youjun, E-mail: liyoujunn@126.com; Wang, Nan

miR-130b was significantly up-regulated in osteosarcoma (OS) cells. Naked cuticle homolog 2 (NKD2) inhibited tumor growth and metastasis in OS by suppressing Wnt signaling. We used three miRNA target analysis tools to identify potential targets of miR-130b, and found that NKD2 is a potential target of miR-130b. Based on these findings, we hypothesize that miR-130b might target NKD2 and regulate the Wnt signaling to promote OS growth. We detected the expression of miR-130b and NKD2 mRNA and protein by quantitative Real-Time PCR (qRT-PCR) and western blot assays, respectively, and found up-regulation of miR-130b and down-regulation of NKD2 mRNA and proteinmore » exist in OS cell lines. MTT and flow cytometry assays showed that miR-130b inhibitors inhibit proliferation and promote apoptosis in OS cells. Furthermore, we showed that NKD2 is a direct target of miR-130b, and miR-130b regulated proliferation and apoptosis of OS cells by targeting NKD2. We further investigated whether miR-130b and NKD2 regulate OS cell proliferation and apoptosis by inhibiting Wnt signaling, and the results confirmed our speculation that miR-130b targets NKD2 and regulates the Wnt signaling to promote proliferation and inhibit apoptosis of OS cells. These findings will offer new clues for OS development and progression, and novel potential therapeutic targets for OS. - Highlights: • miR-130b is up-regulated and NKD2 is down-regulated in osteosarcoma cell lines. • Down-regulation of miR-130b inhibits proliferation of osteosarcoma cells. • Down-regulation of miR-130b promotes apoptosis of osteosarcoma cells. • miR-130b directly targets NKD2. • NKD2 regulates OS cell proliferation and apoptosis by inhibiting the Wnt signaling.« less

Identifying therapeutic targets in gastric cancer: the current status and future direction

PubMed Central

Yu, Beiqin; Xie, Jingwu

2016-01-01

Gastric cancer is the third leading cause of cancer-related death worldwide. Our basic understanding of gastric cancer biology falls behind that of many other cancer types. Current standard treatment options for gastric cancer have not changed for the last 20 years. Thus, there is an urgent need to establish novel strategies to treat this deadly cancer. Successful clinical trials with Gleevec in CML and gastrointestinal stromal tumors have set up an example for targeted therapy of cancer. In this review, we will summarize major progress in classification, therapeutic options of gastric cancer. We will also discuss molecular mechanisms for drug resistance in gastric cancer. In addition, we will attempt to propose potential future directions in gastric cancer biology and drug targets. PMID:26373844

Knockdown of miR-21 in human breast cancer cell lines inhibits proliferation, in vitro migration and in vivo tumor growth

PubMed Central

2011-01-01

Introduction MicroRNAs (miRNAs) are a class of small non-coding RNAs (20 to 24 nucleotides) that post-transcriptionally modulate gene expression. A key oncomir in carcinogenesis is miR-21, which is consistently up-regulated in a wide range of cancers. However, few functional studies are available for miR-21, and few targets have been identified. In this study, we explored the role of miR-21 in human breast cancer cells and tissues, and searched for miR-21 targets. Methods We used in vitro and in vivo assays to explore the role of miR-21 in the malignant progression of human breast cancer, using miR-21 knockdown. Using LNA silencing combined to microarray technology and target prediction, we screened for potential targets of miR-21 and validated direct targets by using luciferase reporter assay and Western blot. Two candidate target genes (EIF4A2 and ANKRD46) were selected for analysis of correlation with clinicopathological characteristics and prognosis using immunohistochemistry on cancer tissue microrrays. Results Anti-miR-21 inhibited growth and migration of MCF-7 and MDA-MB-231 cells in vitro, and tumor growth in nude mice. Knockdown of miR-21 significantly increased the expression of ANKRD46 at both mRNA and protein levels. Luciferase assays using a reporter carrying a putative target site in the 3' untranslated region of ANKRD46 revealed that miR-21 directly targeted ANKRD46. miR-21 and EIF4A2 protein were inversely expressed in breast cancers (rs = -0.283, P = 0.005, Spearman's correlation analysis). Conclusions Knockdown of miR-21 in MCF-7 and MDA-MB-231 cells inhibits in vitro and in vivo growth as well as in vitro migration. ANKRD46 is newly identified as a direct target of miR-21 in BC. These results suggest that inhibitory strategies against miR-21 using peptide nucleic acids (PNAs)-antimiR-21 may provide potential therapeutic applications in breast cancer treatment. PMID:21219636

Knockdown of miR-21 in human breast cancer cell lines inhibits proliferation, in vitro migration and in vivo tumor growth.

PubMed

Yan, Li Xu; Wu, Qi Nian; Zhang, Yan; Li, Yang Yang; Liao, Ding Zhun; Hou, Jing Hui; Fu, Jia; Zeng, Mu Sheng; Yun, Jing Ping; Wu, Qiu Liang; Zeng, Yi Xin; Shao, Jian Yong

2011-01-10

MicroRNAs (miRNAs) are a class of small non-coding RNAs (20 to 24 nucleotides) that post-transcriptionally modulate gene expression. A key oncomir in carcinogenesis is miR-21, which is consistently up-regulated in a wide range of cancers. However, few functional studies are available for miR-21, and few targets have been identified. In this study, we explored the role of miR-21 in human breast cancer cells and tissues, and searched for miR-21 targets. We used in vitro and in vivo assays to explore the role of miR-21 in the malignant progression of human breast cancer, using miR-21 knockdown. Using LNA silencing combined to microarray technology and target prediction, we screened for potential targets of miR-21 and validated direct targets by using luciferase reporter assay and Western blot. Two candidate target genes (EIF4A2 and ANKRD46) were selected for analysis of correlation with clinicopathological characteristics and prognosis using immunohistochemistry on cancer tissue microrrays. Anti-miR-21 inhibited growth and migration of MCF-7 and MDA-MB-231 cells in vitro, and tumor growth in nude mice. Knockdown of miR-21 significantly increased the expression of ANKRD46 at both mRNA and protein levels. Luciferase assays using a reporter carrying a putative target site in the 3' untranslated region of ANKRD46 revealed that miR-21 directly targeted ANKRD46. miR-21 and EIF4A2 protein were inversely expressed in breast cancers (rs = -0.283, P = 0.005, Spearman's correlation analysis). Knockdown of miR-21 in MCF-7 and MDA-MB-231 cells inhibits in vitro and in vivo growth as well as in vitro migration. ANKRD46 is newly identified as a direct target of miR-21 in BC. These results suggest that inhibitory strategies against miR-21 using peptide nucleic acids (PNAs)-antimiR-21 may provide potential therapeutic applications in breast cancer treatment.

Targeting IL11 Receptor in Leukemia and Lymphoma: A Functional Ligand-Directed Study and Hematopathology Analysis of Patient-Derived Specimens.

PubMed

Karjalainen, Katja; Jaalouk, Diana E; Bueso-Ramos, Carlos; Bover, Laura; Sun, Yan; Kuniyasu, Akihiko; Driessen, Wouter H P; Cardó-Vila, Marina; Rietz, Cecilia; Zurita, Amado J; O'Brien, Susan; Kantarjian, Hagop M; Cortes, Jorge E; Calin, George A; Koivunen, Erkki; Arap, Wadih; Pasqualini, Renata

2015-07-01

The IL11 receptor (IL11R) is an established molecular target in primary tumors of bone, such as osteosarcoma, and in secondary bone metastases from solid tumors, such as prostate cancer. However, its potential role in management of hematopoietic malignancies has not yet been determined. Here, we evaluated the IL11R as a candidate therapeutic target in human leukemia and lymphoma. First, we show that the IL11R protein is expressed in a variety of human leukemia- and lymphoma-derived cell lines and in a large panel of bone marrow samples from leukemia and lymphoma patients, whereas expression is absent from nonmalignant control bone marrow. Moreover, a targeted peptidomimetic prototype (termed BMTP-11), specifically bound to leukemia and lymphoma cell membranes, induced ligand-receptor internalization mediated by the IL11R, and resulted in a specific dose-dependent cell death induction in these cells. Finally, a pilot drug lead-optimization program yielded a new myristoylated BMTP-11 analogue with an apparent improved antileukemia cell profile. These results indicate (i) that the IL11R is a suitable cell surface target for ligand-directed applications in human leukemia and lymphoma and (ii) that BMTP-11 and its derivatives have translational potential against this group of malignant diseases. ©2015 American Association for Cancer Research.

Targeting interleukin-11 receptor in leukemia and lymphoma: A functional ligand-directed study and hematopathology analysis of patient-derived specimens

PubMed Central

Karjalainen, Katja; Jaalouk, Diana E.; Bueso-Ramos, Carlos; Bover, Laura; Sun, Yan; Kuniyasu, Akihiko; Driessen, Wouter H. P.; Cardó-Vila, Marina; Rietz, Cecilia; Zurita, Amado J.; O’Brien, Susan; Kantarjian, Hagop M.; Cortes, Jorge E.; Calin, George A.; Koivunen, Erkki; Arap, Wadih; Pasqualini, Renata

2015-01-01

Purpose The interleukin-11 receptor (IL-11R) is an established molecular target in primary tumors of bone, such as osteosarcoma, and in secondary bone metastases from solid tumors such as prostate cancer. However, its potential role in management of hematopoietic malignancies has not yet been determined. Here we evaluated the IL-11R as a candidate therapeutic target in human leukemia and lymphoma. Experimental Design and Results First, we show that the IL-11R protein is expressed in a variety of human leukemia- and lymphoma derived cell lines and in a large panel of bone marrow samples from leukemia and lymphoma patients, while expression is absent from non-malignant control bone marrow. Moreover, a targeted peptidomimetic prototype (termed BMTP-11) specifically bound to leukemia and lymphoma cell membranes, induced ligand-receptor internalization mediated by the IL-11R, and resulted in a specific dose-dependent cell death induction in these cells. Finally, a pilot drug lead-optimization program yielded a new myristoylated BMTP-11 analog with an apparent improved anti-leukemia cell profile. Conclusion These results indicate (i) that the IL-11R is a suitable cell surface target for ligand-directed applications in human leukemia and lymphoma and (ii) that BMTP-11 and its derivatives have translational potential against this group of malignant diseases. PMID:25779950

miRNAs as potential therapeutic targets for age-related macular degeneration.

PubMed

Wang, Shusheng; Koster, Kyle M; He, Yuguang; Zhou, Qinbo

2012-03-01

Since their recent discovery, miRNAs have been shown to play critical roles in a variety of pathophysiological processes. Such processes include pathological angiogenesis, the oxidative stress response, immune response and inflammation, all of which have been shown to have important and interdependent roles in the pathogenesis and progression of age-related macular degeneration (AMD). Here we present a brief review of the pathological processes involved in AMD and review miRNAs and other noncoding RNAs involved in regulating these processes. Specifically, we discuss several candidate miRNAs that show promise as AMD therapeutic targets due to their direct involvement in choroidal neovascularization or retinal pigment epithelium atrophy. We discuss potential miRNA-based therapeutics and delivery methods for AMD and provide future directions for the field of miRNA research with respect to AMD. We believe the future of miRNAs in AMD therapy is promising.

Podocytes from the diagnostic and therapeutic point of view.

PubMed

Müller-Deile, Janina; Schiffer, Mario

2017-08-01

The central role of podocytes in glomerular diseases makes this cell type an interesting diagnostic tool as well as a therapeutic target. In this review, we discuss the current literature on the use of podocytes and podocyte-specific markers as non-invasive diagnostic tools in different glomerulopathies. Furthermore, we highlight the direct effects of drugs currently used to treat primary glomerular diseases and describe their direct cellular effects on podocytes. A new therapeutic potential is seen in drugs targeting the podocytic actin cytoskeleton which is essential for podocyte foot process structure and function. Incubation of cultured human podocyte cell lines with sera from patients with active glomerular diseases is currently also used to identify novel circulating factors with pathophysiological relevance for the glomerular filtration barrier. In addition, treatment of detached urinary podocytes from patients with substances that restore their cytoskeleton might serve as a novel personalized tool to estimate their potential for podocyte recovery ex vivo.

Non-Steroidal Anti-inflammatory Drugs As Host-Directed Therapy for Tuberculosis: A Systematic Review

PubMed Central

Kroesen, Vera M.; Gröschel, Matthias I.; Martinson, Neil; Zumla, Alimuddin; Maeurer, Markus; van der Werf, Tjip S.; Vilaplana, Cristina

2017-01-01

Lengthy, antimicrobial therapy targeting the pathogen is the mainstay of conventional tuberculosis treatment, complicated by emerging drug resistances. Host-directed therapies, including non-steroidal anti-inflammatory drugs (NSAIDs), in contrast, target host factors to mitigate disease severity. In the present Systematic Review, we investigate whether NSAIDs display any effects as therapy of TB and discuss possible mechanisms of action of NSAIDs as adjunctive therapy of TB. Ten studies, seven preclinical studies in mice and three clinical trials, were included and systematically reviewed. Our results point toward a beneficial effect of NSAIDs as adjunct to current TB therapy regimens, mediated by decreased lung pathology balancing host-immune reaction. The determination of the best timing for their administration in order to obtain the potential beneficial effects needs further investigation. Even if the preclinical evidence requires clinical evaluation, NSAIDs might represent a potential safe, simple, and cheap improvement in therapy of TB. PMID:28713389

Passive range estimation using dual baseline triangulation

NASA Astrophysics Data System (ADS)

Pieper, Ronald J.; Cooper, Alfred W.; Pelegris, G.

1996-03-01

Modern combat systems based on active radar sensing suffer disadvantages against low-flying targets in cluttered backgrounds. Use of passive infrared sensors with these systems, either in cooperation or as an alternative, shows potential for improving target detection and declaration range for targets crossing the horizon. Realization of this potential requires fusion of target position data from dissimilar sensors, or passive sensor measurement of target range. The availability of passive sensors that can supply both range and bearing data on such targets would significantly extend the robustness of an integrated ship self-defense system. This paper considers a new method of range determination with passive sensors based on the principle of triangulation, extending the principle to two orthogonal baselines. The performance of single or double baseline triangulation depends on sensor bearing precision and direction to target. An expression for maximum triangulation range at a required accuracy is derived as a function of polar angle relative to the center of the dual-baseline system. Limitations in the dual- baseline model due to the geometrically assessed horizon are also considered.

Targeted therapy in biliary tract cancers-current limitations and potentials in the future.

PubMed

Sahu, Selley; Sun, Weijing

2017-04-01

Biliary tract cancers (BTC)/Cholangiocarcinoma (CCA) is an aggressive biliary tract epithelial malignancy from varying locations within the biliary tree with cholangiocyte depreciation., including intrahepatic cholangiocarcinoma (iCCA) (iCCA), extrahepatic cholangiocarcinoma (eCCA) and gallbladder carcinoma (GBC). The disease is largely heterogeneous in etiology, epidemiology, and molecular profile. There are limited treatment options and low survival rates for those patients with advanced or metastatic disease. Systemic treatment is confined to cytotoxic chemotherapy with the combination of gemcitabine and cisplatin. Lack of a stereotype genetic signature makes difficult in identification of potential actionable target directly, which may also explain lack of obvious clinic benefit with target oriented agents from current studies. It is crucial to understand of BTC carcinogenesis, tumor-stroma interactions, and key molecular pathways, and herald to establish targeted, individualized therapies for the heterogeneous disease, and eventually to improve the survival and overall outcome of patients.

miR-425 inhibits melanoma metastasis through repression of PI3K-Akt pathway by targeting IGF-1.

PubMed

Liu, Pei; Hu, Yaotian; Ma, Ling; Du, Min; Xia, Lin; Hu, Zhensheng

2015-10-01

miR-425 is a potential tumor suppressor in cancer, but its role in melanoma is still unknown. We aim to investigate miR-425 expression in melanoma tissues and cell lines. Next, cell proliferation, cell cycle, apoptosis and metastasis will be studied using lentivirus-mediated gain-of-function studies. The predicted results are stable miR-425 inhibits cell proliferation and metastasis and induced cell apoptosis. It is predicted that IGF-1 is a potential target gene of miR-495 by bioinformatics analysis. Then luciferase assay analysis identifies IGF-1 as a new direct target gene of miR-425 and miR-425 inhibits melanoma cancer progression via IGF-1. Collectively, our findings suggested that miR-425 may function as a tumor suppressor in melanoma by targeting IGF-1. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

Development of a large peptoid-DOTA combinatorial library.

PubMed

Singh, Jaspal; Lopes, Daniel; Gomika Udugamasooriya, D

2016-09-01

Conventional one-bead one-compound (OBOC) library synthesis is typically used to identify molecules with therapeutic value. The design and synthesis of OBOC libraries that contain molecules with imaging or even potentially therapeutic and diagnostic capacities (e.g. theranostic agents) has been overlooked. The development of a therapeutically active molecule with a built-in imaging component for a certain target is a daunting task, and structure-based rational design might not be the best approach. We hypothesize to develop a combinatorial library with potentially therapeutic and imaging components fused together in each molecule. Such molecules in the library can be used to screen, identify, and validate as direct theranostic candidates against targets of interest. As the first step in achieving that aim, we developed an on-bead library of 153,600 Peptoid-DOTA compounds in which the peptoids are the target-recognizing and potentially therapeutic components and the DOTA is the imaging component. We attached the DOTA scaffold to TentaGel beads using one of the four arms of DOTA, and we built a diversified 6-mer peptoid library on the remaining three arms. We evaluated both the synthesis and the mass spectrometric sequencing capacities of the test compounds and of the final library. The compounds displayed unique ionization patterns including direct breakages of the DOTA scaffold into two units, allowing clear decoding of the sequences. Our approach provides a facile synthesis method for the complete on-bead development of large peptidomimetic-DOTA libraries for screening against biological targets for the identification of potential theranostic agents in the future. © 2016 The Authors. Biopolymers Published by Wiley Periodicals, Inc. Biopolymers (Pept Sci) 106: 673-684, 2016. © 2016 The Authors. Biopolymers Published by Wiley Periodicals, Inc.

Structural biology of antibody recognition of carbohydrate epitopes and potential uses for targeted cancer immunotherapies.

PubMed

Dingjan, Tamir; Spendlove, Ian; Durrant, Lindy G; Scott, Andrew M; Yuriev, Elizabeth; Ramsland, Paul A

2015-10-01

Monoclonal antibodies represent the most successful class of biopharmaceuticals for the treatment of cancer. Mechanisms of action of therapeutic antibodies are very diverse and reflect their ability to engage in antibody-dependent effector mechanisms, internalize to deliver cytotoxic payloads, and display direct effects on cells by lysis or by modulating the biological pathways of their target antigens. Importantly, one of the universal changes in cancer is glycosylation and carbohydrate-binding antibodies can be produced to selectively recognize tumor cells over normal tissues. A promising group of cell surface antibody targets consists of carbohydrates presented as glycolipids or glycoproteins. In this review, we outline the basic principles of antibody-based targeting of carbohydrate antigens in cancer. We also present a detailed structural view of antibody recognition and the conformational properties of a series of related tissue-blood group (Lewis) carbohydrates that are being pursued as potential targets of cancer immunotherapy. Copyright © 2015 Elsevier Ltd. All rights reserved.

Through-the-Wall Localization of a Moving Target by Two Independent Ultra Wideband (UWB) Radar Systems

PubMed Central

Kocur, Dušan; Švecová, Mária; Rovňáková, Jana

2013-01-01

In the case of through-the-wall localization of moving targets by ultra wideband (UWB) radars, there are applications in which handheld sensors equipped only with one transmitting and two receiving antennas are applied. Sometimes, the radar using such a small antenna array is not able to localize the target with the required accuracy. With a view to improve through-the-wall target localization, cooperative positioning based on a fusion of data retrieved from two independent radar systems can be used. In this paper, the novel method of the cooperative localization referred to as joining intersections of the ellipses is introduced. This method is based on a geometrical interpretation of target localization where the target position is estimated using a properly created cluster of the ellipse intersections representing potential positions of the target. The performance of the proposed method is compared with the direct calculation method and two alternative methods of cooperative localization using data obtained by measurements with the M-sequence UWB radars. The direct calculation method is applied for the target localization by particular radar systems. As alternative methods of cooperative localization, the arithmetic average of the target coordinates estimated by two single independent UWB radars and the Taylor series method is considered. PMID:24021968

Through-the-wall localization of a moving target by two independent ultra wideband (UWB) radar systems.

PubMed

Kocur, Dušan; Svecová, Mária; Rovňáková, Jana

2013-09-09

In the case of through-the-wall localization of moving targets by ultra wideband (UWB) radars, there are applications in which handheld sensors equipped only with one transmitting and two receiving antennas are applied. Sometimes, the radar using such a small antenna array is not able to localize the target with the required accuracy. With a view to improve through-the-wall target localization, cooperative positioning based on a fusion of data retrieved from two independent radar systems can be used. In this paper, the novel method of the cooperative localization referred to as joining intersections of the ellipses is introduced. This method is based on a geometrical interpretation of target localization where the target position is estimated using a properly created cluster of the ellipse intersections representing potential positions of the target. The performance of the proposed method is compared with the direct calculation method and two alternative methods of cooperative localization using data obtained by measurements with the M-sequence UWB radars. The direct calculation method is applied for the target localization by particular radar systems. As alternative methods of cooperative localization, the arithmetic average of the target coordinates estimated by two single independent UWB radars and the Taylor series method is considered.

Meeting report from the Prostate Cancer Foundation PSMA-directed radionuclide scientific working group.

PubMed

Miyahira, Andrea K; Pienta, Kenneth J; Morris, Michael J; Bander, Neil H; Baum, Richard P; Fendler, Wolfgang P; Goeckeler, William; Gorin, Michael A; Hennekes, Hartwig; Pomper, Martin G; Sartor, Oliver; Tagawa, Scott T; Williams, Scott; Soule, Howard R

2018-05-01

The Prostate Cancer Foundation (PCF) convened a PSMA-Directed Radionuclide Scientific Working Group on November 14, 2017, at Weill Cornell Medicine, New York, NY. The meeting was attended by 35 global investigators with expertise in prostate cancer biology, radionuclide therapy, molecular imaging, prostate-specific membrane antigen (PSMA)-targeted agents, drug development, and prostate cancer clinical trials. The goal of this meeting was to discuss the potential for using PSMA-targeted radionuclide agents for the treatment of advanced prostate cancer and to define the studies and clinical trials necessary for validating and optimizing the use of these agents. Several major topic areas were discussed including the overview of PSMA biology, lessons and applications of PSMA-targeted PET imaging, the nuances of designing PSMA-targeted radionuclide agents, clinical experiences with PSMA-targeted radionuclides, PCF-funded projects to accelerate PSMA-targeted radionuclide therapy, and barriers to the use of radionuclide treatments in widespread clinical practice. This article reviews the major topics discussed at the meeting with the goal of promoting research that will validate and optimize the use of PSMA-targeted radionuclide therapies for the treatment of advanced prostate cancer. © 2018 Wiley Periodicals, Inc.

Understanding the Role of Intrinsic Disorder of Viral Proteins in the Oncogenicity of Different Types of HPV.

PubMed

Tamarozzi, Elvira Regina; Giuliatti, Silvana

2018-01-09

Intrinsic disorder is very important in the biological function of several proteins, and is directly linked to their foldability during interaction with their targets. There is a close relationship between the intrinsically disordered proteins and the process of carcinogenesis involving viral pathogens. Among these pathogens, we have highlighted the human papillomavirus (HPV) in this study. HPV is currently among the most common sexually transmitted infections, besides being the cause of several types of cancer. HPVs are divided into two groups, called high- and low-risk, based on their oncogenic potential. The high-risk HPV E6 protein has been the target of much research, in seeking treatments against HPV, due to its direct involvement in the process of cell cycle control. To understand the role of intrinsic disorder of the viral proteins in the oncogenic potential of different HPV types, the structural characteristics of intrinsically disordered regions of high and low-risk HPV E6 proteins were analyzed. In silico analyses of primary sequences, prediction of tertiary structures, and analyses of molecular dynamics allowed the observation of the behavior of such disordered regions in these proteins, thereby proving a direct relationship of structural variation with the degree of oncogenicity of HPVs. The results obtained may contribute to the development of new therapies, targeting the E6 oncoprotein, for the treatment of HPV-associated diseases.

The role of visual processing in motor learning and control: Insights from electroencephalography.

PubMed

Krigolson, Olav E; Cheng, Darian; Binsted, Gord

2015-05-01

Traditionally our understanding of goal-directed action been derived from either behavioral findings or neuroanatomically derived imaging (i.e., fMRI). While both of these approaches have proven valuable, they lack the ability to determine a direct locus of function while concurrently having the necessary temporal precision needed to understand millisecond scale neural interactions respectively. In this review we summarize some seminal behavioral findings across three broad areas (target perturbation, feed-forward control, and feedback processing) and for each discuss the application of electroencephalography (EEG) to the understanding of the temporal nature of visual cue utilization during movement planning, control, and learning using four existing scalp potentials. Specifically, we examine the appropriateness of using the N100 potential as an indicator of corrective behaviors in response to target perturbation, the N200 as an index of movement planning, the P300 potential as a metric of feed-forward processes, and the feedback-related negativity as an index of motor learning. Although these existing components have potential for insight into cognitive contributions and the timing of the neural processes that contribute to motor control further research is needed to expand the control-related potentials and to develop methods to permit their accurate characterization across a wide range of behavioral tasks. Copyright © 2015 Elsevier B.V. All rights reserved.

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

NASA Astrophysics Data System (ADS)

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

2016-04-01

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

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

PubMed Central

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

2016-01-01

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

Direct-acting antivirals and host-targeting strategies to combat enterovirus infections.

PubMed

Bauer, Lisa; Lyoo, Heyrhyoung; van der Schaar, Hilde M; Strating, Jeroen Rpm; van Kuppeveld, Frank Jm

2017-06-01

Enteroviruses (e.g., poliovirus, enterovirus-A71, coxsackievirus, enterovirus-D68, rhinovirus) include many human pathogens causative of various mild and more severe diseases, especially in young children. Unfortunately, antiviral drugs to treat enterovirus infections have not been approved yet. Over the past decades, several direct-acting inhibitors have been developed, including capsid binders, which block virus entry, and inhibitors of viral enzymes required for genome replication. Capsid binders and protease inhibitors have been clinically evaluated, but failed due to limited efficacy or toxicity issues. As an alternative approach, host-targeting inhibitors with potential broad-spectrum activity have been identified. Furthermore, drug repurposing screens have recently uncovered promising new inhibitors with disparate viral and host targets. Together, these findings raise hope for the development of (broad-range) anti-enteroviral drugs. Copyright © 2017 Elsevier B.V. All rights reserved.

MicroRNA-mediated gene regulation: potential applications for plant genetic engineering.

PubMed

Zhou, Man; Luo, Hong

2013-09-01

Food security is one of the most important issues challenging the world today. Any strategies to solve this problem must include increasing crop yields and quality. MicroRNA-based genetic modification technology (miRNA-based GM tech) can be one of the most promising solutions that contribute to agricultural productivity directly by developing superior crop cultivars with enhanced biotic and abiotic stress tolerance and increased biomass yields. Indirectly, the technology may increase usage of marginal soils and decrease pesticide use, among other benefits. This review highlights the most recent progress of transgenic studies utilizing various miRNAs and their targets for plant trait modifications, and analyzes the potential of miRNA-mediated gene regulation for use in crop improvement. Strategies for manipulating miRNAs and their targets in transgenic plants including constitutive, stress-induced, or tissue-specific expression of miRNAs or their targets, RNA interference, expressing miRNA-resistant target genes, artificial target mimic and artificial miRNAs were discussed. We also discussed potential risks of utilizing miRNA-based GM tech. In general, miRNAs and their targets not only provide an invaluable source of novel transgenes, but also inspire the development of several new GM strategies, allowing advances in breeding novel crop cultivars with agronomically useful characteristics.

Molecular Triage Trials in Colorectal Cancer.

PubMed

O'Hara, Mark H; Hamilton, Stanley R; O'Dwyer, Peter J

2016-01-01

Advances in the understanding of genomic alterations in cancer, and the various therapies targeted to these alterations have permitted the design of trials directed to bringing this science to the clinic, with the ultimate goal of tailoring therapy to the individual. There is a high need for advances in targeted therapy in colorectal cancer, a disease in which only 2 classes of targeted therapies are approved for use in colorectal cancer, despite the majority of colorectal cancers containing a potentially targetable mutation. Here we outline the key elements to the design of these clinical trials and summarize the current active molecular triage trials in colorectal cancer.

Insights into the key roles of proteoglycans in breast cancer biology and translational medicine

PubMed Central

Theocharis, Achilleas D.; Skandalis, Spyros S.; Neill, Thomas; Multhaupt, Hinke A. B.; Hubo, Mario; Frey, Helena; Gopal, Sandeep; Gomes, Angélica; Afratis, Nikos; Lim, Hooi Ching; Couchman, John R.; Filmus, Jorge; Sanderson, Ralph D.; Schaefer, Liliana; Iozzo, Renato V.; Karamanos, Nikos K.

2015-01-01

Proteoglycans control numerous normal and pathological processes, among which are morphogenesis, tissue repair, inflammation, vascularization and cancer metastasis. During tumor development and growth, proteoglycan expression is markedly modified in the tumor microenvironment. Altered expression of proteoglycans on tumor and stromal cell membranes affects cancer cell signaling, growth and survival, cell adhesion, migration and angiogenesis. Despite the high complexity and heterogeneity of breast cancer, the rapid evolution in our knowledge that proteoglycans are among the key players in the breast tumor microenvironment suggests their potential as pharmacological targets in this type of cancer. It has been recently suggested that pharmacological treatment may target proteoglycan metabolism, their utilization as targets for immunotherapy or their direct use as therapeutic agents. The diversity inherent in the proteoglycans that will be presented herein provides the potential for multiple layers of regulation of breast tumor behavior. This review summarizes recent developments concerning the biology of selected proteoglycans in breast cancer, and presents potential targeted therapeutic approaches based on their novel key roles in breast cancer. PMID:25829250

Factors affecting consumer usage and acceptance of child restraints

DOT National Transportation Integrated Search

1983-09-01

This study was designed to focus on two factors with potential relevance to the child restraint device (CRD) usage problem: CRD design and directions for use; problems of initial users and repeated users were targeted for consideration. Ultimate obje...

Simultaneous targeting of prostate stem cell antigen and prostate-specific membrane antigen improves the killing of prostate cancer cells using a novel modular T cell-retargeting system.

PubMed

Arndt, Claudia; Feldmann, Anja; Koristka, Stefanie; Cartellieri, Marc; Dimmel, Maria; Ehninger, Armin; Ehninger, Gerhard; Bachmann, Michael

2014-09-01

Recently, we described a novel modular platform technology in which T cell-recruitment and tumor-targeting domains of conventional bispecific antibodies are split to independent components, a universal effector module (EM) and replaceable monospecific/monovalent target modules (TMs) that form highly efficient T cell-retargeting complexes. Theoretically, our unique strategy should allow us to simultaneously retarget T cells to different tumor antigens by combining the EM with two or more different monovalent/monospecific TMs or even with bivalent/bispecific TMs, thereby overcoming limitations of a monospecific treatment such as the selection of target-negative tumor escape variants. In order to advance our recently introduced prostate stem cell antigen (PSCA)-specific modular system for a dual-targeting of prostate cancer cells, two additional TMs were constructed: a monovalent/monospecific TM directed against the prostate-specific membrane antigen (PSMA) and a bivalent/bispecific TM (bsTM) with specificity for PSMA and PSCA. The functionality of the novel dual-targeting strategies was analyzed by performing T cell activation and chromium release assays. Similar to the PSCA-specific modular system, the novel PSMA-specific modular system mediates an efficient target-dependent and -specific tumor cell lysis at low E:T ratios and picomolar Ab concentrations. Moreover, by combination of the EM with either the bispecific TM directed to PSMA and PSCA or both monospecifc TMs directed to either PSCA or PSMA, dual-specific targeting complexes were formed which allowed us to kill potential escape variants expressing only one or the other target antigen. Overall, the novel modular system represents a promising tool for multiple tumor targeting. © 2014 Wiley Periodicals, Inc.

Heart failure—potential new targets for therapy

PubMed Central

Nabeebaccus, Adam; Zheng, Sean; Shah, Ajay M.

2016-01-01

Abstract Introduction/background Heart failure is a major cause of cardiovascular morbidity and mortality. This review covers current heart failure treatment guidelines, emerging therapies that are undergoing clinical trial, and potential new therapeutic targets arising from basic science advances. Sources of data A non-systematic search of MEDLINE was carried out. International guidelines and relevant reviews were searched for additional articles. Areas of agreement Angiotensin-converting enzyme inhibitors and beta-blockers are first line treatments for chronic heart failure with reduced left ventricular function. Areas of controversy Treatment strategies to improve mortality in heart failure with preserved left ventricular function are unclear. Growing points Many novel therapies are being tested for clinical efficacy in heart failure, including those that target natriuretic peptides and myosin activators. A large number of completely novel targets are also emerging from laboratory-based research. Better understanding of pathophysiological mechanisms driving heart failure in different settings (e.g. hypertension, post-myocardial infarction, metabolic dysfunction) may allow for targeted therapies. Areas timely for developing research Therapeutic targets directed towards modifying the extracellular environment, angiogenesis, cell viability, contractile function and microRNA-based therapies. PMID:27365454

Evaluating whether direct-to-consumer marketing can increase demand for evidence-based practice among parents of adolescents with substance use disorders: rationale and protocol.

PubMed

Becker, Sara J

2015-02-10

Fewer than one in 10 adolescents with substance use disorders (ASUDs) will receive specialty treatment, and even fewer will receive treatment designated as evidence-based practice (EBP). Traditional efforts to increase the utilization of EBP by ASUDs typically focus on practitioners-either in substance use clinics or allied health settings. Direct-to-consumer (DTC) marketing that directly targets parents of ASUDs represents a potentially complementary paradigm that has yet to be evaluated. The current study is the first to evaluate the relevance of a well-established marketing framework (the Marketing Mix) and measurement approach (measurement of perceived service quality [PSQ]) with parents of ASUDs in need of treatment. A mixed-methods design is employed across three study phases, consistent with well-established methods used in the field of marketing science. Phase 1 consists of formative qualitative research with parents (and a supplementary sample of adolescents) in order to evaluate and potentially adapt a conceptual framework (Marketing Mix) and measure of PSQ. Phase 2 is a targeted survey of ASUD parents to elucidate their marketing preferences, using the adapted Marketing Mix framework, and to establish the psychometric properties of the PSQ measure. The survey will also gather data on parents' preferences for different targeted marketing messages. Phase 3 is a two-group randomized controlled trial comparing the effectiveness of targeted marketing messages versus standard clinical information. Key outcomes will include parents' ratings of PSQ (using the new measure), behavioral intentions to seek out information about EBP, and actual information-seeking behavior. The current study will inform the field whether a well-established marketing framework and measurement approach can be used to increase demand for EBP among parents of ASUDs. Results of this study will have the potential to immediately inform DTC marketing efforts by professional organizations, federal agencies, clinicians, and clinical researchers.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gulec, Cagri, E-mail: cagri.gulec@gmail.com; Coban, Neslihan, E-mail: neslic@istanbul.edu.tr; Ozsait-Selcuk, Bilge, E-mail: ozsaitb@istanbul.edu.tr

ROR-alpha is a nuclear receptor, activity of which can be modulated by natural or synthetic ligands. Due to its possible involvement in, and potential therapeutic target for atherosclerosis, we aimed to identify ROR-alpha target genes in monocytic and endothelial cell lines. We performed chromatin immunoprecipitation (ChIP) followed by tiling array (ChIP-on-chip) for ROR-alpha in monocytic cell line THP1 and endothelial cell line HUVEC. Following bioinformatic analysis of the array data, we tested four candidate genes in terms of dependence of their expression level on ligand-mediated ROR-alpha activity, and two of them in terms of promoter occupancy by ROR-alpha. Bioinformatic analysesmore » of ChIP-on-chip data suggested that ROR-alpha binds to genomic regions near the transcription start site (TSS) of more than 3000 genes in THP1 and HUVEC. Potential ROR-alpha target genes in both cell types seem to be involved mainly in membrane receptor activity, signal transduction and ion transport. While SPP1 and IKBKA were shown to be direct target genes of ROR-alpha in THP1 monocytes, inflammation related gene HMOX1 and heat shock protein gene HSPA8 were shown to be potential target genes of ROR-alpha. Our results suggest that ROR-alpha may regulate signaling receptor activity, and transmembrane transport activity through its potential target genes. ROR-alpha seems also to play role in cellular sensitivity to environmental substances like arsenite and chloroprene. Although, the expression analyses have shown that synthetic ROR-alpha ligands can modulate some of potential ROR-alpha target genes, functional significance of ligand-dependent modulation of gene expression needs to be confirmed with further analyses.« less

Proteomic Identification of Putative MicroRNA394 Target Genes in Arabidopsis thaliana Identifies Major Latex Protein Family Members Critical for Normal Development*

PubMed Central

Litholdo, Celso G.; Parker, Benjamin L.; Eamens, Andrew L.; Larsen, Martin R.; Cordwell, Stuart J.; Waterhouse, Peter M.

2016-01-01

Expression of the F-Box protein Leaf Curling Responsiveness (LCR) is regulated by microRNA, miR394, and alterations to this interplay in Arabidopsis thaliana produce defects in leaf polarity and shoot apical meristem organization. Although the miR394-LCR node has been documented in Arabidopsis, the identification of proteins targeted by LCR F-box itself has proven problematic. Here, a proteomic analysis of shoot apices from plants with altered LCR levels identified a member of the Latex Protein (MLP) family gene as a potential LCR F-box target. Bioinformatic and molecular analyses also suggested that other MLP family members are likely to be targets for this post-translational regulation. Direct interaction between LCR F-Box and MLP423 was validated. Additional MLP members had reduction in protein accumulation, in varying degrees, mediated by LCR F-Box. Transgenic Arabidopsis lines, in which MLP28 expression was reduced through an artificial miRNA technology, displayed severe developmental defects, including changes in leaf patterning and morphology, shoot apex defects, and eventual premature death. These phenotypic characteristics resemble those of Arabidopsis plants modified to over-express LCR. Taken together, the results demonstrate that MLPs are driven to degradation by LCR, and indicate that MLP gene family is target of miR394-LCR regulatory node, representing potential targets for directly post-translational regulation mediated by LCR F-Box. In addition, MLP28 family member is associated with the LCR regulation that is critical for normal Arabidopsis development. PMID:27067051

Multifunctional Nanocarriers for diagnostics, drug delivery and targeted treatment across blood-brain barrier: perspectives on tracking and neuroimaging.

PubMed

Bhaskar, Sonu; Tian, Furong; Stoeger, Tobias; Kreyling, Wolfgang; de la Fuente, Jesús M; Grazú, Valeria; Borm, Paul; Estrada, Giovani; Ntziachristos, Vasilis; Razansky, Daniel

2010-03-03

Nanotechnology has brought a variety of new possibilities into biological discovery and clinical practice. In particular, nano-scaled carriers have revolutionalized drug delivery, allowing for therapeutic agents to be selectively targeted on an organ, tissue and cell specific level, also minimizing exposure of healthy tissue to drugs. In this review we discuss and analyze three issues, which are considered to be at the core of nano-scaled drug delivery systems, namely functionalization of nanocarriers, delivery to target organs and in vivo imaging. The latest developments on highly specific conjugation strategies that are used to attach biomolecules to the surface of nanoparticles (NP) are first reviewed. Besides drug carrying capabilities, the functionalization of nanocarriers also facilitate their transport to primary target organs. We highlight the leading advantage of nanocarriers, i.e. their ability to cross the blood-brain barrier (BBB), a tightly packed layer of endothelial cells surrounding the brain that prevents high-molecular weight molecules from entering the brain. The BBB has several transport molecules such as growth factors, insulin and transferrin that can potentially increase the efficiency and kinetics of brain-targeting nanocarriers. Potential treatments for common neurological disorders, such as stroke, tumours and Alzheimer's, are therefore a much sought-after application of nanomedicine. Likewise any other drug delivery system, a number of parameters need to be registered once functionalized NPs are administered, for instance their efficiency in organ-selective targeting, bioaccumulation and excretion. Finally, direct in vivo imaging of nanomaterials is an exciting recent field that can provide real-time tracking of those nanocarriers. We review a range of systems suitable for in vivo imaging and monitoring of drug delivery, with an emphasis on most recently introduced molecular imaging modalities based on optical and hybrid contrast, such as fluorescent protein tomography and multispectral optoacoustic tomography. Overall, great potential is foreseen for nanocarriers in medical diagnostics, therapeutics and molecular targeting. A proposed roadmap for ongoing and future research directions is therefore discussed in detail with emphasis on the development of novel approaches for functionalization, targeting and imaging of nano-based drug delivery systems, a cutting-edge technology poised to change the ways medicine is administered.

Cell cycle proteins as promising targets in cancer therapy.

PubMed

Otto, Tobias; Sicinski, Piotr

2017-01-27

Cancer is characterized by uncontrolled tumour cell proliferation resulting from aberrant activity of various cell cycle proteins. Therefore, cell cycle regulators are considered attractive targets in cancer therapy. Intriguingly, animal models demonstrate that some of these proteins are not essential for proliferation of non-transformed cells and development of most tissues. By contrast, many cancers are uniquely dependent on these proteins and hence are selectively sensitive to their inhibition. After decades of research on the physiological functions of cell cycle proteins and their relevance for cancer, this knowledge recently translated into the first approved cancer therapeutic targeting of a direct regulator of the cell cycle. In this Review, we focus on proteins that directly regulate cell cycle progression (such as cyclin-dependent kinases (CDKs)), as well as checkpoint kinases, Aurora kinases and Polo-like kinases (PLKs). We discuss the role of cell cycle proteins in cancer, the rationale for targeting them in cancer treatment and results of clinical trials, as well as the future therapeutic potential of various cell cycle inhibitors.

microRNA-22 acts as a metastasis suppressor by targeting metadherin in gastric cancer.

PubMed

Tang, Yunyun; Liu, Xiaoping; Su, Bo; Zhang, Zhiwei; Zeng, Xi; Lei, Yanping; Shan, Jian; Wu, Yongjun; Tang, Hailin; Su, Qi

2015-01-01

microRNA (miR)-22 has been reported to be downregulated in hepatocellular, lung, colorectal, ovarian and breast cancer, acting as a tumor suppressor. The present study investigated the potential effects of miR-22 on gastric cancer invasion and metastasis and the molecular mechanism. miR-22 expression was examined in tumor tissues of in 89 gastric cancer patients by in situ hybridization (ISH) analysis. Additionally, the association between miR-22 levels and clinicopathological parameters was analyzed. A luciferase assay was conducted for target identification. The ability of invasion and metastasis of gastric cancer cells in vitro and in vivo was evaluated by cell migration and invasion assays and in a xenograft model. The results showed that miR-22 was downregulated in the gastric cancer specimens and significantly correlated with the advanced clinical stage and lymph node metastasis. In addition, metadherin (MTDH) was shown to be a direct target of miR-22 and the expression of MTDH was inversely correlated with miR-22 expression in gastric cancer. Ectopic expression of miR-22 suppressed cell invasion and metastasis in vitro and in vivo. The present study suggested that miR-22 may be a valuable prognostic factor in gastric cancer. miR-22 inhibited gastric cancer cell invasion and metastasis by directly targeting MTDH. The novel miR-22/MTDH link confirmed in the present study provided a novel, potential therapeutic target for the treatment of gastric cancer.

Uncovering potential anti-neuroinflammatory components of Modified Wuziyanzong Prescription through a target-directed molecular docking fingerprint strategy.

PubMed

Chen, Jinfeng; Wang, Jinlong; Lu, Yingyuan; Zhao, Shaoyang; Yu, Qian; Wang, Xuemei; Tu, Pengfei; Zeng, Kewu; Jiang, Yong

2018-05-01

Neuroinflammation is a main factor in the pathogenesis of neurodegenerative diseases, such as Alzheimer disease. Our previous studies indicated that the modified Wuziyanzong Prescription (MWP) can suppress neuroinflammatory responses via nuclear factor-kappa B (NF-κB) and mitogen-activated protein kinases (MAPKs) signaling pathways. However, the anti-neuroinflammatory components of MWP remain unclear. Herein, a target-directed molecular docking fingerprint (TMDF) strategy, via integrating the chemical profiling and molecular docking approaches, was developed to identify the potential anti-neuroinflammatory components of MWP. First, as many as 120 possible structures, including 49 flavonoids, 28 phenylpropionic acids, 18 amides, 10 carotenoids, eight phenylethanoid glycosides, four lignans, two iridoids, and one triterpenoid were deduced by the source attribution and structural classification-assisted strategy. Then, their geometries were docked against five major targets of the NF-κB and MAPKs signaling cascades, including p38-α, IKKβ, ERK1, ERK2, and TRAF6. The docking results revealed diverse contributions of different components towards the protein targets. Collectively, prenylated flavonoids showed intensive or moderate anti-neuroinflammatory activities, while phenylpropanoids, amides, phenylethanoid glycosides, lignans, and triterpenoids exhibited moderate or weak anti-neuroinflammatory effects. The anti-neuroinflammatory activities of four retrieved prenylated flavonoids were tested by Western blotting assay, and the results mostly agreed with those predicted by the docking method. These gained information demonstrates that the established TMDF strategy could be a rapid and feasible methodology to investigate the potential active components in herbal compound prescriptions. Copyright © 2018 Elsevier B.V. All rights reserved.

Pyrrole-indolinone SU11652 targets the nucleoside diphosphate kinase from Leishmania parasites.

PubMed

Vieira, Plínio Salmazo; Souza, Tatiana de Arruda Campos Brasil; Honorato, Rodrigo Vargas; Zanphorlin, Letícia Maria; Severiano, Kelven Ulisses; Rocco, Silvana Aparecida; de Oliveira, Arthur Henrique Cavalcante; Cordeiro, Artur Torres; Oliveira, Paulo Sérgio Lopes; de Giuseppe, Priscila Oliveira; Murakami, Mário Tyago

2017-07-01

Nucleoside diphosphate kinases (NDKs) are key enzymes in the purine-salvage pathway of trypanosomatids and have been associated with the maintenance of host-cell integrity for the benefit of the parasite, being potential targets for rational drug discovery and design. The NDK from Leishmania major (LmNDK) and mutants were expressed and purified to homogeneity. Thermal shift assays were employed to identify potential inhibitors for LmNDK. Calorimetric experiments, site-directed mutagenesis and molecular docking analysis were performed to validate the interaction and to evaluate the structural basis of ligand recognition. Furthermore, the anti-leishmanial activity of the newly identified and validated compound was tested in vitro against different Leishmania species. The molecule SU11652, a Sunitinib analog, was identified as a potential inhibitor for LmNDK and structural studies indicated that this molecule binds to the active site of LmNDK in a similar conformation to nucleotides, mimicking natural substrates. Isothermal titration calorimetry experiments combined with site-directed mutagenesis revealed that the residues H50 and H117, considered essential for catalysis, play an important role in ligand binding. In vitro cell studies showed that SU11652 had similar efficacy to Amphotericin b against some Leishmania species. Together, our results indicate the pyrrole-indolinone SU11652 as a promising scaffold for the rational design of new drugs targeting the enzyme NDK from Leishmania parasites. Copyright © 2017 Elsevier Inc. All rights reserved.

Structure and specificity of the RNA-guided endonuclease Cas9 during DNA interrogation, target binding and cleavage

PubMed Central

Josephs, Eric A.; Kocak, D. Dewran; Fitzgibbon, Christopher J.; McMenemy, Joshua; Gersbach, Charles A.; Marszalek, Piotr E.

2015-01-01

CRISPR-associated endonuclease Cas9 cuts DNA at variable target sites designated by a Cas9-bound RNA molecule. Cas9's ability to be directed by single ‘guide RNA’ molecules to target nearly any sequence has been recently exploited for a number of emerging biological and medical applications. Therefore, understanding the nature of Cas9's off-target activity is of paramount importance for its practical use. Using atomic force microscopy (AFM), we directly resolve individual Cas9 and nuclease-inactive dCas9 proteins as they bind along engineered DNA substrates. High-resolution imaging allows us to determine their relative propensities to bind with different guide RNA variants to targeted or off-target sequences. Mapping the structural properties of Cas9 and dCas9 to their respective binding sites reveals a progressive conformational transformation at DNA sites with increasing sequence similarity to its target. With kinetic Monte Carlo (KMC) simulations, these results provide evidence of a ‘conformational gating’ mechanism driven by the interactions between the guide RNA and the 14th–17th nucleotide region of the targeted DNA, the stabilities of which we find correlate significantly with reported off-target cleavage rates. KMC simulations also reveal potential methodologies to engineer guide RNA sequences with improved specificity by considering the invasion of guide RNAs into targeted DNA duplex. PMID:26384421

Recent Advances in Monoclonal Antibody Therapies for Multiple Sclerosis.

PubMed

Wootla, Bharath; Watzlawik, Jens O; Stavropoulos, Nikolaos; Wittenberg, Nathan J; Dasari, Harika; Abdelrahim, Murtada A; Henley, John R; Oh, Sang-Hyun; Warrington, Arthur E; Rodriguez, Moses

2016-06-01

Multiple sclerosis (MS) is the most common chronic inflammatory, demyelinating disease of the CNS and results in neurological disability. Existing immunomodulatory and immunosuppressive approaches lower the number of relapses but do not cure or reverse existing deficits nor improve long-term disability in MS patients. Monogenic antibodies were described as treatment options for MS, however the immunogenicity of mouse antibodies hampered the efficacy of potential therapeutics in humans. Availability of improved antibody production technologies resulted in a paradigm shift in MS treatment strategies. In this review, an overview of immunotherapies for MS that use conventional monoclonal antibodies reactive to immune system and their properties and mechanisms of action will be discussed, including recent advances in MS therapeutics and highlight natural autoantibodies (NAbs) that directly target CNS cells. Recent challenges for MS therapy are the identification of relevant molecular and cellular targets, time frame of treatment, and antibody toxicity profiles to identify safe treatment options for MS patients. The application of monoclonal antibody therapies with better biological efficacy associated with minimum side effects possesses huge clinical potential. Advances in monoclonal antibody technologies that directly target cells of nervous system may promote the CNS regeneration field from bench to bedside.

Recent Advances in Monoclonal Antibody Therapies for Multiple Sclerosis

PubMed Central

Stavropoulos, Nikolaos; Wittenberg, Nathan J.; Dasari, Harika; Abdelrahim, Murtada A.; Henley, John R.; Oh, Sang-Hyun; Warrington, Arthur E.; Rodriguez, Moses

2016-01-01

Introduction Multiple sclerosis (MS) is the most common chronic inflammatory, demyelinating disease of the CNS and results in neurological disability. Existing immunomodulatory and immunosuppressive approaches lower the number of relapses but do not cure or reverse existing deficits nor improve long-term disability in MS patients. Areas Covered Monogenic antibodies were described as treatment options for MS, however the immunogenicity of mouse antibodies hampered the efficacy of potential therapeutics in humans. Availability of improved antibody production technologies resulted in a paradigm shift in MS treatment strategies. In this review, an overview of immunotherapies for MS that use conventional monoclonal antibodies reactive to immune system and their properties and mechanisms of action will be discussed, including recent advances in MS therapeutics and highlight natural autoantibodies (NAbs) that directly target CNS cells. Expert Opinion Recent challenges for MS therapy are the identification of relevant molecular and cellular targets, time frame of treatment, and antibody toxicity profiles to identify safe treatment options for MS patients. The application of monoclonal antibody therapies with better biological efficacy associated with minimum side effects possesses huge clinical potential. Advances in monoclonal antibody technologies that directly target cells of nervous system may promote the CNS regeneration field from bench to bedside. PMID:26914737

Causes of CNS inflammation and potential targets for anticonvulsants.

PubMed

Falip, Mercé; Salas-Puig, Xavier; Cara, Carlos

2013-08-01

Inflammation is one of the most important endogenous defence mechanisms in an organism. It has been suggested that inflammation plays an important role in the pathophysiology of a number of human epilepsies and convulsive disorders, and there is clinical and experimental evidence to suggest that inflammatory processes within the CNS may either contribute to or be a consequence of epileptogenesis. This review discusses evidence from human studies on the role of inflammation in epilepsy and highlights potential new targets in the inflammatory cascade for antiepileptic drugs. A number of mechanisms have been shown to be involved in CNS inflammatory reactions. These include an inflammatory response at the level of the blood-brain barrier (BBB), immune-mediated damage to the CNS, stress-induced release of inflammatory mediators and direct neuronal dysfunction or damage as a result of inflammatory reactions. Mediators of inflammation in the CNS include interleukin (IL)-1β, tumour necrosis factor-α, nuclear factor-κB and toll-like receptor-4 (TLR4). IL-1β, BBB and high-mobility group box-1-TLR4 signalling appear to be the most promising targets for anticonvulsant agents directed at inflammation. Such agents may provide effective therapy for drug-resistant epilepsies in the future.

The Human Respiratory Syncytial Virus Nonstructural Protein 1 Regulates Type I and Type II Interferon Pathways*

PubMed Central

Hastie, Marcus L.; Headlam, Madeleine J.; Patel, Nirav B.; Bukreyev, Alexander A.; Buchholz, Ursula J.; Dave, Keyur A.; Norris, Emma L.; Wright, Cassandra L.; Spann, Kirsten M.; Collins, Peter L.; Gorman, Jeffrey J.

2012-01-01

Respiratory syncytial viruses encode a nonstructural protein (NS1) that interferes with type I and III interferon and other antiviral responses. Proteomic studies were conducted on human A549 type II alveolar epithelial cells and type I interferon-deficient Vero cells (African green monkey kidney cells) infected with wild-type and NS1-deficient clones of human respiratory syncytial virus to identify other potential pathway and molecular targets of NS1 interference. These analyses included two-dimensional differential gel electrophoresis and quantitative Western blotting. Surprisingly, NS1 was found to suppress the induction of manganese superoxide dismutase (SOD2) expression in A549 cells and to a much lesser degree Vero cells in response to infection. Because SOD2 is not directly inducible by type I interferons, it served as a marker to probe the impact of NS1 on signaling of other cytokines known to induce SOD2 expression and/or indirect effects of type I interferon signaling. Deductive analysis of results obtained from cell infection and cytokine stimulation studies indicated that interferon-γ signaling was a potential target of NS1, possibly as a result of modulation of STAT1 levels. However, this was not sufficient to explain the magnitude of the impact of NS1 on SOD2 induction in A549 cells. Vero cell infection experiments indicated that NS1 targeted a component of the type I interferon response that does not directly induce SOD2 expression but is required to induce another initiator of SOD2 expression. STAT2 was ruled out as a target of NS1 interference using quantitative Western blot analysis of infected A549 cells, but data were obtained to indicate that STAT1 was one of a number of potential targets of NS1. A label-free mass spectrometry-based quantitative approach is proposed as a means of more definitive identification of NS1 targets. PMID:22322095

Transcranial direct current stimulation in obsessive-compulsive disorder: emerging clinical evidence and considerations for optimal montage of electrodes.

PubMed

Senço, Natasha M; Huang, Yu; D'Urso, Giordano; Parra, Lucas C; Bikson, Marom; Mantovani, Antonio; Shavitt, Roseli G; Hoexter, Marcelo Q; Miguel, Eurípedes C; Brunoni, André R

2015-07-01

Neuromodulation techniques for obsessive-compulsive disorder (OCD) treatment have expanded with greater understanding of the brain circuits involved. Transcranial direct current stimulation (tDCS) might be a potential new treatment for OCD, although the optimal montage is unclear. To perform a systematic review on meta-analyses of repetitive transcranianal magnetic stimulation (rTMS) and deep brain stimulation (DBS) trials for OCD, aiming to identify brain stimulation targets for future tDCS trials and to support the empirical evidence with computer head modeling analysis. Systematic reviews of rTMS and DBS trials on OCD in Pubmed/MEDLINE were searched. For the tDCS computational analysis, we employed head models with the goal of optimally targeting current delivery to structures of interest. Only three references matched our eligibility criteria. We simulated four different electrodes montages and analyzed current direction and intensity. Although DBS, rTMS and tDCS are not directly comparable and our theoretical model, based on DBS and rTMS targets, needs empirical validation, we found that the tDCS montage with the cathode over the pre-supplementary motor area and extra-cephalic anode seems to activate most of the areas related to OCD.

In trans paired nicking triggers seamless genome editing without double-stranded DNA cutting.

PubMed

Chen, Xiaoyu; Janssen, Josephine M; Liu, Jin; Maggio, Ignazio; 't Jong, Anke E J; Mikkers, Harald M M; Gonçalves, Manuel A F V

2017-09-22

Precise genome editing involves homologous recombination between donor DNA and chromosomal sequences subjected to double-stranded DNA breaks made by programmable nucleases. Ideally, genome editing should be efficient, specific, and accurate. However, besides constituting potential translocation-initiating lesions, double-stranded DNA breaks (targeted or otherwise) are mostly repaired through unpredictable and mutagenic non-homologous recombination processes. Here, we report that the coordinated formation of paired single-stranded DNA breaks, or nicks, at donor plasmids and chromosomal target sites by RNA-guided nucleases based on CRISPR-Cas9 components, triggers seamless homology-directed gene targeting of large genetic payloads in human cells, including pluripotent stem cells. Importantly, in addition to significantly reducing the mutagenicity of the genome modification procedure, this in trans paired nicking strategy achieves multiplexed, single-step, gene targeting, and yields higher frequencies of accurately edited cells when compared to the standard double-stranded DNA break-dependent approach.CRISPR-Cas9-based gene editing involves double-strand breaks at target sequences, which are often repaired by mutagenic non-homologous end-joining. Here the authors use Cas9 nickases to generate coordinated single-strand breaks in donor and target DNA for precise homology-directed gene editing.

The future of small molecule inhibitors in lymphoma.

PubMed

Gerecitano, John

2009-09-01

For the many patients with lymphoma that has relapsed after and/or has become refractory to existing treatments, the development of novel therapeutics is imperative. Investigation into intracellular processes that are dysregulated during lymphomagenesis has uncovered several new potential targets for anticancer agents. Although monoclonal antibodies and other immunotherapeutics have led to dramatic advances in the treatment of patients with lymphoma, the parallel development of small molecule inhibitors has been equally exciting. These agents, whose small size allows direct entry into tumor cells, can target distinct proteins or complexes, thereby disrupting molecular processes on which neoplastic cells depend for survival and growth. This review surveys the published literature on many of these new targeted molecules, focusing on some of the most promising agents for which phase 2 data currently exist. It also explores the potential for incorporating these agents into broader multidrug regimens.

EGFR targeted PLGA nanoparticles using gemcitabine for treatment of pancreatic cancer.

PubMed

Aggarwal, Sahil; Yadav, Sachin; Gupta, Swati

2011-02-01

The present study aimed to prepare and characterize anti EGFR monoclonal antibody (mab) conjugated Gemcitabine loaded PLGA nanoparticles for their selective delivery to pancreatic cells and evaluation of the systems in vitro. It was observed that direct covalent coupling of antibodies to glutaraldehyde activated nanoparticles is an appropriate method to achieve cell-type specific drug carrier systems based on polymeric nanoparticles that have potential to be applied for targeted chemotherapy in EGFR positive cancer.

A high-level prokaryotic expression system: synthesis of human interleukin 1 alpha and its receptor antagonist.

PubMed

Birikh, K R; Lebedenko, E N; Boni, I V; Berlin, Y A

1995-10-27

Synthetic intronless genes, coding for human interleukin 1 alpha (IL 1 alpha) and interleukin 1 receptor antagonist (IL1ra), have been expressed efficiently in a specially designed prokaryotic vector, pGMCE (a pGEM1 derivative), where the target gene forms the second part of a two-cistron system. The first part of the system is a translation enhancer-containing mini-cistron, whose termination codon overlaps the start codon of the target gene. In the case of the IL1 alpha gene, the high expression level is largely due to the direct efficient translation initiation at the second cistron, whereas with the IL1ra gene in the same system, the proximal translation initiation region (TIR) provides a high level of coupled expression of the target gene. Thus, pGMCE is a potentially versatile vector for direct prokaryotic expression.

Therapeutic Approaches Targeting MYC-Driven Prostate Cancer

PubMed Central

Rebello, Richard J.; Pearson, Richard B.; Hannan, Ross D.; Furic, Luc

2017-01-01

The transcript encoding the proto-oncogene MYC is commonly overexpressed in prostate cancer (PC). MYC protein abundance is also increased in the majority of cases of advanced and metastatic castrate-resistant PC (mCRPC). Accordingly, the MYC-directed transcriptional program directly contributes to PC by upregulating the expression of a number of pro-tumorigenic factors involved in cell growth and proliferation. A key cellular process downstream of MYC activity is the regulation of ribosome biogenesis which sustains tumor growth. MYC activity also cooperates with the dysregulation of the phosphoinositol-3-kinase (PI3K)/AKT/mTOR pathway to promote PC cell survival. Recent advances in the understanding of these interactions through the use of animal models have provided significant insight into the therapeutic efficacy of targeting MYC activity by interfering with its transcriptional program, and indirectly by targeting downstream cellular events linked to MYC transformation potential. PMID:28212321

A theoretical study on predicted protein targets of apple polyphenols and possible mechanisms of chemoprevention in colorectal cancer

PubMed Central

Scafuri, Bernardina; Marabotti, Anna; Carbone, Virginia; Minasi, Paola; Dotolo, Serena; Facchiano, Angelo

2016-01-01

We investigated the potential role of apple phenolic compounds in human pathologies by integrating chemical characterization of phenolic compounds in three apple varieties, computational approaches to identify potential protein targets of the compounds, bioinformatics analyses on data from public archive of gene expression data, and functional analyses to hypothesize the effects of the selected compounds in molecular pathways. Starting by the analytic characterization of phenolic compounds in three apple varieties, i.e. Annurca, Red Delicious, and Golden Delicious, we used computational approaches to verify by reverse docking the potential protein targets of the identified compounds. Direct docking validation of the potential protein-ligand interactions has generated a short list of human proteins potentially bound by the apple phenolic compounds. By considering the known chemo-preventive role of apple antioxidants’ extracts against some human pathologies, we performed a functional analysis by comparison with experimental gene expression data and interaction networks, obtained from public repositories. The results suggest the hypothesis that chemo-preventive effects of apple extracts in human pathologies, in particular for colorectal cancer, may be the interference with the activity of nucleotide metabolism and methylation enzymes, similarly to some classes of anticancer drugs. PMID:27587238

Emerging role of liver X receptors in cardiac pathophysiology and heart failure.

PubMed

Cannon, Megan V; van Gilst, Wiek H; de Boer, Rudolf A

2016-01-01

Liver X receptors (LXRs) are master regulators of metabolism and have been studied for their pharmacological potential in vascular and metabolic disease. Besides their established role in metabolic homeostasis and disease, there is mounting evidence to suggest that LXRs may exert direct beneficial effects in the heart. Here, we aim to provide a conceptual framework to explain the broad mode of action of LXRs and how LXR signaling may be an important local and systemic target for the treatment of heart failure. We discuss the potential role of LXRs in systemic conditions associated with heart failure, such as hypertension, diabetes, and renal and vascular disease. Further, we expound on recent data that implicate a direct role for LXR activation in the heart, for its impact on cardiomyocyte damage and loss due to ischemia, and effects on cardiac hypertrophy, fibrosis, and myocardial metabolism. Taken together, the accumulating evidence supports the notion that LXRs may represent a novel therapeutic target for the treatment of heart failure.

Spoke rotation reversal in magnetron discharges of aluminium, chromium and titanium

NASA Astrophysics Data System (ADS)

Hecimovic, A.; Maszl, C.; Schulz-von der Gathen, V.; Böke, M.; von Keudell, A.

2016-06-01

The rotation of localised ionisation zones, i.e. spokes, in magnetron discharge are frequently observed. The spokes are investigated by measuring floating potential oscillations with 12 flat probes placed azimuthally around a planar circular magnetron. The 12-probe setup provides sufficient temporal and spatial resolution to observe the properties of various spokes, such as rotation direction, mode number and angular velocity. The spokes are investigated as a function of discharge current, ranging from 10 mA (current density 0.5 mA cm-2) to 140 A (7 A cm-2). In the range from 10 mA to 600 mA the plasma was sustained in DC mode, and in the range from 1 A to 140 A the plasma was pulsed in high-power impulse magnetron sputtering mode. The presence of spokes throughout the complete discharge current range indicates that the spokes are an intrinsic property of a magnetron sputtering plasma discharge. The spokes may disappear at discharge currents above 80 A for Cr, as the plasma becomes homogeneously distributed over the racetrack. Up to discharge currents of several amperes (the exact value depends on the target material), the spokes rotate in a retrograde \\mathbf{E}× \\mathbf{B} direction with angular velocity in the range of 0.2-4 km s-1. Beyond a discharge current of several amperes, the spokes rotate in a \\mathbf{E}× \\mathbf{B} direction with angular velocity in the range of 5-15 km s-1. The spoke rotation reversal is explained by a transition from Ar-dominated to metal-dominated sputtering that shifts the plasma emission zone closer to the target. The spoke itself corresponds to a region of high electron density and therefore to a hump in the electrical potential. The electric field around the spoke dominates the spoke rotation direction. At low power, the plasma is further away from the target and it is dominated by the electric field to the anode, thus retrograde \\mathbf{E}× \\mathbf{B} rotation. At high power, the plasma is closer to the target and it is dominated by the electric field pointing to the target, thus \\mathbf{E}× \\mathbf{B} rotation.

Bringing in the target audience in bystander social marketing materials for communities: suggestions for practitioners.

PubMed

Potter, Sharyn J; Stapleton, Jane G

2011-06-01

The Know Your Power™ social marketing campaign images model active bystander behaviors that target audience members can use in situations where sexual and relationship violence and stalking are occurring, have occurred, or have the potential to occur. In this practitioner note, we describe strategies that we have used to engage target audience members in the development of the social marketing campaign that we hope can be used by practitioners. We give examples from the development and evaluation of the Know Your Power(TM) social marketing campaign that used focus group and other types of feedback from the target audience to inform the direction of the campaign.

Strategies of targeting oral drug delivery systems to the colon and their potential use for the treatment of colorectal cancer.

PubMed

Krishnaiah, Yellela S R; Khan, Mansoor A

2012-01-01

Colorectal cancer (CRC) is the third most common cause of cancer-related death in both men and women. Often, surgical intervention remains the choice in treating CRC. Traditional dosage forms used for treating CRC deliver drug to wanted as well as unwanted sites of drug action resulting in several adverse side effects. Targeted oral drug delivery systems are being investigated to target and deliver chemotherapeutic and chemopreventive agents directly to colon and rectum. Site-specific delivery of a drug to colon increases its concentration at the target site, and thus requires a lower dose with reduced incidence of side effects. The major obstacle to be overcome for successful targeting of drug to colon through oral route is that drug absorption/degradation must be avoided in stomach and small intestine before the dosage form reaches colon. The review includes discussion of physiological factors that must be considered when targeting drugs directly to colorectal region, an outline on drugs used for treatment and prevention of CRC, and a brief description of various types of colon-targeted oral drug delivery systems. The focus is on the assessment of various formulation approaches being investigated for oral colon-specific delivery of drugs used in the treatment and prevention of CRC.

Damnacanthal, a noni anthraquinone, inhibits c-Met and is a potent antitumor compound against Hep G2 human hepatocellular carcinoma cells.

PubMed

García-Vilas, Javier A; Quesada, Ana R; Medina, Miguel A

2015-01-26

Damnacanthal, an anthraquinone present in noni plants, targets several tyrosine kinases and has antitumoral effects. This study aims at getting additional insight on the potential of damnacanthal as a natural antitumor compound. The direct effect of damnacanthal on c-Met was tested by in vitro activity assays. Additionally, Western blots of c-Met phosphorylation in human hepatocellular carcinoma Hep G2 cells were performed. The antitumor effects of damnacanthal were tested by using cell growth, soft agar clonogenic, migration and invasion assays. Their mechanisms were studied by Western blot, and cell cycle, apoptosis and zymographic assays. Results show that damnacanthal targets c-Met both in vitro and in cell culture. On the other hand, damnacanthal also decreases the phosphorylation levels of Akt and targets matrix metalloproteinase-2 secretion in Hep G2 cells. These molecular effects are accompanied by inhibition of the growth and clonogenic potential of Hep G2 hepatocellular carcinoma cells, as well as induction of Hep G2 apoptosis. Since c-Met has been identified as a new potential therapeutical target for personalized treatment of hepatocellular carcinoma, damnacanthal and noni extract supplements containing it could be potentially interesting for the treatment and/or chemoprevention of hepatocellular carcinoma through its inhibitory effects on the HGF/c-Met axis.

miR-503 suppresses tumor cell proliferation and metastasis by directly targeting RNF31 in prostate cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Guo, Jia; Liu, Xiuheng, E-mail: l_xiuheng@163.com; Wang, Min

2015-09-04

Microarray data analyses were performed to search for metastasis-associated oncogenes in prostate cancer (PCa). RNF31 mRNA expressions in tumor tissues and benign prostate tissues were evaluated. The RNF31 protein expression levels were also analyzed by western blot and immunohistochemistry. Luciferase reporter assays were used to identify miRNAs that can regulate RNF31. The effect of RNF31 on PCa progression was studied in vitro and in vivo. We found that RNF31 was significantly increased in PCa and its expression level was highly correlated with seminal vesicle invasion, clinical stage, prostate specific antigen (PSA) level, Gleason score, and BCR. Silence of RNF31 suppressed PCa cellmore » proliferation and metastasis in vitro and in vivo. miR-503 can directly regulate RNF31. Enforced expression of miR-503 inhibited the expression of RNF31 significantly and the restoration of RNF31 expression reversed the inhibitory effects of miR-503 on PCa cell proliferation and metastasis. These findings collectively indicated an oncogene role of RNF31 in PCa progression which can be regulated by miR-503, suggesting that RNF31 could serve as a potential prognostic biomarker and therapeutic target for PCa. - Highlights: • RNF31 is a potential metastasis associated gene and is associated with prostate cancer progression. • Silence of RNF31 inhibits PCa cell colony formation, migration and invasion. • RNF31 as a direct target of miR-503. • miR-503 can regulate cell proliferation, invasion and migration by targeting RNF31. • RNF31 plays an important role in PCa growth and metastasis in vivo.« less

Pretargeting CD45 enhances the selective delivery of radiation to hematolymphoid tissues in nonhuman primates

DOE Office of Scientific and Technical Information (OSTI.GOV)

Green, Damian J.; Pagel, John M.; Nemecek, Eneida R.

2009-08-06

Pretargeted radioimmunotherapy (PRIT) is designed to enhance the directed delivery of radionuclides to malignant cells. Through a series of studies in nineteen nonhuman primates (M. fascicularis) the potential therapeutic advantage of anti-CD45 PRIT was evaluated. Anti-CD45 PRIT demonstrated a significant improvement in target-to-normal organ ratios of absorbed radiation when compared to directly radiolabeled bivalent antibody (conventional radioimmunotherapy [RIT]). Radio-DOTA-biotin administered 48 hours after anti-CD45 streptavidin fusion protein (FP) [BC8 (scFv)4SA] produced markedly lower concentrations of radiation in non-target tissues when compared to conventional RIT. PRIT generated superior target:normal organ ratios in the blood, lung and liver (10.3:1, 18.9:1 and 9.9:1more » respectively) when compared to the conventional RIT controls (2.6:1, 6.4:1 and 2.9:1 respectively). The FP demonstrated superior retention in target tissues relative to comparable directly radiolabeled bivalent anti-CD45 RIT. The time-point of administration of the second step radiolabeled ligand (radio-DOTA-biotin) significantly impacted the biodistribution of radioactivity in target tissues. Rapid clearance of the FP from the circulation rendered unnecessary the addition of a synthetic clearing agent in this model. These results support proceeding to anti-CD45 PRIT clinical trials for patients with both leukemia and lymphoma.« less

Lmx1b-targeted cis-regulatory modules involved in limb dorsalization.

PubMed

Haro, Endika; Watson, Billy A; Feenstra, Jennifer M; Tegeler, Luke; Pira, Charmaine U; Mohan, Subburaman; Oberg, Kerby C

2017-06-01

Lmx1b is a homeodomain transcription factor responsible for limb dorsalization. Despite striking double-ventral (loss-of-function) and double-dorsal (gain-of-function) limb phenotypes, no direct gene targets in the limb have been confirmed. To determine direct targets, we performed a chromatin immunoprecipitation against Lmx1b in mouse limbs at embryonic day 12.5 followed by next-generation sequencing (ChIP-seq). Nearly 84% ( n =617) of the Lmx1b-bound genomic intervals (LBIs) identified overlap with chromatin regulatory marks indicative of potential cis -regulatory modules (PCRMs). In addition, 73 LBIs mapped to CRMs that are known to be active during limb development. We compared Lmx1b-bound PCRMs with genes regulated by Lmx1b and found 292 PCRMs within 1 Mb of 254 Lmx1b-regulated genes. Gene ontological analysis suggests that Lmx1b targets extracellular matrix production, bone/joint formation, axonal guidance, vascular development, cell proliferation and cell movement. We validated the functional activity of a PCRM associated with joint-related Gdf5 that provides a mechanism for Lmx1b-mediated joint modification and a PCRM associated with Lmx1b that suggests a role in autoregulation. This is the first report to describe genome-wide Lmx1b binding during limb development, directly linking Lmx1b to targets that accomplish limb dorsalization. © 2017. Published by The Company of Biologists Ltd.

Deregulated MicroRNAs in Biliary Tract Cancer: Functional Targets and Potential Biomarkers

PubMed Central

Beyreis, Marlena; Wagner, Andrej; Pichler, Martin; Neureiter, Daniel

2016-01-01

Biliary tract cancer (BTC) is still a fatal disease with very poor prognosis. The lack of reliable biomarkers for early diagnosis and of effective therapeutic targets is a major demanding problem in diagnosis and management of BTC. Due to the clinically silent and asymptomatic characteristics of the tumor, most patients are diagnosed at an already advanced stage allowing only for a palliative therapeutic approach. MicroRNAs are small noncoding RNAs well known to regulate various cellular functions and pathologic events including the formation and progression of cancer. Over the last years, several studies have shed light on the role of microRNAs in BTC, making them potentially attractive therapeutic targets and candidates as biomarkers. In this review, we will focus on the role of oncogenic and tumor suppressor microRNAs and their direct targets in BTC. Furthermore, we summarize and discuss data that evaluate the diagnostic power of deregulated microRNAs as possible future biomarkers for BTC. PMID:27957497

Facilitated diffusion in chromatin lattices: mechanistic diversity and regulatory potential.

PubMed

Kampmann, Martin

2005-08-01

The interaction between a protein and a specific DNA site is the molecular basis for vital processes in all organisms. Location of the DNA target site by the protein commonly involves facilitated diffusion. Mechanisms of facilitated diffusion vary among proteins; they include one- and two-dimensional sliding along DNA, direct transfer between uncorrelated sites, as well as combinations of these mechanisms. Facilitated diffusion has almost exclusively been studied in vitro. This review discusses facilitated diffusion in the context of the living cell and proposes a theoretical model for facilitated diffusion in chromatin lattices. Chromatin structure differentially affects proteins in different modes of diffusion. The interplay of facilitated diffusion and chromatin structure can determine the rate of protein association with the target site, the frequency of association-dissociation events at the target site, and, under particular conditions, the occupancy of the target site. Facilitated diffusion is required in vivo for efficient DNA repair and bacteriophage restriction and has potential roles in fine-tuning gene regulatory networks and kinetically compartmentalizing the eukaryotic nucleus.

The next challenge for psycho-oncology in the UK: targeting service quality and outcomes.

PubMed

King, Alex

2016-12-01

The acceptance and provision of psychosocial cancer care in the UK is moving forward positively, aided by patient advocacy and psychologically minded healthcare policies. The unfolding challenge now is of targeting the quality and outcomes of clinical psycho-oncology services. This report outlines the clinically led development of UK-focused guidance to challenge psycho-oncology services to achieve and demonstrate their potential. It discusses how the guidance was particularly framed to encourage small, low-resource services, and outlines the potential benefits for patients. Overall, setting ourselves the challenge of quality on the same terms as physical healthcare, we can shape a direct path to achieving parity of esteem in mental with physical healthcare.

A Dual-Specific Targeting Approach Based on the Simultaneous Recognition of Duplex and Quadruplex Motifs.

PubMed

Nguyen, Thi Quynh Ngoc; Lim, Kah Wai; Phan, Anh Tuân

2017-09-20

Small-molecule ligands targeting nucleic acids have been explored as potential therapeutic agents. Duplex groove-binding ligands have been shown to recognize DNA in a sequence-specific manner. On the other hand, quadruplex-binding ligands exhibit high selectivity between quadruplex and duplex, but show limited discrimination between different quadruplex structures. Here we propose a dual-specific approach through the simultaneous application of duplex- and quadruplex-binders. We demonstrated that a quadruplex-specific ligand and a duplex-specific ligand can simultaneously interact at two separate binding sites of a quadruplex-duplex hybrid harbouring both quadruplex and duplex structural elements. Such a dual-specific targeting strategy would combine the sequence specificity of duplex-binders and the strong binding affinity of quadruplex-binders, potentially allowing the specific targeting of unique quadruplex structures. Future research can be directed towards the development of conjugated compounds targeting specific genomic quadruplex-duplex sites, for which the linker would be highly context-dependent in terms of length and flexibility, as well as the attachment points onto both ligands.

Direct target NOTES: prospective applications for next generation robotic platforms.

PubMed

Atallah, S; Hodges, A; Larach, S W

2018-05-01

A new era in surgical robotics has centered on alternative access to anatomic targets and next generation designs include flexible, single-port systems which follow circuitous rather than straight pathways. Such systems maintain a small footprint and could be utilized for specialized operations based on direct organ target natural orifice transluminal endoscopic surgery (NOTES), of which transanal total mesorectal excision (taTME) is an important derivative. During two sessions, four direct target NOTES operations were conducted on a cadaveric model using a flexible robotic system to demonstrate proof-of-concept of the application of a next generation robotic system to specific types of NOTES operations, all of which required removal of a direct target organ through natural orifice access. These four operations were (a) robotic taTME, (b) robotic transvaginal hysterectomy in conjunction with (c) robotic transvaginal salpingo-oophorectomy, and in an ex vivo model, (d) trans-cecal appendectomy. Feasibility was demonstrated in all cases using the Flex ® Robotic System with Colorectal Drive. During taTME, the platform excursion was 17 cm along a non-linear path; operative time was 57 min for the transanal portion of the dissection. Robotic transvaginal hysterectomy was successfully completed in 78 min with transvaginal extraction of the uterus, although laparoscopic assistance was required. Robotic transvaginal unilateral salpingo-oophorectomy with transvaginal extraction of the ovary and fallopian tube was performed without laparoscopic assistance in 13.5 min. In an ex vivo model, a robotic trans-cecal appendectomy was also successfully performed for the purpose of demonstrating proof-of-concept only; this was completed in 24 min. A flexible robotic system has the potential to access anatomy along circuitous paths, making it a suitable platform for direct target NOTES. The conceptual operations posed could be considered suitable for next generation robotics once the technology is optimized, and after further preclinical validation.

c-Myc inhibits myoblast differentiation and promotes myoblast proliferation and muscle fibre hypertrophy by regulating the expression of its target genes, miRNAs and lincRNAs.

PubMed

Luo, Wen; Chen, Jiahui; Li, Limin; Ren, Xueyi; Cheng, Tian; Lu, Shiyi; Lawal, Raman Akinyanju; Nie, Qinghua; Zhang, Xiquan; Hanotte, Olivier

2018-05-21

The transcription factor c-Myc is an important regulator of cellular proliferation, differentiation and embryogenesis. While c-Myc can inhibit myoblast differentiation, the underlying mechanisms remain poorly understood. Here, we found that c-Myc does not only inhibits myoblast differentiation but also promotes myoblast proliferation and muscle fibre hypertrophy. By performing chromatin immunoprecipitation and high-throughput sequencing (ChIP-seq), we identified the genome-wide binding profile of c-Myc in skeletal muscle cells. c-Myc achieves its regulatory effects on myoblast proliferation and differentiation by targeting the cell cycle pathway. Additionally, c-Myc can regulate cell cycle genes by controlling miRNA expression of which dozens of miRNAs can also be regulated directly by c-Myc. Among these c-Myc-associated miRNAs (CAMs), the roles played by c-Myc-induced miRNAs in skeletal muscle cells are similar to those played by c-Myc, whereas c-Myc-repressed miRNAs play roles that are opposite to those played by c-Myc. The cell cycle, ERK-MAPK and Akt-mediated pathways are potential target pathways of the CAMs during myoblast differentiation. Interestingly, we identified four CAMs that can directly bind to the c-Myc 3' UTR and inhibit c-Myc expression, suggesting that a negative feedback loop exists between c-Myc and its target miRNAs during myoblast differentiation. c-Myc also potentially regulates many long intergenic noncoding RNAs (lincRNAs). Linc-2949 and linc-1369 are directly regulated by c-Myc, and both lincRNAs are involved in the regulation of myoblast proliferation and differentiation by competing for the binding of muscle differentiation-related miRNAs. Our findings do not only provide a genome-wide overview of the role the c-Myc plays in skeletal muscle cells but also uncover the mechanism of how c-Myc and its target genes regulate myoblast proliferation and differentiation, and muscle fibre hypertrophy.

MiR-218 reverses high invasiveness of glioblastoma cells by targeting the oncogenic transcription factor LEF1.

PubMed

Liu, Yanwei; Yan, Wei; Zhang, Wei; Chen, Lingchao; You, Gan; Bao, Zhaoshi; Wang, Yongzhi; Wang, Hongjun; Kang, Chunsheng; Jiang, Tao

2012-09-01

The invasive behavior of glioblastoma multiforme (GBM) cells is one of the most important reasons for the poor prognosis of this cancer. For invasion, tumor cells must acquire an ability to digest the extracellular matrix and infiltrate the normal tissue bordering the tumor. Preventing this by altering effector molecules can significantly improve a patient's prognosis. Accumulating evidence suggests that miRNAs are involved in multiple biological functions, including cell invasion, by altering the expression of multiple target genes. The expression levels of miR-218 correlate with the invasive potential of GBM cells. In this study, we found that miR-218 expression was low in glioma tissues, especially in GBM. The data showed an inverse correlation in 60 GBM tissues between the levels of miR-218 and MMP mRNAs (MMP-2, -7 and -9). Additionally, ectopic expression of miR-218 suppressed the invasion of GBM cells whereas inhibition of miR-218 expression enhanced the invasive ability. Numerous members of the MMP family are downstream effectors of the Wnt/LEF1 pathway. Target prediction databases and luciferase data showed that LEF1 is a new direct target of miR-218. Importantly, western blot assays demonstrated that miR-218 can reduce protein levels of LEF1 and MMP-9. We, therefore, hypothesize that miR-218 directly targets LEF1, resulting in reduced synthesis of MMP-9. Results suggest that miR-218 is involved in the invasive behavior of GBM cells and by targeting LEF1 and blocking the invasive axis, miR-218-LEF1-MMPs, it may be useful for developing potential clinical strategies.

Proteomic Identification of Putative MicroRNA394 Target Genes in Arabidopsis thaliana Identifies Major Latex Protein Family Members Critical for Normal Development.

PubMed

Litholdo, Celso G; Parker, Benjamin L; Eamens, Andrew L; Larsen, Martin R; Cordwell, Stuart J; Waterhouse, Peter M

2016-06-01

Expression of the F-Box protein Leaf Curling Responsiveness (LCR) is regulated by microRNA, miR394, and alterations to this interplay in Arabidopsis thaliana produce defects in leaf polarity and shoot apical meristem organization. Although the miR394-LCR node has been documented in Arabidopsis, the identification of proteins targeted by LCR F-box itself has proven problematic. Here, a proteomic analysis of shoot apices from plants with altered LCR levels identified a member of the Latex Protein (MLP) family gene as a potential LCR F-box target. Bioinformatic and molecular analyses also suggested that other MLP family members are likely to be targets for this post-translational regulation. Direct interaction between LCR F-Box and MLP423 was validated. Additional MLP members had reduction in protein accumulation, in varying degrees, mediated by LCR F-Box. Transgenic Arabidopsis lines, in which MLP28 expression was reduced through an artificial miRNA technology, displayed severe developmental defects, including changes in leaf patterning and morphology, shoot apex defects, and eventual premature death. These phenotypic characteristics resemble those of Arabidopsis plants modified to over-express LCR Taken together, the results demonstrate that MLPs are driven to degradation by LCR, and indicate that MLP gene family is target of miR394-LCR regulatory node, representing potential targets for directly post-translational regulation mediated by LCR F-Box. In addition, MLP28 family member is associated with the LCR regulation that is critical for normal Arabidopsis development. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

A Contingency Management Intervention for Adolescent Marijuana Abuse and Conduct Problems.

ERIC Educational Resources Information Center

Kamon, Jody; Budney, Alan; Stanger, Catherine

2005-01-01

Objective: To describe an innovative treatment for adolescent marijuana abuse and provide initial information about its feasibility, acceptability, and potential efficacy. Method: Provided an intervention composed of (1) a clinic-administered, abstinence-based incentive program; (2) parent-directed contingency management targeting substance use…

The Effects of Mirror Feedback during Target Directed Movements on Ipsilateral Corticospinal Excitability

PubMed Central

Yarossi, Mathew; Manuweera, Thushini; Adamovich, Sergei V.; Tunik, Eugene

2017-01-01

Mirror visual feedback (MVF) training is a promising technique to promote activation in the lesioned hemisphere following stroke, and aid recovery. However, current outcomes of MVF training are mixed, in part, due to variability in the task undertaken during MVF. The present study investigated the hypothesis that movements directed toward visual targets may enhance MVF modulation of motor cortex (M1) excitability ipsilateral to the trained hand compared to movements without visual targets. Ten healthy subjects participated in a 2 × 2 factorial design in which feedback (veridical, mirror) and presence of a visual target (target present, target absent) for a right index-finger flexion task were systematically manipulated in a virtual environment. To measure M1 excitability, transcranial magnetic stimulation (TMS) was applied to the hemisphere ipsilateral to the trained hand to elicit motor evoked potentials (MEPs) in the untrained first dorsal interosseous (FDI) and abductor digiti minimi (ADM) muscles at rest prior to and following each of four 2-min blocks of 30 movements (B1–B4). Targeted movement kinematics without visual feedback was measured before and after training to assess learning and transfer. FDI MEPs were decreased in B1 and B2 when movements were made with veridical feedback and visual targets were absent. FDI MEPs were decreased in B2 and B3 when movements were made with mirror feedback and visual targets were absent. FDI MEPs were increased in B3 when movements were made with mirror feedback and visual targets were present. Significant MEP changes were not present for the uninvolved ADM, suggesting a task-specific effect. Analysis of kinematics revealed learning occurred in visual target-directed conditions, but transfer was not sensitive to mirror feedback. Results are discussed with respect to current theoretical mechanisms underlying MVF-induced changes in ipsilateral excitability. PMID:28553218

Directional Antineutrino Detection

NASA Astrophysics Data System (ADS)

Safdi, Benjamin R.; Suerfu, Burkhant

2015-02-01

We propose the first event-by-event directional antineutrino detector using inverse beta decay (IBD) interactions on hydrogen, with potential applications including monitoring for nuclear nonproliferation, spatially mapping geoneutrinos, characterizing the diffuse supernova neutrino background and searching for new physics in the neutrino sector. The detector consists of adjacent and separated target and capture scintillator planes. IBD events take place in the target layers, which are thin enough to allow the neutrons to escape without scattering elastically. The neutrons are detected in the thicker boron-loaded capture layers. The location of the IBD event and the momentum of the positron are determined by tracking the positron's trajectory through the detector. Our design is a straightforward modification of existing antineutrino detectors; a prototype could be built with existing technology.

Liposomal nanocarriers for tumor imaging.

PubMed

Erdogan, Suna

2009-04-01

Currently used imaging modalities such as scintigraphy, computed tomography, magnetic resonance imaging and ultrasonography require the sufficient intensity of a corresponding signal from an area of interest to differentiate this area from the surrounding tissues. Targeting of various reporter moieties directly to the specific organs, tissues or tumors provide the highest dose of drug directly where it is needed. Many different types of nanoparticles are currently being studied for applications in nanomedicine. Among particulate drug carriers, liposomes are one of the most extensively studied and possess the most suitable characteristics for encapsulation of many drugs, genes, and diagnostic (imaging) agents. Among the many potential targets for such nanocarriers, tumors have been most often investigated. This review attempts to summarize the currently available information regarding liposomal nanocarriers for cancer imaging.

Impaired preparatory re-mapping of stimulus-response associations and rule-implementation in schizophrenic patients--the role for differences in early processing.

PubMed

Finke, Mareike; Barceló, Francisco; Garolera, Maite; Cortiñas, Miriam; Garrido, Gemma; Pajares, Marta; Escera, Carles

2011-07-01

An accurate representation of task-set information is needed for successful goal directed behavior. Recent studies point to disturbances in the early processing stages as plausible causes for task-switching deficits in schizophrenia. A task-cueing protocol was administered to a group of schizophrenic patients and compared with a sample of age-matched healthy controls. Patients responded slower and less accurate compared with controls in all conditions. The concurrent recording of event-related brain potentials to contextual cues and target events revealed abnormalities in the early processing of both cue-locked and target-locked N1 potentials. Abnormally enhanced target-locked P2 amplitudes were observed in schizophrenic patients for task-switch trials only, suggesting disrupted stimulus evaluation and memory retrieval processes. The endogenous P3 potentials discriminated between task conditions but without further differences between groups. These results suggest that the observed impairments in task-switching behavior were not specifically related to anticipatory set-shifting, but derived from a deficit in the implementation of task-set representations at target onset in the presence of irrelevant and conflicting information. Copyright © 2011 Elsevier B.V. All rights reserved.

A Cost Benefit Analysis Between the Current Naval Officer Retention Bonus Plan and the Enlisted Retention Bonus Plan

DTIC Science & Technology

2016-06-01

that personnel targeted for retention had a direct ability to affect the success of the transaction and company. High potential, job function, job level...and job title rounded out the top five reasons personnel were targeted for retention . In brief, this study found that slightly more than half of...lower income may value the job security provided by service in the military, thus making retention in the military a more attractive option. 4

Unleashing the power of inhibitors of oncogenic kinases through BH3 mimetics.

PubMed

Cragg, Mark S; Harris, Claire; Strasser, Andreas; Scott, Clare L

2009-05-01

Therapeutic targeting of tumours on the basis of molecular analysis is a new paradigm for cancer treatment but has yet to fulfil expectations. For many solid tumours, targeted therapeutics, such as inhibitors of oncogenic kinase pathways, elicit predominantly disease-stabilizing, cytostatic responses, rather than tumour regression. Combining oncogenic kinase inhibitors with direct activators of the apoptosis machinery, such as the BH3 mimetic ABT-737, may unlock potent anti-tumour potential to produce durable clinical responses with less collateral damage.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Xia, Ying; Gao, Yan, E-mail: gaoyanhdhos@126.com

Highlights: • miR-181b is upregulated in human ovarian cancer tissues. • miR-181b promotes ovarian cancer cell proliferation and invasion. • LATS2 is a direct target of miR-181b. • LATS2 is involved in miR-181b-induced ovarian cancer cell growth and invasion. - Abstract: MicroRNAs (miRNAs) are strongly implicated in tumorigenesis and metastasis. In this study, we showed significant upregulation of miR-181b in ovarian cancer tissues, compared with the normal ovarian counterparts. Forced expression of miR-181b led to remarkably enhanced proliferation and invasion of ovarian cancer cells while its knockdown induced significant suppression of these cellular events. The tumor suppressor gene, LATS2 (largemore » tumor suppressor 2), was further identified as a novel direct target of miR-181b. Specifically, miR-181b bound directly to the 3′-untranslated region (UTR) of LATS2 and suppressed its expression. Restoration of LATS2 expression partially reversed the oncogenic effects of miR-181b. Our results indicate that miR-181b promotes proliferation and invasion by targeting LATS2 in ovarian cancer cells. These findings support the utility of miR-181b as a potential diagnostic and therapeutic target for ovarian cancer.« less

Antibody targeting facilitates effective intratumoral siRNA nanoparticle delivery to HER2-overexpressing cancer cells

PubMed Central

Palanca-Wessels, Maria C.; Booth, Garrett C.; Convertine, Anthony J.; Lundy, Brittany B.; Berguig, Geoffrey Y.; Press, Michael F.; Stayton, Patrick S.; Press, Oliver W.

2016-01-01

The therapeutic potential of RNA interference (RNAi) has been limited by inefficient delivery of short interfering RNA (siRNA). Tumor-specific recognition can be effectively achieved by antibodies directed against highly expressed cancer cell surface receptors. We investigated the utility of linking an internalizing streptavidin-conjugated HER2 antibody to an endosome-disruptive biotinylated polymeric nanocarrier to improve the functional cytoplasmic delivery of siRNA in breast and ovarian cancer cells in vitro and in an intraperitoneal ovarian cancer xenograft model in vivo, yielding an 80% reduction of target mRNA and protein levels with sustained repression for at least 96 hours. RNAi-mediated site specific cleavage of target mRNA was demonstrated using the 5′ RLM-RACE (RNA ligase mediated-rapid amplification of cDNA ends) assay. Mice bearing intraperitoneal human ovarian tumor xenografts demonstrated increased tumor accumulation of Cy5.5 fluorescently labeled siRNA and 70% target gene suppression after treatment with HER2 antibody-directed siRNA nanocarriers. Detection of the expected mRNA cleavage product by 5′ RLM-RACE assay confirmed that suppression occurs via the expected RNAi pathway. Delivery of siRNA via antibody-directed endosomolytic nanoparticles may be a promising strategy for cancer therapy. PMID:26840082

Antibody targeting facilitates effective intratumoral siRNA nanoparticle delivery to HER2-overexpressing cancer cells.

PubMed

Palanca-Wessels, Maria C; Booth, Garrett C; Convertine, Anthony J; Lundy, Brittany B; Berguig, Geoffrey Y; Press, Michael F; Stayton, Patrick S; Press, Oliver W

2016-02-23

The therapeutic potential of RNA interference (RNAi) has been limited by inefficient delivery of short interfering RNA (siRNA). Tumor-specific recognition can be effectively achieved by antibodies directed against highly expressed cancer cell surface receptors. We investigated the utility of linking an internalizing streptavidin-conjugated HER2 antibody to an endosome-disruptive biotinylated polymeric nanocarrier to improve the functional cytoplasmic delivery of siRNA in breast and ovarian cancer cells in vitro and in an intraperitoneal ovarian cancer xenograft model in vivo, yielding an 80% reduction of target mRNA and protein levels with sustained repression for at least 96 hours. RNAi-mediated site specific cleavage of target mRNA was demonstrated using the 5' RLM-RACE (RNA ligase mediated-rapid amplification of cDNA ends) assay. Mice bearing intraperitoneal human ovarian tumor xenografts demonstrated increased tumor accumulation of Cy5.5 fluorescently labeled siRNA and 70% target gene suppression after treatment with HER2 antibody-directed siRNA nanocarriers. Detection of the expected mRNA cleavage product by 5' RLM-RACE assay confirmed that suppression occurs via the expected RNAi pathway. Delivery of siRNA via antibody-directed endosomolytic nanoparticles may be a promising strategy for cancer therapy.

Multishot Targeted PROPELLER Magnetic Resonance Imaging: Description of the Technique and Initial Applications

PubMed Central

Deng, Jie; Larson, Andrew C.

2010-01-01

Objectives To test the feasibility of combining inner-volume imaging (IVI) techniques with conventional multishot periodically rotated overlapping parallel lines with enhanced reconstruction (PROPELLER) techniques for targeted-PROPELLER magnetic resonance imaging. Materials and Methods Perpendicular section-selective gradients for spatially selective excitation and refocusing RF pulses were applied to limit the refocused field-of-view (FOV) along the phase-encoding direction for each rectangular blade image. We performed comparison studies in phantoms and normal volunteers by using targeted-PROPELLER methods for a wide range of imaging applications that commonly use turbo-spin-echo (TSE) approaches (brain, abdominal, vessel wall, cardiac). Results In these initial studies, we demonstrated the feasibility of using targeted-PROPELLER approaches to limit the imaging FOV thereby reducing the number of blades or permitting increased spatial resolution without commensurate increases in scan time. Both phantom and in vivo motion studies demonstrated the potential for more robust regional self-navigated motion correction compared with conventional full FOV PROPELLER methods. Conclusion We demonstrated that the reduced FOV targeted-PROPELLER technique offers the potential for reducing imaging time, increasing spatial resolution, and targeting specific areas for robust regional motion correction. PMID:19465860

Rethinking Nuclear Receptors as Potential Therapeutic Targets for Retinal Diseases.

PubMed

Choudhary, Mayur; Malek, Goldis

2016-12-01

Collectively, retinal diseases, including age-related macular degeneration, retinitis pigmentosa, and diabetic retinopathy, result in severe vision impairment worldwide. The absence and/or limited availability of successful drug therapies for these blinding disorders necessitates further understanding their pathobiology and identifying new targetable signaling pathways. Nuclear receptors are transcription regulators of many key aspects of human physiology, as well as pathophysiology, with reported roles in development, aging, and disease. Some of the pathways regulated by nuclear receptors include, but are not limited to, angiogenesis, inflammation, and lipid metabolic dysregulation, mechanisms also important in the initiation and development of several retinal diseases. Herein, we present an overview of the biology of three diseases affecting the posterior eye, summarize a growing body of evidence that suggests direct or indirect involvement of nuclear receptors in disease progression, and discuss the therapeutic potential of targeting nuclear receptors for treatment.

Rethinking Nuclear Receptors as Potential Therapeutic Targets for Retinal Diseases

PubMed Central

Choudhary, Mayur; Malek, Goldis

2017-01-01

Collectively, retinal diseases, including age-related macular degeneration, retinitis pigmentosa, and diabetic retinopathy, result in severe vision impairment worldwide. The absence and/or limited availability of successful drug therapies for these blinding disorders necessitates further understanding their pathobiology and identifying new targetable signaling pathways. Nuclear receptors are transcription regulators of many key aspects of human physiology, as well as pathophysiology, with reported roles in development, aging, and disease. Some of the pathways regulated by nuclear receptors include, but are not limited to, angiogenesis, inflammation, and lipid metabolic dysregulation, mechanisms also important in the initiation and development of several retinal diseases. Herein, we present an overview of the biology of three diseases affecting the posterior eye, summarize a growing body of evidence that suggests direct or indirect involvement of nuclear receptors in disease progression, and discuss the therapeutic potential of targeting nuclear receptors for treatment. PMID:27455994

Mesenchymal stem cell-mediated cancer therapy: A dual-targeted strategy of personalized medicine

PubMed Central

Sun, Xu-Yong; Nong, Jiang; Qin, Ke; Warnock, Garth L; Dai, Long-Jun

2011-01-01

Cancer remains one of the leading causes of mortality and morbidity throughout the world. To a significant extent, current conventional cancer therapies are symptomatic and passive in nature. The major obstacle to the development of effective cancer therapy is believed to be the absence of sufficient specificity. Since the discovery of the tumor-oriented homing capacity of mesenchymal stem cells (MSCs), the application of specific anticancer gene-engineered MSCs has held great potential for cancer therapies. The dual-targeted strategy is based on MSCs’ capacity of tumor-directed migration and incorporation and in situ expression of tumor-specific anticancer genes. With the aim of translating bench work into meaningful clinical applications, we describe the tumor tropism of MSCs and their use as therapeutic vehicles, the dual-targeted anticancer potential of engineered MSCs and a putative personalized strategy with anticancer gene-engineered MSCs. PMID:22180830

Targeted gene knock-in by homology-directed genome editing using Cas9 ribonucleoprotein and AAV donor delivery.

PubMed

Gaj, Thomas; Staahl, Brett T; Rodrigues, Gonçalo M C; Limsirichai, Prajit; Ekman, Freja K; Doudna, Jennifer A; Schaffer, David V

2017-06-20

Realizing the full potential of genome editing requires the development of efficient and broadly applicable methods for delivering programmable nucleases and donor templates for homology-directed repair (HDR). The RNA-guided Cas9 endonuclease can be introduced into cells as a purified protein in complex with a single guide RNA (sgRNA). Such ribonucleoproteins (RNPs) can facilitate the high-fidelity introduction of single-base substitutions via HDR following co-delivery with a single-stranded DNA oligonucleotide. However, combining RNPs with transgene-containing donor templates for targeted gene addition has proven challenging, which in turn has limited the capabilities of the RNP-mediated genome editing toolbox. Here, we demonstrate that combining RNP delivery with naturally recombinogenic adeno-associated virus (AAV) donor vectors enables site-specific gene insertion by homology-directed genome editing. Compared to conventional plasmid-based expression vectors and donor templates, we show that combining RNP and AAV donor delivery increases the efficiency of gene addition by up to 12-fold, enabling the creation of lineage reporters that can be used to track the conversion of striatal neurons from human fibroblasts in real time. These results thus illustrate the potential for unifying nuclease protein delivery with AAV donor vectors for homology-directed genome editing. © The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.

Grazing-incidence small-angle X-ray scattering (GISAXS) on small periodic targets using large beams

PubMed Central

Soltwisch, Victor; Probst, Jürgen; Scholze, Frank; Krumrey, Michael

2017-01-01

Grazing-incidence small-angle X-ray scattering (GISAXS) is often used as a versatile tool for the contactless and destruction-free investigation of nano­structured surfaces. However, due to the shallow incidence angles, the footprint of the X-ray beam is significantly elongated, limiting GISAXS to samples with typical target lengths of several millimetres. For many potential applications, the production of large target areas is impractical, and the targets are surrounded by structured areas. Because the beam footprint is larger than the targets, the surrounding structures contribute parasitic scattering, burying the target signal. In this paper, GISAXS measurements of isolated as well as surrounded grating targets in Si substrates with line lengths from 50 µm down to 4 µm are presented. For the isolated grating targets, the changes in the scattering patterns due to the reduced target length are explained. For the surrounded grating targets, the scattering signal of a 15 µm × 15 µm target grating structure is separated from the scattering signal of 100 µm × 100 µm nanostructured surroundings by producing the target with a different orientation with respect to the predominant direction of the surrounding structures. As virtually all litho­graphically produced nanostructures have a predominant direction, the described technique allows GISAXS to be applied in a range of applications, e.g. for characterization of metrology fields in the semiconductor industry, where up to now it has been considered impossible to use this method due to the large beam footprint. PMID:28875030

Grazing-incidence small-angle X-ray scattering (GISAXS) on small periodic targets using large beams.

PubMed

Pflüger, Mika; Soltwisch, Victor; Probst, Jürgen; Scholze, Frank; Krumrey, Michael

2017-07-01

Grazing-incidence small-angle X-ray scattering (GISAXS) is often used as a versatile tool for the contactless and destruction-free investigation of nano-structured surfaces. However, due to the shallow incidence angles, the footprint of the X-ray beam is significantly elongated, limiting GISAXS to samples with typical target lengths of several millimetres. For many potential applications, the production of large target areas is impractical, and the targets are surrounded by structured areas. Because the beam footprint is larger than the targets, the surrounding structures contribute parasitic scattering, burying the target signal. In this paper, GISAXS measurements of isolated as well as surrounded grating targets in Si substrates with line lengths from 50 µm down to 4 µm are presented. For the isolated grating targets, the changes in the scattering patterns due to the reduced target length are explained. For the surrounded grating targets, the scattering signal of a 15 µm × 15 µm target grating structure is separated from the scattering signal of 100 µm × 100 µm nanostructured surroundings by producing the target with a different orientation with respect to the predominant direction of the surrounding structures. As virtually all litho-graphically produced nanostructures have a predominant direction, the described technique allows GISAXS to be applied in a range of applications, e.g.  for characterization of metrology fields in the semiconductor industry, where up to now it has been considered impossible to use this method due to the large beam footprint.

New Wnt/β-catenin target genes promote experimental metastasis and migration of colorectal cancer cells through different signals.

PubMed

Qi, Jingjing; Yu, Yong; Akilli Öztürk, Özlem; Holland, Jane D; Besser, Daniel; Fritzmann, Johannes; Wulf-Goldenberg, Annika; Eckert, Klaus; Fichtner, Iduna; Birchmeier, Walter

2016-10-01

We have previously identified a 115-gene signature that characterises the metastatic potential of human primary colon cancers. The signature included the canonical Wnt target gene BAMBI, which promoted experimental metastasis in mice. Here, we identified three new direct Wnt target genes from the signature, and studied their functions in epithelial-mesenchymal transition (EMT), cell migration and experimental metastasis. We examined experimental liver metastases following injection of selected tumour cells into spleens of NOD/SCID mice. Molecular and cellular techniques were used to identify direct transcription target genes of Wnt/β-catenin signals. Microarray analyses and experiments that interfered with cell migration through inhibitors were performed to characterise downstream signalling systems. Three new genes from the colorectal cancer (CRC) metastasis signature, BOP1, CKS2 and NFIL3, were identified as direct transcription targets of β-catenin/TCF4. Overexpression and knocking down of these genes in CRC cells promoted and inhibited, respectively, experimental metastasis in mice, EMT and cell motility in culture. Cell migration was repressed by interfering with distinct signalling systems through inhibitors of PI3K, JNK, p38 mitogen-activated protein kinase and/or mTOR. Gene expression profiling identified a series of migration-promoting genes, which were induced by BOP1, CKS2 and NFIL3, and could be repressed by inhibitors that are specific to these pathways. We identified new direct Wnt/β-catenin target genes, BOP1, CKS2 and NFIL3, which induced EMT, cell migration and experimental metastasis of CRC cells. These genes crosstalk with different downstream signalling systems, and activate migration-promoting genes. These pathways and downstream genes may serve as therapeutic targets in the treatment of CRC metastasis. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

Genome-Wide Mapping of Collier In Vivo Binding Sites Highlights Its Hierarchical Position in Different Transcription Regulatory Networks

PubMed Central

Dubois, Laurence; Bataillé, Laetitia; Painset, Anaïs; Le Gras, Stéphanie; Jost, Bernard; Crozatier, Michèle; Vincent, Alain

2015-01-01

Collier, the single Drosophila COE (Collier/EBF/Olf-1) transcription factor, is required in several developmental processes, including head patterning and specification of muscle and neuron identity during embryogenesis. To identify direct Collier (Col) targets in different cell types, we used ChIP-seq to map Col binding sites throughout the genome, at mid-embryogenesis. In vivo Col binding peaks were associated to 415 potential direct target genes. Gene Ontology analysis revealed a strong enrichment in proteins with DNA binding and/or transcription-regulatory properties. Characterization of a selection of candidates, using transgenic CRM-reporter assays, identified direct Col targets in dorso-lateral somatic muscles and specific neuron types in the central nervous system. These data brought new evidence that Col direct control of the expression of the transcription regulators apterous and eyes-absent (eya) is critical to specifying neuronal identities. They also showed that cross-regulation between col and eya in muscle progenitor cells is required for specification of muscle identity, revealing a new parallel between the myogenic regulatory networks operating in Drosophila and vertebrates. Col regulation of eya, both in specific muscle and neuronal lineages, may illustrate one mechanism behind the evolutionary diversification of Col biological roles. PMID:26204530

Toward a more ecologically valid measure of speech understanding in background noise.

PubMed

Jerger, J; Greenwald, R; Wambacq, I; Seipel, A; Moncrieff, D

2000-05-01

In an attempt to develop a more ecologically valid measure of speech understanding in a background of competing speech, we constructed a quasidichotic procedure based on the monitoring of continuous speech from loudspeakers placed directly to the listener's right and left sides. The listener responded to the presence of incongruous or anomalous words imbedded within the context of two children's fairy tales. Attention was directed either to the right or to the left side in blocks of 25 utterances. Within each block, there were target (anomalous) and nontarget (nonanomalous) words. Responses to target words were analyzed separately for attend-right and attend-left conditions. Our purpose was twofold: (1) to evaluate the feasibility of such an approach for obtaining electrophysiologic performance measures in the sound field and (2) to gather normative interaural symmetry data for the new technique in young adults with normal hearing. Event-related potentials to target and nontarget words at 30 electrode sites were obtained in 20 right-handed young adults with normal hearing. Waveforms and associated topographic maps were characterized by a slight negativity in the region of 400 msec (N400) and robust positivity in the region of 900 msec (P900). Norms for interaural symmetry of the P900 event-related potential in young adults were derived.

Human portable preconcentrator system

DOEpatents

Linker, Kevin L.; Bouchier, Francis A.; Hannum, David W.; Rhykerd, Jr., Charles L.

2003-01-01

A preconcentrator system and apparatus suited to human portable use wherein sample potentially containing a target chemical substance is drawn into a chamber and through a pervious screen. The screen is adapted to capture target chemicals and then, upon heating, to release those chemicals into the chamber. Chemicals captured and then released in this fashion are then carried to a portable chemical detection device such as a portable ion mobility spectrometer. In the preferred embodiment, the means for drawing sample into the chamber comprises a reversible fan which, when operated in reverse direction, creates a backpressure that facilitates evolution of captured target chemicals into the chamber when the screen is heated.

Nanocarriers in advanced drug targeting: setting novel paradigm in cancer therapeutics.

PubMed

Akhter, Md Habban; Rizwanullah, Md; Ahmad, Javed; Ahsan, Mohamed Jawed; Mujtaba, Md Ali; Amin, Saima

2018-08-01

Cancer has been growing nowadays consequently high number of death ascertained worldwide. The medical intervention involves chemotherapy, radiation therapy and surgical removal. This conventional technique lacking targeting potential and harm the normal cells. In drug treatment regimen, the combination therapy is preferred than single drug treatment module due to higher internalization of chemotherapeutics in the cancer cells both by enhance permeation retention effect and by direct cell apoptosis. The cancer therapeutics involves different methodologies of delivering active moiety to the target site. The active and passive transport mode of chemotherapeutic targeting utilizes advance nanocarriers. The nanotechnological strategic treatment applying advance nanocarrier greatly helps in mitigating the cancer prevalence. The nanocarrier-incorporating nanodrug directed for specific area appealed scientist across the globe and issues to be addressed in this regard. Therefore, various techniques and approaches invented to meet the objectives. With the advances in nanomedicine and drug delivery, this review briefly focused on various modes of nanodrug delivery including nanoparticles, liposomes, dendrimer, quantum dots, carbon nanotubes, metallic nanoparticles, nanolipid carrier (NLC), gold nanoshell, nanosize cantilevers and nanowire that looks promising and generates a novel horizon in cancer therapeutics.

A compound chimeric antigen receptor strategy for targeting multiple myeloma.

PubMed

Chen, K H; Wada, M; Pinz, K G; Liu, H; Shuai, X; Chen, X; Yan, L E; Petrov, J C; Salman, H; Senzel, L; Leung, E L H; Jiang, X; Ma, Y

2018-02-01

Current clinical outcomes using chimeric-antigen receptors (CARs) against multiple myeloma show promise in the eradication of bulk disease. However, these anti-BCMA (CD269) CARs observe relapse as a common phenomenon after treatment due to the reemergence of either antigen-positive or -negative cells. Hence, the development of improvements in CAR design to target antigen loss and increase effector cell persistency represents a critical need. Here, we report on the anti-tumor activity of a CAR T-cell possessing two complete and independent CAR receptors against the multiple myeloma antigens BCMA and CS1. We determined that the resulting compound CAR (cCAR) T-cell possesses consistent, potent and directed cytotoxicity against each target antigen population. Using multiple mouse models of myeloma and mixed cell populations, we are further able to show superior in vivo survival by directed cytotoxicity against multiple populations compared to a single-expressing CAR T-cell. These findings indicate that compound targeting of BCMA and CS1 on myeloma cells can potentially be an effective strategy for augmenting the response against myeloma bulk disease and for initiation of broader coverage CAR therapy.

MiR-30c: a novel regulator of salt tolerance in tilapia.

PubMed

Yan, Biao; Guo, Jin-Tao; Zhao, Li-Hui; Zhao, Jin-Liang

2012-08-24

miRNAs comprise a class of ~22 nt noncoding RNAs that modulate the stability and/or translational potential of their mRNA targets. Emerging data suggest that stress conditions can alter the biogenesis of miRNAs, thereby changing the expression of mRNA targets. Here, we reveal that miR-30c, a kidney-enriched miRNA, emerges as a crucial osmoregulator in Nile tilapia. miR-30c loss of function leads to an inability to respond to osmotic stress. We identify HSP70 as one of the direct regulatory targets of miR-30c. miR-30c directly regulates HSP70 by targeting its 3'-UTR, and inhibition of miR-30c substantially increases HSP70 mRNA level in vivo. Taken together, our experiments suggest that miRNAs participate in a regulatory circuit that allows rapid gene program transitions in response to osmotic stress. miR-30c may be developed as a molecular marker to assist to breed or genetically engineer salt tolerant species. Copyright © 2012 Elsevier Inc. All rights reserved.

Optimized T-cell receptor-mimic chimeric antigen receptor T cells directed toward the intracellular Wilms Tumor 1 antigen

PubMed Central

Rafiq, S; Purdon, TJ; Daniyan, AF; Koneru, M; Dao, T; Liu, C; Scheinberg, DA; Brentjens, RJ

2017-01-01

CD19-directed chimeric antigen receptor (CAR) T cells are clinically effective in a limited set of leukemia patients. However, CAR T-cell therapy thus far has been largely restricted to targeting extracellular tumor-associated antigens (TAA). Herein, we report a T-cell receptor-mimic (TCRm) CAR, termed WT1-28z, that is reactive to a peptide portion of the intracellular onco-protein Wilms Tumor 1(WT1), as it is expressed on the surface of the tumor cell in the context of HLA-A*02:01. T cells modified to express WT1-28z specifically targeted and lysed HLA-A*02:01+ WT1+ tumors and enhanced survival of mice engrafted with HLA-A*02:01+, WT1+ leukemia or ovarian tumors. This in vivo functional validation of TCRm CAR T cells provides the proof-of-concept necessary to expand the range of TAA that can be effectively targeted for immunotherapy to include attractive intracellular targets, and may hold great potential to expand on the success of CAR T-cell therapy. PMID:27924074

Phospholipase D2 Mediates Survival Signaling through Direct Regulation of Akt in Glioblastoma Cells*♦

PubMed Central

Bruntz, Ronald C.; Taylor, Harry E.; Lindsley, Craig W.; Brown, H. Alex

2014-01-01

The lack of innovative drug targets for glioblastoma multiforme (GBM) limits patient survival to approximately 1 year following diagnosis. The pro-survival kinase Akt provides an ideal target for the treatment of GBM as Akt signaling is frequently activated in this cancer type. However, the central role of Akt in physiological processes limits its potential as a therapeutic target. In this report, we show that the lipid-metabolizing enzyme phospholipase D (PLD) is a novel regulator of Akt in GBM. Studies using a combination of small molecule PLD inhibitors and siRNA knockdowns establish phosphatidic acid, the product of the PLD reaction, as an essential component for the membrane recruitment and activation of Akt. Inhibition of PLD enzymatic activity and subsequent Akt activation decreases GBM cell viability by specifically inhibiting autophagic flux. We propose a mechanism whereby phosphorylation of beclin1 by Akt prevents binding of Rubicon (RUN domain cysteine-rich domain containing beclin1-interacting protein), an interaction known to inhibit autophagic flux. These findings provide a novel framework through which Akt inhibition can be achieved without directly targeting the kinase. PMID:24257753

Micro-Doppler analysis of multiple frequency continuous wave radar signatures

NASA Astrophysics Data System (ADS)

Anderson, Michael G.; Rogers, Robert L.

2007-04-01

Micro-Doppler refers to Doppler scattering returns produced by non rigid-body motion. Micro-Doppler gives rise to many detailed radar image features in addition to those associated with bulk target motion. Targets of different classes (for example, humans, animals, and vehicles) produce micro-Doppler images that are often distinguishable even by nonexpert observers. Micro-Doppler features have great potential for use in automatic target classification algorithms. Although the potential benefit of using micro-Doppler in classification algorithms is high, relatively little experimental (non-synthetic) micro-Doppler data exists. Much of the existing experimental data comes from highly cooperative targets (human or vehicle targets directly approaching the radar). This research involved field data collection and analysis of micro-Doppler radar signatures from non-cooperative targets. The data was collected using a low cost Xband multiple frequency continuous wave (MFCW) radar with three transmit frequencies. The collected MFCW radar signatures contain data from humans, vehicles, and animals. The presented data includes micro-Doppler signatures previously unavailable in the literature such as crawling humans and various animal species. The animal micro-Doppler signatures include deer, dog, and goat datasets. This research focuses on the analysis of micro-Doppler from noncooperative targets approaching the radar at various angles, maneuvers, and postures.

Development of companion diagnostics

DOE PAGES

Mankoff, David A.; Edmonds, Christine E.; Farwell, Michael D.; ...

2015-12-12

The goal of individualized and targeted treatment and precision medicine requires the assessment of potential therapeutic targets to direct treatment selection. The biomarkers used to direct precision medicine, often termed companion diagnostics, for highly targeted drugs have thus far been almost entirely based on in vitro assay of biopsy material. Molecular imaging companion diagnostics offer a number of features complementary to those from in vitro assay, including the ability to measure the heterogeneity of each patient’s cancer across the entire disease burden and to measure early changes in response to treatment. We discuss the use of molecular imaging methods asmore » companion diagnostics for cancer therapy with the goal of predicting response to targeted therapy and measuring early (pharmacodynamic) response as an indication of whether the treatment has “hit” the target. We also discuss considerations for probe development for molecular imaging companion diagnostics, including both small-molecule probes and larger molecules such as labeled antibodies and related constructs. We then describe two examples where both predictive and pharmacodynamic molecular imaging markers have been tested in humans: endocrine therapy for breast cancer and human epidermal growth factor receptor type 2–targeted therapy. Lastly, the review closes with a summary of the items needed to move molecular imaging companion diagnostics from early studies into multicenter trials and into the clinic.« less

Development of companion diagnostics

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mankoff, David A.; Edmonds, Christine E.; Farwell, Michael D.

The goal of individualized and targeted treatment and precision medicine requires the assessment of potential therapeutic targets to direct treatment selection. The biomarkers used to direct precision medicine, often termed companion diagnostics, for highly targeted drugs have thus far been almost entirely based on in vitro assay of biopsy material. Molecular imaging companion diagnostics offer a number of features complementary to those from in vitro assay, including the ability to measure the heterogeneity of each patient’s cancer across the entire disease burden and to measure early changes in response to treatment. We discuss the use of molecular imaging methods asmore » companion diagnostics for cancer therapy with the goal of predicting response to targeted therapy and measuring early (pharmacodynamic) response as an indication of whether the treatment has “hit” the target. We also discuss considerations for probe development for molecular imaging companion diagnostics, including both small-molecule probes and larger molecules such as labeled antibodies and related constructs. We then describe two examples where both predictive and pharmacodynamic molecular imaging markers have been tested in humans: endocrine therapy for breast cancer and human epidermal growth factor receptor type 2–targeted therapy. Lastly, the review closes with a summary of the items needed to move molecular imaging companion diagnostics from early studies into multicenter trials and into the clinic.« less

Development of Companion Diagnostics

PubMed Central

Mankoff, David A.; Edmonds, Christine E.; Farwell, Michael D.; Pryma, Daniel A.

2016-01-01

The goal of individualized and targeted treatment and precision medicine requires the assessment of potential therapeutic targets to direct treatment selection. The biomarkers used to direct precision medicine, often termed companion diagnostics, for highly targeted drugs have thus far been almost entirely based on in vitro assay of biopsy material. Molecular imaging companion diagnostics offer a number of features complementary to those from in vitro assay, including the ability to measure the heterogeneity of each patient’s cancer across the entire disease burden and to measure early changes in response to treatment. We discuss the use of molecular imaging methods as companion diagnostics for cancer therapy with the goal of predicting response to targeted therapy and measuring early (pharmacodynamic) response as an indication of whether the treatment has “hit” the target. We also discuss considerations for probe development for molecular imaging companion diagnostics, including both small-molecule probes and larger molecules such as labeled antibodies and related constructs. We then describe two examples where both predictive and pharmacodynamic molecular imaging markers have been tested in humans: endocrine therapy for breast cancer and human epidermal growth factor receptor type 2–targeted therapy. The review closes with a summary of the items needed to move molecular imaging companion diagnostics from early studies into multicenter trials and into the clinic. PMID:26687857

Effect of target animacy on hand preference in Sichuan snub-nosed monkeys (Rhinopithecus roxellana).

PubMed

Zhao, Dapeng; Tian, Xiangling; Liu, Xinchen; Chen, Zhuoyue; Li, Baoguo

2016-09-01

Twenty-eight captive Sichuan snub-nosed monkeys (Rhinopithecus roxellana) were involved in the current study. Many individuals showed handedness, with a modest tendency toward left-hand use especially for animate targets, although no group-level handedness was found. There was no significant gender difference in the direction and strength of hand preference for both targets. Females showed a significantly higher overall rate of actions toward animate targets than inanimate targets for both hands, whereas males displayed almost the reversed pattern. There were no significant interactions between lateral hand use and target animacy for either males or females. Most individuals showed rightward or leftward laterality shift trends between inanimate and animate targets. These findings to some extent support the existence of a potential trend concerning a categorical neural distinction between targets demanding functional manipulation (inanimate objects) and those demanding social manipulation (animate objects), even though specialized hand preference based on target animacy has not been fully established in this arboreal Old World monkey species.

[Effects of target tree tending on community structure and diversity in subtropical natural secondary shrubs].

PubMed

Zhang, Hui; Zhou, Guo Mo; Bai, Shang Bin; Wang, Yi Xiang; You, Yu Jie; Zhu, Ting Ting; Zhang, Hua Feng

2017-05-18

The typical natural secondary shrub community was chosen in Lin'an of Zhejiang Pro-vince to discover its possibility of restoration to arbor forest with three kinds of forest management models being taken, i.e., no care as control, closed forest management and target tree tending. Over four years growth, compared with control, closed forest management significantly increased average DBH and height by 130% and 50%, respectively, while 260% and 110% for target tree tending. In target tree tending plots, larger trees had been emerging with 4.5-8.5 cm diameter class and 4.5-8.5 m height class and formed a new storey of 4 m compared with control. The species biodiversity indexes at shrub layer were significantly increased in closed management plots, and did not decrease in target tree tending plots. Closed forest management did not change the tree species composition, following its previous succession direction. However, target tree tending increased the importance value of target species with the high potential succession direction of mixed coniferous-broadleaved forest. The results revealed that the secondary shrub community with target tree tending achieved more desired goals on DBH and height growth of dominant trees and species composition improvement compared with closed management. If the secondary shrub community could be managed when the operational conditions existed, target tree tending model should be selected to accelerate the restoration of shrub toward arbor forest.

Achondroplasia: pathogenesis and implications for future treatment.

PubMed

Laederich, Melanie B; Horton, William A

2010-08-01

Although the genetic defect underlying achondroplasia has been known for over a decade, no effective therapies to stimulate bone growth have emerged. Here we review the recent literature and summarize the molecular mechanisms underlying disease pathology and examine their potential as therapeutic targets. Currently used preclinical models are discussed in the context of recent advances with a special focus on C-type natriuretic peptide. Research on the mutation in Fibroblast Growth Factor Receptor 3 (FGFR3) that causes achondroplasia suggests that disease results from increased signal transduction from the mutant receptor. Thus, current therapeutic strategies have focused on reducing signals emanating from FGFR3. First-generation therapies directly targeting FGFR3, such as kinase inhibitors and neutralizing antibodies, designed for targeting FGFR3 in cancer, are still in the preclinical phase and have yet to translate into the management of achondroplasia. Counteracting signal transduction pathways downstream of FGFR3 holds promise with the discovery that administration of C-type natriuretic peptide to achondroplastic mice ameliorates their clinical phenotype. However, more research into long-term effectiveness and safety of this strategy is needed. Direct targeting of therapeutic agents to growth plate cartilage may enhance efficacy and minimize side effects of these and future therapies. Current research into the pathogenesis of achondroplasia has expanded our understanding of the mechanisms of FGFR3-induced disease and has increased the number of approaches that we may use to potentially correct it. Further research is needed to validate these approaches in preclinical models of achondroplasia.

miR-23a acts as an oncogene in pancreatic carcinoma by targeting FOXP2.

PubMed

Diao, Hongliang; Ye, Zhou; Qin, Renyi

2018-03-01

MicroRNAs have been reported to play an important role in tumor development and progression by targeting oncogenes and tumor suppressors. miR-23a has been described as significantly upregulated in multiple cancers and involved in tumorigenesis. The aim of this study was to evaluate the potential roles of miR-23a in pancreatic ductal adenocarcinoma (PDAC). We found that miR-23a level was significantly increased in tissues of PDAC compared with that in the control by real-time PCR. FOXP2 expression was downregulated and inversely correlated with miR-23a. miR-23a directly targeted the 3'-untranslated region of FOXP2 mRNA and repressed its expression. Mechanistically, enhancement of miR-23a by transfection with mimics in Aspc-1 cells significantly promoted cell proliferation and invasion, while miR-23a inhibitors transfection in SW1990 cells induced an inhibitory effect. Moreover, restoration of FOXP2 impaired the pro-proliferation and proinvasion effects of miR-23a, indicating FOXP2 is a direct mediator of miR-23a functions. In conclusion, our findings suggest a novel miR-23a/FOXP2 link contributing to PDAC development and invasion. It may be a potential diagnostic and therapeutic target for PDAC. © American Federation for Medical Research (unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

PHASE II CALDERON PROCESS TO PRODUCE DIRECT REDUCED IRON RESEARCH AND DEVELOPMENT PROJECT

DOE Office of Scientific and Technical Information (OSTI.GOV)

Albert Calderon

2003-04-28

This project was initially targeted to the making of coke for blast furnaces by using proprietary technology of Calderon in a phased approach, and Phase I was successfully completed. The project was then re-directed to the making of iron units. U.S. Steel teamed up with Calderon for a joint effort which will last 30 months to produce directly reduced iron with the potential of converting it into molten iron or steel consistent with the Roadmap recommendations of 1998 prepared by the Steel Industry in cooperation with the Department of Energy.

PHASE II CALDERON PROCESS TO PRODUCE DIRECT REDUCED IRON RESEARCH AND DEVELOPMENT PROJECT

DOE Office of Scientific and Technical Information (OSTI.GOV)

Albert Calderon

2003-01-28

This project was initially targeted to the making of coke for blast furnaces by using proprietary technology of Calderon in a phased approach, and Phase I was successfully completed. The project was then re-directed to the making of iron units. U.S. Steel teamed up with Calderon for a joint effort which will last 30 months to produce directly reduced iron with the potential of converting it into molten iron or steel consistent with the Roadmap recommendations of 1998 prepared by the Steel Industry in cooperation with the Department of Energy.

Whole-Genome Analysis of the SHORT-ROOT Developmental Pathway in Arabidopsis

PubMed Central

Busch, Wolfgang; Cui, Hongchang; Wang, Jean Y; Blilou, Ikram; Hassan, Hala; Nakajima, Keiji; Matsumoto, Noritaka; Lohmann, Jan U; Scheres, Ben

2006-01-01

Stem cell function during organogenesis is a key issue in developmental biology. The transcription factor SHORT-ROOT (SHR) is a critical component in a developmental pathway regulating both the specification of the root stem cell niche and the differentiation potential of a subset of stem cells in the Arabidopsis root. To obtain a comprehensive view of the SHR pathway, we used a statistical method called meta-analysis to combine the results of several microarray experiments measuring the changes in global expression profiles after modulating SHR activity. Meta-analysis was first used to identify the direct targets of SHR by combining results from an inducible form of SHR driven by its endogenous promoter, ectopic expression, followed by cell sorting and comparisons of mutant to wild-type roots. Eight putative direct targets of SHR were identified, all with expression patterns encompassing subsets of the native SHR expression domain. Further evidence for direct regulation by SHR came from binding of SHR in vivo to the promoter regions of four of the eight putative targets. A new role for SHR in the vascular cylinder was predicted from the expression pattern of several direct targets and confirmed with independent markers. The meta-analysis approach was then used to perform a global survey of the SHR indirect targets. Our analysis suggests that the SHR pathway regulates root development not only through a large transcription regulatory network but also through hormonal pathways and signaling pathways using receptor-like kinases. Taken together, our results not only identify the first nodes in the SHR pathway and a new function for SHR in the development of the vascular tissue but also reveal the global architecture of this developmental pathway. PMID:16640459

Improving the Performance of an Auditory Brain-Computer Interface Using Virtual Sound Sources by Shortening Stimulus Onset Asynchrony

PubMed Central

Sugi, Miho; Hagimoto, Yutaka; Nambu, Isao; Gonzalez, Alejandro; Takei, Yoshinori; Yano, Shohei; Hokari, Haruhide; Wada, Yasuhiro

2018-01-01

Recently, a brain-computer interface (BCI) using virtual sound sources has been proposed for estimating user intention via electroencephalogram (EEG) in an oddball task. However, its performance is still insufficient for practical use. In this study, we examine the impact that shortening the stimulus onset asynchrony (SOA) has on this auditory BCI. While very short SOA might improve its performance, sound perception and task performance become difficult, and event-related potentials (ERPs) may not be induced if the SOA is too short. Therefore, we carried out behavioral and EEG experiments to determine the optimal SOA. In the experiments, participants were instructed to direct attention to one of six virtual sounds (target direction). We used eight different SOA conditions: 200, 300, 400, 500, 600, 700, 800, and 1,100 ms. In the behavioral experiment, we recorded participant behavioral responses to target direction and evaluated recognition performance of the stimuli. In all SOA conditions, recognition accuracy was over 85%, indicating that participants could recognize the target stimuli correctly. Next, using a silent counting task in the EEG experiment, we found significant differences between target and non-target sound directions in all but the 200-ms SOA condition. When we calculated an identification accuracy using Fisher discriminant analysis (FDA), the SOA could be shortened by 400 ms without decreasing the identification accuracies. Thus, improvements in performance (evaluated by BCI utility) could be achieved. On average, higher BCI utilities were obtained in the 400 and 500-ms SOA conditions. Thus, auditory BCI performance can be optimized for both behavioral and neurophysiological responses by shortening the SOA. PMID:29535602

Breakthrough Therapies: Cystic Fibrosis (CF) Potentiators and Correctors

PubMed Central

Solomon, George M.; Marshall, Susan G.; Ramsey, Bonnie W.; Rowe, Steven M.

2015-01-01

Cystic Fibrosis is caused by mutations in the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) gene resulting in abnormal protein function. Recent advances of targeted molecular therapies and high throughput screening have resulted in multiple drug therapies that target many important mutations in the CFTR protein. In this review, we provide the latest results and current progress of CFTR modulators for the treatment of cystic fibrosis, focusing on potentiators of CFTR channel gating and Phe508del processing correctors for the Phe508del CFTR mutation. Special emphasis is placed on the molecular basis underlying these new therapies and emerging results from the latest clinical trials. The future directions for augmenting the rescue of Phe508del with CFTR modulators is also emphasized. PMID:26097168

Past, present and future targets for immunotherapy in ovarian cancer

PubMed Central

Schwab, Carlton L; English, Diana P; Roque, Dana M; Pasternak, Monica; Santin, Alessandro D

2015-01-01

Ovarian cancer is the leading cause of death from gynecologic malignancy in the US. Treatments have improved with conventional cytotoxic chemotherapy and advanced surgical techniques but disease recurrence is common and fatal in nearly all cases. Current evidence suggests that the immune system and its ability to recognize and eliminate microscopic disease is paramount in preventing recurrence. Ovarian cancer immunotherapy is targeting tumors through active, passive and adoptive approaches. The goal of immunotherapy is to balance the activation of the immune system against cancer while preventing the potential for tremendous toxicity elicited by immune modulation. In this paper we will review the different immunotherapies available for ovarian cancer as well as current ongoing studies and potential future directions. PMID:25524384

Amyotrophic Lateral Sclerosis: A Focus on Disease Progression

PubMed Central

Calvo, Ana C.; Manzano, Raquel; Mendonça, Deise M. F.; Muñoz, María J.; Zaragoza, Pilar

2014-01-01

Since amyotrophic lateral sclerosis (ALS) was discovered and described in 1869 as a neurodegenerative disease in which motor neuron death is induced, a wide range of biomarkers have been selected to identify therapeutic targets. ALS shares altered molecular pathways with other neurodegenerative diseases, such as Alzheimer's, Huntington's, and Parkinson's diseases. However, the molecular targets that directly influence its aggressive nature remain unknown. What is the first link in the neurodegenerative chain of ALS that makes this disease so peculiar? In this review, we will discuss the progression of the disease from the viewpoint of the potential biomarkers described to date in human and animal model samples. Finally, we will consider potential therapeutic strategies for ALS treatment and future, innovative perspectives. PMID:25157374

The Potential Role of Aerobic Exercise to Modulate Cardiotoxicity of Molecularly Targeted Cancer Therapeutics

PubMed Central

Lakoski, Susan; Mackey, John R.; Douglas, Pamela S.; Haykowsky, Mark J.; Jones, Lee W.

2013-01-01

Molecularly targeted therapeutics (MTT) are the future of cancer systemic therapy. They have already moved from palliative therapy for advanced solid malignancies into the setting of curative-intent treatment for early-stage disease. Cardiotoxicity is a frequent and potentially serious adverse complication of some targeted therapies, leading to a broad range of potentially life-threatening complications, therapy discontinuation, and poor quality of life. Low-cost pleiotropic interventions are therefore urgently required to effectively prevent and/or treat MTT-induced cardiotoxicity. Aerobic exercise therapy has the unique capacity to modulate, without toxicity, multiple gene expression pathways in several organ systems, including a plethora of cardiac-specific molecular and cell-signaling pathways implicated in MTT-induced cardiac toxicity. In this review, we examine the molecular signaling of antiangiogenic and HER2-directed therapies that may underpin cardiac toxicity and the hypothesized molecular mechanisms underlying the cardioprotective properties of aerobic exercise. It is hoped that this knowledge can be used to maximize the benefits of small molecule inhibitors, while minimizing cardiac damage in patients with solid malignancies. PMID:23335619

Single-step generation of rabbits carrying a targeted allele of the tyrosinase gene using CRISPR/Cas9.

PubMed

Honda, Arata; Hirose, Michiko; Sankai, Tadashi; Yasmin, Lubna; Yuzawa, Kazuaki; Honsho, Kimiko; Izu, Haruna; Iguchi, Atsushi; Ikawa, Masahito; Ogura, Atsuo

2015-01-01

Targeted genome editing of nonrodent mammalian species has provided the potential for highly accurate interventions into gene function in humans and the generation of useful animal models of human diseases. Here we show successful clustered regularly interspaced short palindromic repeat (CRISPR) and CRISPR-associated (Cas)-mediated gene targeting via circular plasmid injection in rabbits. The rabbit tyrosinase gene (TYR) was effectively disrupted, and we confirmed germline transmission by pronuclear injection of a circular plasmid expressing humanized Cas9 (hCas9) and single-guide RNA. Direct injection into pronuclear stage zygotes was possible following an in vitro validation assay. Neither off-target mutagenesis nor hCas9 transgenesis was detected in any of the genetically targeted pups and embryos examined. Gene targeting with this rapid and simplified strategy will help accelerate the development of translational research using other nonrodent mammalian species.

Single-step generation of rabbits carrying a targeted allele of the tyrosinase gene using CRISPR/Cas9

PubMed Central

Honda, Arata; Hirose, Michiko; Sankai, Tadashi; Yasmin, Lubna; Yuzawa, Kazuaki; Honsho, Kimiko; Izu, Haruna; Iguchi, Atsushi; Ikawa, Masahito; Ogura, Atsuo

2014-01-01

Targeted genome editing of nonrodent mammalian species has provided the potential for highly accurate interventions into gene function in humans and the generation of useful animal models of human diseases. Here we show successful clustered regularly interspaced short palindromic repeat (CRISPR) and CRISPR-associated (Cas)-mediated gene targeting via circular plasmid injection in rabbits. The rabbit tyrosinase gene (TYR) was effectively disrupted, and we confirmed germline transmission by pronuclear injection of a circular plasmid expressing humanized Cas9 (hCas9) and single-guide RNA. Direct injection into pronuclear stage zygotes was possible following an in vitro validation assay. Neither off-target mutagenesis nor hCas9 transgenesis was detected in any of the genetically targeted pups and embryos examined. Gene targeting with this rapid and simplified strategy will help accelerate the development of translational research using other nonrodent mammalian species. PMID:25195632

Targeted polymeric nanoparticles for cancer gene therapy

PubMed Central

Kim, Jayoung; Wilson, David R.; Zamboni, Camila G.; Green, Jordan J.

2015-01-01

In this article, advances in designing polymeric nanoparticles for targeted cancer gene therapy are reviewed. Characterization and evaluation of biomaterials, targeting ligands, and transcriptional elements are each discussed. Advances in biomaterials have driven improvements to nanoparticle stability and tissue targeting, conjugation of ligands to the surface of polymeric nanoparticles enable binding to specific cancer cells, and the design of transcriptional elements has enabled selective DNA expression specific to the cancer cells. Together, these features have improved the performance of polymeric nanoparticles as targeted non-viral gene delivery vectors to treat cancer. As polymeric nanoparticles can be designed to be biodegradable, non-toxic, and to have reduced immunogenicity and tumorigenicity compared to viral platforms, they have significant potential for clinical use. Results of polymeric gene therapy in clinical trials and future directions for the engineering of nanoparticle systems for targeted cancer gene therapy are also presented. PMID:26061296

Transdominant Rev and Protease Mutant Proteins of HIV-SIV as Potential Antiviral Agents in Vitro and in Vivo (AIDS)

DTIC Science & Technology

1993-10-30

hammerhead ribozymes (7-9) and a hairpin ribozyme (10) directed against HIV-l RNA has been shown to confer significant resistance to HIV-I infection...antisense oligodeoxynucleotides (ODN) directed to the Rev Response Element (RRE) and ribozymes that target viral mRNAs. The ribozyme approach, in...particular, has yielded extremely encouraging positive data. We showed that a hairpin ribozyme designed to cleave HIV-1 RNA in the 5’ leader sequence

Studies of Positron Generation from Ultraintense Laser-Matter Interactions

NASA Astrophysics Data System (ADS)

Williams, Gerald Jackson

Laser-produced pair jets possess unique characteristics that offer great potential for their use in laboratory-astrophysics experiments to study energetic phenomenon such as relativistic shock accelerations. High-flux, high-energy positron sources may also be used to study relativistic pair plasmas and useful as novel diagnostic tools for high energy density conditions. Copious amounts of positrons are produced with MeV energies from directly irradiating targets with ultraintense lasers where relativistic electrons, accelerated by the laser field, drive positron-electron pair production. Alternatively, laser wakefield accelerated electrons can produce pairs by the same mechanisms inside a secondary converter target. This dissertation describes a series of novel experiments that investigate the characteristics and scaling of pair production from ultraintense lasers, which are designed to establish a robust platform for laboratory-based relativistic pair plasmas. Results include a simple power-law scaling to estimate the effective positron yield for elemental targets for any Maxwellian electron source, typical of direct laser-target interactions. To facilitate these measurements, a solenoid electromagnetic coil was constructed to focus emitted particles, increasing the effective collection angle of the detector and enabling the investigation of pair production from thin targets and low-Z materials. Laser wakefield electron sources were also explored as a compact, high repetition rate platform for the production of high energy pairs with potential applications to the creation of charge-neutral relativistic pair plasmas. Plasma accelerators can produce low-divergence electron beams with energies approaching a GeV at Hz frequencies. It was found that, even for high-energy positrons, energy loss and scattering mechanisms in the target create a fundamental limit to the divergence and energy spectrum of the emitted positrons. The potential future application of laser-generated pairs was considered by exploring the feasibility of radiographing an imploding inertial confinement fusion capsule at ignition- relevant conditions. For an in-flight areal density of 0.02-0.2 g/cm2, currently available positron sources can make density and spatial measurements of deuterium-tritium fuel cores where additional complications of full-scale experiments are expected to reduce the measurement sensitivity.

Chemokines beyond chemo-attraction: CXCL10 and its significant role in cancer and autoimmunity.

PubMed

Karin, Nathan; Razon, Hila

2018-09-01

Chemokines are mostly known for their chemotactic properties, and less for their ability to direct the biological function of target cells, including T cells. The current review focuses on a key chemokine named CXCL10 and its role in directing the migratory propertied and biological function of CD4+ and CD8+ T cells in the context of cancer and inflammatory autoimmunity. CXCR3 is a chemokine receptor that is abundant on CD4+ T cells, CD8+ T cells and NK cells. It has three known ligands: CXCL9, CXCL10 and CXCL11. Different studies, including those coming form our laboratory, indicated that aside of attracting CD8+ and CD4+ effector T cells to tumor sites and sites of inflammation CXCL10 directs the polarization and potentiates the biological function of these cells. This makes CXCL10 a "key driver chemokine" and a valid target for therapy of autoimmune diseases such as Inflammatory Bowl's Disease, Multiple Sclerosis, Rheumatoid arthritis and others. As for cancer this motivated different groups, including our group to develop CXCL10 based therapies for cancer due to its ability to enhance T-dependent anti cancer immunity. The current review summarizes these findings and their potential translational implication. Copyright © 2018 Elsevier Ltd. All rights reserved.

Nanocapsule-mediated cytosolic siRNA delivery for anti-inflammatory treatment.

PubMed

Jiang, Ying; Hardie, Joseph; Liu, Yuanchang; Ray, Moumita; Luo, Xiang; Das, Riddha; Landis, Ryan F; Farkas, Michelle E; Rotello, Vincent M

2018-06-05

The use of nanoparticle-stabilized nanocapsules for cytosolic siRNA delivery for immunomodulation in vitro and in vivo is reported. These NPSCs deliver siRNA directly to the cytosol of macrophages in vitro with concomitant knockdown of gene expression. In vivo studies showed directed delivery of NPSCs to the spleen, enabling gene silencing of macrophages, with preliminary studies showing 70% gene knockdown at a siRNA dose of 0.28 mg/kg. Significantly, the delivery of siRNA targeting tumor necrosis factor-α efficiently silenced TNF-α expression in LPS-challenged mice, demonstrating efficacy in modulating immune response in an organ-selective manner. This research highlights the potential of the NPSC platform for targeted immunotherapy and further manipulation of the immune system. Copyright © 2018 Elsevier B.V. All rights reserved.

Thermal-electric numerical simulation of a surface ion source for the production of radioactive ion beams

NASA Astrophysics Data System (ADS)

Manzolaro, Mattia; Meneghetti, Giovanni; Andrighetto, Alberto

2010-11-01

In a facility for the production of radioactive ion beams (RIBs), the target system and the ion source are the most critical objects. In the context of the Selective Production of Exotic Species (SPES) project, a proton beam directly impinges a Uranium Carbide production target, generating approximately 10 13 fissions per second. The radioactive isotopes produced by the 238U fissions are then directed to the ion source to acquire a charge state. After that, the radioactive ions obtained are transported electrostatically to the subsequent areas of the facility. In this work the surface ion source at present adopted for the SPES project is studied by means of both analytical and numerical thermal-electric models. The theoretical results are compared with temperature and electric potential difference measurements.

Grand canonical electronic density-functional theory: Algorithms and applications to electrochemistry

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sundararaman, Ravishankar; Goddard, III, William A.; Arias, Tomas A.

First-principles calculations combining density-functional theory and continuum solvation models enable realistic theoretical modeling and design of electrochemical systems. When a reaction proceeds in such systems, the number of electrons in the portion of the system treated quantum mechanically changes continuously, with a balancing charge appearing in the continuum electrolyte. A grand-canonical ensemble of electrons at a chemical potential set by the electrode potential is therefore the ideal description of such systems that directly mimics the experimental condition. We present two distinct algorithms: a self-consistent field method and a direct variational free energy minimization method using auxiliary Hamiltonians (GC-AuxH), to solvemore » the Kohn-Sham equations of electronic density-functional theory directly in the grand canonical ensemble at fixed potential. Both methods substantially improve performance compared to a sequence of conventional fixed-number calculations targeting the desired potential, with the GC-AuxH method additionally exhibiting reliable and smooth exponential convergence of the grand free energy. Lastly, we apply grand-canonical density-functional theory to the under-potential deposition of copper on platinum from chloride-containing electrolytes and show that chloride desorption, not partial copper monolayer formation, is responsible for the second voltammetric peak.« less

Grand canonical electronic density-functional theory: Algorithms and applications to electrochemistry.

PubMed

Sundararaman, Ravishankar; Goddard, William A; Arias, Tomas A

2017-03-21

First-principles calculations combining density-functional theory and continuum solvation models enable realistic theoretical modeling and design of electrochemical systems. When a reaction proceeds in such systems, the number of electrons in the portion of the system treated quantum mechanically changes continuously, with a balancing charge appearing in the continuum electrolyte. A grand-canonical ensemble of electrons at a chemical potential set by the electrode potential is therefore the ideal description of such systems that directly mimics the experimental condition. We present two distinct algorithms: a self-consistent field method and a direct variational free energy minimization method using auxiliary Hamiltonians (GC-AuxH), to solve the Kohn-Sham equations of electronic density-functional theory directly in the grand canonical ensemble at fixed potential. Both methods substantially improve performance compared to a sequence of conventional fixed-number calculations targeting the desired potential, with the GC-AuxH method additionally exhibiting reliable and smooth exponential convergence of the grand free energy. Finally, we apply grand-canonical density-functional theory to the under-potential deposition of copper on platinum from chloride-containing electrolytes and show that chloride desorption, not partial copper monolayer formation, is responsible for the second voltammetric peak.

Grand canonical electronic density-functional theory: Algorithms and applications to electrochemistry

DOE PAGES

Sundararaman, Ravishankar; Goddard, III, William A.; Arias, Tomas A.

2017-03-16

First-principles calculations combining density-functional theory and continuum solvation models enable realistic theoretical modeling and design of electrochemical systems. When a reaction proceeds in such systems, the number of electrons in the portion of the system treated quantum mechanically changes continuously, with a balancing charge appearing in the continuum electrolyte. A grand-canonical ensemble of electrons at a chemical potential set by the electrode potential is therefore the ideal description of such systems that directly mimics the experimental condition. We present two distinct algorithms: a self-consistent field method and a direct variational free energy minimization method using auxiliary Hamiltonians (GC-AuxH), to solvemore » the Kohn-Sham equations of electronic density-functional theory directly in the grand canonical ensemble at fixed potential. Both methods substantially improve performance compared to a sequence of conventional fixed-number calculations targeting the desired potential, with the GC-AuxH method additionally exhibiting reliable and smooth exponential convergence of the grand free energy. Lastly, we apply grand-canonical density-functional theory to the under-potential deposition of copper on platinum from chloride-containing electrolytes and show that chloride desorption, not partial copper monolayer formation, is responsible for the second voltammetric peak.« less

Multi-Target State Extraction for the SMC-PHD Filter

PubMed Central

Si, Weijian; Wang, Liwei; Qu, Zhiyu

2016-01-01

The sequential Monte Carlo probability hypothesis density (SMC-PHD) filter has been demonstrated to be a favorable method for multi-target tracking. However, the time-varying target states need to be extracted from the particle approximation of the posterior PHD, which is difficult to implement due to the unknown relations between the large amount of particles and the PHD peaks representing potential target locations. To address this problem, a novel multi-target state extraction algorithm is proposed in this paper. By exploiting the information of measurements and particle likelihoods in the filtering stage, we propose a validation mechanism which aims at selecting effective measurements and particles corresponding to detected targets. Subsequently, the state estimates of the detected and undetected targets are performed separately: the former are obtained from the particle clusters directed by effective measurements, while the latter are obtained from the particles corresponding to undetected targets via clustering method. Simulation results demonstrate that the proposed method yields better estimation accuracy and reliability compared to existing methods. PMID:27322274

Synthesis of a multi-functional DNA nanosphere barcode system for direct cell detection.

PubMed

Han, Sangwoo; Lee, Jae Sung; Lee, Jong Bum

2017-09-28

Nucleic acid-based technologies have been applied to numerous biomedical applications. As a novel material for target detection, DNA has been used to construct a barcode system with a range of structures. This paper reports multi-functionalized DNA nanospheres (DNANSs) by rolling circle amplification (RCA) with several functionalized nucleotides. DNANSs with a barcode system were designed to exhibit fluorescence for coding enhanced signals and contain biotin for more functionalities, including targeting through the biotin-streptavidin (biotin-STA) interaction. Functionalized deoxynucleotide triphosphates (dNTPs) were mixed in the RCA process and functional moieties can be expressed on the DNANSs. The anti-epidermal growth factor receptor antibodies (anti-EGFR Abs) can be conjugated on DNANSs for targeting cancer cells specifically. As a proof of concept, the potential of the multi-functional DNANS barcode was demonstrated by direct cell detection as a simple detection method. The DNANS barcode provides a new route for the simple and rapid selective recognition of cancer cells.

microRNA-598 inhibits cell proliferation and invasion of glioblastoma by directly targeting metastasis associated in colon cancer-1.

PubMed

Wang, Ning; Zhang, Yang; Liang, Huaxin

2018-02-14

The dysregulation of microRNAs (miRNAs) expression is closely related with tumorigenesis and tumour development in glioblastoma (GBM). In this study, we found that miRNA-598 (miR-598) expression was significantly downregulated in GBM tissues and cell lines. Restoring miR-598 expression inhibited cell proliferation and invasion in GBM. Moreover, we validated that metastasis associated in colon cancer-1 (MACC1) is a novel target of miR-598 in GBM. Recovered MACC1 expression reversed the inhibitory effects of miR-598 overexpression on GBM cells. In addition, miR-598 overexpression suppressed the Met/AKT pathway activation in GBM. Our results provided compelling evidence that miR-598 serves tumour suppressive roles in GBM and that its anti-oncogenic effects are mediated chiefly through the direct suppression of MACC1 expression and regulation of the Met/AKT signalling pathway. Therefore, miR-598 is a potential target in the treatment of GBM.

CRISPR/Cas9-mediated correction of human genetic disease.

PubMed

Men, Ke; Duan, Xingmei; He, Zhiyao; Yang, Yang; Yao, Shaohua; Wei, Yuquan

2017-05-01

The clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated (Cas) protein 9 system (CRISPR/Cas9) provides a powerful tool for targeted genetic editing. Directed by programmable sequence-specific RNAs, this system introduces cleavage and double-stranded breaks at target sites precisely. Compared to previously developed targeted nucleases, the CRISPR/Cas9 system demonstrates several promising advantages, including simplicity, high specificity, and efficiency. Several broad genome-editing studies with the CRISPR/Cas9 system in different species in vivo and ex vivo have indicated its strong potential, raising hopes for therapeutic genome editing in clinical settings. Taking advantage of non-homologous end-joining (NHEJ) and homology directed repair (HDR)-mediated DNA repair, several studies have recently reported the use of CRISPR/Cas9 to successfully correct disease-causing alleles ranging from single base mutations to large insertions. In this review, we summarize and discuss recent preclinical studies involving the CRISPR/Cas9-mediated correction of human genetic diseases.

Do Brief Alcohol Interventions Reduce Tobacco Use among Adolescents and Young Adults? A Systematic Review and Meta-Analysis

PubMed Central

Hennessy, Emily A.; Tanner-Smith, Emily E.; Steinka-Fry, Katarzyna T.

2015-01-01

This meta-analysis synthesizes studies of brief interventions (BIs) that targeted alcohol consumption and reported both alcohol and tobacco outcomes. It examines whether BIs reduce alcohol and tobacco use for adolescents and young adults among interventions that (1) directly targeted tobacco and alcohol use, or (2) did not target tobacco use but measured it as a secondary outcome. Multiple databases and grey literature sources were searched (1980–2012) resulting in the identification of 18 randomized or controlled quasi-experimental studies (5949 participants). Analyses were conducted using random effects inverse-variance weighted three-level models. BIs were associated with a significant reduction in alcohol consumption relative to control groups (ḡ = 0.11, 95% CI [0.04, 0.17]) but not with a significant decrease in tobacco use (ḡ = 0.07, 95% CI [−0.01, 0.16]). Directly addressing tobacco was not a significant moderator affecting tobacco use outcomes. Post-hoc exploratory analysis revealed potential questions to address with future research. PMID:26130030

Biomarkers and patient selection for PI3K/Akt/mTOR targeted therapies: current status and future directions.

PubMed

Bartlett, John M S

2010-11-01

The phosphatidylinositol 3-kinase (PI3K)/Akt/ mammalian target of rapamycin (mTOR) pathway regulates a broad spectrum of physiologic and pathologic processes. In breast cancer mutation, amplification, deletion, methylation, and posttranslational modifications lead to significant dysregulation of this pathway leading to more aggressive and potentially drug-resistant disease. Multiple novel agents, targeting different nodes within the pathway are currently under development by both commercial and academic partners. The key to the successful validation of these markers is selection of the appropriate patient groups using biomarkers. This article reviews current progress in this area, highlighting the key molecular alterations described in genes within the PI3K/Akt/mTOR pathway that may have an effect on response to current and future therapeutic interventions. Herein, gaps in current knowledge are highlighted and suggestions for future research directions given that may facilitate biomarker development in partnership with current drug development.

Endogenous miRNA and Target Concentrations Determine Susceptibility to Potential ceRNA Competition

PubMed Central

Bosson, Andrew D.; Zamudio, Jesse R.; Sharp, Phillip A.

2016-01-01

SUMMARY Target competition (ceRNA crosstalk) within miRNA-regulated gene networks has been proposed to influence biological systems. To assess target competition, we characterize and quantitate miRNA networks in two cell types. Argonaute iCLIP reveals that hierarchical binding of high- to low-affinity miRNA targets is a key characteristic of in vivo activity. Quantification of cellular miRNA and mRNA/ncRNA target pool levels indicates that miRNA:target pool ratios and an affinity partitioned target pool accurately predict in vivo Ago binding profiles and miRNA susceptibility to target competition. Using single-cell reporters, we directly test predictions and estimate that ~3,000 additional high-affinity target sites can affect active miRNA families with low endogenous miRNA:target ratios, such as miR-92/25. In contrast, the highly expressed miR-294 and let-7 families are not susceptible to increases of nearly 10,000 sites. These results show differential susceptibility based on endogenous miRNA:target pool ratios and provide a physiological context for ceRNA competition in vivo. PMID:25449132

Target-directed catalytic metallodrugs

PubMed Central

Joyner, J.C.; Cowan, J.A.

2013-01-01

Most drugs function by binding reversibly to specific biological targets, and therapeutic effects generally require saturation of these targets. One means of decreasing required drug concentrations is incorporation of reactive metal centers that elicit irreversible modification of targets. A common approach has been the design of artificial proteases/nucleases containing metal centers capable of hydrolyzing targeted proteins or nucleic acids. However, these hydrolytic catalysts typically provide relatively low rate constants for target inactivation. Recently, various catalysts were synthesized that use oxidative mechanisms to selectively cleave/inactivate therapeutic targets, including HIV RRE RNA or angiotensin converting enzyme (ACE). These oxidative mechanisms, which typically involve reactive oxygen species (ROS), provide access to comparatively high rate constants for target inactivation. Target-binding affinity, co-reactant selectivity, reduction potential, coordination unsaturation, ROS products (metal-associated vs metal-dissociated; hydroxyl vs superoxide), and multiple-turnover redox chemistry were studied for each catalyst, and these parameters were related to the efficiency, selectivity, and mechanism(s) of inactivation/cleavage of the corresponding target for each catalyst. Important factors for future oxidative catalyst development are 1) positioning of catalyst reduction potential and redox reactivity to match the physiological environment of use, 2) maintenance of catalyst stability by use of chelates with either high denticity or other means of stabilization, such as the square planar geometric stabilization of Ni- and Cu-ATCUN complexes, 3) optimal rate of inactivation of targets relative to the rate of generation of diffusible ROS, 4) targeting and linker domains that afford better control of catalyst orientation, and 5) general bio-availability and drug delivery requirements. PMID:23828584

77 FR 43601 - Government-Owned Inventions; Availability for Licensing

Federal Register 2010, 2011, 2012, 2013, 2014

2012-07-25

... of the patent applications. Novel Analogues of the Asthma Drug Fenoterol as Liver and Brain Cancer... as MNF, that inhibit the growth of various types of cancers, including brain, liver, colon, and lung..., represents one of the first potential drugs directed at this target. MNF crosses the blood brain barrier and...

Biological control agents elevate hantavirus by subsidizing deer mouse populations

Treesearch

Dean E. Pearson; Ragan M. Callaway

2006-01-01

Biological control of exotic invasive plants using exotic insects is practiced under the assumption that biological control agents are safe if they do not directly attack non-target species. We tested this assumption by evaluating the potential for two host-specific biological control agents (Urophora spp.), widely established in North America for spotted...

Developing Classroom Web Sites for 21st Century Learning

ERIC Educational Resources Information Center

Tingen, Jennifer; Philbeck, Lauren; Holcomb, Lori B.

2011-01-01

Classroom Web sites have the potential to support and enhance student learning by targeting 21st century skills, such as collaboration among teachers, students, parents, and other teachers, media literacy, and interpersonal and self-directional skills, as well as thinking and problem-solving skills. Web 2.0 tools such as blogs, vokis, and podcasts…

Evaluation of potential internal target volume of liver tumors using cine-MRI

DOE Office of Scientific and Technical Information (OSTI.GOV)

Akino, Yuichi, E-mail: akino@radonc.med.osaka-u.ac.jp; Oh, Ryoong-Jin; Masai, Norihisa

2014-11-01

Purpose: Four-dimensional computed tomography (4DCT) is widely used for evaluating moving tumors, including lung and liver cancers. For patients with unstable respiration, however, the 4DCT may not visualize tumor motion properly. High-speed magnetic resonance imaging (MRI) sequences (cine-MRI) permit direct visualization of respiratory motion of liver tumors without considering radiation dose exposure to patients. Here, the authors demonstrated a technique for evaluating internal target volume (ITV) with consideration of respiratory variation using cine-MRI. Methods: The authors retrospectively evaluated six patients who received stereotactic body radiotherapy (SBRT) to hepatocellular carcinoma. Before acquiring planning CT, sagittal and coronal cine-MRI images were acquiredmore » for 30 s with a frame rate of 2 frames/s. The patient immobilization was conducted under the same condition as SBRT. Planning CT images were then acquired within 15 min from cine-MRI image acquisitions, followed by a 4DCT scan. To calculate tumor motion, the motion vectors between two continuous frames of cine-MRI images were calculated for each frame using the pyramidal Lucas–Kanade method. The target contour was delineated on one frame, and each vertex of the contour was shifted and copied onto the following frame using neighboring motion vectors. 3D trajectory data were generated with the centroid of the contours on sagittal and coronal images. To evaluate the accuracy of the tracking method, the motion of clearly visible blood vessel was analyzed with the motion tracking and manual detection techniques. The target volume delineated on the 50% (end-exhale) phase of 4DCT was translated with the trajectory data, and the distribution of the occupancy probability of target volume was calculated as potential ITV (ITV {sub Potential}). The concordance between ITV {sub Potential} and ITV estimated with 4DCT (ITV {sub 4DCT}) was evaluated using the Dice’s similarity coefficient (DSC). Results: The distance between blood vessel positions determined with motion tracking and manual detection was analyzed. The mean and SD of the distance were less than 0.80 and 0.52 mm, respectively. The maximum ranges of tumor motion on cine-MRI were 2.4 ± 1.4 mm (range, 1.0–5.0 mm), 4.4 ± 3.3 mm (range, 0.8–9.4 mm), and 14.7 ± 5.9 mm (range, 7.4–23.4 mm) in lateral, anterior–posterior, and superior–inferior directions, respectively. The ranges in the superior–inferior direction were larger than those estimated with 4DCT images for all patients. The volume of ITV {sub Potential} was 160.3% ± 13.5% (range, 142.0%–179.2%) of the ITV {sub 4DCT}. The maximum DSC values were observed when the cutoff value of 24.7% ± 4.0% (range, 20%–29%) was applied. Conclusions: The authors demonstrated a novel method of calculating 3D motion and ITV {sub Potential} of liver cancer using orthogonal cine-MRI. Their method achieved accurate calculation of the respiratory motion of moving structures. Individual evaluation of the ITV {sub Potential} will aid in improving respiration management and treatment planning.« less

Exploiting differential RNA splicing patterns: a potential new group of therapeutic targets in cancer.

PubMed

Jyotsana, Nidhi; Heuser, Michael

2018-02-01

Mutations in genes associated with splicing have been found in hematologic malignancies, but also in solid cancers. Aberrant cancer specific RNA splicing either results from mutations or misexpression of the spliceosome genes directly, or from mutations in splice sites of oncogenes or tumor suppressors. Areas covered: In this review, we present molecular targets of aberrant splicing in various malignancies, information on existing and emerging therapeutics against such targets, and strategies for future drug development. Expert opinion: Alternative splicing is an important mechanism that controls gene expression, and hence pharmacologic and genetic control of aberrant alternative RNA splicing has been proposed as a potential therapy in cancer. To identify and validate aberrant RNA splicing patterns as therapeutic targets we need to (1) characterize the most common genetic aberrations of the spliceosome and of splice sites, (2) understand the dysregulated downstream pathways and (3) exploit in-vivo disease models of aberrant splicing. Antisense oligonucleotides show promising activity, but will benefit from improved delivery tools. Inhibitors of mutated splicing factors require improved specificity, as alternative and aberrant splicing are often intertwined like two sides of the same coin. In summary, targeting aberrant splicing is an early but emerging field in cancer treatment.

Basic/Translational Development of Forthcoming Opioid- and Nonopioid-Targeted Pain Therapeutics.

PubMed

Knezevic, Nebojsa Nick; Yekkirala, Ajay; Yaksh, Tony L

2017-11-01

Opioids represent an efficacious therapeutic modality for some, but not all pain states. Singular reliance on opioid therapy for pain management has limitations, and abuse potential has deleterious consequences for patient and society. Our understanding of pain biology has yielded insights and opportunities for alternatives to conventional opioid agonists. The aim is to have efficacious therapies, with acceptable side effect profiles and minimal abuse potential, which is to say an absence of reinforcing activity in the absence of a pain state. The present work provides a nonexclusive overview of current drug targets and potential future directions of research and development. We discuss channel activators and blockers, including sodium channel blockers, potassium channel activators, and calcium channel blockers; glutamate receptor-targeted agents, including N-methyl-D-aspartate, α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid, and metabotropic receptors. Furthermore, we discuss therapeutics targeted at γ-aminobutyric acid, α2-adrenergic, and opioid receptors. We also considered antagonists of angiotensin 2 and Toll receptors and agonists/antagonists of adenosine, purine receptors, and cannabinoids. Novel targets considered are those focusing on lipid mediators and anti-inflammatory cytokines. Of interest is development of novel targeting strategies, which produce long-term alterations in pain signaling, including viral transfection and toxins. We consider issues in the development of druggable molecules, including preclinical screening. While there are examples of successful translation, mechanistically promising preclinical candidates may unexpectedly fail during clinical trials because the preclinical models may not recapitulate the particular human pain condition being addressed. Molecular target characterization can diminish the disconnect between preclinical and humans' targets, which should assist in developing nonaddictive analgesics.

Proprioceptive assessment in clinical settings: Evaluation of joint position sense in upper limb post-stroke using a robotic manipulator

PubMed Central

Kager, Simone; Budhota, Aamani; Deshmukh, Vishwanath A.; Kuah, Christopher W. K.; Yam, Lester H. L.; Xiang, Liming; Chua, Karen S. G.; Masia, Lorenzo; Campolo, Domenico

2017-01-01

Proprioception is a critical component for motor functions and directly affects motor learning after neurological injuries. Conventional methods for its assessment are generally ordinal in nature and hence lack sensitivity. Robotic devices designed to promote sensorimotor learning can potentially provide quantitative precise, accurate, and reliable assessments of sensory impairments. In this paper, we investigate the clinical applicability and validity of using a planar 2 degrees of freedom robot to quantitatively assess proprioceptive deficits in post-stroke participants. Nine stroke survivors and nine healthy subjects participated in the study. Participants’ hand was passively moved to the target position guided by the H-Man robot (Criterion movement) and were asked to indicate during a second passive movement towards the same target (Matching movement) when they felt that they matched the target position. The assessment was carried out on a planar surface for movements in the forward and oblique directions in the contralateral and ipsilateral sides of the tested arm. The matching performance was evaluated in terms of error magnitude (absolute and signed) and its variability. Stroke patients showed higher variability in the estimation of the target position compared to the healthy participants. Further, an effect of target was found, with lower absolute errors in the contralateral side. Pairwise comparison between individual stroke participant and control participants showed significant proprioceptive deficits in two patients. The proposed assessment of passive joint position sense was inherently simple and all participants, regardless of motor impairment level, could complete it in less than 10 minutes. Therefore, the method can potentially be carried out to detect changes in proprioceptive deficits in clinical settings. PMID:29161264

Targeting Gas6/TAM in cancer cells and tumor microenvironment.

PubMed

Wu, Guiling; Ma, Zhiqiang; Cheng, Yicheng; Hu, Wei; Deng, Chao; Jiang, Shuai; Li, Tian; Chen, Fulin; Yang, Yang

2018-01-31

Growth arrest-specific 6, also known as Gas6, is a human gene encoding the Gas6 protein, which was originally found to be upregulated in growth-arrested fibroblasts. Gas6 is a member of the vitamin K-dependent family of proteins expressed in many human tissues and regulates several biological processes in cells, including proliferation, survival and migration, by binding to its receptors Tyro3, Axl and Mer (TAM). In recent years, the roles of Gas6/TAM signalling in cancer cells and the tumour microenvironment have been studied, and some progress has made in targeted therapy, providing new potential directions for future investigations of cancer treatment. In this review, we introduce the Gas6 and TAM receptors and describe their involvement in different cancers and discuss the roles of Gas6 in cancer cells, the tumour microenvironment and metastasis. Finally, we introduce recent studies on Gas6/TAM targeting in cancer therapy, which will assist in the experimental design of future analyses and increase the potential use of Gas6 as a therapeutic target for cancer.

Therapeutic microRNAs targeting the NF-kappa B Signaling Circuits of Cancers

PubMed Central

Tong, Lingying; Yuan, Ye; Wu, Shiyong

2014-01-01

MicroRNAs (miRNAs) not only directly regulate NF-κB expression, but also up- or down-regulate NF-κB activity via upstream and downstream signaling pathways of NF-κB. In many cancer cells, miRNA expressions are altered accompanied with an elevation of NF-κB, which often plays a role in promoting cancer development and progression as well as hindering the effectiveness of chemo and radiation therapies. Thus NF-κB-targeting miRNAs have been identified and characterized as potential therapeutics for cancer treatment and sensitizers of chemo and radiotherapies. However, due to cross-targeting and instability of miRNAs, some limitations of using miRNA as cancer therapeutics still exist. In this review, the mechanisms for miRNA-mediated alteration of NF-κB expression and activation in different types of cancers will be discussed. The results of therapeutic use of NF-κB-targeting miRNA for cancer treatment will be examined. Some limitations, challenges and potential strategies in future development of miRNA as cancer therapeutics are also assessed. PMID:25220353

Combined-modality treatment of solid tumors using radiotherapy and molecular targeted agents.

PubMed

Ma, Brigette B Y; Bristow, Robert G; Kim, John; Siu, Lillian L

2003-07-15

Molecular targeted agents have been combined with radiotherapy (RT) in recent clinical trials in an effort to optimize the therapeutic index of RT. The appeal of this strategy lies in their potential target specificity and clinically acceptable toxicity. This article integrates the salient, published research findings into the underlying molecular mechanisms, preclinical efficacy, and clinical applicability of combining RT with molecular targeted agents. These agents include inhibitors of intracellular signal transduction molecules, modulators of apoptosis, inhibitors of cell cycle checkpoints control, antiangiogenic agents, and cyclo-oxygenase-2 inhibitors. Molecular targeted agents can have direct effects on the cytoprotective and cytotoxic pathways implicated in the cellular response to ionizing radiation (IR). These pathways involve cellular proliferation, DNA repair, cell cycle progression, nuclear transcription, tumor angiogenesis, and prostanoid-associated inflammation. These pathways can also converge to alter RT-induced apoptosis, terminal growth arrest, and reproductive cell death. Pharmacologic modulation of these pathways may potentially enhance tumor response to RT though inhibition of tumor repopulation, improvement of tumor oxygenation, redistribution during the cell cycle, and alteration of intrinsic tumor radiosensitivity. Combining RT and molecular targeted agents is a rational approach in the treatment of solid tumors. Translation of this approach from promising preclinical data to clinical trials is actively underway.

Inhibition of microRNA-1 attenuates hypoxia/re-oxygenation-induced apoptosis of cardiomyocytes by directly targeting Bcl-2 but not GADD45Beta

PubMed Central

Zhai, Changlin; Tang, Guanmin; Peng, Lei; Hu, Huilin; Qian, Gang; Wang, Shijun; Yao, Jiankang; Zhang, Xiaoping; Fang, Ying; Yang, Shuang; Zhang, Xiumei

2015-01-01

MicroRNAs are small non-coding RNAs that are able to regulate gene expression and play important roles in some biological and pathological processes, including the myocardial ischemia/reperfusion (I/R) injury. Recent findings demonstrated that miR-1 exacerbated I/R-induced injury. This study was to investigate theanti-apoptotic property of miR-1 inhibition and the potential regulatory mechanism. Results showed miR-1 expression reduced in the heart of rats undergoing myocardial I/R and the cardiomyocytes receiving hypoxia/reoxygenation (H/R) injury, but the serum miR-1 expression increased. The targets of miR-1 were predicted by cDNA microarray, and Bcl-2 and GADD45β were selected as candidate targets. Western blot assay and qPCR showed Bcl-2 and GADD45β protein and mRNA expressions increased after I/R injury and H/R injury. Bcl-2 was a direct target of miR-1 as shown in previous studies. Luciferase assay and Western blot assay revealed GADD45β was a direct target of miR-1, and miR-1 suppressed GADD45β expression via binding to its 3’UTR. Furthermore, miR-1 inhibition increased Bcl-2 expression and reduced IA/AAR (infarct area/area at risk) ratio and cell apoptosis in rats undergoing myocardial I/R as well as in cardiomyocytes receiving H/R injury. Importantly, Bcl-2 knockdown restored these consequences following miR-1 inhibition. However, GADD45β knockdown reduced IA/AAR ratio and cell apoptosis in vivo and in vitro, but failed torestore above consequences after miR-1 inhibition. In conclusion miR-1 inhibition protects against H/R-induced apoptosis of myocytes by directly targeting Bcl-2 but not GADD45β. PMID:26692938

Plant-Derived Polyphenols in Human Health: Biological Activity, Metabolites and Putative Molecular Targets.

PubMed

Olivares-Vicente, Marilo; Barrajon-Catalan, Enrique; Herranz-Lopez, Maria; Segura-Carretero, Antonio; Joven, Jorge; Encinar, Jose Antonio; Micol, Vicente

2018-01-01

Hibiscus sabdariffa, Lippia citriodora, Rosmarinus officinalis and Olea europaea, are rich in bioactive compounds that represent most of the phenolic compounds' families and have exhibited potential benefits in human health. These plants have been used in folk medicine for their potential therapeutic properties in human chronic diseases. Recent evidence leads to postulate that polyphenols may account for such effects. Nevertheless, the compounds or metabolites that are responsible for reaching the molecular targets are unknown. data based on studies directly using complex extracts on cellular models, without considering metabolic aspects, have limited applicability. In contrast, studies exploring the absorption process, metabolites in the blood circulation and tissues have become essential to identify the intracellular final effectors that are responsible for extracts bioactivity. Once the cellular metabolites are identified using high-resolution mass spectrometry, docking techniques suppose a unique tool for virtually screening a large number of compounds on selected targets in order to elucidate their potential mechanisms. we provide an updated overview of the in vitro and in vivo studies on the toxicity, absorption, permeability, pharmacokinetics and cellular metabolism of bioactive compounds derived from the abovementioned plants to identify the potential compounds that are responsible for the observed health effects. we propose the use of targeted metabolomics followed by in silico studies to virtually screen identified metabolites on selected protein targets, in combination with the use of the candidate metabolites in cellular models, as the methods of choice for elucidating the molecular mechanisms of these compounds. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Direct-drive inertial confinement fusion: A review

NASA Astrophysics Data System (ADS)

Craxton, R. S.; Anderson, K. S.; Boehly, T. R.; Goncharov, V. N.; Harding, D. R.; Knauer, J. P.; McCrory, R. L.; McKenty, P. W.; Meyerhofer, D. D.; Myatt, J. F.; Schmitt, A. J.; Sethian, J. D.; Short, R. W.; Skupsky, S.; Theobald, W.; Kruer, W. L.; Tanaka, K.; Betti, R.; Collins, T. J. B.; Delettrez, J. A.; Hu, S. X.; Marozas, J. A.; Maximov, A. V.; Michel, D. T.; Radha, P. B.; Regan, S. P.; Sangster, T. C.; Seka, W.; Solodov, A. A.; Soures, J. M.; Stoeckl, C.; Zuegel, J. D.

2015-11-01

The direct-drive, laser-based approach to inertial confinement fusion (ICF) is reviewed from its inception following the demonstration of the first laser to its implementation on the present generation of high-power lasers. The review focuses on the evolution of scientific understanding gained from target-physics experiments in many areas, identifying problems that were demonstrated and the solutions implemented. The review starts with the basic understanding of laser-plasma interactions that was obtained before the declassification of laser-induced compression in the early 1970s and continues with the compression experiments using infrared lasers in the late 1970s that produced thermonuclear neutrons. The problem of suprathermal electrons and the target preheat that they caused, associated with the infrared laser wavelength, led to lasers being built after 1980 to operate at shorter wavelengths, especially 0.35 μm—the third harmonic of the Nd:glass laser—and 0.248 μm (the KrF gas laser). The main physics areas relevant to direct drive are reviewed. The primary absorption mechanism at short wavelengths is classical inverse bremsstrahlung. Nonuniformities imprinted on the target by laser irradiation have been addressed by the development of a number of beam-smoothing techniques and imprint-mitigation strategies. The effects of hydrodynamic instabilities are mitigated by a combination of imprint reduction and target designs that minimize the instability growth rates. Several coronal plasma physics processes are reviewed. The two-plasmon-decay instability, stimulated Brillouin scattering (together with cross-beam energy transfer), and (possibly) stimulated Raman scattering are identified as potential concerns, placing constraints on the laser intensities used in target designs, while other processes (self-focusing and filamentation, the parametric decay instability, and magnetic fields), once considered important, are now of lesser concern for mainline direct-drive target concepts. Filamentation is largely suppressed by beam smoothing. Thermal transport modeling, important to the interpretation of experiments and to target design, has been found to be nonlocal in nature. Advances in shock timing and equation-of-state measurements relevant to direct-drive ICF are reported. Room-temperature implosions have provided an increased understanding of the importance of stability and uniformity. The evolution of cryogenic implosion capabilities, leading to an extensive series carried out on the 60-beam OMEGA laser [Boehly et al., Opt. Commun. 133, 495 (1997)], is reviewed together with major advances in cryogenic target formation. A polar-drive concept has been developed that will enable direct-drive-ignition experiments to be performed on the National Ignition Facility [Haynam et al., Appl. Opt. 46(16), 3276 (2007)]. The advantages offered by the alternative approaches of fast ignition and shock ignition and the issues associated with these concepts are described. The lessons learned from target-physics and implosion experiments are taken into account in ignition and high-gain target designs for laser wavelengths of 1/3 μm and 1/4 μm. Substantial advances in direct-drive inertial fusion reactor concepts are reviewed. Overall, the progress in scientific understanding over the past five decades has been enormous, to the point that inertial fusion energy using direct drive shows significant promise as a future environmentally attractive energy source.

A new O6-alkylguanine-DNA alkyltransferase inhibitor associated with a nitrosourea (cystemustine) validates a strategy of melanoma-targeted therapy in murine B16 and human-resistant M4Beu melanoma xenograft models.

PubMed

Rapp, Maryse; Maurizis, Jean C; Papon, Janine; Labarre, Pierre; Wu, Ting-Di; Croisy, Alain; Guerquin-Kern, Jean L; Madelmont, Jean C; Mounetou, Emmanuelle

2008-07-01

Chemoresistance to O(6)-alkylating agents is a major barrier to successful treatment of melanoma. It is mainly due to a DNA repair suicide protein, O(6)-alkylguanine-DNA alkyltransferase (AGT). Although AGT inactivation is a powerful clinical strategy for restoring tumor chemosensitivity, it was limited by increased toxicity to nontumoral cells resulting from a lack of tumor selectivity. Achieving enhanced chemosensitization via AGT inhibition preferably in the tumor should protect normal tissue. To this end, we have developed a strategy to target AGT inhibitors. In this study, we tested a new potential melanoma-directed AGT inhibitor [2-amino-6-(4-iodobenzyloxy)-9-[4-(diethylamino) ethylcarbamoylbenzyl] purine; IBgBZ] designed as a conjugate of O(6)-(4-iododbenzyl)guanine (IBg) as the AGT inactivator and a N,N-diethylaminoethylenebenzamido (BZ) moiety as the carrier to the malignant melanocytes. IBgBZ demonstrated AGT inactivation ability and potentiation of O(6)-alkylating agents (cystemustine, a chloroethylnitrosourea) in M4Beu highly chemoresistant human melanoma cells both in vitro and in tumor models. The biodisposition study on mice bearing B16 melanoma, the standard model for the evaluation of melanoma-directed agents, and the secondary ion mass spectrometry imaging confirmed the concentration of IBgBZ in the tumor and in particular in the intracytoplasmic melanosomes. These results validate the potential of IBgBZ as a new, more tumor-selective, AGT inhibitor in a strategy of melanoma-targeted therapy.

Immunological Effects of Conventional Chemotherapy and Targeted Anticancer Agents.

PubMed

Galluzzi, Lorenzo; Buqué, Aitziber; Kepp, Oliver; Zitvogel, Laurence; Kroemer, Guido

2015-12-14

The tremendous clinical success of checkpoint blockers illustrates the potential of reestablishing latent immunosurveillance for cancer therapy. Although largely neglected in the clinical practice, accumulating evidence indicates that the efficacy of conventional and targeted anticancer agents does not only involve direct cytostatic/cytotoxic effects, but also relies on the (re)activation of tumor-targeting immune responses. Chemotherapy can promote such responses by increasing the immunogenicity of malignant cells, or by inhibiting immunosuppressive circuitries that are established by developing neoplasms. These immunological "side" effects of chemotherapy are desirable, and their in-depth comprehension will facilitate the design of novel combinatorial regimens with improved clinical efficacy. Copyright © 2015 Elsevier Inc. All rights reserved.

Towards the discovery of drug-like RNA ligands?

PubMed

Foloppe, Nicolas; Matassova, Natalia; Aboul-Ela, Fareed

2006-11-01

Targeting RNA with small molecule drugs is an area of great potential for therapeutic treatment of infections and possibly genetic and autoimmune diseases. However, a mature set of precedents and established methodology is lacking. The physicochemical properties of RNA raise specific issues and obstacles to development, and contribute to explain the distinct characteristics of natural RNA ligands, including antibiotics. Yet, RNA-targeting strategies are being implemented to reinvigorate antibacterial discovery by using the ribosomal X-ray structures to modify known antibiotics. To exploit further these structures, we suggest the use of existing protein kinase-directed libraries of drug-like compounds to target the A-site of the bacterial ribosome, on the basis of a specific structural hypothesis.

Rapid inverse planning for pressure-driven drug infusions in the brain.

PubMed

Rosenbluth, Kathryn H; Martin, Alastair J; Mittermeyer, Stephan; Eschermann, Jan; Dickinson, Peter J; Bankiewicz, Krystof S

2013-01-01

Infusing drugs directly into the brain is advantageous to oral or intravenous delivery for large molecules or drugs requiring high local concentrations with low off-target exposure. However, surgeons manually planning the cannula position for drug delivery in the brain face a challenging three-dimensional visualization task. This study presents an intuitive inverse-planning technique to identify the optimal placement that maximizes coverage of the target structure while minimizing the potential for leakage outside the target. The technique was retrospectively validated using intraoperative magnetic resonance imaging of infusions into the striatum of non-human primates and into a tumor in a canine model and applied prospectively to upcoming human clinical trials.

Research on the method of precise alignment technology of atmospheric laser communication

NASA Astrophysics Data System (ADS)

Chen, Wen-jian; Gao, Wei; Duan, Yuan-yuan; Ma, Shi-wei; Chen, Jian

2016-10-01

Atmosphere laser communication takes advantage of laser as the carrier transmitting the voice, data, and image information in the atmosphere. Because of its high reliability, strong anti-interference ability, the advantages of easy installation, it has great potential and development space in the communications field. In the process of establish communication, the capture, targeting and tracking of the communication signal is the key technology. This paper introduce a method of targeting the signal spot in the process of atmosphere laser communication, which through the way of making analog signal addition and subtraction directly and normalized to obtain the target azimuth information to drive the servo system to achieve precise alignment of tracking.

Trispecific antibodies for CD16A-directed NK cell engagement and dual-targeting of tumor cells.

PubMed

Gantke, Thorsten; Weichel, Michael; Herbrecht, Carmen; Reusch, Uwe; Ellwanger, Kristina; Fucek, Ivica; Eser, Markus; Müller, Thomas; Griep, Remko; Molkenthin, Vera; Zhukovsky, Eugene A; Treder, Martin

2017-09-01

Bispecific antibodies that redirect the lytic activity of cytotoxic immune effector cells, such as T- and NK cells, onto tumor cells have emerged as a highly attractive and clinically validated treatment modality for hematological malignancies. Advancement of this therapeutic concept into solid tumor indications, however, is hampered by the scarcity of targetable antigens that are surface-expressed on tumor cells but demonstrate only limited expression on healthy tissues. To overcome this limitation, the concept of dual-targeting, i.e. the simultaneous targeting of two tumor-expressed surface antigens with limited co-expression on non-malignant cells, with multispecific antibodies has been proposed to increase tumor selectivity of antibody-induced effector cell cytotoxicity. Here, a novel CD16A (FcγRIIIa)-directed trispecific, tetravalent antibody format, termed aTriFlex, is described, that is capable of redirecting NK cell cytotoxicity to two surface-expressed antigens. Using a BCMA/CD200-based in vitro model system, the potential use of aTriFlex antibodies for dual-targeting and selective induction of NK cell-mediated target cell lysis was investigated. Bivalent bispecific target cell binding was found to result in significant avidity gains and up to 17-fold increased in vitro potency. These data suggest trispecific aTriFlex antibodies may support dual-targeting strategies to redirect NK cell cytotoxicity with increased selectivity to enable targeting of solid tumor antigens. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Folate-targeted nanoparticles for rheumatoid arthritis therapy.

PubMed

Nogueira, Eugénia; Gomes, Andreia C; Preto, Ana; Cavaco-Paulo, Artur

2016-05-01

Rheumatoid arthritis (RA) is the most common inflammatory rheumatic disease, affecting almost 1% of the world population. Although the cause of RA remains unknown, the complex interaction between immune mediators (cytokines and effector cells) is responsible for the joint damage that begins at the synovial membrane. Activated macrophages are critical in the pathogenesis of RA and showed specifically express a receptor for the vitamin folic acid (FA), folate receptor β (FRβ). This particular receptor allows internalization of FA-coupled cargo. In this review we will address the potential of nanoparticles as an effective drug delivery system for therapies that will directly target activated macrophages. Special attention will be given to stealth degree of the nanoparticles as a strategy to avoid clearance by macrophages of the mononuclear phagocytic system (MPS). This review summarizes the application of FA-target nanoparticles as drug delivery systems for RA and proposes prospective future directions. Rheumatoid arthritis is a debilitating autoimmune disease of the joints which affects many people worldwide. Up till now, there is a lack of optimal therapy against this disease. In this review article, the authors outlined in depth the current mechanism of disease for rheumatoid arthritis and described the latest research in using folic acid-targeted nanoparticles to target synovial macrophages in the fight against rheumatoid arthritis. Copyright © 2016 Elsevier Inc. All rights reserved.

miR-144 suppresses proliferation and induces apoptosis of osteosarcoma cells via direct regulation of mTOR expression.

PubMed

Ren, Yuan-Fei; Zhang, Tie-Hui; Zhong, Sheng; Zhao, Yan-Tao; Lv, Ya-Nan

2018-01-01

Studied as a type of tumor suppressor, microRNA (miR) performs an important role in growth and apoptosis of various human carcinomas. However, the effects of miR-l44 on osteosarcoma growth and apoptosis, as well as possible underlying mechanisms, remain unclear. The present study investigated the expression of miR-144 in osteosarcoma MG-63 and U-2 OS cell lines compared with osteoblast cells. In order to elucidate the effects of miR-144 on osteosarcoma, miR-144 was upregulated in MG-63 and U-2 OS cells by transfecting chemically synthesized miR-144 mimics. Bioinformatics analysis of potential miR-144 target genes was performed using TargetScanHuman 7.0 and confirmed by luciferase assay. This analysis identified mammalian target of rapamycin (mTOR) as a target of miR-144. The present results indicated that the overexpression of miR-144 may significantly inhibit proliferation and promote apoptosis of MG-63 and U-2 cells compared with scramble control. Furthermore, the effects of miR-144 on osteosarcoma were associated with the mTOR signaling pathway via directly targeting the 3' untranslated region of mTOR mRNA, resulting in a decrease in the level of mTOR protein. In summary, miR-144 was demonstrated to act as a tumor suppressor, which inhibits proliferation and promotes apoptosis of osteosarcoma cell lines. In addition, this effect was mediated by direct targeting on mTOR following inhibition of the mTOR signaling pathway. The present study suggested that miR-144 may be a candidate for the gene therapy of osteosarcoma.

MicroRNA-106a-5p facilitates human glioblastoma cell proliferation and invasion by targeting adenomatosis polyposis coli protein

DOE Office of Scientific and Technical Information (OSTI.GOV)

Li, Dazhi; Wang, Zengliang; Chen, Zigui

The invasive behavior of glioblastoma multiforme (GBM) cells is an important reason for its poor prognosis. Tumor cells acquire an ability to digest the extracellular matrix and infiltrate the adjacent normal tissue during invasion. Restraining GBM invasion by changing effector molecules can significantly improve the patient's prognosis. MiRNAs are involved in multiple biological functions via suppressing target genes. In this study, we found that miR-106a-5p expression was high in GBM tissues and cells. The data showed an inverse correlation in GBM tissues between the levels of miR-106a-5p and adenomatosis polyposis coli (APC) mRNAs.Additionally, ectopic expression of miR-106a-5pfacilitated the invasion ofmore » GBM cells whereas inhibition of miR-106a-5p expression weakened the invasive ability. Numerous transcription factors are downstream effectors of the Wnt/β-catenin pathway. Target prediction databases and luciferase data showed that APC is a new direct target of miR-106a-5p. Importantly, westernblot assays demonstrated that miR-106a-5p can reduce APC protein level and enhance target proteins of Wnt/β-catenin pathway. Thus, we hypothesize that miR-106a-5p directly targets APC, resulting in the activation of Wnt/β-catenin pathway. Our results suggest that miR-106a-5p is involved in the invasive behavior of GBM cells and by targeting APC and activating Wnt/β-catenin pathway, it provides a theoretical basis for developing potential clinical strategies. - Highlights: • miR-106a-5p is upregulated in human glioblastoma. • Upregulation of miR-106a-5p promotes glioma cell proliferation and invasion. • miR-106a-5p inactivates the Wnt/β-catenin pathway by directly targeting APC.« less

Mediation misgivings: ambiguous clinical and public health interpretations of natural direct and indirect effects.

PubMed

Naimi, Ashley I; Kaufman, Jay S; MacLehose, Richard F

2014-10-01

Recent methodological innovation is giving rise to an increasing number of applied papers in medical and epidemiological journals in which natural direct and indirect effects are estimated. However, there is a longstanding debate on whether such effects are relevant targets of inference in population health. In light of the repeated calls for a more pragmatic and consequential epidemiology, we review three issues often raised in this debate: (i) the use of composite cross-world counterfactuals and the need for cross-world independence assumptions; (ii) interventional vs non-interventional identifiability; and (iii) the interpretational ambiguity of natural direct and indirect effect estimates. We use potential outcomes notation and directed acyclic graphs to explain 'cross-world' assumptions, illustrate implications of this assumption via regression models and discuss ensuing issues of interpretation. We argue that the debate on the relevance of natural direct and indirect effects rests on whether one takes as a target of inference the mathematical object per se, or the change in the world that the mathematical object represents. We further note that public health questions may be better served by estimating controlled direct effects. © The Author 2014; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.

SPR Biosensors in Direct Molecular Fishing: Implications for Protein Interactomics.

PubMed

Florinskaya, Anna; Ershov, Pavel; Mezentsev, Yuri; Kaluzhskiy, Leonid; Yablokov, Evgeniy; Medvedev, Alexei; Ivanov, Alexis

2018-05-18

We have developed an original experimental approach based on the use of surface plasmon resonance (SPR) biosensors, applicable for investigation of potential partners involved in protein⁻protein interactions (PPI) as well as protein⁻peptide or protein⁻small molecule interactions. It is based on combining a SPR biosensor, size exclusion chromatography (SEC), mass spectrometric identification of proteins (LC-MS/MS) and direct molecular fishing employing principles of affinity chromatography for isolation of potential partner proteins from the total lysate of biological samples using immobilized target proteins (or small non-peptide compounds) as ligands. Applicability of this approach has been demonstrated within the frame of the Human Proteome Project (HPP) and PPI regulation by a small non-peptide biologically active compound, isatin.

Novel treatment strategies for brain tumors and metastases

PubMed Central

El-Habashy, Salma E.; Nazief, Alaa M.; Adkins, Chris E.; Wen, Ming Ming; El-Kamel, Amal H.; Hamdan, Ahmed M.; Hanafy, Amira S.; Terrell, Tori O.; Mohammad, Afroz S.; Lockman, Paul R.; Nounou, Mohamed Ismail

2015-01-01

This review summarizes patent applications in the past 5 years for the management of brain tumors and metastases. Most of the recent patents discuss one of the following strategies: the development of new drug entities that specifically target the brain cells, the blood–brain barrier and the tumor cells, tailor-designing a novel carrier system that is able to perform multitasks and multifunction as a drug carrier, targeting vehicle and even as a diagnostic tool, direct conjugation of a US FDA approved drug with a targeting moiety, diagnostic moiety or PK modifying moiety, or the use of innovative nontraditional approaches such as genetic engineering, stem cells and vaccinations. Until now, there has been no optimal strategy to deliver therapeutic agents to the CNS for the treatment of brain tumors and metastases. Intensive research efforts are actively ongoing to take brain tumor targeting, and novel and targeted CNS delivery systems to potential clinical application. PMID:24998288

miR-181b Promotes hepatic stellate cells proliferation by targeting p27 and is elevated in the serum of cirrhosis patients

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wang, Baocan; Li, Wenxi; Guo, Kun

2012-04-27

Highlights: Black-Right-Pointing-Pointer miR-181a and miR-181b, especially, miR-181b could be induced by transforming growth factor-beta 1 (TGF-{beta}1) in hepatic stellate cells. Black-Right-Pointing-Pointer miR-181b could promote HSC-T6 cell proliferation by directly targeting the negative cell regulator-p27 in HSC-T6 cell. Black-Right-Pointing-Pointer miR-181b was identified as potential serum diagnostic marker for liver cirrhosis patients. -- Abstract: MicroRNAs, as a kind of negative gene regulators, were demonstrated to be involved in many types of diseases. In this study, we found that transforming growth factor-beta 1 could induce the expression of miR-181a and miR-181b, and miR-181b increased in the much higher folds than miR-181a. Because ofmore » the important role of transforming growth factor-beta 1 in HSC activation and liver cirrhosis, we investigate the effect of miR-181a and miR-181b on HSC proliferation. The results showed that miR-181b could promote HSC-T6 cell proliferation by regulating cell cycle. Further study showed p27, the cell cycle regulator, was the direct target of miR-181b in HSC-T6 cell. But miR-181a had no effects on HSC-T6 cell proliferation and cell cycle, and did not target p27. Interestingly, miR-181b is elevated significantly in serum of liver cirrhosis cases comparing to that of normal persons, whereas miR-181a expression was in the similar level with that of normal persons. These results suggested that miR-181b could be induced by TGF-{beta}1 and promote the growth of HSCs by directly targeting p27. The elevation of miR-181b in serum suggested that it may be potential diagnostic biomarkers for cirrhosis. As for miR-181a, it may work in TGF-{beta}1 pathway by a currently unknown mechanism.« less

Spatial and polarity precision of concentric high-definition transcranial direct current stimulation (HD-tDCS).

PubMed

Alam, Mahtab; Truong, Dennis Q; Khadka, Niranjan; Bikson, Marom

2016-06-21

Transcranial direct current stimulation (tDCS) is a non-invasive neuromodulation technique that applies low amplitude current via electrodes placed on the scalp. Rather than directly eliciting a neuronal response, tDCS is believed to modulate excitability-enhancing or suppressing neuronal activity in regions of the brain depending on the polarity of stimulation. The specificity of tDCS to any therapeutic application derives in part from how electrode configuration determines the brain regions that are stimulated. Conventional tDCS uses two relatively large pads (>25 cm(2)) whereas high-definition tDCS (HD-tDCS) uses arrays of smaller electrodes to enhance brain targeting. The 4  ×  1 concentric ring HD-tDCS (one center electrode surrounded by four returns) has been explored in application where focal targeting of cortex is desired. Here, we considered optimization of concentric ring HD-tDCS for targeting: the role of electrodes in the ring and the ring's diameter. Finite element models predicted cortical electric field generated during tDCS. High resolution MRIs were segmented into seven tissue/material masks of varying conductivities. Computer aided design (CAD) model of electrodes, gel, and sponge pads were incorporated into the segmentation. Volume meshes were generated and the Laplace equation ([Formula: see text] · (σ [Formula: see text] V)  =  0) was solved for cortical electric field, which was interpreted using physiological assumptions to correlate with stimulation and modulation. Cortical field intensity was predicted to increase with increasing ring diameter at the cost of focality while uni-directionality decreased. Additional surrounding ring electrodes increased uni-directionality while lowering cortical field intensity and increasing focality; though, this effect saturated and more than 4 surround electrode would not be justified. Using a range of concentric HD-tDCS montages, we showed that cortical region of influence can be controlled while balancing other design factors such as intensity at the target and uni-directionality. Furthermore, the evaluated concentric HD-tDCS approaches can provide categorical improvements in targeting compared to conventional tDCS. Hypothesis driven clinical trials, based on specific target engagement, would benefit by this more precise method of stimulation that could avoid potentially confounding brain regions.

Chapter 17. Extension of endogenous primers as a tool to detect micro-RNA targets.

PubMed

Vatolin, Sergei; Weil, Robert J

2008-01-01

Mammalian cells express a large number of small, noncoding RNAs, including micro-RNAs (miRNAs), that can regulate both the level of a target mRNA and the protein produced by the target mRNA. Recognition of miRNA targets is a complicated process, as a single target mRNA may be regulated by several miRNAs. The potential for combinatorial miRNA-mediated regulation of miRNA targets complicates diagnostic and therapeutic applications of miRNAs. Despite significant progress in understanding the biology of miRNAs and advances in computational predictions of miRNA targets, methods that permit direct physical identification of miRNA-mRNA complexes in eukaryotic cells are still required. Several groups have utilized coimmunoprecipitation of RNA associated with a protein(s) that is part of the RNA silencing macromolecular complex. This chapter describes a detailed but straightforward strategy that identifies miRNA targets based on the assumption that small RNAs base paired with a complementary target mRNA can be used as a primer to synthesize cDNA that may be used for cloning, identification, and functional analysis.

Small molecules targeting heterotrimeric G proteins.

PubMed

Ayoub, Mohammed Akli

2018-05-05

G protein-coupled receptors (GPCRs) represent the largest family of cell surface receptors regulating many human and animal physiological functions. Their implication in human pathophysiology is obvious with almost 30-40% medical drugs commercialized today directly targeting GPCRs as molecular entities. However, upon ligand binding GPCRs signal inside the cell through many key signaling, adaptor and regulatory proteins, including various classes of heterotrimeric G proteins. Therefore, G proteins are considered interesting targets for the development of pharmacological tools that are able to modulate their interaction with the receptors, as well as their activation/deactivation processes. In this review, old attempts and recent advances in the development of small molecules that directly target G proteins will be described with an emphasis on their utilization as pharmacological tools to dissect the mechanisms of activation of GPCR-G protein complexes. These molecules constitute a further asset for research in the "hot" areas of GPCR biology, areas such as multiple G protein coupling/signaling, GPCR-G protein preassembly, and GPCR functional selectivity or bias. Moreover, this review gives a particular focus on studies in vitro and in vivo supporting the potential applications of such small molecules in various GPCR/G protein-related diseases. Copyright © 2018 Elsevier B.V. All rights reserved.

Molecular mechanisms of flavonoids in melanin synthesis and the potential for the prevention and treatment of melanoma

PubMed Central

Liu-Smith, Feng; Meyskens, Frank

2016-01-01

Flavonoids are becoming popular nutraceuticals. Different flavonoids show similar or distinct biological effects on different tissues or cell types, which may limit or define their usefulness in cancer prevention and/or treatment application. This review focuses on a few selected flavonoids and discusses their functions in normal and transformed pigment cells, including cyanidin, apigenin, genistein, fisetin, EGCG, luteolin, baicalein, quercetin and kaempferol. Flavonoids exhibit melanogenic or anti-melanogenic effects mainly via transcriptional factor MiTF and/or the melanogenesis enzymes tyrosinase, DCT2 or TYRP-1. To identify a direct target has been a challenge as most studies were not able to discriminate whether the effect(s) of the flavonoid were from direct targeting or represented indirect effects. Flavonoids exhibit an anti-melanoma effect via inhibiting cell proliferation and invasion and inducing apoptosis. The mechanisms are also multi-fold, via ROS-scavenging, immune-modulation, cell cycle regulation and epigenetic modification including DNA methylation and histone deacetylation. In summary, although many flavonoid compounds are extremely promising nutraceuticals, their detailed molecular mechanism and their multi-target (simultaneously targeting multiple molecules) nature warrant further investigation before advancement to translation studies or clinical trials. PMID:26865001

Current status of renin-aldosterone angiotensin system-targeting anti-hypertensive drugs as therapeutic options for Alzheimer's disease.

PubMed

Ashby, Emma Louise; Kehoe, Patrick G

2013-10-01

Hypertension is a modifiable risk factor for Alzheimer's disease (AD) and other dementias. Yet, despite this well-documented association, few of the current strategies to treat AD are directed at this possible target. The renin-aldosterone angiotensin system (RAAS) is a centrally active modifiable pathway that is involved in cerebral blood flow regulation. Currently, three classes of RAAS-targeting drugs are licensed for treatment of peripheral hypertension--angiotensin-converting enzyme inhibitors (ACE-Is), angiotensin II receptor blockers (ARBs) and direct renin inhibitors (DRIs). All of these are generally well tolerated and have been shown to offer varying degrees of protection on aspects of cognition and dementia, thus making them an attractive therapeutic option for AD. This review summarises existing evidence regarding the plausibility of using RAAS-targeting drugs as a strategy to treat AD and highlights unresolved aspects to such approaches, namely the potential impact of altering angiotensin II-mediated processes in the central nervous system. Continued biochemical research of the RAAS pathway in combination with formal investigation of current RAAS-modifying drugs in randomised clinical trials is now necessary to determine their therapeutic value in AD.

miR-4458 suppresses glycolysis and lactate production by directly targeting hexokinase2 in colon cancer cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Qin, Yaguang; Cheng, Chuanyao; Lu, Hong, E-mail: honglu6512@163.com

miR-4458, a new tumor-suppressor, was reported to down-regulated in human hepatocellular carcinoma. The expression status, roles and inhibitory mechanisms of miR-4458 in other tumors still need to be clarified. The aim of this study is to investigate the effects of miR-4458 and to elucidate the potential mechanism in colon cancer cells. Using bioinformatic databases, we predicted that hexokinase2 (HK2), a rate-limiting enzyme in the glycolytic pathway, was a target of miR-4458, so the effects of miR-4458 on glycolysis and lactate production was assessed in colon cancer cells. We found that miR-4458 was down-regulated and HK2 was up-regulated in colon cancermore » cells. Overexpression of miR-4458 inhibited proliferation, glycolysis, and lactate production under both normoxic and hypoxic conditions. Luciferase activity assays showed that HK2 was a direct target of miR-4458. Moreover, knockdown of HK2 by specific RNAi also suppressed proliferation, glycolysis, and lactate production under both normoxic and hypoxic conditions. In conclusion, our findings suggested that miR-4458 inhibited the progression of colon cancer cells by inhibition of glycolysis and lactate production via directly targeting HK2 mRNA. - Highlights: • miR-4458 is down-regulated in colon cancer cells. • miR-4458 suppresses proliferation, glycolysis, and lactate production. • HK2 is a target of miR-4458. • HK2 knockdown inhibits proliferation, glycolysis, and lactate production.« less

Direct Imaging of Cerebral Thromboemboli Using Computed Tomography and Fibrin-targeted Gold Nanoparticles

PubMed Central

Kim, Jeong-Yeon; Ryu, Ju Hee; Schellingerhout, Dawid; Sun, In-Cheol; Lee, Su-Kyoung; Jeon, Sangmin; Kim, Jiwon; Kwon, Ick Chan; Nahrendorf, Matthias; Ahn, Cheol-Hee; Kim, Kwangmeyung; Kim, Dong-Eog

2015-01-01

Computed tomography (CT) is the current standard for time-critical decision-making in stroke patients, informing decisions on thrombolytic therapy with tissue plasminogen activator (tPA), which has a narrow therapeutic index. We aimed to develop a CT-based method to directly visualize cerebrovascular thrombi and guide thrombolytic therapy. Glycol-chitosan-coated gold nanoparticles (GC-AuNPs) were synthesized and conjugated to fibrin-targeting peptides, forming fib-GC-AuNP. This targeted imaging agent and non-targeted control agent were characterized in vitro and in vivo in C57Bl/6 mice (n = 107) with FeCl3-induced carotid thrombosis and/or embolic ischemic stroke. Fibrin-binding capacity was superior with fib-GC-AuNPs compared to GC-AuNPs, with thrombi visualized as high density on microCT (mCT). mCT imaging using fib-GC-AuNP allowed the prompt detection and quantification of cerebral thrombi, and monitoring of tPA-mediated thrombolytic effect, which reflected histological stroke outcome. Furthermore, recurrent thrombosis could be diagnosed by mCT without further nanoparticle administration for up to 3 weeks. fib-GC-AuNP-based direct cerebral thrombus imaging greatly enhance the value and information obtainable by regular CT, has multiple uses in basic / translational vascular research, and will likely allow personalized thrombolytic therapy in clinic by a) optimizing tPA-dosing to match thrombus burden, b) enabling the rational triage of patients to more radical therapies such as endovascular clot-retrieval, and c) potentially serving as a theranostic platform for targeted delivery of concurrent thrombolysis. PMID:26199648

A T-cell-directed chimeric antigen receptor for the selective treatment of T-cell malignancies.

PubMed

Mamonkin, Maksim; Rouce, Rayne H; Tashiro, Haruko; Brenner, Malcolm K

2015-08-20

Options for targeted therapy of T-cell malignancies remain scarce. Recent clinical trials demonstrated that chimeric antigen receptors (CARs) can effectively redirect T lymphocytes to eradicate lymphoid malignancies of B-cell origin. However, T-lineage neoplasms remain a more challenging task for CAR T cells due to shared expression of most targetable surface antigens between normal and malignant T cells, potentially leading to fratricide of CAR T cells or profound immunodeficiency. Here, we report that T cells transduced with a CAR targeting CD5, a common surface marker of normal and neoplastic T cells, undergo only limited fratricide and can be expanded long-term ex vivo. These CD5 CAR T cells effectively eliminate malignant T-cell acute lymphoblastic leukemia (T-ALL) and T-cell lymphoma lines in vitro and significantly inhibit disease progression in xenograft mouse models of T-ALL. These data support the therapeutic potential of CD5 CAR in patients with T-cell neoplasms. © 2015 by The American Society of Hematology.

A T-cell–directed chimeric antigen receptor for the selective treatment of T-cell malignancies

PubMed Central

Mamonkin, Maksim; Rouce, Rayne H.; Tashiro, Haruko

2015-01-01

Options for targeted therapy of T-cell malignancies remain scarce. Recent clinical trials demonstrated that chimeric antigen receptors (CARs) can effectively redirect T lymphocytes to eradicate lymphoid malignancies of B-cell origin. However, T-lineage neoplasms remain a more challenging task for CAR T cells due to shared expression of most targetable surface antigens between normal and malignant T cells, potentially leading to fratricide of CAR T cells or profound immunodeficiency. Here, we report that T cells transduced with a CAR targeting CD5, a common surface marker of normal and neoplastic T cells, undergo only limited fratricide and can be expanded long-term ex vivo. These CD5 CAR T cells effectively eliminate malignant T-cell acute lymphoblastic leukemia (T-ALL) and T-cell lymphoma lines in vitro and significantly inhibit disease progression in xenograft mouse models of T-ALL. These data support the therapeutic potential of CD5 CAR in patients with T-cell neoplasms. PMID:26056165

Elastic scattering and breakup reactions of the exotic nucleus 8B on nuclear targets

NASA Astrophysics Data System (ADS)

Lukyanov, V. K.; Kadrev, D. N.; Antonov, A. N.; Zemlyanaya, E. V.; Lukyanov, K. V.; Gaidarov, M. K.; Spasova, K.

2018-05-01

Microscopic calculations of the optical potentials (OPs) and elastic scattering cross sections of the proton-rich nucleus 8B on 12C, 58Ni and 208Pb targets are presented. The density distributions of 8B obtained within the variational Monte Carlo (VMC) model and the three-cluster model (3CM) are used to construct the optical potentials (OP). The real part of the hybrid OP (ReOP) is calculated using the folding model with the direct and exchange terms included, while the imaginary part (ImOP) is obtained on the base of the high energy approximation (HEA). In addition, the cluster model, in which 8B consists of a proton halo and a 7Be core is applied to calculate the breakup cross sections of 8B on 9Be, 12C and 197Au targets, as well as the momentum distributions of 7Be fragments. A comparison with the available experimental data is made and a good agreement is obtained.

Prostate Stem Cell Antigen: A Prospective Therapeutic and Diagnostic Target

PubMed Central

Raff, Adam B.; Gray, Andrew; Kast, W. Martin

2009-01-01

The development of novel clinical tools to combat cancer is an intense field of research and recent efforts have been directed at the identification of proteins that may provide diagnostic, prognostic and/or therapeutic applications due to their restricted expression. To date, a number of protein candidates have emerged as potential clinical tools in the treatment of prostate cancer. Discovered over ten year ago, prostate stem cell antigen (PSCA) is a cell surface antigen that belongs to the Ly-6/Thy-1 family of glycosylphosphatidylinositol-anchored proteins. PSCA is highly overexpressed in human prostate cancer, with limited expression in normal tissues, making it an ideal target for both diagnosis and therapy. Several studies have now clearly correlated the expression of PSCA with relevant clinical benchmarks, such as Gleason score and metastasis, while others have demonstrated the efficacy of PSCA targeting in treatment through various modalities. The purpose of this review is to present the current body of knowledge about PSCA and its potential role in the treatment of human prostate cancer. PMID:18838214

Signal amplification by rolling circle amplification on DNA microarrays

PubMed Central

Nallur, Girish; Luo, Chenghua; Fang, Linhua; Cooley, Stephanie; Dave, Varshal; Lambert, Jeremy; Kukanskis, Kari; Kingsmore, Stephen; Lasken, Roger; Schweitzer, Barry

2001-01-01

While microarrays hold considerable promise in large-scale biology on account of their massively parallel analytical nature, there is a need for compatible signal amplification procedures to increase sensitivity without loss of multiplexing. Rolling circle amplification (RCA) is a molecular amplification method with the unique property of product localization. This report describes the application of RCA signal amplification for multiplexed, direct detection and quantitation of nucleic acid targets on planar glass and gel-coated microarrays. As few as 150 molecules bound to the surface of microarrays can be detected using RCA. Because of the linear kinetics of RCA, nucleic acid target molecules may be measured with a dynamic range of four orders of magnitude. Consequently, RCA is a promising technology for the direct measurement of nucleic acids on microarrays without the need for a potentially biasing preamplification step. PMID:11726701

Liver-directed lentiviral gene therapy in a dog model of hemophilia B.

PubMed

Cantore, Alessio; Ranzani, Marco; Bartholomae, Cynthia C; Volpin, Monica; Valle, Patrizia Della; Sanvito, Francesca; Sergi, Lucia Sergi; Gallina, Pierangela; Benedicenti, Fabrizio; Bellinger, Dwight; Raymer, Robin; Merricks, Elizabeth; Bellintani, Francesca; Martin, Samia; Doglioni, Claudio; D'Angelo, Armando; VandenDriessche, Thierry; Chuah, Marinee K; Schmidt, Manfred; Nichols, Timothy; Montini, Eugenio; Naldini, Luigi

2015-03-04

We investigated the efficacy of liver-directed gene therapy using lentiviral vectors in a large animal model of hemophilia B and evaluated the risk of insertional mutagenesis in tumor-prone mouse models. We showed that gene therapy using lentiviral vectors targeting the expression of a canine factor IX transgene in hepatocytes was well tolerated and provided a stable long-term production of coagulation factor IX in dogs with hemophilia B. By exploiting three different mouse models designed to amplify the consequences of insertional mutagenesis, we showed that no genotoxicity was detected with these lentiviral vectors. Our findings suggest that lentiviral vectors may be an attractive candidate for gene therapy targeted to the liver and may be potentially useful for the treatment of hemophilia. Copyright © 2015, American Association for the Advancement of Science.

Secure Embedded Systems

DTIC Science & Technology

2016-02-26

UAS) to illustrate how we use cryptography to ensure confidentiality and integrity. Using this example, we demonstrate the identification of...potential attack targets by considering the CONOPS, the development of countermeasures to these attacks, and the design and implementation of a cryptography ...based security architecture. Because cryptography does not directly enable availability, we also provide insight into the ongoing research that

Genetic determinants and potential therapeutic targets for pancreatic adenocarcinoma.

PubMed

Reznik, Robert; Hendifar, Andrew E; Tuli, Richard

2014-01-01

Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer deaths in both men and women in the United States, carrying a 5-year survival rate of approximately 5%, which is the poorest prognosis of any solid tumor type. Given the dismal prognosis associated with PDAC, a more thorough understanding of risk factors and genetic predisposition has important implications not only for cancer prevention, but also for screening techniques and the development of personalized therapies. While screening of the general population is not recommended or practicable with current diagnostic methods, studies are ongoing to evaluate its usefulness in people with at least 5- to 10-fold increased risk of PDAC. In order to help identify high-risk populations who would be most likely to benefit from early detection screening tests for pancreatic cancer, discovery of additional pancreatic cancer susceptibility genes is crucial. Thus, specific gene-based, gene-product, and marker-based testing for the early detection of pancreatic cancer are currently being developed, with the potential for these to be useful as potential therapeutic targets as well. The goal of this review is to provide an overview of the genetic basis for PDAC with a focus on germline and familial determinants. A discussion of potential therapeutic targets and future directions in screening and treatment is also provided.

Genetic determinants and potential therapeutic targets for pancreatic adenocarcinoma

PubMed Central

Reznik, Robert; Hendifar, Andrew E.; Tuli, Richard

2014-01-01

Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer deaths in both men and women in the United States, carrying a 5-year survival rate of approximately 5%, which is the poorest prognosis of any solid tumor type. Given the dismal prognosis associated with PDAC, a more thorough understanding of risk factors and genetic predisposition has important implications not only for cancer prevention, but also for screening techniques and the development of personalized therapies. While screening of the general population is not recommended or practicable with current diagnostic methods, studies are ongoing to evaluate its usefulness in people with at least 5- to 10-fold increased risk of PDAC. In order to help identify high-risk populations who would be most likely to benefit from early detection screening tests for pancreatic cancer, discovery of additional pancreatic cancer susceptibility genes is crucial. Thus, specific gene-based, gene-product, and marker-based testing for the early detection of pancreatic cancer are currently being developed, with the potential for these to be useful as potential therapeutic targets as well. The goal of this review is to provide an overview of the genetic basis for PDAC with a focus on germline and familial determinants. A discussion of potential therapeutic targets and future directions in screening and treatment is also provided. PMID:24624093

A Computerized Microelectrode Recording to Magnetic Resonance Imaging Mapping System for Subthalamic Nucleus Deep Brain Stimulation Surgery.

PubMed

Dodani, Sunjay S; Lu, Charles W; Aldridge, J Wayne; Chou, Kelvin L; Patil, Parag G

2018-06-01

Accurate electrode placement is critical to the success of deep brain stimulation (DBS) surgery. Suboptimal targeting may arise from poor initial target localization, frame-based targeting error, or intraoperative brain shift. These uncertainties can make DBS surgery challenging. To develop a computerized system to guide subthalamic nucleus (STN) DBS electrode localization and to estimate the trajectory of intraoperative microelectrode recording (MER) on magnetic resonance (MR) images algorithmically during DBS surgery. Our method is based upon the relationship between the high-frequency band (HFB; 500-2000 Hz) signal from MER and voxel intensity on MR images. The HFB profile along an MER trajectory recorded during surgery is compared to voxel intensity profiles along many potential trajectories in the region of the surgically planned trajectory. From these comparisons of HFB recordings and potential trajectories, an estimate of the MER trajectory is calculated. This calculated trajectory is then compared to actual trajectory, as estimated by postoperative high-resolution computed tomography. We compared 20 planned, calculated, and actual trajectories in 13 patients who underwent STN DBS surgery. Targeting errors for our calculated trajectories (2.33 mm ± 0.2 mm) were significantly less than errors for surgically planned trajectories (2.83 mm ± 0.2 mm; P = .01), improving targeting prediction in 70% of individual cases (14/20). Moreover, in 4 of 4 initial MER trajectories that missed the STN, our method correctly indicated the required direction of targeting adjustment for the DBS lead to intersect the STN. A computer-based algorithm simultaneously utilizing MER and MR information potentially eases electrode localization during STN DBS surgery.

Control of Aedes albopictus with attractive toxic sugar baits (ATSB) and potential impact on non-target organisms in St. Augustine, Florida

PubMed Central

Revay, Edita E.; Müller, Gunter C.; Qualls, Whitney A.; Kline, Daniel; Naranjo, Diana P.; Arheart, Kristopher L.; Kravchenko, Vasiliy D.; Yfremova, Zoya; Hausmann, Axel; Beier, John C.; Schlein, Yosef; Xue, Rui-De

2013-01-01

The purpose of this study was to test the efficacy of bait stations and foliar applications containing attractive toxic sugar baits (ATSB) and eugenol to control Aedes albopictus. At the same time the potential impact of these control methods was evaluated on non-target organisms. The study was conducted at five tire sites in St. Augustine, Florida. Aedes albopictus populations were significantly reduced with ATSB-eugenol applications applied directly to non-flowering vegetation and as bait stations compared with non-attractive sugar baits and control. The application of ATSB made to non-flowering vegetation resulted in more significant reductions of mosquito populations compared to the application of ATSB presented in a bait station. Over 5.5% of the non-targets were stained in the flowering vegetation application site. However, when the attractive sugar bait application was made to non-flowering vegetation or presented in bait stations the impact on non-target insects was very low for all non-target orders as only 0.6% of the individual insects were stained with the dye from the sugar solutions, respectively. There were no significant differences between the staining of mosquitoes collected in flowering vegetation (206/1000) or non-flowering vegetation (242/1000) sites during the non-target evaluation. Our field studies support the use of eugenol as an active ingredient for controlling the dengue vector Ae. albopictus when used as an ATSB toxin and demonstrates potential use in sub-tropical and tropical environments for dengue control. PMID:24122115

Acceleration of recovery in acute renal failure: from cellular mechanisms of tubular repair to innovative targeted therapies.

PubMed

Abbate, M; Remuzzi, G

1996-05-01

Kidney repair from injury is a major focus of interest for research, both clinical and basic, in the field of acute renal failure. This is so because very little progress has been made during the past several years to improve mortality in hospitalized patients with acute renal failure despite the unique potential of the kidney for complete structural and functional recovery. Novel therapeutic options have recently emerged from the knowledge of molecular mechanisms of tissue injury after ischemia, including pathways of endothelial-leukocyte interaction and epithelial cell aggregation mediated by integrin molecules. These strategies are promising because they may target early mechanisms of leukocyte infiltration and tubular obstruction. However, it seems clear that additional interventions should address the reparative program that potentially leads to the full restoration of kidney structure and function. Thus, acceleration of repair from acute renal failure is achieved experimentally by growth factors which besides different renal actions seem to have in common the ability to stimulate proliferation of surviving tubular epithelial cells. We direct attention to cellular processes which characterize, and possibly have role in, renal repair from acute tubular injury as potential targets of therapy. In addition to proliferation, they include epithelial differentiation and apoptosis. Further investigation in the biology of repair should set the stage for rational design of targeted therapies which may accelerate the pace of recovery and hopefully decrease mortality in such a dramatic and potentially reversible setting.

A Unique Role for Endothelial Cell Kinesin Light Chain 1, Variant 1 in Leukocyte Transendothelial Migration

PubMed Central

Cyrus, Bita F.; Muller, William A.

2017-01-01

A reservoir of parajunctional membrane in endothelial cells, the lateral border recycling compartment (LBRC), is critical for transendothelial migration (TEM). We have previously shown that targeted recycling of the LBRC to the site of TEM requires microtubules and a kinesin molecular motor. However, the identity of the kinesin and mechanism of cargo binding were not known. We show that microinjection of endothelial cells with a monoclonal antibody specific for kinesin-1 significantly blocked LBRC-targeted recycling and TEM. In complementary experiments, knocking down KIF5B, a ubiquitous kinesin-1 isoform, in endothelial cells significantly decreased targeted recycling of the LBRC and leukocyte TEM. Kinesin heavy chains move cargo along microtubules by one of many kinesin light chains (KLCs), which directly bind the cargo. Knocking down KLC 1 isoform variant 1 (KLC1C) significantly decreased LBRC-targeted recycling and TEM, whereas knocking down other isoforms of KLC1 had no effect. Re-expression of KLC1C resistant to the knockdown shRNA restored targeted recycling and TEM. Thus kinesin-1 and KLC1C are specifically required for targeted recycling and TEM. These data suggest that of the many potential combinations of the 45 kinesin family members and multiple associated light chains, KLC1C links the LBRC to kinesin-1 (KIF5B) during targeted recycling and TEM. Thus, KLC1C can potentially be used as a target for anti-inflammatory therapy. PMID:26994343

Progress and Future Directions in Research on the Psychosis Prodrome: A Review for Clinicians

PubMed Central

Woodberry, Kristen A; Shapiro, Daniel I; Bryant, Caitlin; Seidman, Larry J.

2016-01-01

The psychosis prodrome, or period of clinical and functional decline leading up to acute psychosis, offers a unique opportunity for identifying mechanisms of psychosis onset and testing early intervention strategies. We summarize major findings and emerging directions in prodromal research and provide recommendations for clinicians working with individuals suspected to be at high risk for psychosis. The past two decades of research have led to three major advances. First, tools and criteria have been developed that can reliably identify imminent risk for a psychotic disorder. Second, longitudinal clinical and psychobiological data from large multisite studies are strengthening individual risk assessment and offering insights into potential mechanisms of illness onset. Third, psychosocial and pharmacological interventions are demonstrating promise for delaying or preventing the onset of psychosis in help-seeking, high-risk individuals. The dynamic psychobiological processes implicated in both risk and onset of psychosis, including altered gene expression, cognitive dysfunction, inflammation, gray and white matter brain changes, and vulnerability-stress interactions suggest a wide range of potential treatment targets and strategies. The expansion of resources devoted to early intervention and prodromal research worldwide raises hope for investigating them. Future directions include identifying psychosis-specific risk and resilience factors in children, adolescents, and non-help-seeking community samples, improving study designs to test hypothesized mechanisms of change, and intervening with strategies that better engage youth, their environmental contexts, and neurodevelopmental targets to improve functional outcomes. Prospective research on putatively prodromal samples has the potential to substantially reshape our understanding of mental illness and our efforts to combat it. PMID:26954594

Modeling trans-spinal direct current stimulation for the modulation of the lumbar spinal motor pathways

NASA Astrophysics Data System (ADS)

Kuck, A.; Stegeman, D. F.; van Asseldonk, E. H. F.

2017-10-01

Objective. Trans-spinal direct current stimulation (tsDCS) is a potential new technique for the treatment of spinal cord injury (SCI). TsDCS aims to facilitate plastic changes in the neural pathways of the spinal cord with a positive effect on SCI recovery. To establish tsDCS as a possible treatment option for SCI, it is essential to gain a better understanding of its cause and effects. We seek to understand the acute effect of tsDCS, including the generated electric field (EF) and its polarization effect on the spinal circuits, to determine a cellular target. We further ask how these findings can be interpreted to explain published experimental results. Approach. We use a realistic full body finite element volume conductor model to calculate the EF of a 2.5 mA direct current for three different electrode configurations. We apply the calculated electric field to realistic motoneuron models to investigate static changes in membrane resting potential. The results are combined with existing knowledge about the theoretical effect on a neuronal level and implemented into an existing lumbar spinal network model to simulate the resulting changes on a network level. Main results. Across electrode configurations, the maximum EF inside the spinal cord ranged from 0.47 V m-1 to 0.82 V m-1. Axon terminal polarization was identified to be the dominant cellular target. Also, differences in electrode placement have a large influence on axon terminal polarization. Comparison between the simulated acute effects and the electrophysiological long-term changes observed in human tsDCS studies suggest an inverse relationship between the two. Significance. We provide methods and knowledge for better understanding the effects of tsDCS and serve as a basis for a more targeted and optimized application of tsDCS.

Hippocampal-targeted Theta-burst Stimulation Enhances Associative Memory Formation.

PubMed

Tambini, Arielle; Nee, Derek Evan; D'Esposito, Mark

2018-06-19

The hippocampus plays a critical role in episodic memory, among other cognitive functions. However, few tools exist to causally manipulate hippocampal function in healthy human participants. Recent work has targeted hippocampal-cortical networks by performing TMS to a region interconnected with the hippocampus, posterior inferior parietal cortex (pIPC). Such hippocampal-targeted TMS enhances associative memory and influences hippocampal functional connectivity. However, it is currently unknown which stages of mnemonic processing (encoding or retrieval) are affected by hippocampal-targeted TMS. Here, we examined whether hippocampal-targeted TMS influences the initial encoding of associations (vs. items) into memory. To selectively influence encoding and not retrieval, we performed continuous theta-burst TMS before participants encoded object-location associations and assessed memory after the direct effect of stimulation dissipated. Relative to control TMS and baseline memory, pIPC TMS enhanced associative memory success and confidence. Item memory was unaffected, demonstrating a selective influence on associative versus item memory. The strength of hippocampal-pIPC functional connectivity predicted TMS-related memory benefits, which was mediated by parahippocampal and retrosplenial cortices. Our findings indicate that hippocampal-targeted TMS can specifically modulate the encoding of new associations into memory without directly influencing retrieval processes and suggest that the ability to influence associative memory may be related to the fidelity of hippocampal TMS targeting. Our results support the notion that pIPC TMS may serve as a potential tool for manipulating hippocampal function in healthy participants. Nonetheless, future work combining hippocampal-targeted continuous theta-burst TMS with neuroimaging is needed to better understand the neural basis of TMS-induced memory changes.

Gene-set analysis based on the pharmacological profiles of drugs to identify repurposing opportunities in schizophrenia.

PubMed

de Jong, Simone; Vidler, Lewis R; Mokrab, Younes; Collier, David A; Breen, Gerome

2016-08-01

Genome-wide association studies (GWAS) have identified thousands of novel genetic associations for complex genetic disorders, leading to the identification of potential pharmacological targets for novel drug development. In schizophrenia, 108 conservatively defined loci that meet genome-wide significance have been identified and hundreds of additional sub-threshold associations harbour information on the genetic aetiology of the disorder. In the present study, we used gene-set analysis based on the known binding targets of chemical compounds to identify the 'drug pathways' most strongly associated with schizophrenia-associated genes, with the aim of identifying potential drug repositioning opportunities and clues for novel treatment paradigms, especially in multi-target drug development. We compiled 9389 gene sets (2496 with unique gene content) and interrogated gene-based p-values from the PGC2-SCZ analysis. Although no single drug exceeded experiment wide significance (corrected p<0.05), highly ranked gene-sets reaching suggestive significance including the dopamine receptor antagonists metoclopramide and trifluoperazine and the tyrosine kinase inhibitor neratinib. This is a proof of principle analysis showing the potential utility of GWAS data of schizophrenia for the direct identification of candidate drugs and molecules that show polypharmacy. © The Author(s) 2016.

Analysis of EEG Related Saccadic Eye Movement

NASA Astrophysics Data System (ADS)

Funase, Arao; Kuno, Yoshiaki; Okuma, Shigeru; Yagi, Tohru

Our final goal is to establish the model for saccadic eye movement that connects the saccade and the electroencephalogram(EEG). As the first step toward this goal, we recorded and analyzed the saccade-related EEG. In the study recorded in this paper, we tried detecting a certain EEG that is peculiar to the eye movement. In these experiments, each subject was instructed to point their eyes toward visual targets (LEDs) or the direction of the sound sources (buzzers). In the control cases, the EEG was recorded in the case of no eye movemens. As results, in the visual experiments, we found that the potential of EEG changed sharply on the occipital lobe just before eye movement. Furthermore, in the case of the auditory experiments, similar results were observed. In the case of the visual experiments and auditory experiments without eye movement, we could not observed the EEG changed sharply. Moreover, when the subject moved his/her eyes toward a right-side target, a change in EEG potential was found on the right occipital lobe. On the contrary, when the subject moved his/her eyes toward a left-side target, a sharp change in EEG potential was found on the left occipital lobe.

Meta-analysis of human gene expression in response to Mycobacterium tuberculosis infection reveals potential therapeutic targets.

PubMed

Wang, Zhang; Arat, Seda; Magid-Slav, Michal; Brown, James R

2018-01-10

With the global emergence of multi-drug resistant strains of Mycobacterium tuberculosis, new strategies to treat tuberculosis are urgently needed such as therapeutics targeting potential human host factors. Here we performed a statistical meta-analysis of human gene expression in response to both latent and active pulmonary tuberculosis infections from nine published datasets. We found 1655 genes that were significantly differentially expressed during active tuberculosis infection. In contrast, no gene was significant for latent tuberculosis. Pathway enrichment analysis identified 90 significant canonical human pathways, including several pathways more commonly related to non-infectious diseases such as the LRRK2 pathway in Parkinson's disease, and PD-1/PD-L1 signaling pathway important for new immuno-oncology therapies. The analysis of human genome-wide association studies datasets revealed tuberculosis-associated genetic variants proximal to several genes in major histocompatibility complex for antigen presentation. We propose several new targets and drug-repurposing opportunities including intravenous immunoglobulin, ion-channel blockers and cancer immuno-therapeutics for development as combination therapeutics with anti-mycobacterial agents. Our meta-analysis provides novel insights into host genes and pathways important for tuberculosis and brings forth potential drug repurposing opportunities for host-directed therapies.

Evaluation and control of miRNA-like off-target repression for RNA interference.

PubMed

Seok, Heeyoung; Lee, Haejeong; Jang, Eun-Sook; Chi, Sung Wook

2018-03-01

RNA interference (RNAi) has been widely adopted to repress specific gene expression and is easily achieved by designing small interfering RNAs (siRNAs) with perfect sequence complementarity to the intended target mRNAs. Although siRNAs direct Argonaute (Ago), a core component of the RNA-induced silencing complex (RISC), to recognize and silence target mRNAs, they also inevitably function as microRNAs (miRNAs) and suppress hundreds of off-targets. Such miRNA-like off-target repression is potentially detrimental, resulting in unwanted toxicity and phenotypes. Despite early recognition of the severity of miRNA-like off-target repression, this effect has often been overlooked because of difficulties in recognizing and avoiding off-targets. However, recent advances in genome-wide methods and knowledge of Ago-miRNA target interactions have set the stage for properly evaluating and controlling miRNA-like off-target repression. Here, we describe the intrinsic problems of miRNA-like off-target effects caused by canonical and noncanonical interactions. We particularly focus on various genome-wide approaches and chemical modifications for the evaluation and prevention of off-target repression to facilitate the use of RNAi with secured specificity.

Rapid screening and identification of chemical hazards in surface and drinking water using high resolution mass spectrometry and a case-control filter.

PubMed

Kaserzon, Sarit L; Heffernan, Amy L; Thompson, Kristie; Mueller, Jochen F; Gomez Ramos, Maria Jose

2017-09-01

Access to clean, safe drinking water poses a serious challenge to regulators, and requires analytical strategies capable of rapid screening and identification of potentially hazardous chemicals, specifically in situations when threats to water quality or security require rapid investigations and potential response. This study describes a fast and efficient chemical hazard screening strategy for characterising trace levels of polar organic contaminants in water matrices, based on liquid chromatography high resolution mass spectrometry with post-acquisition 'case-control' data processing. This method allowed for a rapid response time of less than 24 h for the screening of target, suspect and non-target unknown chemicals via direct injection analysis, and a second, more sensitive analysis option requiring sample pre-concentration. The method was validated by fortifying samples with a range of pesticides, pharmaceuticals and personal care products (n = 46); with >90% of target compounds positively screened in samples at 1 ng mL -1 , and 46% at 0.1 ng mL -1 when analysed via direct injection. To simulate a contamination event samples were fortified with compounds not present in the commercial library (designated 'non-target compounds'; fipronil and fenitrothion), tentatively identified at 0.2 and 1 ng mL -1 , respectively; and a compound not included in any known commercial library or public database (designated 'unknown' compounds; 8Cl - perfluorooctanesulfonic acid), at 0.8 ng mL -1 . The method was applied to two 'real-case' scenarios: (1) the assessment of drinking water safety during a high-profile event in Brisbane, Australia; and (2) to screen treated, re-circulated drinking water and pre-treated (raw) water. The validated workflow was effective for rapid prioritisation and screening of suspect and non-target potential hazards at trace levels, and could be applied to a wide range of matrices and investigations where comparison of organic contaminants between an affected and control site and or timeframe is warranted. Copyright © 2017 Elsevier Ltd. All rights reserved.

Trace detection of explosives using an in-line high-volume sampler, preconcentrator, and Fido explosives detector

NASA Astrophysics Data System (ADS)

Ingram, Russ; Sikes, John

2010-04-01

This paper shall demonstrate the results of a prototype system to detect explosive objects and obscured contaminated targets. By combining a high volume sampling nozzle with an inline 2-stage preconcentrator and a Fido, greater standoff is achieved than with the Fido alone. The direct application of this system is on the Autonomous Mine Detection System (AMDS) but could be deployed on a large variety of robotic platforms. It is being developed under the auspices of the U.S. Army RDECOM CERDEC Night Vision and Electronic Sensors Directorate, Countermine Division. This device is one of several detection tools and technologies to be used on the AMDS. These systems will have multiple, and at times, overlapping objectives. One objective is trace detection on the surface of an unknown potential target. By increasing the standoff capabilities of the detector, the fine manipulation of the robot deploying the detector is less critical. Current detectors used on robotic systems must either be directly in the vapor plume or make direct contact with the target. By increasing the standoff, detection is more easily and quickly achieved. The end result detector must overcome cross-contamination, sample throughput, and environmental issues. The paper will provide preliminary results of the prototype system to include data, and where feasible, video of testing results.

Design and synthesis of a biotinylated chemical probe for detecting the molecular targets of an inhibitor of the production of the Pseudomonas aeruginosa virulence factor pyocyanin.

PubMed

Baker, Ysobel R; Galloway, Warren R J D; Hodgkinson, James T; Spring, David R

2013-09-25

Pseudomonas aeruginosa is a human pathogen associated with a variety of life-threatening nosocomial infections. This organism produces a range of virulence factors which actively cause damage to host tissues. One such virulence factor is pyocyanin, known to play a crucial role in the pathogenesis of P. aeruginosa infections. Previous studies had identified a novel compound capable of strongly inhibiting the production of pyocyanin. It was postulated that this inhibition results from modulation of an intercellular communication system termed quorum sensing, via direct binding of the compound with the LasR protein receptor. This raised the possibility that the compound could be an antagonist of quorum sensing in P. aeruginosa, which could have important implications as this intercellular signaling mechanism is known to regulate many additional facets of P. aeruginosa pathogenicity. However, there was no direct evidence for the binding of the active compound to LasR (or any other targets). Herein we describe the design and synthesis of a biotin-tagged version of the active compound. This could potentially be used as an affinity-based chemical probe to ascertain, in a direct fashion, the active compound's macromolecular biological targets, and thus better delineate the mechanism by which it reduces the level of pyocyanin production.

The Extended-Image Tracking Technique Based on the Maximum Likelihood Estimation

NASA Technical Reports Server (NTRS)

Tsou, Haiping; Yan, Tsun-Yee

2000-01-01

This paper describes an extended-image tracking technique based on the maximum likelihood estimation. The target image is assume to have a known profile covering more than one element of a focal plane detector array. It is assumed that the relative position between the imager and the target is changing with time and the received target image has each of its pixels disturbed by an independent additive white Gaussian noise. When a rotation-invariant movement between imager and target is considered, the maximum likelihood based image tracking technique described in this paper is a closed-loop structure capable of providing iterative update of the movement estimate by calculating the loop feedback signals from a weighted correlation between the currently received target image and the previously estimated reference image in the transform domain. The movement estimate is then used to direct the imager to closely follow the moving target. This image tracking technique has many potential applications, including free-space optical communications and astronomy where accurate and stabilized optical pointing is essential.

Polysaccharide-based micro/nanocarriers for oral colon-targeted drug delivery.

PubMed

Zhang, Lin; Sang, Yuan; Feng, Jing; Li, Zhaoming; Zhao, Aili

2016-08-01

Oral colon-targeted drug delivery has attracted many researchers because of its distinct advantages of increasing the bioavailability of the drug at the target site and reducing the side effects. Polysaccharides that are precisely activated by the physiological environment of the colon hold greater promise for colon targeting. Considerable research efforts have been directed towards developing polysaccharide-based micro/nanocarriers. Types of polysaccharides for colon targeting and in vitro/in vivo assessments of polysaccharide-based carriers for oral colon-targeted drug delivery are summarised. Polysaccharide-based microspheres have gained increased importance not just for the delivery of the drugs for the treatment of local diseases associated with the colon (colon cancer, inflammatory bowel disease (IBD), amoebiasis and irritable bowel syndrome (IBS)), but also for it's potential for the delivery of anti-rheumatoid arthritis and anti-chronic stable angina drugs. Besides, Polysaccharide-based micro/nanocarriers such as microbeads, microcapsules, microparticles, nanoparticles, nanogels and nanospheres are also introduced in this review.

Coincidence studies of diffraction structures in binary encounter electron spectra

DOE Office of Scientific and Technical Information (OSTI.GOV)

Liao, C.; Hagmann, S.; Richard, P.

The authors have measured binary encounter electron (BEe) production in collisions of 0.3 MeV/u Cu{sup q+} (q=4,12) projectiles on H{sub 2} targets from 0 to 70 degrees with respect to the beam direction. Prominent features are the appearance of the BEe peak splitting and a very strong forward peaked angular distribution which are attributed to the diffractive scattering of the quasifree target electrons in the short range potential of the projectile. Using electron-projectile final charge state coincidence techniques, different collision reaction channels can be separated. Measurements of this type are being pursued.

Encoding and Decoding of Multi-Channel ICMS in Macaque Somatosensory Cortex.

PubMed

Dadarlat, Maria C; Sabes, Philip N

2016-01-01

Naturalistic control of brain-machine interfaces will require artificial proprioception, potentially delivered via intracortical microstimulation (ICMS). We have previously shown that multi-channel ICMS can guide a monkey reaching to unseen targets in a planar workspace. Here, we expand on that work, asking how ICMS is decoded into target angle and distance by analyzing the performance of a monkey when ICMS feedback was degraded. From the resulting pattern of errors, we found that the animal's estimate of target direction was consistent with a weighted circular-mean strategy-close to the optimal decoding strategy given the ICMS encoding. These results support our previous finding that animals can learn to use this artificial sensory feedback in an efficient and naturalistic manner.

[Advances in nanoparticle-targeting tumor associated macrophages for cancer imaging and therapy].

PubMed

Fengliang, Guo; Guping, Tang; Qinglian, H U

2017-03-25

Tumor tissues are composed of tumor cells and complicate microenvironment. Tumor associated macrophages (TAMs) as an important component in tumor microenvironment, play fundamental roles in tumor progression, metastasis and microenvironment regulation. Recently, studies have found that nanotechnology, as an emerging platform, provides unique potential for cancer imaging and therapy. With the nanotechnology, TAMs imaging presents direct evidence for cancer development, progression, and the effectiveness of cancer treatments; it also can regulate the immunosuppression of tumor microenvironment and improve therapeutic efficiency through TAMs targeted killing or phenotypic transformation. In this article, we illustrate the function of TAMs and review the latest development in nano-carriers and their applications in tumor associated macrophage targeting cancer imaging and therapy.

Direct-drive inertial confinement fusion: A review

DOE Office of Scientific and Technical Information (OSTI.GOV)

Craxton, R. S.; Anderson, K. S.; Boehly, T. R.

The direct-drive, laser-based approach to inertial confinement fusion (ICF) is reviewed from its inception following the demonstration of the first laser to its implementation on the present generation of high-power lasers. The review focuses on the evolution of scientific understanding gained from target-physics experiments in many areas, identifying problems that were demonstrated and the solutions implemented. The review starts with the basic understanding of laser–plasma interactions that was obtained before the declassification of laser-induced compression in the early 1970s and continues with the compression experiments using infrared lasers in the late 1970s that produced thermonuclear neutrons. The problem of suprathermalmore » electrons and the target preheat that they caused, associated with the infrared laser wavelength, led to lasers being built after 1980 to operate at shorter wavelengths, especially 0.35 μm—the third harmonic of the Nd:glass laser—and 0.248 μm (the KrF gas laser). The main physics areas relevant to direct drive are reviewed. The primary absorption mechanism at short wavelengths is classical inverse bremsstrahlung. Nonuniformities imprinted on the target by laser irradiation have been addressed by the development of a number of beam-smoothing techniques and imprint-mitigation strategies. The effects of hydrodynamic instabilities are mitigated by a combination of imprint reduction and target designs that minimize the instability growth rates. Several coronal plasma physics processes are reviewed. The two-plasmon–decay instability, stimulated Brillouin scattering (together with cross-beam energy transfer), and (possibly) stimulated Raman scattering are identified as potential concerns, placing constraints on the laser intensities used in target designs, while other processes (self-focusing and filamentation, the parametric decay instability, and magnetic fields), once considered important, are now of lesser concern for mainline direct-drive target concepts. Filamentation is largely suppressed by beam smoothing. Thermal transport modeling, important to the interpretation of experiments and to target design, has been found to be nonlocal in nature. Advances in shock timing and equation-of-state measurements relevant to direct-drive ICF are reported. Room-temperature implosions have provided an increased understanding of the importance of stability and uniformity. The evolution of cryogenic implosion capabilities, leading to an extensive series carried out on the 60-beam OMEGA laser [Boehly et al., Opt. Commun. 133, 495 (1997)], is reviewed together with major advances in cryogenic target formation. A polar-drive concept has been developed that will enable direct-drive–ignition experiments to be performed on the National Ignition Facility [Haynam et al., Appl. Opt. 46(16), 3276 (2007)]. The advantages offered by the alternative approaches of fast ignition and shock ignition and the issues associated with these concepts are described. The lessons learned from target-physics and implosion experiments are taken into account in ignition and high-gain target designs for laser wavelengths of 1/3 μm and 1/4 μm. Substantial advances in direct-drive inertial fusion reactor concepts are reviewed. Overall, the progress in scientific understanding over the past five decades has been enormous, to the point that inertial fusion energy using direct drive shows significant promise as a future environmentally attractive energy source.« less

Direct-drive inertial confinement fusion: A review

DOE PAGES

Craxton, R. S.; Anderson, K. S.; Boehly, T. R.; ...

2015-11-25

In this study, the direct-drive, laser-based approach to inertial confinement fusion (ICF) is reviewed from its inception following the demonstration of the first laser to its implementation on the present generation of high-power lasers. The review focuses on the evolution of scientific understanding gained from target-physics experiments in many areas, identifying problems that were demonstrated and the solutions implemented. The review starts with the basic understanding of laser–plasma interactions that was obtained before the declassification of laser-induced compression in the early 1970s and continues with the compression experiments using infrared lasers in the late 1970s that produced thermonuclear neutrons. Themore » problem of suprathermal electrons and the target preheat that they caused, associated with the infrared laser wavelength, led to lasers being built after 1980 to operate at shorter wavelengths, especially 0.35 um—the third harmonic of the Nd:glass laser—and 0.248 um (the KrF gas laser). The main physics areas relevant to direct drive are reviewed. The primary absorption mechanism at short wavelengths is classical inverse bremsstrahlung. Nonuniformities imprinted on the target by laser irradiation have been addressed by the development of a number of beam-smoothing techniques and imprint-mitigation strategies. The effects of hydrodynamic instabilities are mitigated by a combination of imprint reduction and target designs that minimize the instability growth rates. Several coronal plasma physics processes are reviewed. The two-plasmon–decay instability, stimulated Brillouin scattering (together with cross-beam energy transfer), and (possibly) stimulated Raman scattering are identified as potential concerns, placing constraints on the laser intensities used in target designs, while other processes (self-focusing and filamentation, the parametric decay instability, and magnetic fields), once considered important, are now of lesser concern for mainline direct-drive target concepts. Filamentation is largely suppressed by beam smoothing. Thermal transport modeling, important to the interpretation of experiments and to target design, has been found to be non-local in nature. Advances in shock timing and equation-of-state measurements relevant to direct-drive ICF are reported. Room-temperature implosions have provided an increased understanding of the importance of stability and uniformity. The evolution of cryogenic implosion capabilities, leading to an extensive series carried out on the 60-beam OMEGA laser [T. R. Boehly et al., Opt. Commun. 133, 495 (1997)], is reviewed together with major advances in cryogenic target formation. A polar-drive concept has been developed that will enable direct-drive–ignition experiments to be performed on the National Ignition Facility [C. A. Haynam et al., Appl. Opt. 46 (16), 3276 (2007)]. The advantages offered by the alternative approaches of fast ignition and shock ignition and the issues associated with these concepts are described. The lessons learned from target-physics and implosion experiments are taken into account in ignition and high-gain target designs for laser wavelengths of 1/3 μm and 1/4 μm. Substantial advances in direct-drive inertial fusion reactor concepts are reviewed. Overall, the progress in scientific understanding over the past five decades has been enormous, to the point that inertial fusion energy using direct drive shows significant promise as a future environmentally attractive energy source.« less

Direct-drive inertial confinement fusion: A review

DOE Office of Scientific and Technical Information (OSTI.GOV)

Craxton, R. S.; Anderson, K. S.; Boehly, T. R.

In this study, the direct-drive, laser-based approach to inertial confinement fusion (ICF) is reviewed from its inception following the demonstration of the first laser to its implementation on the present generation of high-power lasers. The review focuses on the evolution of scientific understanding gained from target-physics experiments in many areas, identifying problems that were demonstrated and the solutions implemented. The review starts with the basic understanding of laser–plasma interactions that was obtained before the declassification of laser-induced compression in the early 1970s and continues with the compression experiments using infrared lasers in the late 1970s that produced thermonuclear neutrons. Themore » problem of suprathermal electrons and the target preheat that they caused, associated with the infrared laser wavelength, led to lasers being built after 1980 to operate at shorter wavelengths, especially 0.35 um—the third harmonic of the Nd:glass laser—and 0.248 um (the KrF gas laser). The main physics areas relevant to direct drive are reviewed. The primary absorption mechanism at short wavelengths is classical inverse bremsstrahlung. Nonuniformities imprinted on the target by laser irradiation have been addressed by the development of a number of beam-smoothing techniques and imprint-mitigation strategies. The effects of hydrodynamic instabilities are mitigated by a combination of imprint reduction and target designs that minimize the instability growth rates. Several coronal plasma physics processes are reviewed. The two-plasmon–decay instability, stimulated Brillouin scattering (together with cross-beam energy transfer), and (possibly) stimulated Raman scattering are identified as potential concerns, placing constraints on the laser intensities used in target designs, while other processes (self-focusing and filamentation, the parametric decay instability, and magnetic fields), once considered important, are now of lesser concern for mainline direct-drive target concepts. Filamentation is largely suppressed by beam smoothing. Thermal transport modeling, important to the interpretation of experiments and to target design, has been found to be non-local in nature. Advances in shock timing and equation-of-state measurements relevant to direct-drive ICF are reported. Room-temperature implosions have provided an increased understanding of the importance of stability and uniformity. The evolution of cryogenic implosion capabilities, leading to an extensive series carried out on the 60-beam OMEGA laser [T. R. Boehly et al., Opt. Commun. 133, 495 (1997)], is reviewed together with major advances in cryogenic target formation. A polar-drive concept has been developed that will enable direct-drive–ignition experiments to be performed on the National Ignition Facility [C. A. Haynam et al., Appl. Opt. 46 (16), 3276 (2007)]. The advantages offered by the alternative approaches of fast ignition and shock ignition and the issues associated with these concepts are described. The lessons learned from target-physics and implosion experiments are taken into account in ignition and high-gain target designs for laser wavelengths of 1/3 μm and 1/4 μm. Substantial advances in direct-drive inertial fusion reactor concepts are reviewed. Overall, the progress in scientific understanding over the past five decades has been enormous, to the point that inertial fusion energy using direct drive shows significant promise as a future environmentally attractive energy source.« less

Targeting the RAS oncogene

PubMed Central

Takashima, Asami

2013-01-01

Introduction The Ras proteins (K-Ras, N-Ras, H-Ras) are GTPases that function as molecular switches for a variety of critical cellular activities and their function is tightly and temporally regulated in normal cells. Oncogenic mutations in the RAS genes, which create constitutively-active Ras proteins, can result in uncontrolled proliferation or survival in tumor cells. Areas covered The paper discusses three therapeutic approaches targeting the Ras pathway in cancer: 1) Ras itself, 2) Ras downstream pathways, and 3) synthetic lethality. The most adopted approach is targeting Ras downstream signaling, and specifically the PI3K-AKT-mTOR and Raf-MEK pathways, as they are frequently major oncogenic drivers in cancers with high Ras signaling. Although direct targeting of Ras has not been successful clinically, newer approaches being investigated in preclinical studies, such as RNA interference-based and synthetic lethal approaches, promise great potential for clinical application. Expert opinion The challenges of current and emerging therapeutics include the lack of “tumor specificity” and their limitation to those cancers which are “dependent” upon aberrant Ras signaling for survival. While the newer approaches have the potential to overcome these limitations, they also highlight the importance of robust preclinical studies and bidirectional translational research for successful clinical development of Ras-related targeted therapies. PMID:23360111

Targeted Delivery of Toxoplasma gondii Antigens to Dendritic Cells Promote Immunogenicity and Protective Efficiency against Toxoplasmosis

PubMed Central

Lakhrif, Zineb; Moreau, Alexis; Hérault, Bruno; Di-Tommaso, Anne; Juste, Matthieu; Moiré, Nathalie; Dimier-Poisson, Isabelle; Mévélec, Marie-Noëlle; Aubrey, Nicolas

2018-01-01

Toxoplasmosis is a major public health problem and the development of a human vaccine is of high priority. Efficient vaccination against Toxoplasma gondii requires both a mucosal and systemic Th1 immune response. Moreover, dendritic cells play a critical role in orchestrating the innate immune functions and driving specific adaptive immunity to T. gondii. In this study, we explore an original vaccination strategy that combines administration via mucosal and systemic routes of fusion proteins able to target the major T. gondii surface antigen SAG1 to DCs using an antibody fragment single-chain fragment variable (scFv) directed against DEC205 endocytic receptor. Our results show that SAG1 targeting to DCs by scFv via intranasal and subcutaneous administration improved protection against chronic T. gondii infection. A marked reduction in brain parasite burden is observed when compared with the intranasal or the subcutaneous route alone. DC targeting improved both local and systemic humoral and cellular immune responses and potentiated more specifically the Th1 response profile by more efficient production of IFN-γ, interleukin-2, IgG2a, and nasal IgA. This study provides evidence of the potential of DC targeting for the development of new vaccines against a range of Apicomplexa parasites. PMID:29515595

Transgenic Clustered Regularly Interspaced Short Palindromic Repeat/Cas9-Mediated Viral Gene Targeting for Antiviral Therapy of Bombyx mori Nucleopolyhedrovirus.

PubMed

Chen, Shuqing; Hou, Chengxiang; Bi, Honglun; Wang, Yueqiang; Xu, Jun; Li, Muwang; James, Anthony A; Huang, Yongping; Tan, Anjiang

2017-04-15

We developed a novel antiviral strategy by combining transposon-based transgenesis and the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated 9 (Cas9) system for the direct cleavage of Bombyx mori nucleopolyhedrovirus (BmNPV) genome DNA to promote virus clearance in silkworms. We demonstrate that transgenic silkworms constitutively expressing Cas9 and guide RNAs targeting the BmNPV immediate early-1 ( ie-1 ) and me53 genes effectively induce target-specific cleavage and subsequent mutagenesis, especially large (∼7-kbp) segment deletions in BmNPV genomes, and thus exhibit robust suppression of BmNPV proliferation. Transgenic animals exhibited higher and inheritable resistance to BmNPV infection than wild-type animals. Our approach will not only contribute to modern sericulture but also shed light on future antiviral therapy. IMPORTANCE Pathogen genome targeting has shown its potential in antiviral research. However, transgenic CRISPR/Cas9 system-mediated viral genome targeting has not been reported as an antiviral strategy in a natural animal host of a virus. Our data provide an effective approach against BmNPV infection in a real-world biological system and demonstrate the potential of transgenic CRISPR/Cas9 systems in antiviral research in other species. Copyright © 2017 Chen et al.

Transgenic Clustered Regularly Interspaced Short Palindromic Repeat/Cas9-Mediated Viral Gene Targeting for Antiviral Therapy of Bombyx mori Nucleopolyhedrovirus

PubMed Central

Chen, Shuqing; Hou, Chengxiang; Bi, Honglun; Wang, Yueqiang; Xu, Jun; Li, Muwang; James, Anthony A.

2017-01-01

ABSTRACT We developed a novel antiviral strategy by combining transposon-based transgenesis and the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated 9 (Cas9) system for the direct cleavage of Bombyx mori nucleopolyhedrovirus (BmNPV) genome DNA to promote virus clearance in silkworms. We demonstrate that transgenic silkworms constitutively expressing Cas9 and guide RNAs targeting the BmNPV immediate early-1 (ie-1) and me53 genes effectively induce target-specific cleavage and subsequent mutagenesis, especially large (∼7-kbp) segment deletions in BmNPV genomes, and thus exhibit robust suppression of BmNPV proliferation. Transgenic animals exhibited higher and inheritable resistance to BmNPV infection than wild-type animals. Our approach will not only contribute to modern sericulture but also shed light on future antiviral therapy. IMPORTANCE Pathogen genome targeting has shown its potential in antiviral research. However, transgenic CRISPR/Cas9 system-mediated viral genome targeting has not been reported as an antiviral strategy in a natural animal host of a virus. Our data provide an effective approach against BmNPV infection in a real-world biological system and demonstrate the potential of transgenic CRISPR/Cas9 systems in antiviral research in other species. PMID:28122981

High-throughput chinmedomics-based prediction of effective components and targets from herbal medicine AS1350

PubMed Central

Liu, Qi; Zhang, Aihua; Wang, Liang; Yan, Guangli; Zhao, Hongwei; Sun, Hui; Zou, Shiyu; Han, Jinwei; Ma, Chung Wah; Kong, Ling; Zhou, Xiaohang; Nan, Yang; Wang, Xijun

2016-01-01

This work was designed to explore the effective components and targets of herbal medicine AS1350 and its effect on “Kidney-Yang Deficiency Syndrome” (KYDS) based on a chinmedomics strategy which is capable of directly discovering and predicting the effective components, and potential targets, of herbal medicine. Serum samples were analysed by UPLC-MS combined with pattern recognition analysis to identify the biomarkers related to the therapeutic effects. Interestingly, the effectiveness of AS1350 against KYDS was proved by the chinmedomics method and regulated the biomarkers and targeting of metabolic disorders. Some 48 marker metabolites associated with alpha-linolenic acid metabolism, fatty acid metabolism, sphingolipids metabolism, phospholipid metabolism, steroid hormone biosynthesis, and amino acid metabolism were identified. The correlation coefficient between the constituents in vivo and the changes of marker metabolites were calculated by PCMS software and the potential effective constituents of AS1350 were also confirmed. By using chinmedomics technology, the components in AS1350 protecting against KYDS by re-balancing metabolic disorders of fatty acid metabolism, lipid metabolism, steroid hormone biosynthesis, etc. were deduced. These data indicated that the phenotypic characterisations of AS1350 altering the metabolic signatures of KYDS were multi-component, multi-pathway, multi-target, and overall regulation in nature. PMID:27910928

Dual targeting of therapeutics to endothelial cells: collaborative enhancement of delivery and effect.

PubMed

Greineder, Colin F; Brenza, Jacob B; Carnemolla, Ronald; Zaitsev, Sergei; Hood, Elizabeth D; Pan, Daniel C; Ding, Bi-Sen; Esmon, Charles T; Chacko, Ann Marie; Muzykantov, Vladimir R

2015-08-01

Anchoring pharmacologic agents to the vascular lumen has the potential to modulate critical processes at the blood-tissue interface, avoiding many of the off-target effects of systemically circulating agents. We report a novel strategy for endothelial dual targeting of therapeutics, which both enhances drug delivery and enables targeted agents to partner enzymatically to generate enhanced biologic effect. Based on the recent discovery that paired antibodies directed to adjacent epitopes of platelet endothelial cell adhesion molecule (PECAM)-1 stimulate each other's binding, we fused single-chain fragments (scFv) of paired anti-mouse PECAM-1 antibodies to recombinant murine thrombomodulin (TM) and endothelial protein C receptor (EPCR), endothelial membrane proteins that partner in activation of protein C (PC). scFv/TM and scFv/EPCR bound to mouse endothelial PECAM-1 with high affinity (EC50 1.5 and 3.8 nM, respectively), and codelivery induced a 5-fold increase in PC activation not seen when TM and EPCR are anchored to distinct cell adhesion molecules. In a mouse model of acute lung injury, dual targeting reduces both the expression of lung inflammatory markers and trans-endothelial protein leak by as much as 40%, as compared to either agent alone. These findings provide proof of principle for endothelial dual targeting, an approach with numerous potential biomedical applications. © FASEB.

Prostate Bed Motion During Intensity-Modulated Radiotherapy Treatment

DOE Office of Scientific and Technical Information (OSTI.GOV)

Klayton, Tracy; Price, Robert; Buyyounouski, Mark K.

Purpose: Conformal radiation therapy in the postprostatectomy setting requires accurate setup and localization of the prostatic fossa. In this series, we report prostate bed localization and motion characteristics, using data collected from implanted radiofrequency transponders. Methods and Materials: The Calypso four-dimensional localization system uses three implanted radiofrequency transponders for daily target localization and real-time tracking throughout a course of radiation therapy. We reviewed the localization and tracking reports for 20 patients who received ultrasonography-guided placement of Calypso transponders within the prostate bed prior to a course of intensity-modulated radiation therapy at Fox Chase Cancer Center. Results: At localization, prostate bedmore » displacement relative to bony anatomy exceeded 5 mm in 9% of fractions in the anterior-posterior (A-P) direction and 21% of fractions in the superior-inferior (S-I) direction. The three-dimensional vector length from skin marks to Calypso alignment exceeded 1 cm in 24% of all 652 fractions with available setup data. During treatment, the target exceeded the 5-mm tracking limit for at least 30 sec in 11% of all fractions, generally in the A-P or S-I direction. In the A-P direction, target motion was twice as likely to move posteriorly, toward the rectum, than anteriorly. Fifteen percent of all treatments were interrupted for repositioning, and 70% of patients were repositioned at least once during their treatment course. Conclusion: Set-up errors and motion of the prostatic fossa during radiotherapy are nontrivial, leading to potential undertreatment of target and excess normal tissue toxicity if not taken into account during treatment planning. Localization and real-time tracking of the prostate bed via implanted Calypso transponders can be used to improve the accuracy of plan delivery.« less

Resveratrol Directly Targets COX-2 to Inhibit Carcinogenesis

PubMed Central

Zykova, Tatyana A.; Zhu, Feng; Zhai, Xiuhong; Ma, Wei-ya; Ermakova, Svetlana P.; Lee, Ki Won; Bode, Ann M.; Dong, Zigang

2008-01-01

Targeted molecular cancer therapies can potentially deliver treatment directly to a specific protein or gene to optimize efficacy and reduce adverse side effects often associated with traditional chemotherapy. Key oncoprotein and oncogene targets are rapidly being identified based on their expression, pathogenesis and clinical outcome. One such protein target is cyclooxygenase-2 (COX-2), which is highly expressed in various cancers. Research findings suggest that resveratrol (3,5,4'-trihydroxy-trans-stilbene) demonstrates non-selective COX-2 inhibition. We report herein that resveratrol (RSVL) directly binds with COX-2 and this binding is absolutely required for RSVL's inhibition of the ability of human colon adenocarcinoma HT-29 cells to form colonies in soft agar. Binding of COX-2 with RSVL was compared with two RSVL analogues, 3,3’,4’,5’5’-pentahydroxy-trans-stilbene (RSVL-2) or 3,4’,5-trimethoxy-trans-stilbene (RSVL-3). The results indicated that COX-2 binds with RSVL-2 more strongly than with RSVL, but does not bind with RSVL-3. RSVL or RSVL-2, but not RSVL-3, inhibited COX-2-mediated PGE2 production in vitro and ex vivo. HT-29 human colon adenocarcinoma cells express high levels of COX-2 and either RSVL or RSVL-2, but not RSVL-3, suppressed anchorage independent growth of these cells in soft agar. RSVL or RSVL-2 (not RSVL-3) suppressed growth of COX-2+/+ cells by 60 or 80%, respectively. Notably, cells deficient in COX-2 were unresponsive to RSVL or RSVL-2. These data suggest that the anticancer effects of RSVL or RSLV-2 might be mediated directly through COX-2. PMID:18381589

miR-221 and miR-222 expression affects the proliferation potential of human prostate carcinoma cell lines by targeting p27Kip1.

PubMed

Galardi, Silvia; Mercatelli, Neri; Giorda, Ezio; Massalini, Simone; Frajese, Giovanni Vanni; Ciafrè, Silvia Anna; Farace, Maria Giulia

2007-08-10

MicroRNAs are short regulatory RNAs that negatively modulate protein expression at a post-transcriptional level and are deeply involved in the pathogenesis of several types of cancers. Here we show that miR-221 and miR-222, encoded in tandem on chromosome X, are overexpressed in the PC3 cellular model of aggressive prostate carcinoma, as compared with LNCaP and 22Rv1 cell line models of slowly growing carcinomas. In all cell lines tested, we show an inverse relationship between the expression of miR-221 and miR-222 and the cell cycle inhibitor p27(Kip1). We recognize two target sites for the microRNAs in the 3' untranslated region of p27 mRNA, and we show that miR-221/222 ectopic overexpression directly results in p27 down-regulation in LNCaP cells. In those cells, we demonstrate that the ectopic overexpression of miR-221/222 strongly affects their growth potential by inducing a G(1) to S shift in the cell cycle and is sufficient to induce a powerful enhancement of their colony-forming potential in soft agar. Consistently, miR-221 and miR-222 knock-down through antisense LNA oligonucleotides increases p27(Kip1) in PC3 cells and strongly reduces their clonogenicity in vitro. Our results suggest that miR-221/222 can be regarded as a new family of oncogenes, directly targeting the tumor suppressor p27(Kip1), and that their overexpression might be one of the factors contributing to the oncogenesis and progression of prostate carcinoma through p27(Kip1) down-regulation.

New drostanolone metabolites in human urine by liquid chromatography time-of-flight tandem mass spectrometry and their application for doping control.

PubMed

Liu, Yang; Lu, Jianghai; Yang, Sheng; Zhang, Qingying; Xu, Youxuan

2016-04-01

Drostanolone is one of the most frequently detected anabolic androgenic steroids in doping control analysis. Here, we studied drostanolone urinary metabolic profiles using liquid chromatography quadruple time of flight mass spectrometry (LC-QTOF-MS) in full scan and targeted MS/MS modes with accurate mass measurement. The drug was administered to one healthy male volunteer and liquid-liquid extraction along with direct-injection were used to analyze urine samples. Chromatographic peaks for potential metabolites were identified with the theoretical [M-H](-) as a target ion in a full scan experiment and actual deprotonated ions were analyzed in targeted MS/MS mode. Eleven metabolites including five new sulfates, five glucuronide conjugates, and one free metabolite were confirmed for drostanolone. Due to the absence of useful fragment ions to illustrate the steroid ring structure of drostanolone phase II metabolites, gas chromatography mass spectrometry (GC-MS) was used to obtain structural details of the trimethylsilylated phase I metabolite released after enzymatic hydrolysis and a potential structure was proposed using a combined MS approach. Metabolite detection times were recorded and S4 (2α-methyl-5α-androstan-17-one-6β-ol-3α-sulfate) and G1 (2α-methyl-5α-androstan-17-one-3α-glucuronide) were thought to be new potential biomarkers for drostanolone misuse which can be detected up to 24days by liquid-liquid extraction and 7days by direct-injection analysis after intramuscular injection. S4 and G1 were also detected in two drostanolone-positive routine urine samples. Copyright © 2016 Elsevier Inc. All rights reserved.

Safety studies with the oral rabies virus vaccine strain SPBN GASGAS in the small Indian mongoose (Herpestes auropunctatus).

PubMed

Ortmann, Steffen; Vos, Ad; Kretzschmar, Antje; Walther, Nomusa; Kaiser, Christiane; Freuling, Conrad; Lojkic, Ivana; Müller, Thomas

2018-03-13

Oral vaccination of the small Indian mongoose against rabies has been suggested as a potential tool to eliminate mongoose-mediated rabies on several Caribbean islands. A recently developed oral rabies virus vaccine strain, SPBN GASGAS, has already been shown to be efficacious in this reservoir species. Since, all available oral rabies vaccines are based on replication-competent viruses and vaccine baits are distributed unsupervised in the environment, enhanced safety standards for such vaccine types are required. The results of safety studies, including overdose, repeated doses, dissemination and different routes of administration, in the target species are presented. It was shown that the construct was apathogenic, irrespective of dose and route of administration. Even when it was inoculated directly in the brain, it did not induce rabies infection. Furthermore, the vaccine strain did not spread within the target species after direct oral instillation beyond the site of entry. The vaccine strain SPBN GASGAS meets the safety requirements for live rabies virus vaccines in this target species, the small Indian mongoose.

Refining the treatment of advanced nonsmall cell lung cancer

PubMed Central

Ogita, Shin; Wozniak, Antoinette J

2010-01-01

Metastatic nonsmall cell lung cancer (NSCLC) is a debilitating and deadly disease with virtually no chance for long-term survival. Chemotherapy has improved both survival and quality of life for patients with advanced disease. Overall survival of patients with metastatic NSCLC has gradually increased from 8 to 12 months over the past three decades with the introduction of new chemotherapeutic drugs and agents directed at novel targets in the cancer cell. Epidermal growth factor receptor and vascular endothelial growth factor are two such targets. Recent developments also include treatment based on histology and the use of maintenance therapy. It has been recognized that lung cancer is a very complex disease. It is common practice to include a number of scientific correlative studies in the design of clinical trials in order to determine predictive markers of benefit from treatment. This article will review the current approach to the treatment of advanced NSCLC including the use of chemotherapy and molecularly targeted agents. Future directions including the use of potentially predictive biomarkers and innovative clinical trials aimed at a more individualized approach to treatment will also be discussed. PMID:28210103

miR-133 inhibits pituitary tumor cell migration and invasion via down-regulating FOXC1 expression.

PubMed

Wang, D S; Zhang, H Q; Zhang, B; Yuan, Z B; Yu, Z K; Yang, T; Zhang, S Q; Liu, Y; Jia, X X

2016-03-24

Many studies have shown that microRNA (miR)-133 functions as a tumor suppressor in a variety of metastatic cancers, including breast cancer, gastric cancer, and liver fibrosis. However, the influence of miR-133 on pituitary tumor malignancy has not yet been reported. The purpose of this study was to explore the role of miR-133 in pituitary tumor cell migration and invasive ability and the molecular mechanisms involved. Our findings suggest that in pituitary adenoma cell lines, through direct targeting and negative control of forkhead box C1 (FOXC1), miR-133 can inhibit pituitary adenoma cell migration and invasion. In addition, epithelial-to-mesenchymal transition can be induced by miR-133. Additionally, a negative correlation was found between FOXC1 and miR-133 expression when comparing their expression levels between cancerous tissue and adjacent normal tissue. This suggests that miR-133 can inhibit cell migration and invasion by directly targeting FOXC1, implying that miR-133 could be a potential therapeutic target for treatment of invasive pituitary adenoma.

Building Parental Capacity to Improve Child Development: Impact Evaluation of an Early Childhood Stimulation Program in Bangladesh

ERIC Educational Resources Information Center

Chinen, Marjorie; Bos, Hans; Murray, Matthew; Hamadani, Jena; Hossain, Najmul; Mahmud, Minhaj

2015-01-01

Globally, at least 200 million children younger than five years old are falling short of their potential for development and growth. There is some evidence that improvements to children's health, nutrition, and development outcomes can be made through programs that provide direct learning experiences to children and families; are targeted toward…

A Novel Differentiation Therapy Approach to Reduce the Metastatic Potential of Basal, Highly Metastatic, Triple-Negative Breast Cancers

DTIC Science & Technology

2011-05-01

task 1 b) GATA3 was shown to directly modulate expression of genes regulating the cell cycle (Pei et al., 2009; Molenaar et al., 2010) and GATA3...downstream target of GATA3 and restrains mammary luminal progenitor cell proliferation and tumorigenesis. Cancer Ce/l15:389-401. Molenaar JJ, Ebus

Developmental Phenotypes and Causal Pathways in Attention Deficit/Hyperactivity Disorder: Potential Targets for Early Intervention?

ERIC Educational Resources Information Center

Sonuga-Barke, Edmund J. S.; Halperin, Jeffrey M.

2010-01-01

Early intervention approaches have rarely been implemented for the prevention of attention deficit/hyperactivity disorder (ADHD). In this paper we explore whether such an approach may represent an important new direction for therapeutic innovation. We propose that such an approach is most likely to be of value when grounded in and informed by…

Antibody-directed targeting of lysostaphin adsorbed onto polylactide nanoparticles increases its antimicrobial activity against S. aureus in vitro

NASA Astrophysics Data System (ADS)

Satishkumar, R.; Vertegel, A. A.

2011-12-01

The objective of this paper was to study the effect of antibody-directed targeting of S. aureus by comparing the activities of lysostaphin conjugated to biodegradable polylactide nanoparticles (NPs) in the presence and in the absence of co-immobilized anti-S. aureus antibody. Lysostaphin-antibody-NP conjugates were synthesized through physical adsorption at different enzyme:antibody:NP ratios. The synthesized enzyme-NP conjugates were characterized by means of dynamic light scattering and zeta potential analysis, and the total protein binding yield on the NPs was characterized using Alexa Fluor 350 and 594 dyes for the S. aureus antibody and lysostaphin respectively. We observed enhanced antimicrobial activity for both enzyme-coated and enzyme-antibody-coated NPs for lysostaphin coatings corresponding to ~ 40% of the initial monolayer and higher compared to the free enzyme case (p < 0.05). At the highest antibody coating concentration, bacterial lysis rates for antibody-coated samples were significantly higher than for lysostaphin-coated samples lacking the antibody (p < 0.05). Such enzyme-NP conjugates thus have the potential for becoming novel therapeutic agents for treating antibiotic-resistant S. aureus infections.

A Novel Atypical PKC-Iota Inhibitor, Echinochrome A, Enhances Cardiomyocyte Differentiation from Mouse Embryonic Stem Cells.

PubMed

Kim, Hyoung Kyu; Cho, Sung Woo; Heo, Hye Jin; Jeong, Seung Hun; Kim, Min; Ko, Kyung Soo; Rhee, Byoung Doo; Mishchenko, Natalia P; Vasileva, Elena A; Fedoreyev, Sergey A; Stonik, Valentin A; Han, Jin

2018-06-02

Echinochrome A (EchA) is a marine bioproduct extracted from sea urchins having antioxidant, antimicrobial, anti-inflammatory, and chelating effects, and is the active component of the clinical drug histochrome. We investigated the potential use of Ech A for inducing cardiomyocyte differentiation from mouse embryonic stem cells (mESCs). We also assessed the effects of Ech A on mitochondrial mass, inner membrane potential (Δψm), reactive oxygen species generation, and levels of Ca 2+ . To identify the direct target of Ech A, we performed in vitro kinase activity and surface plasmon resonance binding assays. Ech A dose-dependently enhanced cardiomyocyte differentiation with higher beating rates. Ech A (50 μM) increased the mitochondrial mass and membrane potential but did not alter the mitochondrial superoxide and Ca 2+ levels. The in vitro kinase activity of the atypical protein kinase C-iota (PKCι) was significantly decreased by 50 μM of Ech A with an IC 50 for PKCι activity of 107 μM. Computational protein-ligand docking simulation results suggested the direct binding of Ech A to PKCι, and surface plasmon resonance confirmed the direct binding with a low K D of 6.3 nM. Therefore, Ech A is a potential drug for enhancing cardiomyocyte differentiation from mESCs through direct binding to PKCι and inhibition of its activity.

microRNA-497 overexpression decreases proliferation, migration and invasion of human retinoblastoma cells via targeting vascular endothelial growth factor A

PubMed Central

Li, Jianjun; Zhang, Yinghui; Wang, Xiuchao; Zhao, Ruibo

2017-01-01

The expression level and roles of microRNA-497 (miR-497) have been frequently reported in previous studies on cancer. However, its expression, function and associated molecular mechanisms in retinoblastoma remain unknown. In the present study, miR-497 expression levels in human retinoblastoma tissues, normal retinal tissues and retinoblastoma cell lines were determined using reverse transcription-quantitative polymerase chain reaction. In addition, a Cell Counting Kit-8 assay, cell migration assay, cell invasion assay, western blot analysis and Dual-Luciferase reporter assay were used to explore the expression, functions and molecular mechanisms of miR-497 in human retinoblastoma. It was demonstrated that miR-497 was significantly downregulated in retinoblastoma tissues and cell lines compared with normal retinal tissues. Ectopic expression of miR-497 decreased the proliferation, migration and invasion of retinoblastoma cells. Furthermore, VEGFA was verified as a potential direct target of miR-497 in vitro. Taken together, the results indicate that miR-497 functions as a tumor suppressor in the carcinogenesis and progression of retinoblastoma via targeting VEGFA. miR-497 should be investigated as a potential therapeutic target for the treatment of retinoblastoma. PMID:28588740

Stress-induced molecules MICA as potential target for radioimmunotherapy of cancer

NASA Astrophysics Data System (ADS)

Abakushina, E. V.; Anokhin, Yu N.; Abakushin, D. N.; Kaprin, A. D.

2017-01-01

Improving the treatment of cancer, increasing their effectiveness and safety is the main objective in the medicine. Molecular nuclear medicine plays an important role in the therapy of cancer. Radioimmunotherapy (RIT) involves the use of antibodies conjugated with therapeutic radionuclides. More often for RIT use the radiolabeled monoclonal antibodies against tumor-associated antigens. Encouraging results have been achieved with this technology in the management of hematologic malignancies. On the contrary, solid tumors have been less responsive. Despite these encouraging results, new potential target for radioimmunodetection and RIT should be found. It was found to increase the level of tumor-associated molecules MICA in the serum of cancer patients. Use of anti-MICA monoclonal antibodies capable a specifically attach to cancer cell via NKG2D ligands and destroy it, is a very promising direction, both therapeutic and diagnostic standpoint.

Experimental validation of predicted cancer genes using FRET

NASA Astrophysics Data System (ADS)

Guala, Dimitri; Bernhem, Kristoffer; Ait Blal, Hammou; Jans, Daniel; Lundberg, Emma; Brismar, Hjalmar; Sonnhammer, Erik L. L.

2018-07-01

Huge amounts of data are generated in genome wide experiments, designed to investigate diseases with complex genetic causes. Follow up of all potential leads produced by such experiments is currently cost prohibitive and time consuming. Gene prioritization tools alleviate these constraints by directing further experimental efforts towards the most promising candidate targets. Recently a gene prioritization tool called MaxLink was shown to outperform other widely used state-of-the-art prioritization tools in a large scale in silico benchmark. An experimental validation of predictions made by MaxLink has however been lacking. In this study we used Fluorescence Resonance Energy Transfer, an established experimental technique for detection of protein-protein interactions, to validate potential cancer genes predicted by MaxLink. Our results provide confidence in the use of MaxLink for selection of new targets in the battle with polygenic diseases.

Microscopic modeling of direct pre-equilibrium emission from neutron induced reactions on even and odd actinides

NASA Astrophysics Data System (ADS)

Dupuis, M.; Hilaire, S.; Péru, S.; Bauge, E.; Kerveno, M.; Dessagne, P.; Henning, G.

2017-09-01

Direct inelastic scattering to discrete excitations and pre-equilibrium emission are described within a microscopic model. Nuclear structure information are obtained in the (Quasi) Random Phase Approximation ((Q)RPA) framework implemented with the Gogny force. The relevant optical and transition potentials are build considering the JLM folding model. Various successful applications are shown for (n,n), (n,n'), (n,xn) and (n,xnγ) reactions for spherical and axially deformed even-even or odd targets. The rearrangement corrections to transition potentials and the contribution of unnatural parity excitations to pre-equilibrium emission are discussed. Our model predictions for (n,n'γ) reactions, for intra- and inter-band transitions in 238U, and for the 239Pu(n,2n) cross section are analyzed.

Targeted Metabolomics Approach To Detect the Misuse of Steroidal Aromatase Inhibitors in Equine Sports by Biomarker Profiling.

PubMed

Chan, George Ho Man; Ho, Emmie Ngai Man; Leung, David Kwan Kon; Wong, Kin Sing; Wan, Terence See Ming

2016-01-05

The use of anabolic androgenic steroids (AAS) is prohibited in both human and equine sports. The conventional approach in doping control testing for AAS (as well as other prohibited substances) is accomplished by the direct detection of target AAS or their characteristic metabolites in biological samples using hyphenated techniques such as gas chromatography or liquid chromatography coupled with mass spectrometry. Such an approach, however, falls short when dealing with unknown designer steroids where reference materials and their pharmacokinetics are not available. In addition, AASs with fast elimination times render the direct detection approach ineffective as the detection window is short. A targeted metabolomics approach is a plausible alternative to the conventional direct detection approach for controlling the misuse of AAS in sports. Because the administration of AAS of the same class may trigger similar physiological responses or effects in the body, it may be possible to detect such administrations by monitoring changes in the endogenous steroidal expression profile. This study attempts to evaluate the viability of using the targeted metabolomics approach to detect the administration of steroidal aromatase inhibitors, namely androst-4-ene-3,6,17-trione (6-OXO) and androsta-1,4,6-triene-3,17-dione (ATD), in horses. Total (free and conjugated) urinary concentrations of 31 endogenous steroids were determined by gas chromatography-tandem mass spectrometry for a group of 2 resting and 2 in-training thoroughbred geldings treated with either 6-OXO or ATD. Similar data were also obtained from a control (untreated) group of in-training thoroughbred geldings (n = 28). Statistical processing and chemometric procedures using principle component analysis and orthogonal projection to latent structures-discriminant analysis (OPLS-DA) have highlighted 7 potential biomarkers that could be used to differentiate urine samples obtained from the control and the treated groups. On the basis of this targeted metabolomic approach, the administration of 6-OXO and ATD could be detected for much longer relative to that of the conventional direct detection approach.

BPA Directly Decreases GnRH Neuronal Activity via Noncanonical Pathway.

PubMed

Klenke, Ulrike; Constantin, Stephanie; Wray, Susan

2016-05-01

Peripheral feedback of gonadal estrogen to the hypothalamus is critical for reproduction. Bisphenol A (BPA), an environmental pollutant with estrogenic actions, can disrupt this feedback and lead to infertility in both humans and animals. GnRH neurons are essential for reproduction, serving as an important link between brain, pituitary, and gonads. Because GnRH neurons express several receptors that bind estrogen, they are potential targets for endocrine disruptors. However, to date, direct effects of BPA on GnRH neurons have not been shown. This study investigated the effects of BPA on GnRH neuronal activity using an explant model in which large numbers of primary GnRH neurons are maintained and express many of the receptors found in vivo. Because oscillations in intracellular calcium have been shown to correlate with electrical activity in GnRH neurons, calcium imaging was used to assay the effects of BPA. Exposure to 50μM BPA significantly decreased GnRH calcium activity. Blockage of γ-aminobutyric acid ergic and glutamatergic input did not abrogate the inhibitory BPA effect, suggesting direct regulation of GnRH neurons by BPA. In addition to estrogen receptor-β, single-cell RT-PCR analysis confirmed that GnRH neurons express G protein-coupled receptor 30 (G protein-coupled estrogen receptor 1) and estrogen-related receptor-γ, all potential targets for BPA. Perturbation studies of the signaling pathway revealed that the BPA-mediated inhibition of GnRH neuronal activity occurred independent of estrogen receptors, GPER, or estrogen-related receptor-γ, via a noncanonical pathway. These results provide the first evidence of a direct effect of BPA on GnRH neurons.

Ecological risk assessment for DvSnf7 RNA: A plant-incorporated protectant with targeted activity against western corn rootworm.

PubMed

Bachman, Pamela M; Huizinga, Kristin M; Jensen, Peter D; Mueller, Geoffrey; Tan, Jianguo; Uffman, Joshua P; Levine, Steven L

2016-11-01

MON 87411 maize, which expresses DvSnf7 RNA, was developed to provide an additional mode of action to confer protection against corn rootworm (Diabrotica spp.). A critical step in the registration of a genetically engineered crop with an insecticidal trait is performing an ecological risk assessment to evaluate the potential for adverse ecological effects. For MON 87411, an assessment plan was developed that met specific protection goals by characterizing the routes and levels of exposure, and testing representative functional taxa that would be directly or indirectly exposed in the environment. The potential for toxicity of DvSnf7 RNA was evaluated with a harmonized battery of non-target organisms (NTOs) that included invertebrate predators, parasitoids, pollinators, soil biota as well as aquatic and terrestrial vertebrate species. Laboratory tests evaluated ecologically relevant endpoints such as survival, growth, development, and reproduction and were of sufficient duration to assess the potential for adverse effects. No adverse effects were observed with any species tested at, or above, the maximum expected environmental concentration (MEEC). All margins of exposure for NTOs were >10-fold the MEEC. Therefore, it is reasonable to conclude that exposure to DvSnf7 RNA, both directly and indirectly, is safe for NTOs at the expected field exposure levels. Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.

Development and Potential Applications of CRISPR-Cas9 Genome Editing Technology in Sarcoma

PubMed Central

Liu, Tang; Shen, Jacson K.; Li, Zhihong; Choy, Edwin; Hornicek, Francis J.; Duan, Zhenfeng

2016-01-01

Sarcomas include some of the most aggressive tumors and typically respond poorly to chemotherapy. In recent years, specific gene fusion/mutations and gene over-expression/activation have been shown to drive sarcoma pathogenesis and development. These emerging genomic alterations may provide targets for novel therapeutic strategies and have the potential to transform sarcoma patient care. The RNA-guided nuclease CRISPR-Cas9 (Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-associated protein-9 nuclease) is a convenient and versatile platform for site-specific genome editing and epigenome targeted modulation. Given that sarcoma is believed to develop as a result of genetic alterations in mesenchymal progenitor/stem cells, CRISPR-Cas9 genome editing technologies hold extensive application potentials in sarcoma models and therapies. We review the development and mechanisms of the CRISPR-Cas9 system in genome editing and introduce its application in sarcoma research and potential therapy in clinic. Additionally, we propose future directions and discuss the challenges faced with these applications, providing concise and enlightening information for readers interested in this area. PMID:26806808

Development and potential applications of CRISPR-Cas9 genome editing technology in sarcoma.

PubMed

Liu, Tang; Shen, Jacson K; Li, Zhihong; Choy, Edwin; Hornicek, Francis J; Duan, Zhenfeng

2016-04-01

Sarcomas include some of the most aggressive tumors and typically respond poorly to chemotherapy. In recent years, specific gene fusion/mutations and gene over-expression/activation have been shown to drive sarcoma pathogenesis and development. These emerging genomic alterations may provide targets for novel therapeutic strategies and have the potential to transform sarcoma patient care. The RNA-guided nuclease CRISPR-Cas9 (Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-associated protein-9 nuclease) is a convenient and versatile platform for site-specific genome editing and epigenome targeted modulation. Given that sarcoma is believed to develop as a result of genetic alterations in mesenchymal progenitor/stem cells, CRISPR-Cas9 genome editing technologies hold extensive application potentials in sarcoma models and therapies. We review the development and mechanisms of the CRISPR-Cas9 system in genome editing and introduce its application in sarcoma research and potential therapy in clinic. Additionally, we propose future directions and discuss the challenges faced with these applications, providing concise and enlightening information for readers interested in this area. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Influence of Concurrent Finger Movements on Transcranial Direct Current Stimulation (tDCS)-Induced Aftereffects.

PubMed

Shirota, Yuichiro; Terney, Daniella; Antal, Andrea; Paulus, Walter

2017-01-01

Transcranial direct current stimulation (tDCS) has been reported to have bidirectional influence on the amplitude of motor-evoked potentials (MEPs) in resting participants in a polarity-specific manner: anodal tDCS increased and cathodal tDCS decreased them. More recently, the effects of tDCS have been shown to depend on a number of additional factors. We investigated whether a small variety of movements involving target and non-target muscles could differentially modify the efficacy of tDCS. MEPs were elicited from the right first dorsal interosseous muscle, defined as the target muscle, by single pulse transcranial magnetic stimulation (TMS) over the primary motor cortex (M1). During M1 tDCS, which lasted for 10 min applying anodal, cathodal, or sham condition, the participants were instructed to squeeze a ball with their right hand (Task 1), to move their right index finger only in the medial (Task 2), in the lateral direction (Task 3), or in medial and lateral direction alternatively (Task 4). Anodal tDCS reduced MEP amplitudes measured in Task 1 and Task 2, but to a lesser extent in the latter. In Task 3, anodal tDCS led to greater MEP amplitudes than cathodal stimulation. Alternating movements resulted in no effect of tDCS on MEP amplitude (Task 4). The results are congruent with the current notion that the aftereffects of tDCS are highly variable relying on a number of factors including the type of movements executed during stimulation.

Enabling fiber optic serotyping of pathogenic bacteria through improved anti-fouling functional surfaces

NASA Astrophysics Data System (ADS)

Janssen, K. P. F.; Knez, K.; Vanysacker, L.; Schrooten, J.; Spasic, D.; Lammertyn, J.

2012-06-01

Significant research efforts are continually being directed towards the development of sensitive and accurate surface plasmon resonance biosensors for sequence specific DNA detection. These sensors hold great potential for applications in healthcare and diagnostics. However, the performance of these sensors in practical usage scenarios is often limited due to interference from the sample matrix. This work shows how the co-immobilization of glycol (PEG) diluents or ‘back filling’ of the DNA sensing layer can successfully address these problems. A novel SPR based melting assay is used for the analysis of a synthetic oligomer target as well as PCR amplified genomic DNA extracted from Legionella pneumophila. The benefits of sensing layer back filling on the assay performance are first demonstrated through melting analysis of the oligomer target and it is shown how back filling enables accurate discrimination of Legionella pneumophila serogroups directly from the PCR reaction product with complete suppression of sensor fouling.

Engineering synthetic vaccines using cues from natural immunity

PubMed Central

Irvine, Darrell J.; Swartz, Melody A.; Szeto, Gregory L.

2014-01-01

Vaccines aim to protect against or treat diseases through manipulation of the immune response, promoting either immunity or tolerance. The former generate antibodies and T-cells poised to protect against future pathogen encounter or attack diseased cells such as tumors; the latter, which are far less developed, block pathogenic autoreactive T-cells and autoantibodies that target self tissue. Enormous challenges remain, however, as a consequence of our incomplete understanding of human immunity. A rapidly growing field of research is the design of synthetic materials in vaccines to 1) target organs, tissues, cells, or intracellular compartments; 2) co-deliver immunomodulatory signals that control the quality of the immune response; or 3) directly act as immune regulators, and there exists great potential for well-defined materials to further our understanding of immunity. Here we describe recent advances in the design of synthetic materials to direct immune responses, highlighting successes and challenges in prophylactic, therapeutic, and tolerance-inducing vaccines. PMID:24150416

Spore: Spawning Evolutionary Misconceptions?

NASA Astrophysics Data System (ADS)

Bean, Thomas E.; Sinatra, Gale M.; Schrader, P. G.

2010-10-01

The use of computer simulations as educational tools may afford the means to develop understanding of evolution as a natural, emergent, and decentralized process. However, special consideration of developmental constraints on learning may be necessary when using these technologies. Specifically, the essentialist (biological forms possess an immutable essence), teleological (assignment of purpose to living things and/or parts of living things that may not be purposeful), and intentionality (assumption that events are caused by an intelligent agent) biases may be reinforced through the use of computer simulations, rather than addressed with instruction. We examine the video game Spore for its depiction of evolutionary content and its potential to reinforce these cognitive biases. In particular, we discuss three pedagogical strategies to mitigate weaknesses of Spore and other computer simulations: directly targeting misconceptions through refutational approaches, targeting specific principles of scientific inquiry, and directly addressing issues related to models as cognitive tools.

Dissecting engineered cell types and enhancing cell fate conversion via CellNet

PubMed Central

Morris, Samantha A.; Cahan, Patrick; Li, Hu; Zhao, Anna M.; San Roman, Adrianna K.; Shivdasani, Ramesh A.; Collins, James J.; Daley, George Q.

2014-01-01

SUMMARY Engineering clinically relevant cells in vitro holds promise for regenerative medicine, but most protocols fail to faithfully recapitulate target cell properties. To address this, we developed CellNet, a network biology platform that determines whether engineered cells are equivalent to their target tissues, diagnoses aberrant gene regulatory networks, and prioritizes candidate transcriptional regulators to enhance engineered conversions. Using CellNet, we improved B cell to macrophage conversion, transcriptionally and functionally, by knocking down predicted B cell regulators. Analyzing conversion of fibroblasts to induced hepatocytes (iHeps), CellNet revealed an unexpected intestinal program regulated by the master regulator Cdx2. We observed long-term functional engraftment of mouse colon by iHeps, thereby establishing their broader potential as endoderm progenitors and demonstrating direct conversion of fibroblasts into intestinal epithelium. Our studies illustrate how CellNet can be employed to improve direct conversion and to uncover unappreciated properties of engineered cells. PMID:25126792

Ningnanmycin inhibits tobacco mosaic virus virulence by binding directly to its coat protein discs

PubMed Central

Li, Xiangyang; Hao, Gefei; Wang, Qingmin; Chen, Zhuo; Ding, Yan; Yu, Lu; Hu, Deyu; Song, Baoan

2017-01-01

Tobacco mosaic virus (TMV) causes severe plant diseases worldwide; however, effective antiviral agents for controlling TMV infections are not available. This lack of effective antiviral agents is mainly due to the poor understanding of potential targets associated with TMV infections. During infection, the coat protein (CP), which is delivered by viral particles into susceptible host cells, provides protection for viral RNA. Here, we found that Ningnanmycin (NNM), a commercially used plant antibacterial agent, inhibits the assembly of the CP by directly binding several residues. These interactions cause the disassembly of the CP from discs into monomers, leading to an almost complete loss of pathogenicity. Substitutions in the involved binding residues resulted in mutants that were significantly less sensitive to NNM. Thus, targeting the binding of viral CPs through small molecular agents offers an effective strategy to study the mechanism of NNM. PMID:29137277

Thermal-electric coupled-field finite element modeling and experimental testing of high-temperature ion sources for the production of radioactive ion beams

NASA Astrophysics Data System (ADS)

Manzolaro, M.; Meneghetti, G.; Andrighetto, A.; Vivian, G.; D'Agostini, F.

2016-02-01

In isotope separation on line facilities the target system and the related ion source are two of the most critical components. In the context of the selective production of exotic species (SPES) project, a 40 MeV 200 μA proton beam directly impinges a uranium carbide target, generating approximately 1013 fissions per second. The radioactive isotopes produced in this way are then directed to the ion source, where they can be ionized and finally accelerated to the subsequent areas of the facility. In this work both the surface ion source and the plasma ion source adopted for the SPES facility are presented and studied by means of numerical thermal-electric models. Then, numerical results are compared with temperature and electric potential difference measurements, and finally the main advantages of the proposed simulation approach are discussed.

TRPM3 and miR-204 establish a regulatory circuit that controls oncogenic autophagy in clear cell renal cell carcinoma

PubMed Central

Hall, Daniel P.; Cost, Nicholas G.; Hegde, Shailaja; Kellner, Emily; Mikhaylova, Olga; Stratton, Yiwen; Ehmer, Birgit; Abplanalp, William A.; Pandey, Raghav; Biesiada, Jacek; Harteneck, Christian; Plas, David R.; Meller, Jarek; Czyzyk-Krzeska, Maria F.

2014-01-01

Summary Autophagy promotes tumor growth by generating nutrients from the degradation of intracellular structures. Here we establish, using shRNAs, a dominant negative mutant, and a pharmacologic inhibitor, mefenamic acid (MFA), that the Transient Receptor Potential Melastatin 3 (TRPM3) channel promotes growth of clear cell renal cell carcinoma (ccRCC) and stimulates MAP1LC3A (LC3A) and MAP1LC3B (LC3B) autophagy. Increased expression of TRPM3 in RCC leads to Ca2+ influx, activation of CAMKK2, AMPK, and ULK1, and phagophore formation. In addition, TRPM3 Ca2+ and Zn2+ fluxes inhibit miR-214 which directly targets LC3A and LC3B. The von Hippel-Lindau tumor suppressor (VHL) represses TRPM3 through miR-204 directly and indirectly through another miR-204 target, Caveolin 1 (CAV1). PMID:25517751

Targeted intracellular voltage recordings from dendritic spines using quantum-dot-coated nanopipettes

NASA Astrophysics Data System (ADS)

Jayant, Krishna; Hirtz, Jan J.; Plante, Ilan Jen-La; Tsai, David M.; de Boer, Wieteke D. A. M.; Semonche, Alexa; Peterka, Darcy S.; Owen, Jonathan S.; Sahin, Ozgur; Shepard, Kenneth L.; Yuste, Rafael

2017-05-01

Dendritic spines are the primary site of excitatory synaptic input onto neurons, and are biochemically isolated from the parent dendritic shaft by their thin neck. However, due to the lack of direct electrical recordings from spines, the influence that the neck resistance has on synaptic transmission, and the extent to which spines compartmentalize voltage, specifically excitatory postsynaptic potentials, albeit critical, remains controversial. Here, we use quantum-dot-coated nanopipette electrodes (tip diameters ∼15-30 nm) to establish the first intracellular recordings from targeted spine heads under two-photon visualization. Using simultaneous somato-spine electrical recordings, we find that back propagating action potentials fully invade spines, that excitatory postsynaptic potentials are large in the spine head (mean 26 mV) but are strongly attenuated at the soma (0.5-1 mV) and that the estimated neck resistance (mean 420 MΩ) is large enough to generate significant voltage compartmentalization. Nanopipettes can thus be used to electrically probe biological nanostructures.

Targeted intracellular voltage recordings from dendritic spines using quantum-dot-coated nanopipettes

PubMed Central

Jayant, Krishna; Hirtz, Jan J.; Plante, Ilan Jen-La; Tsai, David M.; De Boer, Wieteke D. A. M.; Semonche, Alexa; Peterka, Darcy S.; Owen, Jonathan S.; Sahin, Ozgur; Shepard, Kenneth L.; Yuste, Rafael

2017-01-01

Dendritic spines are the primary site of excitatory synaptic input onto neurons, and are biochemically isolated from the parent dendritic shaft by their thin neck. However, due to the lack of direct electrical recordings from spines, the influence that the neck resistance has on synaptic transmission, and the extent to which spines compartmentalize voltage, specifically excitatory postsynaptic potentials, albeit critical, remains controversial. Here, we use quantum-dot-coated nanopipette electrodes (tip diameters ~15–30 nm) to establish the first intracellular recordings from targeted spine heads under two-photon visualization. Using simultaneous somato-spine electrical recordings, we find that back propagating action potentials fully invade spines, that excitatory postsynaptic potentials are large in the spine head (mean 26 mV) but are strongly attenuated at the soma (0.5–1 mV) and that the estimated neck resistance (mean 420 MΩ) is large enough to generate significant voltage compartmentalization. Nanopipettes can thus be used to electrically probe biological nanostructures. PMID:27941898

Targeted intracellular voltage recordings from dendritic spines using quantum-dot-coated nanopipettes.

PubMed

Jayant, Krishna; Hirtz, Jan J; Plante, Ilan Jen-La; Tsai, David M; De Boer, Wieteke D A M; Semonche, Alexa; Peterka, Darcy S; Owen, Jonathan S; Sahin, Ozgur; Shepard, Kenneth L; Yuste, Rafael

2017-05-01

Dendritic spines are the primary site of excitatory synaptic input onto neurons, and are biochemically isolated from the parent dendritic shaft by their thin neck. However, due to the lack of direct electrical recordings from spines, the influence that the neck resistance has on synaptic transmission, and the extent to which spines compartmentalize voltage, specifically excitatory postsynaptic potentials, albeit critical, remains controversial. Here, we use quantum-dot-coated nanopipette electrodes (tip diameters ∼15-30 nm) to establish the first intracellular recordings from targeted spine heads under two-photon visualization. Using simultaneous somato-spine electrical recordings, we find that back propagating action potentials fully invade spines, that excitatory postsynaptic potentials are large in the spine head (mean 26 mV) but are strongly attenuated at the soma (0.5-1 mV) and that the estimated neck resistance (mean 420 MΩ) is large enough to generate significant voltage compartmentalization. Nanopipettes can thus be used to electrically probe biological nanostructures.

Understanding the carbon dioxide gaps.

PubMed

Scheeren, Thomas W L; Wicke, Jannis N; Teboul, Jean-Louis

2018-06-01

The current review attempts to demonstrate the value of several forms of carbon dioxide (CO2) gaps in resuscitation of the critically ill patient as monitor for the adequacy of the circulation, as target for fluid resuscitation and also as predictor for outcome. Fluid resuscitation is one of the key treatments in many intensive care patients. It remains a challenge in daily practice as both a shortage and an overload in intravascular volume are potentially harmful. Many different approaches have been developed for use as target of fluid resuscitation. CO2 gaps can be used as surrogate for the adequacy of cardiac output (CO) and as marker for tissue perfusion and are therefore a potential target for resuscitation. CO2 gaps are easily measured via point-of-care analysers. We shed light on its potential use as nowadays it is not widely used in clinical practice despite its potential. Many studies were conducted on partial CO2 pressure differences or CO2 content (cCO2) differences either alone, or in combination with other markers for outcome or resuscitation adequacy. Furthermore, some studies deal with CO2 gap to O2 gap ratios as target for goal-directed fluid therapy or as marker for outcome. CO2 gap is a sensitive marker of tissue hypoperfusion, with added value over traditional markers of tissue hypoxia in situations in which an oxygen diffusion barrier exists such as in tissue oedema and impaired microcirculation. Venous-to-arterial cCO2 or partial pressure gaps can be used to evaluate whether attempts to increase CO should be made. Considering the potential of the several forms of CO2 measurements and its ease of use via point-of-care analysers, it is recommendable to implement CO2 gaps in standard clinical practice.

Fluorescence Cross-Correlation Spectroscopy Reveals Mechanistic Insights into the Effect of 2′-O-Methyl Modified siRNAs in Living Cells

PubMed Central

Ohrt, Thomas; Staroske, Wolfgang; Mütze, Jörg; Crell, Karin; Landthaler, Markus; Schwille, Petra

2011-01-01

RNA interference (RNAi) offers a powerful tool to specifically direct the degradation of complementary RNAs, and thus has great therapeutic potential for targeting diseases. Despite the reported preferences of RNAi, there is still a need for new techniques that will allow for a detailed mechanistic characterization of RNA-induced silencing complex (RISC) assembly and activity to further improve the biocompatibility of modified siRNAs. In contrast to previous reports, we investigated the effects of 2′-O-methyl (2′OMe) modifications introduced at specific positions within the siRNA at the early and late stages of RISC assembly, as well as their influence on target recognition and cleavage directly in living cells. We found that six to 10 2′OMe nucleotides on the 3′-end inhibit passenger-strand release as well as target-RNA cleavage without changing the affinity, strand asymmetry, or target recognition. 2′OMe modifications introduced at the 5′-end reduced activated RISC stability, whereas incorporations at the cleavage site showed only minor effects on passenger-strand release when present on the passenger strand. Our new fluorescence cross-correlation spectroscopy assays resolve different steps and stages of RISC assembly and target recognition with heretofore unresolved detail in living cells, which is needed to develop therapeutic siRNAs with optimized in vivo properties. PMID:21689532

ESAT-6 Targeting to DEC205+ Antigen Presenting Cells Induces Specific-T Cell Responses against ESAT-6 and Reduces Pulmonary Infection with Virulent Mycobacterium tuberculosis.

PubMed

Silva-Sánchez, Aarón; Meza-Pérez, Selene; Flores-Langarica, Adriana; Donis-Maturano, Luis; Estrada-García, Iris; Calderón-Amador, Juana; Hernández-Pando, Rogelio; Idoyaga, Juliana; Steinman, Ralph M; Flores-Romo, Leopoldo

2015-01-01

Airways infection with Mycobacterium tuberculosis (Mtb) is contained mostly by T cell responses, however, Mtb has developed evasion mechanisms which affect antigen presenting cell (APC) maturation/recruitment delaying the onset of Ag-specific T cell responses. Hypothetically, bypassing the natural infection routes by delivering antigens directly to APCs may overcome the pathogen's naturally evolved evasion mechanisms, thus facilitating the induction of protective immune responses. We generated a murine monoclonal fusion antibody (α-DEC-ESAT) to deliver Early Secretory Antigen Target (ESAT)-6 directly to DEC205+ APCs and to assess its in vivo effects on protection associated responses (IFN-γ production, in vivo CTL killing, and pulmonary mycobacterial load). Treatment with α-DEC-ESAT alone induced ESAT-6-specific IFN-γ producing CD4+ T cells and prime-boost immunization prior to Mtb infection resulted in early influx (d14 post-infection) and increased IFN-γ+ production by specific T cells in the lungs, compared to scarce IFN-γ production in control mice. In vivo CTL killing was quantified in relevant tissues upon transferring target cells loaded with mycobacterial antigens. During infection, α-DEC-ESAT-treated mice showed increased target cell killing in the lungs, where histology revealed cellular infiltrate and considerably reduced bacterial burden. Targeting the mycobacterial antigen ESAT-6 to DEC205+ APCs before infection expands specific T cell clones responsible for early T cell responses (IFN-γ production and CTL activity) and substantially reduces lung bacterial burden. Delivering mycobacterial antigens directly to APCs provides a unique approach to study in vivo the role of APCs and specific T cell responses to assess their potential anti-mycobacterial functions.

ESAT-6 Targeting to DEC205+ Antigen Presenting Cells Induces Specific-T Cell Responses against ESAT-6 and Reduces Pulmonary Infection with Virulent Mycobacterium tuberculosis

PubMed Central

Silva-Sánchez, Aarón; Meza-Pérez, Selene; Flores-Langarica, Adriana; Donis-Maturano, Luis; Estrada-García, Iris; Calderón-Amador, Juana; Hernández-Pando, Rogelio; Idoyaga, Juliana; Flores-Romo, Leopoldo

2015-01-01

Airways infection with Mycobacterium tuberculosis (Mtb) is contained mostly by T cell responses, however, Mtb has developed evasion mechanisms which affect antigen presenting cell (APC) maturation/recruitment delaying the onset of Ag-specific T cell responses. Hypothetically, bypassing the natural infection routes by delivering antigens directly to APCs may overcome the pathogen’s naturally evolved evasion mechanisms, thus facilitating the induction of protective immune responses. We generated a murine monoclonal fusion antibody (α-DEC-ESAT) to deliver Early Secretory Antigen Target (ESAT)-6 directly to DEC205+ APCs and to assess its in vivo effects on protection associated responses (IFN-γ production, in vivo CTL killing, and pulmonary mycobacterial load). Treatment with α-DEC-ESAT alone induced ESAT-6-specific IFN-γ producing CD4+ T cells and prime-boost immunization prior to Mtb infection resulted in early influx (d14 post-infection) and increased IFN-γ+ production by specific T cells in the lungs, compared to scarce IFN-γ production in control mice. In vivo CTL killing was quantified in relevant tissues upon transferring target cells loaded with mycobacterial antigens. During infection, α-DEC-ESAT-treated mice showed increased target cell killing in the lungs, where histology revealed cellular infiltrate and considerably reduced bacterial burden. Targeting the mycobacterial antigen ESAT-6 to DEC205+ APCs before infection expands specific T cell clones responsible for early T cell responses (IFN-γ production and CTL activity) and substantially reduces lung bacterial burden. Delivering mycobacterial antigens directly to APCs provides a unique approach to study in vivo the role of APCs and specific T cell responses to assess their potential anti-mycobacterial functions. PMID:25915045

Insulin-Like Growth Factor 2 Silencing Restores Taxol Sensitivity in Drug Resistant Ovarian Cancer

PubMed Central

Brouwer-Visser, Jurriaan; Lee, Jiyeon; McCullagh, KellyAnne; Cossio, Maria J.; Wang, Yanhua; Huang, Gloria S.

2014-01-01

Drug resistance is an obstacle to the effective treatment of ovarian cancer. We and others have shown that the insulin-like growth factor (IGF) signaling pathway is a novel potential target to overcome drug resistance. The purpose of this study was to validate IGF2 as a potential therapeutic target in drug resistant ovarian cancer and to determine the efficacy of targeting IGF2 in vivo. An analysis of The Cancer Genome Atlas (TCGA) data in the serous ovarian cancer cohort showed that high IGF2 mRNA expression is significantly associated with shortened interval to disease progression and death, clinical indicators of drug resistance. In a genetically diverse panel of ovarian cancer cell lines, the IGF2 mRNA levels measured in cell lines resistant to various microtubule-stabilizing agents including Taxol were found to be significantly elevated compared to the drug sensitive cell lines. The effect of IGF2 knockdown on Taxol resistance was investigated in vitro and in vivo. Transient IGF2 knockdown significantly sensitized drug resistant cells to Taxol treatment. A Taxol-resistant ovarian cancer xenograft model, developed from HEY-T30 cells, exhibited extreme drug resistance, wherein the maximal tolerated dose of Taxol did not delay tumor growth in mice. Blocking the IGF1R (a transmembrane receptor that transmits signals from IGF1 and IGF2) using a monoclonal antibody did not alter the response to Taxol. However, stable IGF2 knockdown using short-hairpin RNA in HEY-T30 effectively restored Taxol sensitivity. These findings validate IGF2 as a potential therapeutic target in drug resistant ovarian cancer and show that directly targeting IGF2 may be a preferable strategy compared with targeting IGF1R alone. PMID:24932685

Efficient modification of CCR5 in primary human hematopoietic cells using a megaTAL nuclease and AAV donor template.

PubMed

Sather, Blythe D; Romano Ibarra, Guillermo S; Sommer, Karen; Curinga, Gabrielle; Hale, Malika; Khan, Iram F; Singh, Swati; Song, Yumei; Gwiazda, Kamila; Sahni, Jaya; Jarjour, Jordan; Astrakhan, Alexander; Wagner, Thor A; Scharenberg, Andrew M; Rawlings, David J

2015-09-30

Genetic mutations or engineered nucleases that disrupt the HIV co-receptor CCR5 block HIV infection of CD4(+) T cells. These findings have motivated the engineering of CCR5-specific nucleases for application as HIV therapies. The efficacy of this approach relies on efficient biallelic disruption of CCR5, and the ability to efficiently target sequences that confer HIV resistance to the CCR5 locus has the potential to further improve clinical outcomes. We used RNA-based nuclease expression paired with adeno-associated virus (AAV)-mediated delivery of a CCR5-targeting donor template to achieve highly efficient targeted recombination in primary human T cells. This method consistently achieved 8 to 60% rates of homology-directed recombination into the CCR5 locus in T cells, with over 80% of cells modified with an MND-GFP expression cassette exhibiting biallelic modification. MND-GFP-modified T cells maintained a diverse repertoire and engrafted in immune-deficient mice as efficiently as unmodified cells. Using this method, we integrated sequences coding chimeric antigen receptors (CARs) into the CCR5 locus, and the resulting targeted CAR T cells exhibited antitumor or anti-HIV activity. Alternatively, we introduced the C46 HIV fusion inhibitor, generating T cell populations with high rates of biallelic CCR5 disruption paired with potential protection from HIV with CXCR4 co-receptor tropism. Finally, this protocol was applied to adult human mobilized CD34(+) cells, resulting in 15 to 20% homologous gene targeting. Our results demonstrate that high-efficiency targeted integration is feasible in primary human hematopoietic cells and highlight the potential of gene editing to engineer T cell products with myriad functional properties. Copyright © 2015, American Association for the Advancement of Science.

Inhibition of KLF7-Targeting MicroRNA 146b Promotes Sciatic Nerve Regeneration.

PubMed

Li, Wen-Yuan; Zhang, Wei-Ting; Cheng, Yong-Xia; Liu, Yan-Cui; Zhai, Feng-Guo; Sun, Ping; Li, Hui-Ting; Deng, Ling-Xiao; Zhu, Xiao-Feng; Wang, Ying

2018-06-01

A previous study has indicated that Krüppel-like factor 7 (KLF7), a transcription factor that stimulates Schwann cell (SC) proliferation and axonal regeneration after peripheral nerve injury, is a promising therapeutic transcription factor in nerve injury. We aimed to identify whether inhibition of microRNA-146b (miR-146b) affected SC proliferation, migration, and myelinated axon regeneration following sciatic nerve injury by regulating its direct target KLF7. SCs were transfected with miRNA lentivirus, miRNA inhibitor lentivirus, or KLF7 siRNA lentivirus in vitro. The expression of miR146b and KLF7, as well as SC proliferation and migration, were subsequently evaluated. In vivo, an acellular nerve allograft (ANA) followed by injection of GFP control vector or a lentiviral vector encoding an miR-146b inhibitor was used to assess the repair potential in a model of sciatic nerve gap. miR-146b directly targeted KLF7 by binding to the 3'-UTR, suppressing KLF7. Up-regulation of miR-146b and KLF7 knockdown significantly reduced the proliferation and migration of SCs, whereas silencing miR-146b resulted in increased proliferation and migration. KLF7 protein was localized in SCs in which miR-146b was expressed in vivo. Similarly, 4 weeks after the ANA, anti-miR-146b increased KLF7 and its target gene nerve growth factor cascade, promoting axonal outgrowth. Closer analysis revealed improved nerve conduction and sciatic function index score, and enhanced expression of neurofilaments, P0 (anti-peripheral myelin), and myelinated axon regeneration. Our findings provide new insight into the regulation of KLF7 by miR-146b during peripheral nerve regeneration and suggest a potential therapeutic strategy for peripheral nerve injury.

Spatial attention during saccade decisions.

PubMed

Jonikaitis, Donatas; Klapetek, Anna; Deubel, Heiner

2017-07-01

Behavioral measures of decision making are usually limited to observations of decision outcomes. In the present study, we made use of the fact that oculomotor and sensory selection are closely linked to track oculomotor decision making before oculomotor responses are made. We asked participants to make a saccadic eye movement to one of two memorized target locations and observed that visual sensitivity increased at both the chosen and the nonchosen saccade target locations, with a clear bias toward the chosen target. The time course of changes in visual sensitivity was related to saccadic latency, with the competition between the chosen and nonchosen targets resolved faster before short-latency saccades. On error trials, we observed an increased competition between the chosen and nonchosen targets. Moreover, oculomotor selection and visual sensitivity were influenced by top-down and bottom-up factors as well as by selection history and predicted the direction of saccades. Our findings demonstrate that saccade decisions have direct visual consequences and show that decision making can be traced in the human oculomotor system well before choices are made. Our results also indicate a strong association between decision making, saccade target selection, and visual sensitivity. NEW & NOTEWORTHY We show that saccadic decisions can be tracked by measuring spatial attention. Spatial attention is allocated in parallel to the two competing saccade targets, and the time course of spatial attention differs for fast-slow and for correct-erroneous decisions. Saccade decisions take the form of a competition between potential saccade goals, which is associated with spatial attention allocation to those locations. Copyright © 2017 the American Physiological Society.

Epidermal Growth Factor Receptor Tyrosine Kinase: A Potential Target in Treatment of Non-Small-Cell Lung Carcinoma.

PubMed

Prabhu, Venugopal Vinod; Devaraj, Niranjali

2017-01-01

Lung cancer is responsible for 1.6 million deaths. Approximately 80%-85% of lung cancers are of the non-small-cell variety, which includes squamous cell carcinoma, adenocarcinoma, and large-cell carcinoma. Knowing the stage of cancer progression is a requisite for determining which management approach-surgery, chemotherapy, radiotherapy, and/or immunotherapy-is optimal. Targeted therapeutic approaches with antiangiogenic monoclonal antibodies or tyrosine kinase inhibitors are one option if tumors harbor oncogene mutations. Another, newer approach is directed against cancer-specific molecules and signaling pathways and thus has more limited nonspecific toxicities. This approach targets the epidermal growth factor receptor (EGFR, HER-1/ErbB1), a receptor tyrosine kinase of the ErbB family, which consists of four closely related receptors: HER-1/ErbB1, HER-2/neu/ErbB2, HER-3/ErbB3, and HER-4/ErbB4. Because EGFR is expressed at high levels on the surface of some cancer cells, it has been recognized as an effective anticancer target. EGFR-targeted therapies include monoclonal antibodies (mAbs) and small-molecule tyrosine kinase inhibitors. Tyrosine kinases are an especially important target because they play an important role in the modulation of growth factor signaling. This review highlights various classes of synthetically derived molecules that have been reported in the last few years as potential EGFR-TK inhibitors (TKIs) and their targeted therapies in NSCLC, along with effective strategies for overcoming EGFR-TKI resistance and efforts to develop a novel potent EGFR-TKI as an efficient target of NSCLC treatment in the foreseeable future.

Emerging applications of label-free optical biosensors

NASA Astrophysics Data System (ADS)

Zanchetta, Giuliano; Lanfranco, Roberta; Giavazzi, Fabio; Bellini, Tommaso; Buscaglia, Marco

2017-01-01

Innovative technical solutions to realize optical biosensors with improved performance are continuously proposed. Progress in material fabrication enables developing novel substrates with enhanced optical responses. At the same time, the increased spectrum of available biomolecular tools, ranging from highly specific receptors to engineered bioconjugated polymers, facilitates the preparation of sensing surfaces with controlled functionality. What remains often unclear is to which extent this continuous innovation provides effective breakthroughs for specific applications. In this review, we address this challenging question for the class of label-free optical biosensors, which can provide a direct signal upon molecular binding without using secondary probes. Label-free biosensors have become a consolidated approach for the characterization and screening of molecular interactions in research laboratories. However, in the last decade, several examples of other applications with high potential impact have been proposed. We review the recent advances in label-free optical biosensing technology by focusing on the potential competitive advantage provided in selected emerging applications, grouped on the basis of the target type. In particular, direct and real-time detection allows the development of simpler, compact, and rapid analytical methods for different kinds of targets, from proteins to DNA and viruses. The lack of secondary interactions facilitates the binding of small-molecule targets and minimizes the perturbation in single-molecule detection. Moreover, the intrinsic versatility of label-free sensing makes it an ideal platform to be integrated with biomolecular machinery with innovative functionality, as in case of the molecular tools provided by DNA nanotechnology.

Development and Characterization of Chitosan Cross-Linked With Tripolyphosphate as a Sustained Release Agent in Tablets, Part I: Design of Experiments and Optimization.

PubMed

Pinto, Colin A; Saripella, Kalyan K; Loka, Nikhil C; Neau, Steven H

2018-04-01

Certain issues with the use of particles of chitosan (Ch) cross-linked with tripolyphosphate (TPP) in sustained release formulations include inefficient drug loading, burst drug release, and incomplete drug release. Acetaminophen was added to Ch:TPP particles to test for advantages of drug addition extragranularly over drug addition made during cross-linking. The influences of Ch concentration, Ch:TPP ratio, temperature, ionic strength, and pH were assessed. Design of experiments allowed identification of factors and 2-factor interactions that have significant effects on average particle size and size distribution, yield, zeta potential, and true density of the particles, as well as drug release from the directly compressed tablets. Statistical model equations directed production of a control batch that minimized span, maximized yield, and targeted a t 50 of 90 min (sample A); sample B that differed by targeting a t 50 of 240-300 min to provide sustained release; and sample C that differed from sample B by maximizing span. Sample B maximized yield and provided its targeted t 50 and the smallest average particle size, with the higher zeta potential and the lower span of samples B and C. Extragranular addition of a drug to Ch:TPP particles achieved 100% drug loading, eliminated a burst drug release, and can accomplish complete drug release. Copyright © 2018 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

Targeted release of transcription factors for cell reprogramming by a natural micro-syringe.

PubMed

Berthoin, Lionel; Toussaint, Bertrand; Garban, Frédéric; Le Gouellec, Audrey; Caulier, Benjamin; Polack, Benoît; Laurin, David

2016-11-20

Ectopic expression of defined transcription factors (TFs) for cell fate handling has proven high potential interest in reprogramming differentiated cells, in particular for regenerative medicine, ontogenesis study and cell based modelling. Pluripotency or transdifferentiation induction as TF mediated differentiation is commonly produced by transfer of genetic information with safety concerns. The direct delivery of proteins could represent a safer alternative but still needs significant advances to be efficient. We have successfully developed the direct delivery of proteins by an attenuated bacterium with a type 3 secretion system that does not require challenging and laborious steps for production and purification of recombinant molecules. Here we show that this natural micro-syringe is able to inject TFs to primary human fibroblasts and cord blood CD34 + hematopoietic stem cells. The signal sequence for vectorization of the TF Oct4 has no effect on DNA binding to its nucleic target. As soon as one hour after injection, vectorized TFs are detectable in the nucleus. The injection process is not associated with toxicity and the bacteria can be completely removed from cell cultures. A three days targeted release of Oct4 or Sox2 embryonic TFs results in the induction of the core pluripotency genes expression in fibroblasts and CD34 + hematopoietic stem cells. This micro-syringe vectorization represents a new strategy for TF delivery and has potential applications for cell fate reprogramming. Copyright © 2016 Elsevier B.V. All rights reserved.

Relativistic Electron Beams, Forward Thomson Scattering, and ``Raman'' Scattering

NASA Astrophysics Data System (ADS)

Simon, A.

1999-11-01

Experiments at LLE (see abstract by D. Hicks at this meeting) show that surprisingly high potentials (+0.5 to 2.0 MV) develop in plasmas irradiated by high-energy lasers. The highly conducting plasma will be a near equipotential and should attract return-current electrons in a radial beam-like distribution, especially in the outer low-density regions. This will initiate the BOT instability, creating large plasma waves with phase velocities close to c. Coherent Thomson scattering of the interaction beam from these waves must occur primarily in the forward direction. This will appear to be ``backward SRS'' upon reflection from a critical surface. We will show that the resulting spectrum is fairly broad and at short wavelengths. Collisional absorption of the scattered EM wave limits the reflectivity to low values (depending on the density scale length). Thus, a distinct difference exists between the spectrum for thick targets (nc surface present) and thin targets (gasbags, etc., from which primarily a narrow absolute-SRS backward emission occurs, at the peak density). The thick-target, reflected-wave angular distribution will be concentrated in the backward direction. The corresponding plasma-wave k-vector will be a fraction of k_0. The variation of the spectrum with potential and angle will be discussed. Comparison will be made with recent results at LLE and LLNL. This work was supported by the U.S. Department of Energy Office of Inertial Confinement Fusion under Cooperative Agreement No. DE-FC03-92SF19460, UR, and NYSERDA.

Protospacer Adjacent Motif (PAM)-Distal Sequences Engage CRISPR Cas9 DNA Target Cleavage

PubMed Central

Ethier, Sylvain; Schmeing, T. Martin; Dostie, Josée; Pelletier, Jerry

2014-01-01

The clustered regularly interspaced short palindromic repeat (CRISPR)-associated enzyme Cas9 is an RNA-guided nuclease that has been widely adapted for genome editing in eukaryotic cells. However, the in vivo target specificity of Cas9 is poorly understood and most studies rely on in silico predictions to define the potential off-target editing spectrum. Using chromatin immunoprecipitation followed by sequencing (ChIP-seq), we delineate the genome-wide binding panorama of catalytically inactive Cas9 directed by two different single guide (sg) RNAs targeting the Trp53 locus. Cas9:sgRNA complexes are able to load onto multiple sites with short seed regions adjacent to 5′NGG3′ protospacer adjacent motifs (PAM). Yet among 43 ChIP-seq sites harboring seed regions analyzed for mutational status, we find editing only at the intended on-target locus and one off-target site. In vitro analysis of target site recognition revealed that interactions between the 5′ end of the guide and PAM-distal target sequences are necessary to efficiently engage Cas9 nucleolytic activity, providing an explanation for why off-target editing is significantly lower than expected from ChIP-seq data. PMID:25275497

Therapeutic Potential of Intravenous Immunoglobulin in Acute Brain Injury

PubMed Central

Thom, Vivien; Arumugam, Thiruma V.; Magnus, Tim; Gelderblom, Mathias

2017-01-01

Acute ischemic and traumatic injury of the central nervous system (CNS) is known to induce a cascade of inflammatory events that lead to secondary tissue damage. In particular, the sterile inflammatory response in stroke has been intensively investigated in the last decade, and numerous experimental studies demonstrated the neuroprotective potential of a targeted modulation of the immune system. Among the investigated immunomodulatory agents, intravenous immunoglobulin (IVIg) stand out due to their beneficial therapeutic potential in experimental stroke as well as several other experimental models of acute brain injuries, which are characterized by a rapidly evolving sterile inflammatory response, e.g., trauma, subarachnoid hemorrhage. IVIg are therapeutic preparations of polyclonal immunoglobulin G, extracted from the plasma of thousands of donors. In clinical practice, IVIg are the treatment of choice for diverse autoimmune diseases and various mechanisms of action have been proposed. Only recently, several experimental studies implicated a therapeutic potential of IVIg even in models of acute CNS injury, and suggested that the immune system as well as neuronal cells can directly be targeted by IVIg. This review gives further insight into the role of secondary inflammation in acute brain injury with an emphasis on stroke and investigates the therapeutic potential of IVIg. PMID:28824617

MALDI-TOF mass spectrometry and high-consequence bacteria: safety and stability of biothreat bacterial sample testing in clinical diagnostic laboratories.

PubMed

Tracz, Dobryan M; Tober, Ashley D; Antonation, Kym S; Corbett, Cindi R

2018-03-01

We considered the application of MALDI-TOF mass spectrometry for BSL-3 bacterial diagnostics, with a focus on the biosafety of live-culture direct-colony testing and the stability of stored extracts. Biosafety level 2 (BSL-2) bacterial species were used as surrogates for BSL-3 high-consequence pathogens in all live-culture MALDI-TOF experiments. Viable BSL-2 bacteria were isolated from MALDI-TOF mass spectrometry target plates after 'direct-colony' and 'on-plate' extraction testing, suggesting that the matrix chemicals alone cannot be considered sufficient to inactivate bacterial culture and spores in all samples. Sampling of the instrument interior after direct-colony analysis did not recover viable organisms, suggesting that any potential risks to the laboratory technician are associated with preparation of the MALDI-TOF target plate before or after testing. Secondly, a long-term stability study (3 years) of stored MALDI-TOF extracts showed that match scores can decrease below the threshold for reliable species identification (<1.7), which has implications for proficiency test panel item storage and distribution.

Comparison of wind tunnel and field experiments to measure potential deposition of fenpropimorph following volatilisation from treated crops.

PubMed

Hassink, Jan; Platz, Klaus; Stadler, Reinhold; Zangmeister, Werner; Fent, Gunnar; Möndel, Martin; Kubiak, Roland

2007-02-01

The potential for short-range transport via air, i.e. volatilisation from the area of application and subsequent deposition on adjacent non-target areas, was investigated for the fungicide fenpropimorph in a wind tunnel system and under outdoor conditions in a higher-tier field study. Fenpropimorph 750 g L(-1) EC was applied post-emergence to cereal along with a reference standard lindane EC. Stainless steel containers of water were placed at different distances downwind of the application area to trap volatile residues during a study period of 24 h following application. Meteorological conditions in the wind tunnel as well as on the field were constantly monitored during the study period. The wind tunnel system was a partly standardised system on a semi-field scale, i.e. wind direction and wind speed (2 m s(-1)) were constant, but temperature and humidity varied according to the conditions outside. In the field experiment, the average wind speed over the 24 h study period was 3 m s(-1) and no rainfall occurred. Three different measuring lines were installed on the non-target area beside the treated field to cover potential variations in the wind direction. However, no significant differences were observed since the wind direction was generally constant. Fenpropimorph was detected in minor amounts of 0.01-0.05% of the applied material in the wind tunnel experiment. Even at a distance of 1 m beside the treated field, no significant deposition occurred (0.04% of applied material after 24 h). In the field, less than 0.1% of the applied fenpropimorph was detected at 0 m directly beside the treated field. At 5 m distance the deposition values were below 0.04%, and at 20 m distance about 0.01%. In general, the amounts of deposited fenpropimorph detected in the partly standardised wind tunnel system and the higher-tier field study were in good agreement.

Antibodies directed against receptor tyrosine kinases

PubMed Central

FAUVEL, Bénédicte; Yasri, Aziz

2014-01-01

Approximately 30 therapeutic monoclonal antibodies have already been approved for cancers and inflammatory diseases, and monoclonal antibodies continue to be one of the fastest growing classes of therapeutic molecules. Because aberrant signaling by receptor tyrosine kinases (RTKs) is a commonly observed factor in cancer, most of the subclasses of RTKs are being extensively studied as potential targets for treating malignancies. The first two RTKs that have been targeted by antibody therapy, with five currently marketed antibodies, are the growth factor receptors EGFR and HER2. However, due to systemic side effects, refractory patients and the development of drug resistance, these treatments are being challenged by emerging therapeutics. This review examines current monoclonal antibody therapies against RTKs. After an analysis of agents that have already been approved, we present an analysis of antibodies in clinical development that target RTKs. Finally, we highlight promising RTKs that are emerging as new oncological targets for antibody-based therapy. PMID:24859229

Clinical proteomics-driven precision medicine for targeted cancer therapy: current overview and future perspectives.

PubMed

Zhou, Li; Wang, Kui; Li, Qifu; Nice, Edouard C; Zhang, Haiyuan; Huang, Canhua

2016-01-01

Cancer is a common disease that is a leading cause of death worldwide. Currently, early detection and novel therapeutic strategies are urgently needed for more effective management of cancer. Importantly, protein profiling using clinical proteomic strategies, with spectacular sensitivity and precision, offer excellent promise for the identification of potential biomarkers that would direct the development of targeted therapeutic anticancer drugs for precision medicine. In particular, clinical sample sources, including tumor tissues and body fluids (blood, feces, urine and saliva), have been widely investigated using modern high-throughput mass spectrometry-based proteomic approaches combined with bioinformatic analysis, to pursue the possibilities of precision medicine for targeted cancer therapy. Discussed in this review are the current advantages and limitations of clinical proteomics, the available strategies of clinical proteomics for the management of precision medicine, as well as the challenges and future perspectives of clinical proteomics-driven precision medicine for targeted cancer therapy.

Medium effects in λK+ pair production by 2.83 GeV protons on nuclei

NASA Astrophysics Data System (ADS)

Paryev, E. Ya.; Hartmann, M.; Kiselev, Yu. T.

2017-12-01

We study ΛK+ pair production in the interaction of protons of 2.83 GeV kinetic energy with C, Cu, Ag, and Au target nuclei in the framework of the nuclear spectral function approach for incoherent primary proton-nucleon and secondary pion-nucleon production processes, and processes associated with the creation of intermediate Σ0K+ pairs. The approach accounts for the initial proton and final Λ hyperon absorption, final K+ meson distortion in nuclei, target nucleon binding, and Fermi motion, as well as nuclear mean-field potential effects on these processes. We calculate the Λ momentum dependence of the absolute ΛK+ yield from the target nuclei considered, in the kinematical conditions of the ANKE experiment, performed at COSY, within the different scenarios for the Λ-nucleus effective scalar potential. We show that the above observable is appreciably sensitive to this potential in the low-momentum region. Therefore, direct comparison of the results of our calculations with the data from the ANKE-at-COSY experiment can help to determine the above potential at finite momenta. We also demonstrate that the two-step pion-nucleon production channels dominate in the low-momentum ΛK+ production in the chosen kinematics and, therefore, they have to be taken into account in the analysis of these data. Supported by the Ministry of Education and Science of the Russian Federation

Program interruptions and short-stay transfers represent potential targets for inpatient rehabilitation care-improvement efforts

PubMed Central

Middleton, Addie; Graham, James E.; Krishnan, Shilpa; Ottenbacher, Kenneth J.

2016-01-01

Objective To present comprehensive descriptive summaries of program interruptions and short-stay transfers among Medicare fee-for-service beneficiaries receiving inpatient rehabilitation following stroke, traumatic brain injury (TBI), and traumatic spinal cord injury (SCI). Design Retrospective cohort study of Medicare beneficiaries with any of the three conditions of interest who were admitted to inpatient rehabilitation directly from an acute hospital between July 1, 2012 and November 15, 2013. Results In the final sample (stroke: n=71 769; TBI: n=7109; SCI: n=659), program interruption rates were 0.9% (stroke), 0.8% (TBI), and 1.4% (SCI). Short-stay transfer rates were 22.3% (stroke), 21.8% (TBI), and 31.6% (SCI). 14.7% of short-stay transfers and 12.3% of interruptions resulting in a return to acute care were identified as potentially preventable among those with stroke, 10.2% of transfers and 11.7% of interruptions among those with TBI, and 3.8% of transfers and 11.1% of interruptions among those with SCI. Conclusions Broad healthcare policies aimed at improving quality and reducing costs are currently being implemented. Reducing program interruptions and short-stay transfers during inpatient rehabilitative care represents a potential target for care-improvement efforts. Future research focused on identifying modifiable risk factors for potentially undesirable outcomes will allow for targeted preventative interventions. PMID:27631389

Program Interruptions and Short-Stay Transfers Represent Potential Targets for Inpatient Rehabilitation Care-Improvement Efforts.

PubMed

Middleton, Addie; Graham, James E; Krishnan, Shilpa; Ottenbacher, Kenneth J

2016-11-01

The objective of this work was to present comprehensive descriptive summaries of program interruptions and short-stay transfers among Medicare fee-for-service beneficiaries receiving inpatient rehabilitation after stroke, traumatic brain injury (TBI), and traumatic spinal cord injury (SCI). Retrospective cohort study of Medicare beneficiaries with any of the 3 conditions of interest who were admitted to inpatient rehabilitation directly from an acute hospital between July 1, 2012, and November 15, 2013. In the final sample (stroke, n = 71 769; TBI, n = 7109; SCI, n = 659), program interruption rates were 0.9% (stroke), 0.8% (TBI), and 1.4% (SCI). Short-stay transfer rates were 22.3% (stroke), 21.8% (TBI), and 31.6% (SCI); 14.7% of short-stay transfers and 12.3% of interruptions resulting in a return to acute care were identified as potentially preventable among those with stroke; 10.2% of transfers and 11.7% of interruptions among those with TBI, and 3.8% of transfers and 11.1% of interruptions among those with SCI. Broad health care policies aimed at improving quality and reducing costs are currently being implemented. Reducing program interruptions and short-stay transfers during inpatient rehabilitative care represents a potential target for care-improvement efforts. Future research focused on identifying modifiable risk factors for potentially undesirable outcomes will allow for targeted preventative interventions.

Harms, benefits, and the nature of interventions in pragmatic clinical trials.

PubMed

Ali, Joseph; Andrews, Joseph E; Somkin, Carol P; Rabinovich, C Egla

2015-10-01

To produce evidence capable of informing healthcare decision making at all critical levels, pragmatic clinical trials are diverse both in terms of the type of intervention (medical, behavioral, and/or technological) and the target of intervention (patients, clinicians, and/or healthcare system processes). Patients and clinicians may be called on to participate as designers, investigators, intermediaries, or subjects of pragmatic clinical trials. Other members of the healthcare team, as well as the healthcare system itself, also may be affected directly or indirectly before, during, or after study implementation. This diversity in the types and targets of pragmatic clinical trial interventions has brought into focus the need to consider whether existing ethics and regulatory principles, policies, and procedures are appropriate for pragmatic clinical trials. Specifically, further examination is needed to identify how the types and targets of pragmatic clinical trial interventions may influence the assessment of net potential risk, understood as the balance of potential harms and benefits. In this article, we build on scholarship seeking to align ethics and regulatory requirements with potential research risks and propose an approach to the assessment of net risks that is sensitive to the diverse nature of pragmatic clinical trial interventions. We clarify the potential harms, burdens, benefits, and advantages of common types of pragmatic clinical trial interventions and discuss implications for patients, clinicians, and healthcare systems. © The Author(s) 2015.

Targeting neuropilin-1 in human leukemia and lymphoma.

PubMed

Karjalainen, Katja; Jaalouk, Diana E; Bueso-Ramos, Carlos E; Zurita, Amado J; Kuniyasu, Akihiko; Eckhardt, Bedrich L; Marini, Frank C; Lichtiger, Benjamin; O'Brien, Susan; Kantarjian, Hagop M; Cortes, Jorge E; Koivunen, Erkki; Arap, Wadih; Pasqualini, Renata

2011-01-20

Targeted drug delivery offers an opportunity for the development of safer and more effective therapies for the treatment of cancer. In this study, we sought to identify short, cell-internalizing peptide ligands that could serve as directive agents for specific drug delivery in hematologic malignancies. By screening of human leukemia cells with a combinatorial phage display peptide library, we isolated a peptide motif, sequence Phe-Phe/Tyr-Any-Leu-Arg-Ser (F(F)/(Y)XLRS), which bound to different leukemia cell lines and to patient-derived bone marrow samples. The motif was internalized through a receptor-mediated pathway, and we next identified the corresponding receptor as the transmembrane glycoprotein neuropilin-1 (NRP-1). Moreover, we observed a potent anti-leukemia cell effect when the targeting motif was synthesized in tandem to the pro-apoptotic sequence (D)(KLAKLAK)₂. Finally, our results confirmed increased expression of NRP-1 in representative human leukemia and lymphoma cell lines and in a panel of bone marrow specimens obtained from patients with acute lymphoblastic leukemia or acute myelogenous leukemia compared with normal bone marrow. These results indicate that NRP-1 could potentially be used as a target for ligand-directed therapy in human leukemias and lymphomas and that the prototype CGFYWLRSC-GG-(D)(KLAKLAK)₂ is a promising drug candidate in this setting.

Emotion and goal-directed behavior: ERP evidence on cognitive and emotional conflict

PubMed Central

Kanske, Philipp; Obermeier, Christian; Schröger, Erich; Kotz, Sonja A.

2015-01-01

Cognitive control supports goal-directed behavior by resolving conflict among opposing action tendencies. Emotion can trigger cognitive control processes, thus speeding up conflict processing when the target dimension of stimuli is emotional. However, it is unclear what role emotionality of the target dimension plays in the processing of emotional conflict (e.g. in irony). In two EEG experiments, we compared the influence of emotional valence of the target (emotional, neutral) in cognitive and emotional conflict processing. To maximally approximate real-life communication, we used audiovisual stimuli. Participants either categorized spoken vowels (cognitive conflict) or their emotional valence (emotional conflict), while visual information was congruent or incongruent. Emotional target dimension facilitated both cognitive and emotional conflict processing, as shown in a reduced reaction time conflict effect. In contrast, the N100 in the event-related potentials showed a conflict-specific reversal: the conflict effect was larger for emotional compared with neutral trials in cognitive conflict and smaller in emotional conflict. Additionally, domain-general conflict effects were observed in the P200 and N200 responses. The current findings confirm that emotions have a strong influence on cognitive and emotional conflict processing. They also highlight the complexity and heterogeneity of the interaction of emotion with different types of conflict. PMID:25925271

Negative Regulation of Anthocynanin Biosynthesis in Arabidopsis by a miR156-Targeted SPL Transcription Factor

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gou, J.Y.; Liu, C.; Felippes, F. F.

2011-04-01

Flavonoids are synthesized through an important metabolic pathway that leads to the production of diverse secondary metabolites, including anthocyanins, flavonols, flavones, and proanthocyanidins. Anthocyanins and flavonols are derived from Phe and share common precursors, dihydroflavonols, which are substrates for both flavonol synthase and dihydroflavonol 4-reductase. In the stems of Arabidopsis thaliana, anthocyanins accumulate in an acropetal manner, with the highest level at the junction between rosette and stem. We show here that this accumulation pattern is under the regulation of miR156-targeted SQUAMOSA PROMOTER BINDING PROTEIN-LIKE (SPL) genes, which are deeply conserved and known to have important roles in regulating phasemore » change and flowering. Increased miR156 activity promotes accumulation of anthocyanins, whereas reduced miR156 activity results in high levels of flavonols. We further provide evidence that at least one of the miR156 targets, SPL9, negatively regulates anthocyanin accumulation by directly preventing expression of anthocyanin biosynthetic genes through destabilization of a MYB-bHLH-WD40 transcriptional activation complex. Our results reveal a direct link between the transition to flowering and secondary metabolism and provide a potential target for manipulation of anthocyanin and flavonol content in plants.« less

Targeted Prostate Thermal Therapy with Catheter-Based Ultrasound Devices and MR Thermal Monitoring

NASA Astrophysics Data System (ADS)

Diederich, Chris; Ross, Anthony; Kinsey, Adam; Nau, Will H.; Rieke, Viola; Butts Pauly, Kim; Sommer, Graham

2006-05-01

Catheter-based ultrasound devices have significant advantages for thermal therapy procedures, including potential for precise spatial and dynamic control of heating patterns to conform to targeted volumes. Interstitial and transurethral ultrasound applicators, with associated treatment strategies, were developed for thermal ablation of prostate combined with MR thermal monitoring. Four types of multielement transurethral applicators were devised, each with different levels of selectivity and intended therapeutic goals: sectored tubular transducer devices with fixed directional heating patterns; planar and lightly focused curvilinear devices with narrow heating patterns; and multi-sectored tubular devices capable of dynamic angular control without applicator movement. These devices are integrated with a 4 mm delivery catheter, incorporate an inflatable cooling balloon (10 mm OD) for positioning within the prostate and capable of rotation via an MR-compatible motor. Similarly, interstitial devices (2.4 mm OD) have been developed for percutaneous implantation with fixed directional heating patterns (e.g., 180 deg.). In vivo experiments in canine prostate (n=15) under MR temperature imaging were used to evaluate the heating technology and develop treatment strategies. MR thermal imaging in a 0.5 T interventional MRI was used to monitor temperature contours and thermal dose in multiple slices through the target volume. Sectored transurethral devices produce directional coagulation zones, extending 15-20 mm radial distance to the outer prostate capsule. The curvilinear applicator produces distinct 2-3 mm wide lesions, and with sequential rotation and modulated dwell time can precisely conform thermal ablation to selected areas or the entire prostate gland. Multi-sectored transurethral applicators can dynamically control the angular heating profile and target large regions of the gland in short treatment times without applicator manipulation. Interstitial implants with directional devices can be used to effectively ablate the posterior peripheral zone of the gland while protecting the rectum. An implant with multi-sectored interstitial devices can effectively control the angular heating pattern without applicator rotation. The MR derived 52 °C and lethal thermal dose contours (t43=240 min) allowed for real-time control of the applicators and effectively defined the extent of thermal damage. Catheter-based ultrasound devices, combined with MR thermal monitoring, can produce relatively fast and precise thermal ablation of prostate, with potential for treatment of cancer or BPH.

Evidence base and future research directions in the management of low back pain.

PubMed

Abbott, Allan

2016-03-18

Low back pain (LBP) is a prevalent and costly condition. Awareness of valid and reliable patient history taking, physical examination and clinical testing is important for diagnostic accuracy. Stratified care which targets treatment to patient subgroups based on key characteristics is reliant upon accurate diagnostics. Models of stratified care that can potentially improve treatment effects include prognostic risk profiling for persistent LBP, likely response to specific treatment based on clinical prediction models or suspected underlying causal mechanisms. The focus of this editorial is to highlight current research status and future directions for LBP diagnostics and stratified care.

MiR-26a enhances invasive capacity by suppressing GSK3β in human lung cancer cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lin, Gaoyang; Liu, Boning; Meng, Zhaowei

Lung cancer is the common cause of death from cancer, and most lung cancer patients die of metastasis. MicroRNAs (miRNAs) function as either oncogenes or tumor suppressors, playing crucial role not only in tumorigenesis, but also in tumor invasion and metastasis. There are several studies showed that miR-26a is involved in carcinogenesis, however, its role in tumor metastasis need to be elucidated. In this study, we showed that ectopic expression of miR-26a enhanced migration and invasion of lung cancer cells. Glycogen synthase kinase-3β (GSK3β) was identified as a direct target of miR-26a. GSK3β expression negatively correlated with miR-26a expression inmore » lung cancer tissues. Silencing of GSK3β achieved similar effect as miR-26a over-expression; over-expression of GSK3β reversed the enhanced effect of miR-26a on lung cancer cell migration and invasion. Further study indicated that miR-26a increased β-catenin expression and nuclear translocation. C-myc and cyclin D1, the downstream genes of β-catenin, were also up-regulated by miR-26a. Furthermore, xenograft study showed that miR-26a promoted lung cancer cell growth in vivo, and suppressed GSK3β expression. Collectively, our results demonstrated that miR-26a enhanced metastatic potential of lung cancer cells via activation of β-catenin pathway by targeting GSK3β, suggesting the potential applicability of miR-26a as a target for cancer treatment. - Highlights: • miR-26a enhances migration and invasion of lung cancer cells. • GSK3β is identified as a direct target of miR-26a. • miR-26a activates β-catenin pathway by targeting GSK3β. • miR-26a promotes lung cancer cell growth in vivo.« less

Identification of Direct Activator of Adenosine Monophosphate-Activated Protein Kinase (AMPK) by Structure-Based Virtual Screening and Molecular Docking Approach.

PubMed

Huang, Tonghui; Sun, Jie; Zhou, Shanshan; Gao, Jian; Liu, Yi

2017-06-30

Adenosine monophosphate-activated protein kinase (AMPK) plays a critical role in the regulation of energy metabolism and has been targeted for drug development of therapeutic intervention in Type II diabetes and related diseases. Recently, there has been renewed interest in the development of direct β1-selective AMPK activators to treat patients with diabetic nephropathy. To investigate the details of AMPK domain structure, sequence alignment and structural comparison were used to identify the key amino acids involved in the interaction with activators and the structure difference between β1 and β2 subunits. Additionally, a series of potential β1-selective AMPK activators were identified by virtual screening using molecular docking. The retrieved hits were filtered on the basis of Lipinski's rule of five and drug-likeness. Finally, 12 novel compounds with diverse scaffolds were obtained as potential starting points for the design of direct β1-selective AMPK activators.

Noninvasive Brain Stimulation in Pediatric Attention-Deficit Hyperactivity Disorder (ADHD): A Review.

PubMed

Rubio, Belen; Boes, Aaron D; Laganiere, Simon; Rotenberg, Alexander; Jeurissen, Danique; Pascual-Leone, Alvaro

2016-05-01

Attention-deficit hyperactivity disorder (ADHD) is one of the most prevalent neurodevelopmental disorders in the pediatric population. The clinical management of ADHD is currently limited by a lack of reliable diagnostic biomarkers and inadequate therapy for a minority of patients who do not respond to standard pharmacotherapy. There is optimism that noninvasive brain stimulation may help to address these limitations. Transcranial magnetic stimulation and transcranial direct current stimulation are 2 methods of noninvasive brain stimulation that modulate cortical excitability and brain network activity. Transcranial magnetic stimulation can be used diagnostically to probe cortical neurophysiology, whereas daily use of repetitive transcranial magnetic stimulation or transcranial direct current stimulation can induce long-lasting and potentially therapeutic changes in targeted networks. In this review, we highlight research showing the potential diagnostic and therapeutic applications of transcranial magnetic stimulation and transcranial direct current stimulation in pediatric ADHD. We also discuss the safety and ethics of using these tools in the pediatric population. © The Author(s) 2015.

The influence of selected potential oncostatics of plant origin on the protein biosynthesis in vitro.

PubMed

Paszkiewicz-Gadek, A; Chlabicz, J; Gałasiński, W

1988-01-01

Five potential oncostatics of plant origin (reserpine, amphotericin B, rutoside, digoxin, dry aloe extract), and cyclic AMP were investigated for their effect on protein synthesis. The solutions of digoxin and dry aloe extract inhibited protein biosynthesis in vitro. The direct inhibiting effect of digoxin on the ribosomes suggests that this drug forms an inactive complex with this organelle. Therefore it can be concluded that ribosome is the target site of digoxin action. Aloin and aloeemodin are responsible for the inhibitory effect of the solution of dry aloe extract. They inhibit markedly [14C]-leucine incorporation into proteins. Aloin and aloeemodin do not influence directly the ribosomes, but they inhibit elongation factors and peptidyltransferase activities in the complete elongation system. Some preliminary experiments have shown that direct interaction between these substances and elongation factor EF-2 should be taken in account. This observation is the subject of further experiments, in which the characteristics of the inhibitory effect of the components isolated from dry aloe extract will be performed.

Targeted Therapies for Advanced Oesophagogastric Cancer: Recent Progress and Future Directions.

PubMed

Young, Kate; Chau, Ian

2016-01-01

The genomic landscape of oesophagogastric (OG) cancer is highly complex. The recent elucidation of some of the pathways involved has suggested a number of novel targets for therapy. This therapy is urgently required as with conventional chemotherapy regimens patients with advanced OG cancer still have a median overall survival of under a year. This review outlines the rationale for the current treatment of OG cancer with chemotherapy and describes both previously conducted and ongoing clinical trials of novel agents in this area. The targets and associated treatments discussed include HER-2, EGFR, VEGF, c-Met, FGFR-2, PI3K, mTOR andIGF-1. To date only two targeted treatments, trastuzumab and ramucirumab, have become part of the treatment paradigm for OG cancer, partly due to difficulties in defining predictive biomarkers in this disease. However, there are a number of promising drugs in the pipeline and this article seeks to describe these and other potential novel approaches including targeting DNA repair deficiencies and the immune system.

Does being attractive always help? Positive and negative effects of attractiveness on social decision making.

PubMed

Agthe, Maria; Spörrle, Matthias; Maner, Jon K

2011-08-01

Previous studies of organizational decision making demonstrate an abundance of positive biases directed toward highly attractive individuals. The current research, in contrast, suggests that when the person being evaluated is of the same sex as the evaluator, attractiveness hurts, rather than helps. Three experiments assessing evaluations of potential job candidates (Studies 1 and 3) and university applicants (Study 2) demonstrated positive biases toward highly attractive other-sex targets but negative biases toward highly attractive same-sex targets. This pattern was mediated by variability in participants' desire to interact with versus avoid the target individual (Studies 1 and 2) and was moderated by participants' level of self-esteem (Study 3); the derogation of attractive same-sex targets was not observed among people with high self-esteem. Findings demonstrate an important exception to the positive effects of attractiveness in organizational settings and suggest that negative responses to attractive same-sex targets stem from perceptions of self-threat.

The bacterial envelope as a target for novel anti-MRSA antibiotics.

PubMed

Van Bambeke, Françoise; Mingeot-Leclercq, Marie-Paule; Struelens, Marc J; Tulkens, Paul M

2008-03-01

Methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-intermediate S. aureus (VISA) are spreading worldwide, making the search for antibiotics directed against new targets a high priority. Drugs that anchor in the bacterial membrane (e.g. ceragenins and lipopeptides) or that target the bacterial membrane and proteic (lipoglycopeptides) or lipidic (glycodepsipeptides) cell wall precursors seem to have the most potential because they show a fast and extensive bactericidal effect and are probably less prone to select for resistance owing to the difficulty in modifying their targets in a way that is compatible with bacterial survival. The efficacy of lipopeptides and lipoglycopeptides has been demonstrated in the treatment of skin and skin structure infections, and bacteremia caused by resistant S. aureus. Ceragenins and glycodepsipeptides are restricted to topical applications because of their unsatisfactory safety profile. The mode of action, pharmacological and microbiological properties and target indications of these anti-MRSA agents, which function by disturbing membrane integrity, are reviewed in this article.

SU-E-J-252: A Motion Algorithm to Extract Physical and Motion Parameters of a Mobile Target in Cone-Beam Computed Tomographic Imaging Retrospective to Image Reconstruction

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ali, I; Ahmad, S; Alsbou, N

Purpose: A motion algorithm was developed to extract actual length, CT-numbers and motion amplitude of a mobile target imaged with cone-beam-CT (CBCT) retrospective to image-reconstruction. Methods: The motion model considered a mobile target moving with a sinusoidal motion and employed three measurable parameters: apparent length, CT number level and gradient of a mobile target obtained from CBCT images to extract information about the actual length and CT number value of the stationary target and motion amplitude. The algorithm was verified experimentally with a mobile phantom setup that has three targets with different sizes manufactured from homogenous tissue-equivalent gel material embeddedmore » into a thorax phantom. The phantom moved sinusoidal in one-direction using eight amplitudes (0–20mm) and a frequency of 15-cycles-per-minute. The model required imaging parameters such as slice thickness, imaging time. Results: This motion algorithm extracted three unknown parameters: length of the target, CT-number-level, motion amplitude for a mobile target retrospective to CBCT image reconstruction. The algorithm relates three unknown parameters to measurable apparent length, CT-number-level and gradient for well-defined mobile targets obtained from CBCT images. The motion model agreed with measured apparent lengths which were dependent on actual length of the target and motion amplitude. The cumulative CT-number for a mobile target was dependent on CT-number-level of the stationary target and motion amplitude. The gradient of the CT-distribution of mobile target is dependent on the stationary CT-number-level, actual target length along the direction of motion, and motion amplitude. Motion frequency and phase did not affect the elongation and CT-number distributions of mobile targets when imaging time included several motion cycles. Conclusion: The motion algorithm developed in this study has potential applications in diagnostic CT imaging and radiotherapy to extract actual length, size and CT-numbers distorted by motion in CBCT imaging. The model provides further information about motion of the target.« less

Promoting International Energy Security. Volume 2: Turkey and the Caspian

DTIC Science & Technology

2012-01-01

RAND reports un- dergo rigorous peer review to ensure that they meet high standards for research quality and objectivity. Promoting International...Russian invasion of Georgia in 2008 did not directly target energy infrastructure, most export routes for oil and natural gas from Azerbai- jan to...particular focus on the three countries with appreciable energy export potential: Azerbai- jan , Kazakhstan, and Turkmenistan. It also provides an

The Changing Face of Hepatitis C: Recent Advances on HCV Inhibitors Targeting NS5A

PubMed

Rai, Diwakar; Wang, Liu; Jiang, Xuemei; Zhan, Peng; Jia, Haiyong; De Clercq, Erik; Liu, Xinyong

2015-05-05

Current treatment for HCV infections consists of approved direct acting antivirals (DAAs), viz. the protease inhibitors (boceprevir, telaprevir, and simeprevir), NS5B polymerase inhibitors (sofosbuvir) and NS5A inhibitor (ledipasvir) in combination with pegylated interferon α and ribavirin). These treatments have made a great improvement in the treatment of chronic HCV infections in recent years, but their adverse side effects, emergence of resistant mutants, high cost, and increased pill burden have limited their clinical use. Recently, with the increasing knowledge in understanding the HCV life cycle, more targets have been recognized. NS5A protein plays a critical role in assembly of infectious HCV particles and offering potential for HCV therapies. Therefore, discovery and development of novel DAAs targeting NS5A with novel mechanisms of action, is of great necessity to improve the quality of existing HCV treatments. In the present review, we discuss recent advances with NS5A inhibitors with potent anti-HCV activity, and the potential for the development of HCV NS5A inhibitors to combat HCV infections.

Plant lectins as defense proteins against phytophagous insects.

PubMed

Vandenborre, Gianni; Smagghe, Guy; Van Damme, Els J M

2011-09-01

One of the most important direct defense responses in plants against the attack by phytophagous insects is the production of insecticidal peptides or proteins. One particular class of entomotoxic proteins present in many plant species is the group of carbohydrate-binding proteins or lectins. During the last decade a lot of progress was made in the study of a few lectins that are expressed in response to herbivory by phytophagous insects and the insecticidal properties of plant lectins in general. This review gives an overview of lectins with high potential for the use in pest control strategies based on their activity towards pest insects. In addition, potential target sites for lectins inside the insect and the mode of action are discussed. In addition, the effect of plant lectins on non-target organisms such as beneficial insects as well as on human/animal consumers is discussed. It can be concluded that some insecticidal lectins are useful tools that can contribute to the development of integrated pest management strategies with minimal effect(s) on non-target organisms. Copyright © 2011 Elsevier Ltd. All rights reserved.

Terrorism in Canada.

PubMed

Kollek, Daniel

2003-01-01

This paper reviews terrorism in Canada, assessing the incidence and nature of terrorist activity, the potential targets of terrorist attacks, risk factors to Canadian nationals and institutions, and the responses of the Canadian government in dealing with the threat and the effectiveness of those responses. Despite the fact that there have been no recent high-profile terrorist events in Canada, this country has a serious terrorism problem, the key manifestation of which is the multitude of terrorist organizations that have designated Canada as a base of operations. In addition, Canadians have been attacked overseas and Canadian organizations, both local and abroad, are potential targets of terrorist activity. Canadian attempts to deal with terrorism through foreign and domestic policy have been ineffective, primarily because the policies have been poorly enforced. Until recently, terrorist organizations legally could raise funds in Canada, in direct contravention of international treaties signed by Canada. It is possible that the ineffectiveness in enforcing the anti-terrorism legislation stems from hope that placating terrorist organizations, and the countries that support them, will prevent Canada from becoming a target. Unfortunately evidence from other countries has shown this strategy to be ineffective.

Optogenetic control of mitochondrial metabolism and Ca2+ signaling by mitochondria-targeted opsins.

PubMed

Tkatch, Tatiana; Greotti, Elisa; Baranauskas, Gytis; Pendin, Diana; Roy, Soumitra; Nita, Luliaoana I; Wettmarshausen, Jennifer; Prigge, Matthias; Yizhar, Ofer; Shirihai, Orian S; Fishman, Daniel; Hershfinkel, Michal; Fleidervish, Ilya A; Perocchi, Fabiana; Pozzan, Tullio; Sekler, Israel

2017-06-27

Key mitochondrial functions such as ATP production, Ca 2+ uptake and release, and substrate accumulation depend on the proton electrochemical gradient (ΔμH + ) across the inner membrane. Although several drugs can modulate ΔμH + , their effects are hardly reversible, and lack cellular specificity and spatial resolution. Although channelrhodopsins are widely used to modulate the plasma membrane potential of excitable cells, mitochondria have thus far eluded optogenetic control. Here we describe a toolkit of optometabolic constructs based on selective targeting of channelrhodopsins with distinct functional properties to the inner mitochondrial membrane of intact cells. We show that our strategy enables a light-dependent control of the mitochondrial membrane potential (Δψ m ) and coupled mitochondrial functions such as ATP synthesis by oxidative phosphorylation, Ca 2+ dynamics, and respiratory metabolism. By directly modulating Δψ m , the mitochondria-targeted opsins were used to control complex physiological processes such as spontaneous beats in cardiac myocytes and glucose-dependent ATP increase in pancreatic β-cells. Furthermore, our optometabolic tools allow modulation of mitochondrial functions in single cells and defined cell regions.

An Essential Role for COPI in mRNA Localization to Mitochondria and Mitochondrial Function.

PubMed

Zabezhinsky, Dmitry; Slobodin, Boris; Rapaport, Doron; Gerst, Jeffrey E

2016-04-19

Nuclear-encoded mRNAs encoding mitochondrial proteins (mMPs) can localize directly to the mitochondrial surface, yet how mMPs target mitochondria and whether RNA targeting contributes to protein import into mitochondria and cellular metabolism are unknown. Here, we show that the COPI vesicle coat complex is necessary for mMP localization to mitochondria and mitochondrial function. COPI inactivation leads to reduced mMP binding to COPI itself, resulting in the dissociation of mMPs from mitochondria, a reduction in mitochondrial membrane potential, a decrease in protein import in vivo and in vitro, and severe deficiencies in mitochondrial respiration. Using a model mMP (OXA1), we observed that COPI inactivation (or mutation of the potential COPI-interaction site) led to altered mRNA localization and impaired cellular respiration. Overall, COPI-mediated mMP targeting is critical for mitochondrial protein import and function, and transcript delivery to the mitochondria or endoplasmic reticulum is regulated by cis-acting RNA sequences and trans-acting proteins. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

A Systems Biology-Based Investigation into the Pharmacological Mechanisms of Sheng-ma-bie-jia-tang Acting on Systemic Lupus Erythematosus by Multi-Level Data Integration.

PubMed

Huang, Lin; Lv, Qi; Liu, Fenfen; Shi, Tieliu; Wen, Chengping

2015-11-12

Sheng-ma-bie-jia-tang (SMBJT) is a Traditional Chinese Medicine (TCM) formula that is widely used for the treatment of Systemic Lupus Erythematosus (SLE) in China. However, molecular mechanism behind this formula remains unknown. Here, we systematically analyzed targets of the ingredients in SMBJT to evaluate its potential molecular mechanism. First, we collected 1,267 targets from our previously published database, the Traditional Chinese Medicine Integrated Database (TCMID). Next, we conducted gene ontology and pathway enrichment analyses for these targets and determined that they were enriched in metabolism (amino acids, fatty acids, etc.) and signaling pathways (chemokines, Toll-like receptors, adipocytokines, etc.). 96 targets, which are known SLE disease proteins, were identified as essential targets and the rest 1,171 targets were defined as common targets of this formula. The essential targets directly interacted with SLE disease proteins. Besides, some common targets also had essential connections to both key targets and SLE disease proteins in enriched signaling pathway, e.g. toll-like receptor signaling pathway. We also found distinct function of essential and common targets in immune system processes. This multi-level approach to deciphering the underlying mechanism of SMBJT treatment of SLE details a new perspective that will further our understanding of TCM formulas.

ROGER a potential orbital space debris removal system

NASA Astrophysics Data System (ADS)

Starke, Juergen; Bischof, Bernd; Foth, W.-O.; -J., J.; Günther

The previous activities in the field of On Orbit Servicing studied in the 1990's included in partic-ular the capability of vehicles in GEO to capture and support satellites (mainly communication satellites) to enable repair and continuation of operations, and finally the controlled transfer the target into a permanent graveyard orbit. The specific capture tools for these applications were mostly based on robotic systems to capture and fix the target under specific dynamic constraints (e.g. slowly tumbling target) without damage, and to allow the stabilization, re-orientation and potential repair of the target and subsequent release or transport to the final disposal orbit. Due to the drastically increasing number of debris particularly in the Low Earth Orbits (SSO) the active debris removal is now necessary to counteract to the predicted debris production cascade (Kessler Syndrome), which means the pollution of the total sphere in low earth orbit and not only the SSO area. In most of the debris congresses it was recommended to start removal with the still integrated systems as soon as possible. In the case of large debris objects, the soft capture system can be replaced by a simpler and robust system able to operate from a safe distance to the target and flexible enough to capture and hold different types of targets such as deactivated and/or defective satellites, upper stages and big fragments. These nominally non -cooperative targets might be partially destroyed by the capture process, but the production of additional debris shall be avoided. A major argument for the commercial applications is a multi-target mission potential, which is possible at GEO because the transfer propellant requirement to the disposal orbit and the return to the orbit of the next potential target is relative low (orbits with similar inclination and altitude). The proposed ROGER system is designed as a spacecraft with rendezvous capabilities including inspection in the vicinity of the target and stabilization and transportation features for the combined configuration. The capture system is a deployable and closable net. The net is ejected from the mother spacecraft at a safe distance to prevent any collision with the target. After transport to the disposal orbit the net will be cut and the spacecraft will return to the operational orbit of the next target. An initial down-scaled demonstration is planned for the net capture system on a parabolic flight in autumn 2010. Further representative demonstrations including, for example, one in LEO are under discussion. The capture system can be used operationally also in other orbits e.g. LEO, but the propellant requirements for transport of the target into a direct controlled re-entry orbit and the subsequent return of the mother spacecraft to a new target orbit will be very high. This could impact the multi mission capability of the system. The potential applications are under discussion with different customers including satellite operators, insurance companies and international organisations. juergen.starke@astrium.eads.net Tel.: +49-421-539-4573

Potential evolution of neurosurgical treatment paradigms for craniopharyngioma based on genomic and transcriptomic characteristics.

PubMed

Robinson, Leslie C; Santagata, Sandro; Hankinson, Todd C

2016-12-01

The recent genomic and transcriptomic characterization of human craniopharyngiomas has provided important insights into the pathogenesis of these tumors and supports that these tumor types are distinct entities. Critically, the insights provided by these data offer the potential for the introduction of novel therapies and surgical treatment paradigms for these tumors, which are associated with high morbidity rates and morbid conditions. Mutations in the CTNNB1 gene are primary drivers of adamantinomatous craniopharyngioma (ACP) and lead to the accumulation of β-catenin protein in a subset of the nuclei within the neoplastic epithelium of these tumors. Dysregulation of epidermal growth factor receptor (EGFR) and of sonic hedgehog (SHH) signaling in ACP suggest that paracrine oncogenic mechanisms may underlie ACP growth and implicate these signaling pathways as potential targets for therapeutic intervention using directed therapies. Recent work shows that ACP cells have primary cilia, further supporting the potential importance of SHH signaling in the pathogenesis of these tumors. While further preclinical data are needed, directed therapies could defer, or replace, the need for radiation therapy and/or allow for less aggressive surgical interventions. Furthermore, the prospect for reliable control of cystic disease without the need for surgery now exists. Studies of papillary craniopharyngioma (PCP) are more clinically advanced than those for ACP. The vast majority of PCPs harbor the BRAF v600e mutation. There are now 2 reports of patients with PCP that had dramatic therapeutic responses to targeted agents. Ongoing clinical and research studies promise to not only advance our understanding of these challenging tumors but to offer new approaches for patient management.

Extended Fitts' model of pointing time in eye-gaze input system - Incorporating effects of target shape and movement direction into modeling.

PubMed

Murata, Atsuo; Fukunaga, Daichi

2018-04-01

This study attempted to investigate the effects of the target shape and the movement direction on the pointing time using an eye-gaze input system and extend Fitts' model so that these factors are incorporated into the model and the predictive power of Fitts' model is enhanced. The target shape, the target size, the movement distance, and the direction of target presentation were set as within-subject experimental variables. The target shape included: a circle, and rectangles with an aspect ratio of 1:1, 1:2, 1:3, and 1:4. The movement direction included eight directions: upper, lower, left, right, upper left, upper right, lower left, and lower right. On the basis of the data for identifying the effects of the target shape and the movement direction on the pointing time, an attempt was made to develop a generalized and extended Fitts' model that took into account the movement direction and the target shape. As a result, the generalized and extended model was found to fit better to the experimental data, and be more effective for predicting the pointing time for a variety of human-computer interaction (HCI) task using an eye-gaze input system. Copyright © 2017. Published by Elsevier Ltd.

Targeting Anti-Cancer Active Compounds: Affinity-Based Chromatographic Assays

PubMed Central

de Moraes, Marcela Cristina; Cardoso, Carmen Lucia; Seidl, Claudia; Moaddel, Ruin; Cass, Quezia Bezerra

2016-01-01

Affinity-based chromatography assays encompass the use of solid supports containing immobilized biological targets to monitor binding events in the isolation , identification and/or characterization of bioactive compounds. This powerful bioanalytical technique allows the screening of potential binders through fast analyses that can be directly performed using isolated substances or complex matrices. An overview of the recent researches in frontal and zonal affinity-based chromatography screening assays, which has been used as a tool in the identification and characterization of new anti-cancer agents, is discussed. In addition, a critical evaluation of the recently emerged ligands fishing assays in complex mixtures is also discussed. PMID:27306095

Laser location and manipulation of a single quantum tunneling channel in an InAs quantum dot.

PubMed

Makarovsky, O; Vdovin, E E; Patané, A; Eaves, L; Makhonin, M N; Tartakovskii, A I; Hopkinson, M

2012-03-16

We use a femtowatt focused laser beam to locate and manipulate a single quantum tunneling channel associated with an individual InAs quantum dot within an ensemble of dots. The intensity of the directed laser beam tunes the tunneling current through the targeted dot with an effective optical gain of 10(7) and modifies the curvature of the dot's confining potential and the spatial extent of its ground state electron eigenfunction. These observations are explained by the effect of photocreated hole charges which become bound close to the targeted dot, thus acting as an optically induced gate electrode.

Sperm fibrous sheath proteins: a potential new class of target antigens for use in human therapeutic cancer vaccines

PubMed Central

Chiriva-Internati, Maurizio; Cobos, Everardo; Da Silva, Diane M.

2008-01-01

Cancer vaccines have been demonstrated to be a promising strategy for treating human neoplastic disease, but one of the limitations of these vaccines remains the paucity of target antigens to which to direct an effective immune response. We hypothesize that sperm fibrous sheath proteins may be a new class of useful antigens for developing successful cancer vaccines. This hypothesis is supported by the expression of two sperm fibrous sheath proteins, called sperm protein 17 and calcium-binding tyrosine-phosphorylation regulated protein, in tumors of unrelated histological origin and their capability to induce T cell-based immune responses. PMID:18433090

Biomimetic High Density Lipoprotein Nanoparticles For Nucleic Acid Delivery

PubMed Central

McMahon, Kaylin M.; Mutharasan, R. Kannan; Tripathy, Sushant; Veliceasa, Dorina; Bobeica, Mariana; Shumaker, Dale K.; Luthi, Andrea J.; Helfand, Brian T.; Ardehali, Hossein; Mirkin, Chad A.; Volpert, Olga; Thaxton, C. Shad

2014-01-01

We report a gold nanoparticle-templated high density lipoprotein (HDL AuNP) platform for gene therapy which combines lipid-based nucleic acid transfection strategies with HDL biomimicry. For proof-of-concept, HDL AuNPs are shown to adsorb antisense cholesterylated DNA. The conjugates are internalized by human cells, can be tracked within cells using transmission electron microscopy (TEM), and regulate target gene expression. Overall, the ability to directly image the AuNP core within cells, the chemical tailorability of the HDL AuNP platform, and the potential for cell-specific targeting afforded by HDL biomimicry make this platform appealing for nucleic acid delivery. PMID:21319839

Direct detection of sub-GeV dark matter with semiconductor targets

DOE PAGES

Essig, Rouven; Fernández-Serra, Marivi; Mardon, Jeremy; ...

2016-05-09

Dark matter in the sub-GeV mass range is a theoretically motivated but largely unexplored paradigm. Such light masses are out of reach for conventional nuclear recoil direct detection experiments, but may be detected through the small ionization signals caused by dark matter-electron scattering. Semiconductors are well-studied and are particularly promising target materials because their O(1 eV) band gaps allow for ionization signals from dark matter particles as light as a few hundred keV. Current direct detection technologies are being adapted for dark matter-electron scattering. In this paper, we provide the theoretical calculations for dark matter-electron scattering rate in semiconductors, overcomingmore » several complications that stem from the many-body nature of the problem. We use density functional theory to numerically calculate the rates for dark matter-electron scattering in silicon and germanium, and estimate the sensitivity for upcoming experiments such as DAMIC and SuperCDMS. We find that the reach for these upcoming experiments has the potential to be orders of magnitude beyond current direct detection constraints and that sub-GeV dark matter has a sizable modulation signal. We also give the first direct detection limits on sub-GeV dark matter from its scattering off electrons in a semiconductor target (silicon) based on published results from DAMIC. We make available publicly our code, QEdark, with which we calculate our results. Our results can be used by experimental collaborations to calculate their own sensitivities based on their specific setup. In conclusion, the searches we propose will probe vast new regions of unexplored dark matter model and parameter space.« less

MiRNA-335 suppresses neuroblastoma cell invasiveness by direct targeting of multiple genes from the non-canonical TGF-β signalling pathway

PubMed Central

Lynch, Jennifer; Fay, Joanna; Meehan, Maria; Bryan, Kenneth; Watters, Karen M.; Murphy, Derek M.; Stallings, Raymond L.

2012-01-01

Transforming growth factor-β (TGF-β) signaling regulates many diverse cellular activities through both canonical (SMAD-dependent) and non-canonical branches, which includes the mitogen-activated protein kinase (MAPK), Rho-like guanosine triphosphatase and phosphatidylinositol-3-kinase/AKT pathways. Here, we demonstrate that miR-335 directly targets and downregulates genes in the TGF-β non-canonical pathways, including the Rho-associated coiled-coil containing protein (ROCK1) and MAPK1, resulting in reduced phosphorylation of downstream pathway members. Specifically, inhibition of ROCK1 and MAPK1 reduces phosphorylation levels of the motor protein myosin light chain (MLC) leading to a significant inhibition of the invasive and migratory potential of neuroblastoma cells. Additionally, miR-335 targets the leucine-rich alpha-2-glycoprotein 1 (LRG1) messenger RNA, which similarly results in a significant reduction in the phosphorylation status of MLC and a decrease in neuroblastoma cell migration and invasion. Thus, we link LRG1 to the migratory machinery of the cell, altering its activity presumably by exerting its effect within the non-canonical TGF-β pathway. Moreover, we demonstrate that the MYCN transcription factor, whose coding sequence is highly amplified in a particularly clinically aggressive neuroblastoma tumor subtype, directly binds to a region immediately upstream of the miR-335 transcriptional start site, resulting in transcriptional repression. We conclude that MYCN contributes to neuroblastoma cell migration and invasion, by directly downregulating miR-335, resulting in the upregulation of the TGF-β signaling pathway members ROCK1, MAPK1 and putative member LRG1, which positively promote this process. Our results provide novel insight into the direct regulation of TGF-β non-canonical signaling by miR-335, which in turn is downregulated by MYCN. PMID:22382496

Asymptotic and near-target direct breakup of 6Li and 7Li

NASA Astrophysics Data System (ADS)

Kalkal, Sunil; Simpson, E. C.; Luong, D. H.; Cook, K. J.; Dasgupta, M.; Hinde, D. J.; Carter, I. P.; Jeung, D. Y.; Mohanto, G.; Palshetkar, C. S.; Prasad, E.; Rafferty, D. C.; Simenel, C.; Vo-Phuoc, K.; Williams, E.; Gasques, L. R.; Gomes, P. R. S.; Linares, R.

2016-04-01

Background: Li,76 and 9Be are weakly bound against breakup into their cluster constituents. Breakup location is important for determining the role of breakup in above-barrier complete fusion suppression. Recent works have pointed out that experimental observables can be used to separate near-target and asymptotic breakup. Purpose: Our purpose is to distinguish near-target and asymptotic direct breakup of Li,76 in reactions with nuclei in different mass regions. Method: Charged particle coincidence measurements are carried out with pulsed Li,76 beams on 58Ni and 64Zn targets at sub-barrier energies and compared with previous measurements using 208Pb and 209Bi targets. A detector array providing a large angular coverage is used, along with time-of-flight information to give definitive particle identification of the direct breakup fragments. Results: In interactions of 6Li with 58Ni and 64Zn, direct breakup occurs only asymptotically far away from the target. However, in interactions with 208Pb and 209Bi, near-target breakup occurs in addition to asymptotic breakup. Direct breakup of 7Li into α -t is not observed in interactions with 58Ni and 64Zn. However, near-target dominated direct breakup was observed in measurements with 208Pb and 209Bi. A modified version of the Monte Carlo classical trajectory model code platypus, which explicitly takes into account lifetimes associated with unbound states, is used to simulate sub-barrier breakup reactions. Conclusions: Near-target breakup in interactions with Li,76 is an important mechanism only for the heavy targets 208Pb and 209Bi. There is insignificant near-target direct breakup of 6Li and no direct breakup of 7Li in reactions with 58Ni and 64Zn. Therefore, direct breakup is unlikely to suppress the above-barrier fusion cross section in reactions of Li,76 with 58Ni and 64Zn nuclei.

Human eosinophils are direct targets to nanoparticles: Zinc oxide nanoparticles (ZnO) delay apoptosis and increase the production of the pro-inflammatory cytokines IL-1β and IL-8.

PubMed

Silva, Luis Rafael; Girard, Denis

2016-09-30

Zinc oxide NPs (ZnO) have been recently proposed as novel candidates for the treatment of allergic inflammatory diseases. Paradoxically, recent data suggested that ZnO could cause eosinophilic airway inflammation in rodents. Despite the above observations, there are currently no studies reporting direct interaction between a given NP and human eosinophils themselves. In this study, freshly isolated human eosinophils were incubated with ZnO and several cellular functions were studied. We found that ZnO delay human eosinophil apoptosis, partially by inhibiting caspases and by preventing caspase-4 and Bcl-xL degradation. ZnO do not induce production of reactive oxygen species but increase de novo protein synthesis. In addition, ZnO were found to increase the production of the proinflammatory IL-1β and IL-8 cytokines. Using a pharmacological approach, we demonstrated that inhibition of caspase-1 reversed the ability of ZnO to induce IL-1β and IL-8 production, whereas inhibition of caspase-4 only reversed that of IL-8. Our results indicate the necessity of conducting studies to determine the potential of using NP as nanotherapies, particularly in diseases in which eosinophils may be involved. We conclude that, indeed, human eosinophils represent potential new direct targets to NPs, ZnO in the present case. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

The E3 ubiquitin ligase Nedd4/Nedd4L is directly regulated by microRNA 1

PubMed Central

Heidersbach, Amy; Kathiriya, Irfan S.; Garay, Bayardo I.; Ivey, Kathryn N.

2017-01-01

miR-1 is a small noncoding RNA molecule that modulates gene expression in heart and skeletal muscle. Loss of Drosophila miR-1 produces defects in somatic muscle and embryonic heart development, which have been partly attributed to miR-1 directly targeting Delta to decrease Notch signaling. Here, we show that overexpression of miR-1 in the fly wing can paradoxically increase Notch activity independently of its effects on Delta. Analyses of potential miR-1 targets revealed that miR-1 directly regulates the 3′UTR of the E3 ubiquitin ligase Nedd4. Analysis of embryonic and adult fly heart revealed that the Nedd4 protein regulates heart development in Drosophila. Larval fly hearts overexpressing miR-1 have profound defects in actin filament organization that are partially rescued by concurrent overexpression of Nedd4. These results indicate that miR-1 and Nedd4 act together in the formation and actin-dependent patterning of the fly heart. Importantly, we have found that the biochemical and genetic relationship between miR-1 and the mammalian ortholog Nedd4-like (Nedd4l) is evolutionarily conserved in the mammalian heart, potentially indicating a role for Nedd4L in mammalian postnatal maturation. Thus, miR-1-mediated regulation of Nedd4/Nedd4L expression may serve to broadly modulate the trafficking or degradation of Nedd4/Nedd4L substrates in the heart. PMID:28246214

Nanotechnology Applications for Glioblastoma

PubMed Central

Nduom, Edjah; Bouras, Alexandros; Kaluzova, Milota; Hadjipanayis, Costas G.

2012-01-01

Synopsis Glioblastoma remains one of the most difficult cancers to treat and represents the most common primary malignancy of the brain. While conventional treatments have found modest success in reducing the initial tumor burden, infiltrating cancer cells beyond the main mass are responsible for tumor recurrence and ultimate patient demise. Targeting the residual infiltrating cancer cells requires the development of new treatment strategies. The emerging field of cancer nanotechnology holds much promise in the use of multifunctional nanoparticles for the imaging and targeted therapy of GBM.. Nanoparticles have emerged as potential “theranostic” agents that can permit the diagnosis and therapeutic treatment of GBM tumors. A recent human clinical trial with magnetic nanoparticles has provided feasibility and efficacy data for potential treatment of GBM patients with thermotherapy. Here we examine the current state of nanotechnology in the treatment of glioblastoma and interesting directions of further study. PMID:22748656

Peripheral elastic and inelastic scattering of 17,18O on light targets at 12 MeV/nucleon

NASA Astrophysics Data System (ADS)

Carstoiu, F.; Al-Abdullah, T.; Gagliardi, C. A.; Trache, L.

2015-02-01

The elastic and inelastic scattering of 17,18O with light targets has been undertaken at 12 MeV/nucleon in order to determine the optical potentials needed for the transfer reaction 13C (17O ,18O )12C . Optical potentials in both incoming and outgoing channels have been determined in a single experiment. This transfer reaction was used to infer the direct capture rate to the 17F ( p ,γ)18Ne which is essential to estimate the production of 18F at stellar energies in ONe novae. We demonstrate the stability of the ANC method and OMP results using good quality elastic and inelastic scattering data with stable beams. The peripherality of our reaction is inferred from a semiclassical decomposition of the total scattering amplitude into barrier and internal barrier components. Comparison between elastic scattering of 17O , 18O and 16O projectiles is made.

How the adoption of impression management goals alters impression formation.

PubMed

Gibson, Bryan; Poposki, Elizabeth M

2010-11-01

Five experiments (N = 390) tested the hypothesis that adopting an impression management goal leads the impression manager to view an interaction partner as having less of the trait he or she is attempting to express. This hypothesis was confirmed for the impression management goals of appearing introverted, extraverted, smart, confident, and happy. Experiment 2 shows that adoption of the impression goal could alter judgments even when participants could not act on the goal. Experiment 3 provides evidence that adopting an impression management goal prompted a comparison mind-set and that this comparison mind-set activation mediated target judgments. Experiment 4 rules out a potential alternative explanation and provides more direct evidence that comparison of the impression manager's self-concept mediates the impression of the target. Experiment 5 eliminates a potential confound and extends the effect to another impression goal. These experiments highlight the dynamic interplay between impression management and impression formation.

mTOR Inhibitors in Children: Current Indications and Future Directions in Neurology.

PubMed

Jeong, Anna; Wong, Michael

2016-12-01

The mammalian/mechanistic target of rapamycin (mTOR) pathway is a key signaling pathway that has been implicated in genetic epilepsy syndromes, neurodegenerative diseases, and conditions associated with autism spectrum disorder and cognitive impairment. The mTOR pathway has become an exciting treatment target for these various disorders, with mTOR inhibitors such as rapamycin being studied for their potential therapeutic applications. In particular, tuberous sclerosis complex (TSC) is a genetic disorder resulting from overactivation of the mTOR pathway, and pharmacologic therapy with mTOR inhibitors has emerged as a viable treatment option for the systemic manifestations of the disease. In this review, we discuss the approved indications for mTOR inhibitors in TSC, the potential future applications of mTOR inhibitors in TSC and other neurological conditions, and the safety considerations applicable to mTOR therapy in the pediatric population.

Optimizing Cognitive Function in Persons With Chronic Pain.

PubMed

Baker, Katharine S; Georgiou-Karistianis, Nellie; Gibson, Stephen J; Giummarra, Melita J

2017-05-01

Cognitive functioning is commonly disrupted in people living with chronic pain, yet it is an aspect of pain that is often not routinely assessed in pain management settings, and there is a paucity of research on treatments or strategies to alleviate the problem. The purpose of this review is to outline recent research on cognitive deficits seen in chronic pain, to give an overview of the mechanisms involved, advocate cognitive functioning as an important target for treatment in pain populations, and discuss ways in which it may be assessed and potentially remediated. A narrative review. There are several options for remediation, including compensatory, restorative, and neuromodulatory approaches to directly modify cognitive functioning, as well as physical, psychological, and medication optimization methods to target secondary factors (mood, sleep, and medications) that may interfere with cognition. We highlight the potential to enhance cognitive functions and identify the major gaps in the research literature.

Why Do People Regulate Their Emotions? A Taxonomy of Motives in Emotion Regulation.

PubMed

Tamir, Maya

2016-08-01

Emotion regulation involves the pursuit of desired emotional states (i.e., emotion goals) in the service of superordinate motives. The nature and consequences of emotion regulation, therefore, are likely to depend on the motives it is intended to serve. Nonetheless, limited attention has been devoted to studying what motivates emotion regulation. By mapping the potential benefits of emotion to key human motives, this review identifies key classes of motives in emotion regulation. The proposed taxonomy distinguishes between hedonic motives that target the immediate phenomenology of emotions, and instrumental motives that target other potential benefits of emotions. Instrumental motives include behavioral, epistemic, social, and eudaimonic motives. The proposed taxonomy offers important implications for understanding the mechanism of emotion regulation, variation across individuals and contexts, and psychological function and dysfunction, and points to novel research directions. © 2015 by the Society for Personality and Social Psychology, Inc.

Dihydroartemisinin selectively inhibits PDGFRα-positive ovarian cancer growth and metastasis through inducing degradation of PDGFRα protein

PubMed Central

Li, Xiaoguang; Ba, Qian; Liu, Yanling; Yue, Qingxi; Chen, Peizhan; Li, Jingquan; Zhang, Haibing; Ying, Hao; Ding, Qiurong; Song, Haiyun; Liu, Hong; Zhang, Ruiwen; Wang, Hui

2017-01-01

To develop traditional medicines as modern pharmacotherapies, understanding their molecular mechanisms of action can be very helpful. We have recently reported that Artemisinin and its derivatives, which are clinically used anti-malarial drugs, have significant effects against ovarian cancer, but the direct molecular targets and related combination therapy have been unclear. Herein, we report that dihydroartemisinin, one of the most active derivatives of Artemisinin, directly targets platelet-derived growth factor receptor-alpha (PDGFRα) to inhibit ovarian cancer cell growth and metastasis. Dihydroartemisinin directly binds to the intercellular domain of PDGFRα, reducing its protein stability by accelerating its ubiquitin-mediated degradation, which further inactivates downstream phosphoinositide 3-Kinase and mitogen-activated protein kinase pathways and subsequently represses epithelial–mesenchymal transition, inhibiting cell growth and metastasis of PDGFRα-positive ovarian cancer in vitro and in vivo. A combinational treatment reveals that dihydroartemisinin sensitizes ovarian cancer cells to PDGFR inhibitors. Our clinical study also finds that PDGFRα is overexpressed and positively correlated with high grade and metastasis in human ovarian cancer. Considering that Artemisinin compounds are currently clinically used drugs with favorable safety profiles, the results from this study will potentiate their use in combination with clinically used PDGFRα inhibitors, leading to maximal therapeutic efficacy with minimal adverse effects in PDGFRα-positive cancer patients. These findings also shed high light on future development of novel Artemisinin-based targeted therapy. PMID:29387451

Dihydroartemisinin selectively inhibits PDGFRα-positive ovarian cancer growth and metastasis through inducing degradation of PDGFRα protein.

PubMed

Li, Xiaoguang; Ba, Qian; Liu, Yanling; Yue, Qingxi; Chen, Peizhan; Li, Jingquan; Zhang, Haibing; Ying, Hao; Ding, Qiurong; Song, Haiyun; Liu, Hong; Zhang, Ruiwen; Wang, Hui

2017-01-01

To develop traditional medicines as modern pharmacotherapies, understanding their molecular mechanisms of action can be very helpful. We have recently reported that Artemisinin and its derivatives, which are clinically used anti-malarial drugs, have significant effects against ovarian cancer, but the direct molecular targets and related combination therapy have been unclear. Herein, we report that dihydroartemisinin, one of the most active derivatives of Artemisinin, directly targets platelet-derived growth factor receptor-alpha (PDGFRα) to inhibit ovarian cancer cell growth and metastasis. Dihydroartemisinin directly binds to the intercellular domain of PDGFRα, reducing its protein stability by accelerating its ubiquitin-mediated degradation, which further inactivates downstream phosphoinositide 3-Kinase and mitogen-activated protein kinase pathways and subsequently represses epithelial-mesenchymal transition, inhibiting cell growth and metastasis of PDGFRα-positive ovarian cancer in vitro and in vivo . A combinational treatment reveals that dihydroartemisinin sensitizes ovarian cancer cells to PDGFR inhibitors. Our clinical study also finds that PDGFRα is overexpressed and positively correlated with high grade and metastasis in human ovarian cancer. Considering that Artemisinin compounds are currently clinically used drugs with favorable safety profiles, the results from this study will potentiate their use in combination with clinically used PDGFRα inhibitors, leading to maximal therapeutic efficacy with minimal adverse effects in PDGFRα-positive cancer patients. These findings also shed high light on future development of novel Artemisinin-based targeted therapy.

The Automaticity of Affordance of Dangerous Object.

PubMed

Zhao, Liang

2016-11-03

Objects observation automatically elicits the activation of a reach-to-grasp response specifically directed to interact with the object, which is termed affordance. Murphy, van Velzen, and de Fockert (2012) found that only when an irrelevant object receives sufficient attention, it can potentiate an action. However, it remains unclear whether the dangerous object would afford an action when it receives insufficient attention. In this study, we manipulated the perceptual load in a letter identification task. Participants were required to identify a target letter with the right or left hand while ignoring a neutral or dangerous graspable object. The target letter was presented either on its own (low perceptual load), alongside five non-target letters (high load), or alongside eight non-target letters (super high load). Under the low perceptual load, for both neutral and dangerous object, responses were faster when the action afforded by the ignored object was congruent (vs. incongruent) with the current target response (t(27) = 4.44, p < .001; t(27) = 7.99, p < .001, respectively). However, during the high perceptual load, for dangerous object, responses were slower when the action afforded by the ignored object was congruent (vs. incongruent) with the current target response (t(27) = 4.97, p < .001). There was not any effect for both neutral object and dangerous object under super high perceptual load. These results suggest the affordance of dangerous object is also sensitive to the perceptual load. An irrelevant dangerous object can't potentiate an action if it receives insufficient attention.

Chemical approaches to targeted protein degradation through modulation of the ubiquitin-proteasome pathway.

PubMed

Collins, Ian; Wang, Hannah; Caldwell, John J; Chopra, Raj

2017-03-15

Manipulation of the ubiquitin-proteasome system to achieve targeted degradation of proteins within cells using chemical tools and drugs has the potential to transform pharmacological and therapeutic approaches in cancer and other diseases. An increased understanding of the molecular mechanism of thalidomide and its analogues following their clinical use has unlocked small-molecule modulation of the substrate specificity of the E3 ligase cereblon (CRBN), which in turn has resulted in the advancement of new immunomodulatory drugs (IMiDs) into the clinic. The degradation of multiple context-specific proteins by these pleiotropic small molecules provides a means to uncover new cell biology and to generate future drug molecules against currently undruggable targets. In parallel, the development of larger bifunctional molecules that bring together highly specific protein targets in complexes with CRBN, von Hippel-Lindau, or other E3 ligases to promote ubiquitin-dependent degradation has progressed to generate selective chemical compounds with potent effects in cells and in vivo models, providing valuable tools for biological target validation and with future potential for therapeutic use. In this review, we survey recent breakthroughs achieved in these two complementary methods and the discovery of new modes of direct and indirect engagement of target proteins with the proteasome. We discuss the experimental characterisation that validates the use of molecules that promote protein degradation as chemical tools, the preclinical and clinical examples disclosed to date, and the future prospects for this exciting area of chemical biology. © 2017 The Author(s).

MiroRNA-188 Acts as Tumor Suppressor in Non-Small-Cell Lung Cancer by Targeting MAP3K3.

PubMed

Zhao, Lili; Ni, Xin; Zhao, Linlin; Zhang, Yao; Jin, Dan; Yin, Wei; Wang, Dandan; Zhang, Wei

2018-04-02

Non-small cell lung cancer (NSCLC) is the most prevalent form of lung cancer. MicroRNAs have been increasingly implicated in NSCLC and may serve as novel therapeutic targets to combat cancer. Here we investigated the functional implication of miR-188 in NSCLC. We first analyzed miR-188 expression in both NSCLC clinical samples and cancer cell lines. Next we investigated its role in A549 and H2126 cells with cell proliferation, migration, and apoptosis assays. To extend the in vitro study, we employed both xenograft model and LSL- K-ras G12D lung cancer model to examine the role of miR-188 in tumorigenesis. Last we tested MAP3K3 as miR-188 target in NSCLC model. MiR-188 expression was significantly downregulated at the NSCLC tumor sites and lung cancer cells. In vitro transfection of miR-188 reduced cell proliferation and migration potential and promoted cell apoptosis. In xenograft model, miR-188 inhibited tumor growth derived from cancer cells. Intranasal miR-188 administration reduced tumor formation in NSCLC animal model. MAP3K3 was validated as direct target of miR-188. Knocking down MAP3K3 in mice also inhibited tumorigenesis in LSL- K-ras G12D model. Our results demonstrate that miR-188 and its downstream target MAP3K3 could be a potential therapeutic target for NSCLC.

Neuropeptide Y Y1 receptors meditate targeted delivery of anticancer drug with encapsulated nanoparticles to breast cancer cells with high selectivity and its potential for breast cancer therapy.

PubMed

Li, Juan; Shen, Zheyu; Ma, Xuehua; Ren, Wenzhi; Xiang, Lingchao; Gong, An; Xia, Tian; Guo, Junming; Wu, Aiguo

2015-03-11

By enabling nanoparticle-based drug delivery system to actively target cancer cells with high selectivity, active targeted molecules have attracted great attention in the application of nanoparticles for anticancer drug delivery. However, the clinical application of most active targeted molecules in breast cancer therapy is limited, due to the low expression of their receptors in breast tumors or coexpression in the normal and tumor breast tissues. Here, a neuropeptide Y Y1 receptors ligand PNBL-NPY, as a novel targeted molecule, is conjugated with anticancer drug doxorubicin encapsulating albumin nanoparticles to investigate the effect of Y1 receptors on the delivery of drug-loaded nanoparticles to breast cancer cells and its potential for breast cancer therapy. The PNBL-NPY can actively recognize and bind to the Y1 receptors that are significantly overexpressed on the surface of the breast cancer cells, and the drug-loaded nanoparticles are delivered directly into the cancer cells through internalization. This system is highly selective and able to distinguish the breast cancer cells from the normal cells, due to normal breast cells that express Y2 receptors only. It is anticipated that this study may provide a guidance in the development of Y1 receptor-based nanoparticulate drug delivery system for a safer and more efficient breast cancer therapy.

Direct-to-consumer genetic testing: where and how does genetic counseling fit?

PubMed

Middleton, Anna; Mendes, Álvaro; Benjamin, Caroline M; Howard, Heidi Carmen

2017-05-01

Direct-to-consumer genetic testing for disease ranges from well-validated diagnostic and predictive tests to 'research' results conferring increased risks. While being targeted at public curious about their health, they are also marketed for use in reproductive decision-making or management of disease. By virtue of being 'direct-to-consumer' much of this testing bypasses traditional healthcare systems. We argue that direct-to-consumer genetic testing companies should make genetic counseling available, pre- as well as post-test. While we do not advocate that mandatory genetic counseling should gate-keep access to direct-to-consumer genetic testing, if the testing process has the potential to cause psychological distress, then companies have a responsibility to provide support and should not rely on traditional healthcare systems to pick up the pieces. A video abstract is available for this article via this link .

An Integrated Analysis of miRNA and mRNA Expressions in Non-Small Cell Lung Cancers

PubMed Central

Ma, Lina; Huang, Yanyan; Zhu, Wangyu; Zhou, Shiquan; Zhou, Jihang; Zeng, Fang; Liu, Xiaoguang; Zhang, Yongkui; Yu, Jun

2011-01-01

Using DNA microarrays, we generated both mRNA and miRNA expression data from 6 non-small cell lung cancer (NSCLC) tissues and their matching normal control from adjacent tissues to identify potential miRNA markers for diagnostics. We demonstrated that hsa-miR-96 is significantly and consistently up-regulated in all 6 NSCLCs. We validated this result in an independent set of 35 paired tumors and their adjacent normal tissues, as well as their sera that are collected before surgical resection or chemotherapy, and the results suggested that hsa-miR-96 may play an important role in NSCLC development and has great potential to be used as a noninvasive marker for diagnosing NSCLC. We predicted potential miRNA target mRNAs based on different methods (TargetScan and miRanda). Further classification of miRNA regulated genes based on their relationship with miRNAs revealed that hsa-miR-96 and certain other miRNAs tend to down-regulate their target mRNAs in NSCLC development, which have expression levels permissive to direct interaction between miRNAs and their target mRNAs. In addition, we identified a significant correlation of miRNA regulation with genes coincide with high density of CpG islands, which suggests that miRNA may represent a primary regulatory mechanism governing basic cellular functions and cell differentiations, and such mechanism may be complementary to DNA methylation in repressing or activating gene expression. PMID:22046296

Highly Sensitive Detection of Target Biomolecules on Cell Surface Using Gold Nanoparticle Conjugated with Aptamer Probe

NASA Astrophysics Data System (ADS)

Kim, Hyonchol; Terazono, Hideyuki; Hayashi, Masahito; Takei, Hiroyuki; Yasuda, Kenji

2012-06-01

A method of gold nanoparticle (Au NP) labeling with backscattered electron (BE) imaging of field emission scanning electron microscopy (FE-SEM) was applied for specific detection of target biomolecules on a cell surface. A single-stranded DNA aptamer, which specifically binds to the target molecule on a human acute lymphoblastic leukemia cell, was conjugated with a 20 nm Au NP and used as a probe to label its target molecule on the cell. The Au NP probe was incubated with the cell, and the interaction was confirmed using BE imaging of FE-SEM through direct counting of the number of Au NPs attached on the target cell surface. Specific Au NP-aptamer probes were observed on a single cell surface and their spatial distributions including submicron-order localizations were also clearly visualized, whereas the nonspecific aptamer probes were not observed on it. The aptamer probe can be potentially dislodged from the cell surface with treatment of nucleases, indicating that Au NP-conjugated aptamer probes can be used as sensitive and reversible probes to label target biomolecules on cells.

Spleen tyrosine kinase (Syk), a novel target of curcumin, is required for B lymphoma growth.

PubMed

Gururajan, Murali; Dasu, Trivikram; Shahidain, Seif; Jennings, C Darrell; Robertson, Darrell A; Rangnekar, Vivek M; Bondada, Subbarao

2007-01-01

Curcumin (diferuloylmethane), a component of dietary spice turmeric (Curcuma longa), has been shown in recent studies to have therapeutic potential in the treatment of cancer, diabetes, arthritis, and osteoporosis. We investigated the ability of curcumin to modulate the growth of B lymphomas. Curcumin inhibited the growth of both murine and human B lymphoma in vitro and murine B lymphoma in vivo. We also demonstrate that curcumin-mediated growth inhibition of B lymphoma is through inhibition of the survival kinase Akt and its key target Bad. However, in vitro kinase assays show that Akt is not a direct target of curcumin. We identified a novel target for curcumin in B lymphoma viz spleen tyrosine kinase (Syk). Syk is constitutively activated in primary tumors and B lymphoma cell lines and curcumin down-modulates Syk activity accompanied by down-regulation of Akt activation. Moreover, we show that overexpression of Akt, a target of Syk, or Bcl-x(L), a target of Akt can overcome curcumin-induced apoptosis of B lymphoma cells. These observations suggest a novel growth promoting role for Syk in lymphoma cells.

Integrated nanotechnology platform for tumor-targeted multimodal imaging and therapeutic cargo release

PubMed Central

Hosoya, Hitomi; Dobroff, Andrey S.; Driessen, Wouter H. P.; Cristini, Vittorio; Brinker, Lina M.; Staquicini, Fernanda I.; Cardó-Vila, Marina; D’Angelo, Sara; Ferrara, Fortunato; Proneth, Bettina; Lin, Yu-Shen; Dunphy, Darren R.; Dogra, Prashant; Melancon, Marites P.; Stafford, R. Jason; Miyazono, Kohei; Gelovani, Juri G.; Kataoka, Kazunori; Brinker, C. Jeffrey; Sidman, Richard L.; Arap, Wadih; Pasqualini, Renata

2016-01-01

A major challenge of targeted molecular imaging and drug delivery in cancer is establishing a functional combination of ligand-directed cargo with a triggered release system. Here we develop a hydrogel-based nanotechnology platform that integrates tumor targeting, photon-to-heat conversion, and triggered drug delivery within a single nanostructure to enable multimodal imaging and controlled release of therapeutic cargo. In proof-of-concept experiments, we show a broad range of ligand peptide-based applications with phage particles, heat-sensitive liposomes, or mesoporous silica nanoparticles that self-assemble into a hydrogel for tumor-targeted drug delivery. Because nanoparticles pack densely within the nanocarrier, their surface plasmon resonance shifts to near-infrared, thereby enabling a laser-mediated photothermal mechanism of cargo release. We demonstrate both noninvasive imaging and targeted drug delivery in preclinical mouse models of breast and prostate cancer. Finally, we applied mathematical modeling to predict and confirm tumor targeting and drug delivery. These results are meaningful steps toward the design and initial translation of an enabling nanotechnology platform with potential for broad clinical applications. PMID:26839407

Integrated nanotechnology platform for tumor-targeted multimodal imaging and therapeutic cargo release.

PubMed

Hosoya, Hitomi; Dobroff, Andrey S; Driessen, Wouter H P; Cristini, Vittorio; Brinker, Lina M; Staquicini, Fernanda I; Cardó-Vila, Marina; D'Angelo, Sara; Ferrara, Fortunato; Proneth, Bettina; Lin, Yu-Shen; Dunphy, Darren R; Dogra, Prashant; Melancon, Marites P; Stafford, R Jason; Miyazono, Kohei; Gelovani, Juri G; Kataoka, Kazunori; Brinker, C Jeffrey; Sidman, Richard L; Arap, Wadih; Pasqualini, Renata

2016-02-16

A major challenge of targeted molecular imaging and drug delivery in cancer is establishing a functional combination of ligand-directed cargo with a triggered release system. Here we develop a hydrogel-based nanotechnology platform that integrates tumor targeting, photon-to-heat conversion, and triggered drug delivery within a single nanostructure to enable multimodal imaging and controlled release of therapeutic cargo. In proof-of-concept experiments, we show a broad range of ligand peptide-based applications with phage particles, heat-sensitive liposomes, or mesoporous silica nanoparticles that self-assemble into a hydrogel for tumor-targeted drug delivery. Because nanoparticles pack densely within the nanocarrier, their surface plasmon resonance shifts to near-infrared, thereby enabling a laser-mediated photothermal mechanism of cargo release. We demonstrate both noninvasive imaging and targeted drug delivery in preclinical mouse models of breast and prostate cancer. Finally, we applied mathematical modeling to predict and confirm tumor targeting and drug delivery. These results are meaningful steps toward the design and initial translation of an enabling nanotechnology platform with potential for broad clinical applications.

Integrated nanotechnology platform for tumor-targeted multimodal imaging and therapeutic cargo release

DOE PAGES

Hosoya, Hitomi; Dobroff, Andrey S.; Driessen, Wouter H. P.; ...

2016-02-02

A major challenge of targeted molecular imaging and drug delivery in cancer is establishing a functional combination of ligand-directed cargo with a triggered release system. Here we develop a hydrogel-based nanotechnology platform that integrates tumor targeting, photon-to-heat conversion, and triggered drug delivery within a single nanostructure to enable multimodal imaging and controlled release of therapeutic cargo. In proof-of-concept experiments, we show a broad range of ligand peptide-based applications with phage particles, heat-sensitive liposomes, or mesoporous silica nanoparticles that self-assemble into a hydrogel for tumor-targeted drug delivery. Because nanoparticles pack densely within the nanocarrier, their surface plasmon resonance shifts to near-infrared,more » thereby enabling a laser-mediated photothermal mechanism of cargo release. We demonstrate both noninvasive imaging and targeted drug delivery in preclinical mouse models of breast and prostate cancer. Finally, we applied mathematical modeling to predict and confirm tumor targeting and drug delivery. We conclude that these results are meaningful steps toward the design and initial translation of an enabling nanotechnology platform with potential for broad clinical applications.« less

Integrated nanotechnology platform for tumor-targeted multimodal imaging and therapeutic cargo release

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hosoya, Hitomi; Dobroff, Andrey S.; Driessen, Wouter H. P.

A major challenge of targeted molecular imaging and drug delivery in cancer is establishing a functional combination of ligand-directed cargo with a triggered release system. Here we develop a hydrogel-based nanotechnology platform that integrates tumor targeting, photon-to-heat conversion, and triggered drug delivery within a single nanostructure to enable multimodal imaging and controlled release of therapeutic cargo. In proof-of-concept experiments, we show a broad range of ligand peptide-based applications with phage particles, heat-sensitive liposomes, or mesoporous silica nanoparticles that self-assemble into a hydrogel for tumor-targeted drug delivery. Because nanoparticles pack densely within the nanocarrier, their surface plasmon resonance shifts to near-infrared,more » thereby enabling a laser-mediated photothermal mechanism of cargo release. We demonstrate both noninvasive imaging and targeted drug delivery in preclinical mouse models of breast and prostate cancer. Finally, we applied mathematical modeling to predict and confirm tumor targeting and drug delivery. We conclude that these results are meaningful steps toward the design and initial translation of an enabling nanotechnology platform with potential for broad clinical applications.« less

Dual targeting of therapeutics to endothelial cells: collaborative enhancement of delivery and effect

PubMed Central

Greineder, Colin F.; Brenza, Jacob B.; Carnemolla, Ronald; Zaitsev, Sergei; Hood, Elizabeth D.; Pan, Daniel C.; Ding, Bi-Sen; Esmon, Charles T.; Chacko, Ann Marie; Muzykantov, Vladimir R.

2015-01-01

Anchoring pharmacologic agents to the vascular lumen has the potential to modulate critical processes at the blood–tissue interface, avoiding many of the off-target effects of systemically circulating agents. We report a novel strategy for endothelial dual targeting of therapeutics, which both enhances drug delivery and enables targeted agents to partner enzymatically to generate enhanced biologic effect. Based on the recent discovery that paired antibodies directed to adjacent epitopes of platelet endothelial cell adhesion molecule (PECAM)-1 stimulate each other’s binding, we fused single-chain fragments (scFv) of paired anti-mouse PECAM-1 antibodies to recombinant murine thrombomodulin (TM) and endothelial protein C receptor (EPCR), endothelial membrane proteins that partner in activation of protein C (PC). scFv/TM and scFv/EPCR bound to mouse endothelial PECAM-1 with high affinity (EC50 1.5 and 3.8 nM, respectively), and codelivery induced a 5-fold increase in PC activation not seen when TM and EPCR are anchored to distinct cell adhesion molecules. In a mouse model of acute lung injury, dual targeting reduces both the expression of lung inflammatory markers and trans-endothelial protein leak by as much as 40%, as compared to either agent alone. These findings provide proof of principle for endothelial dual targeting, an approach with numerous potential biomedical applications.—Greineder, C. F., Brenza, J. B., Carnemolla, R., Zaitsev, S., Hood, E. D., Pan, D. C., Ding, B.-S., Esmon, C. T., Chacko, A. M., Muzykantov, V. R. Dual targeting of therapeutics to endothelial cells: collaborative enhancement of delivery and effect. PMID:25953848

Directional interstitial brachytherapy from simulation to application

NASA Astrophysics Data System (ADS)

Lin, Liyong

Organs at risk (OAR) are sometimes adjacent to or embedded in or overlap with the clinical target volume (CTV) to be treated. The purpose of this PhD study is to develop directionally low energy gamma-emitting interstitial brachytherapy sources. These sources can be applied between OAR to selectively reduce hot spots in the OARs and normal tissues. The reduction of dose over undesired regions can expand patient eligibility or reduce toxicities for the treatment by conventional interstitial brachytherapy. This study covers the development of a directional source from design optimization to construction of the first prototype source. The Monte Carlo code MCNP was used to simulate the radiation transport for the designs of directional sources. We have made a special construction kit to assemble radioactive and gold-shield components precisely into D-shaped titanium containers of the first directional source. Directional sources have a similar dose distribution as conventional sources on the treated side but greatly reduced dose on the shielded side, with a sharp dose gradient between them. A three-dimensional dose deposition kernel for the 125I directional source has been calculated. Treatment plans can use both directional and conventional 125I sources at the same source strength for low-dose-rate (LDR) implants to optimize the dose distributions. For prostate tumors, directional 125I LDR brachytherapy can potentially reduce genitourinary and gastrointestinal toxicities and improve potency preservation for low risk patients. The combination of better dose distribution of directional implants and better therapeutic ratio between tumor response and late reactions enables a novel temporary LDR treatment, as opposed to permanent or high-dose-rate (HDR) brachytherapy for the intermediate risk T2b and high risk T2c tumors. Supplemental external-beam treatments can be shortened with a better brachytherapy boost for T3 tumors. In conclusion, we have successfully finished the design optimization and construction of the first prototype directional source. Potential clinical applications and potential benefits of directional sources have been shown for prostate and breast tumors.

Essential but Not Vulnerable: Indazole Sulfonamides Targeting Inosine Monophosphate Dehydrogenase as Potential Leads against Mycobacterium tuberculosis.

PubMed

Park, Yumi; Pacitto, Angela; Bayliss, Tracy; Cleghorn, Laura A T; Wang, Zhe; Hartman, Travis; Arora, Kriti; Ioerger, Thomas R; Sacchettini, Jim; Rizzi, Menico; Donini, Stefano; Blundell, Tom L; Ascher, David B; Rhee, Kyu; Breda, Ardala; Zhou, Nian; Dartois, Veronique; Jonnala, Surendranadha Reddy; Via, Laura E; Mizrahi, Valerie; Epemolu, Ola; Stojanovski, Laste; Simeons, Fred; Osuna-Cabello, Maria; Ellis, Lucy; MacKenzie, Claire J; Smith, Alasdair R C; Davis, Susan H; Murugesan, Dinakaran; Buchanan, Kirsteen I; Turner, Penelope A; Huggett, Margaret; Zuccotto, Fabio; Rebollo-Lopez, Maria Jose; Lafuente-Monasterio, Maria Jose; Sanz, Olalla; Diaz, Gracia Santos; Lelièvre, Joël; Ballell, Lluis; Selenski, Carolyn; Axtman, Matthew; Ghidelli-Disse, Sonja; Pflaumer, Hannah; Bösche, Markus; Drewes, Gerard; Freiberg, Gail M; Kurnick, Matthew D; Srikumaran, Myron; Kempf, Dale J; Green, Simon R; Ray, Peter C; Read, Kevin; Wyatt, Paul; Barry, Clifton E; Boshoff, Helena I

2017-01-13

A potent, noncytotoxic indazole sulfonamide was identified by high-throughput screening of >100,000 synthetic compounds for activity against Mycobacterium tuberculosis (Mtb). This noncytotoxic compound did not directly inhibit cell wall biogenesis but triggered a slow lysis of Mtb cells as measured by release of intracellular green fluorescent protein (GFP). Isolation of resistant mutants followed by whole-genome sequencing showed an unusual gene amplification of a 40 gene region spanning from Rv3371 to Rv3411c and in one case a potential promoter mutation upstream of guaB2 (Rv3411c) encoding inosine monophosphate dehydrogenase (IMPDH). Subsequent biochemical validation confirmed direct inhibition of IMPDH by an uncompetitive mode of inhibition, and growth inhibition could be rescued by supplementation with guanine, a bypass mechanism for the IMPDH pathway. Beads containing immobilized indazole sulfonamides specifically interacted with IMPDH in cell lysates. X-ray crystallography of the IMPDH-IMP-inhibitor complex revealed that the primary interactions of these compounds with IMPDH were direct pi-pi interactions with the IMP substrate. Advanced lead compounds in this series with acceptable pharmacokinetic properties failed to show efficacy in acute or chronic murine models of tuberculosis (TB). Time-kill experiments in vitro suggest that sustained exposure to drug concentrations above the minimum inhibitory concentration (MIC) for 24 h were required for a cidal effect, levels that have been difficult to achieve in vivo. Direct measurement of guanine levels in resected lung tissue from tuberculosis-infected animals and patients revealed 0.5-2 mM concentrations in caseum and normal lung tissue. The high lesional levels of guanine and the slow lytic, growth-rate-dependent effect of IMPDH inhibition pose challenges to developing drugs against this target for use in treating TB.

Essential but not vulnerable: indazole sulfonamides targeting inosine monophosphate dehydrogenase as potential leads against Mycobacterium tuberculosis

PubMed Central

Park, Yumi; Pacitto, Angela; Bayliss, Tracy; Cleghorn, Laura A. T.; Wang, Zhe; Hartman, Travis; Arora, Kriti; Ioerger, Thomas R.; Sacchettini, Jim; Rizzi, Menico; Donini, Stefano; Blundell, Tom L.; Ascher, David B.; Rhee, Kyu; Breda, Ardala; Zhou, Nian; Dartois, Veronique; Jonnala, Surendranadha Reddy; Via, Laura E.; Mizrahi, Valerie; Epemolu, Ola; Stojanovski, Laste; Simeons, Fred; Osuna-Cabello, Maria; Ellis, Lucy; MacKenzie, Claire J.; Smith, Alasdair R. C.; Davis, Susan H.; Murugesan, Dinakaran; Buchanan, Kirsteen I.; Turner, Penelope A.; Huggett, Margaret; Zuccotto, Fabio; Rebollo-Lopez, Maria Jose; Lafuente-Monasterio, Maria Jose; Sanz, Olalla; Santos Diaz, Gracia; Lelièvre, Joël; Ballell, Lluis; Selenski, Carolyn; Axtman, Matthew; Ghidelli-Disse, Sonja; Pflaumer, Hannah; Bösche, Markus; Drewes, Gerard; Freiberg, Gail M.; Kurnick, Matthew D.; Srikumaran, Myron; Kempf, Dale J.; Green, Simon R.; Ray, Peter C.; Read, Kevin; Wyatt, Paul; Barry, Clifton E; Boshoff, Helena I.

2018-01-01

A potent, non-cytotoxic indazole sulfonamide was identified by high-throughput screening of >100,000 synthetic compounds for activity against Mycobacterium tuberculosis (Mtb). This non-cytotoxic compound did not directly inhibit cell wall biogenesis but triggered a slow lysis of Mtb cells as measured by release of intracellular green fluorescent protein (GFP). Isolation of resistant mutants followed by whole-genome sequencing showed an unusual gene amplification of a 40 gene region spanning Rv3371 to Rv3411c and in one case a potential promoter mutation upstream of guaB2 (Rv3411c) encoding inosine monophosphate dehydrogenase (IMPDH). Subsequent biochemical validation confirmed direct inhibition of IMPDH by an uncompetitive mode of inhibition and growth inhibition could be rescued by supplementation with guanine, a bypass mechanism for the IMPDH pathway. Beads containing immobilized indazole sulfonamides specifically interacted with IMPDH in cell lysates. X-ray crystallography of the IMPDH-IMP-inhibitor complex revealed that the primary interactions of these compounds with IMPDH were direct pi-pi interactions with the IMP substrate. Advanced lead compounds in this series with acceptable pharmacokinetic properties failed to show efficacy in acute or chronic murine models of tuberculosis (TB). Time-kill experiments in vitro suggest that sustained exposure to drug concentrations above MIC for 24 hours were required for a cidal effect, levels that have been difficult to achieve in vivo. Direct measurement of guanine levels in resected lung tissue from tuberculosis infected animals and patients revealed 0.5–2 mM concentrations in caseum and normal lung tissue. The high lesional levels of guanine and the slow lytic, growth-rate dependent, effect of IMPDH inhibition pose challenges to developing drugs against this target for use in treating TB. PMID:27704782

BPA Directly Decreases GnRH Neuronal Activity via Noncanonical Pathway

PubMed Central

Klenke, Ulrike; Constantin, Stephanie

2016-01-01

Peripheral feedback of gonadal estrogen to the hypothalamus is critical for reproduction. Bisphenol A (BPA), an environmental pollutant with estrogenic actions, can disrupt this feedback and lead to infertility in both humans and animals. GnRH neurons are essential for reproduction, serving as an important link between brain, pituitary, and gonads. Because GnRH neurons express several receptors that bind estrogen, they are potential targets for endocrine disruptors. However, to date, direct effects of BPA on GnRH neurons have not been shown. This study investigated the effects of BPA on GnRH neuronal activity using an explant model in which large numbers of primary GnRH neurons are maintained and express many of the receptors found in vivo. Because oscillations in intracellular calcium have been shown to correlate with electrical activity in GnRH neurons, calcium imaging was used to assay the effects of BPA. Exposure to 50μM BPA significantly decreased GnRH calcium activity. Blockage of γ-aminobutyric acid ergic and glutamatergic input did not abrogate the inhibitory BPA effect, suggesting direct regulation of GnRH neurons by BPA. In addition to estrogen receptor-β, single-cell RT-PCR analysis confirmed that GnRH neurons express G protein-coupled receptor 30 (G protein-coupled estrogen receptor 1) and estrogen-related receptor-γ, all potential targets for BPA. Perturbation studies of the signaling pathway revealed that the BPA-mediated inhibition of GnRH neuronal activity occurred independent of estrogen receptors, GPER, or estrogen-related receptor-γ, via a noncanonical pathway. These results provide the first evidence of a direct effect of BPA on GnRH neurons. PMID:26934298

Differentiation of direct and indirect socioeconomic effects on suicide attempts in South Korea

PubMed Central

Ki, Myung; Seong Sohn, Eui; An, Byungduck; Lim, Jiseun

2017-01-01

Abstract Despite the wide recognition of the inverse association between socioeconomic position (SEP) and suicidal behaviors, its underlying process and potential mediators are little known. This study investigated the pathway from SEP to suicide attempts with attention to potential mediators. From the Korean Health and Nutrition Examination Survey 2007–2013, which is a nationwide cross-sectional survey of the health and nutritional status, a total of 34,565 participants (≥30 years) were included in the analysis. To unfold the pathways linking SEP to suicide attempts, the direct and indirect effects of 3 SEP measures (educational attainment, household income, and occupational group) and 3 mediators (physical illness, mental health problems, and problematic drinking) were differentiated using structured equation model (SEM). Most of direct and indirect effects of educational attainment, household income, and occupational group on suicide attempts were significant; Nonemployment status had the largest total (β = 0.291, P < .01) and direct effects (β = 0.212, P < .01), while educational attainment had the largest indirect effect (β = −0.124, P < .01). Educational attainment was mainly mediated by physical illness and problem drinking, whereas household income and occupational group were mainly mediated by anxious or depressed mood and problem drinking. Physical illness played a major role in explaining suicide attempts, compared to mental health problem and problem drinking. Overall, experience of socioeconomic disadvantage increased suicide attempts independently of mental and physical problems. An extension of suicide prevention program is required for comprehensively targeting people with general problems such as physical illness and low SEP, complemented to narrowly targeting high risk group with, such as mental health problem. PMID:29390510

SU-E-J-150: Four-Dimensional Cone-Beam CT Algorithm by Extraction of Physical and Motion Parameter of Mobile Targets Retrospective to Image Reconstruction with Motion Modeling

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ali, I; Ahmad, S; Alsbou, N

Purpose: To develop 4D-cone-beam CT (CBCT) algorithm by motion modeling that extracts actual length, CT numbers level and motion amplitude of a mobile target retrospective to image reconstruction by motion modeling. Methods: The algorithm used three measurable parameters: apparent length and blurred CT number distribution of a mobile target obtained from CBCT images to determine actual length, CT-number value of the stationary target, and motion amplitude. The predictions of this algorithm were tested with mobile targets that with different well-known sizes made from tissue-equivalent gel which was inserted into a thorax phantom. The phantom moved sinusoidally in one-direction to simulatemore » respiratory motion using eight amplitudes ranging 0–20mm. Results: Using this 4D-CBCT algorithm, three unknown parameters were extracted that include: length of the target, CT number level, speed or motion amplitude for the mobile targets retrospective to image reconstruction. The motion algorithms solved for the three unknown parameters using measurable apparent length, CT number level and gradient for a well-defined mobile target obtained from CBCT images. The motion model agreed with measured apparent lengths which were dependent on the actual target length and motion amplitude. The gradient of the CT number distribution of the mobile target is dependent on the stationary CT number level, actual target length and motion amplitude. Motion frequency and phase did not affect the elongation and CT number distribution of the mobile target and could not be determined. Conclusion: A 4D-CBCT motion algorithm was developed to extract three parameters that include actual length, CT number level and motion amplitude or speed of mobile targets directly from reconstructed CBCT images without prior knowledge of the stationary target parameters. This algorithm provides alternative to 4D-CBCT without requirement to motion tracking and sorting of the images into different breathing phases which has potential applications in diagnostic CT imaging and radiotherapy.« less

A motion algorithm to extract physical and motion parameters of mobile targets from cone-beam computed tomographic images.

PubMed

Alsbou, Nesreen; Ahmad, Salahuddin; Ali, Imad

2016-05-17

A motion algorithm has been developed to extract length, CT number level and motion amplitude of a mobile target from cone-beam CT (CBCT) images. The algorithm uses three measurable parameters: Apparent length and blurred CT number distribution of a mobile target obtained from CBCT images to determine length, CT-number value of the stationary target, and motion amplitude. The predictions of this algorithm are tested with mobile targets having different well-known sizes that are made from tissue-equivalent gel which is inserted into a thorax phantom. The phantom moves sinusoidally in one-direction to simulate respiratory motion using eight amplitudes ranging 0-20 mm. Using this motion algorithm, three unknown parameters are extracted that include: Length of the target, CT number level, speed or motion amplitude for the mobile targets from CBCT images. The motion algorithm solves for the three unknown parameters using measured length, CT number level and gradient for a well-defined mobile target obtained from CBCT images. The motion model agrees with the measured lengths which are dependent on the target length and motion amplitude. The gradient of the CT number distribution of the mobile target is dependent on the stationary CT number level, the target length and motion amplitude. Motion frequency and phase do not affect the elongation and CT number distribution of the mobile target and could not be determined. A motion algorithm has been developed to extract three parameters that include length, CT number level and motion amplitude or speed of mobile targets directly from reconstructed CBCT images without prior knowledge of the stationary target parameters. This algorithm provides alternative to 4D-CBCT without requirement of motion tracking and sorting of the images into different breathing phases. The motion model developed here works well for tumors that have simple shapes, high contrast relative to surrounding tissues and move nearly in regular motion pattern that can be approximated with a simple sinusoidal function. This algorithm has potential applications in diagnostic CT imaging and radiotherapy in terms of motion management.

The US ICF Ignition Program and the Inertial Fusion Program

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lindl, J D; Hammel, B A; Logan, B G

2003-07-02

There has been rapid progress in inertial fusion in the past few years. This progress spans the construction of ignition facilities, a wide range of target concepts, and the pursuit of integrated programs to develop fusion energy using lasers, ion beams and z-pinches. Two ignition facilities are under construction (NIF in the U.S. and LMJ in France) and both projects are progressing toward an initial experimental capability. The LIL prototype beamline for LMJ and the first 4 beams of NIF will be available for experiments in 2003. The full 192 beam capability of NIF will be available in 2009 andmore » ignition experiments are expected to begin shortly after that time. There is steady progress in the target science and target fabrication in preparation for indirect drive ignition experiments on NIF. Advanced target designs may lead to 5-10 times more yield than initial target designs. There has also been excellent progress on the science of ion beam and z-pinch driven indirect drive targets. Excellent progress on direct-drive targets has been obtained on the Omega laser at the University of Rochester. This includes improved performance of targets with a pulse shape predicted to result in reduced hydrodynamic instability. Rochester has also obtained encouraging results from initial cryogenic implosions. There is widespread interest in the science of fast ignition because of its potential for achieving higher target gain with lower driver energy and relaxed target fabrication requirements. Researchers from Osaka have achieved outstanding implosion and heating results from the Gekko XII Petawatt facility and implosions suitable for fast ignition have been tested on the Omega laser. A broad based program to develop lasers and ions beams for IFE is under way with excellent progress in drivers, chambers, target fabrication and target injection. KrF and Diode Pumped Solid-State lasers (DPSSL) are being developed in conjunction with drywall chambers and direct drive targets. Induction accelerators for heavy ions are being developed in conjunction with thick-liquid protected wall chambers and indirect-drive targets.« less

Cardiac Gene Expression Knockdown Using Small Inhibitory RNA-Loaded Microbubbles and Ultrasound.

PubMed

Kopechek, Jonathan A; Carson, Andrew R; McTiernan, Charles F; Chen, Xucai; Klein, Edwin C; Villanueva, Flordeliza S

2016-01-01

RNA interference has potential therapeutic value for cardiac disease, but targeted delivery of interfering RNA is a challenge. Custom designed microbubbles, in conjunction with ultrasound, can deliver small inhibitory RNA to target tissues in vivo. The efficacy of cardiac RNA interference using a microbubble-ultrasound theranostic platform has not been demonstrated in vivo. Therefore, our objective was to test the hypothesis that custom designed microbubbles and ultrasound can mediate effective delivery of small inhibitory RNA to the heart. Microbubble and ultrasound mediated cardiac RNA interference was tested in transgenic mice displaying cardiac-restricted luciferase expression. Luciferase expression was assayed in select tissues of untreated mice (n = 14). Mice received intravenous infusion of cationic microbubbles bearing small inhibitory RNA directed against luciferase (n = 9) or control RNA (n = 8) during intermittent cardiac-directed ultrasound at mechanical index of 1.6. Simultaneous echocardiography in a separate group of mice (n = 3) confirmed microbubble destruction and replenishment during treatment. Three days post treatment, cardiac luciferase messenger RNA and protein levels were significantly lower in ultrasound-treated mice receiving microbubbles loaded with small inhibitory RNA directed against luciferase compared to mice receiving microbubbles bearing control RNA (23±7% and 33±7% of control mice, p<0.01 and p = 0.03, respectively). Passive cavitation detection focused on the heart confirmed that insonification resulted in inertial cavitation. In conclusion, small inhibitory RNA-loaded microbubbles and ultrasound directed at the heart significantly reduced the expression of a reporter gene. Ultrasound-targeted destruction of RNA-loaded microbubbles may be an effective image-guided strategy for therapeutic RNA interference in cardiac disease.

Age-related differences in the motor planning of a lower leg target matching task.

PubMed

Davies, Brenda L; Gehringer, James E; Kurz, Max J

2015-12-01

While the development and execution of upper extremity motor plans have been well explored, little is known about how individuals plan and execute rapid, goal-directed motor tasks with the lower extremities. Furthermore, the amount of time needed to integrate the proper amount of visual and proprioceptive feedback before being able to accurately execute a goal-directed movement is not well understood; especially in children. Therefore, the purpose of this study was to initially interrogate how the amount of motor planning time provided to a child before movement execution may influence the preparation and execution of a lower leg goal-directed movement. The results displayed that the amount of pre-movement motor planning time provided may influence the reaction time and accuracy of a goal directed leg movement. All subjects in the study had longer reaction times and less accurate movements when no pre-movement motor planning time was provided. In addition, the children had slower reaction times, slower movements, and less accurate movements than the adults for all the presented targets and motor planning times. These results highlight that children may require more time to successfully plan a goal directed movement with the lower extremity. This suggests that children may potentially have less robust internal models than adults for these types of motor skills. Copyright © 2015 Elsevier B.V. All rights reserved.

Therapeutic Inhibition of miR-4260 Suppresses Colorectal Cancer via Targeting MCC and SMAD4.

PubMed

Xiao, Junjie; Lv, Dongchao; Zhou, Jinzhe; Bei, Yihua; Chen, Ting; Hu, Muren; Zhou, Qiulian; Fu, Siyi; Huang, Qi

2017-01-01

Dysregulation of microRNAs (miRNAs, miRs) and their putative target genes have been increasingly reported to contribute to colorectal cancer. However, miRNAs that directly target the mutated in colorectal cancer (MCC) gene, a tumor suppressor which is downregulated or inactivated in colorectal cancer, remain largely unknown. By using an array-based miRNA analysis, we identified a group of miRNAs that were dysregulated in human metastatic versus non-metastatic colorectal cancer tissues. One of these miRNAs, miR-4260, was predicted to target MCC in the miRDB database. Results using human HCT116 and HT29 colorectal cancer cell lines showed that miR-4260 mimic enhanced cell proliferation and migration and reduced apoptosis induced by the chemotherapeutic agent 5-fluorouracil while miR-4260 inhibitor had inverse effects. Furthermore, miR-4260 negatively regulated MCC as well as SMAD4 by directly binding to the 3'untranslational region (3'UTR). Using siRNAs targeting MCC or SMAD4, we showed that upregulation of MCC and SMAD4 was essential to mediate the functional roles of miR-4260 inhibitor in colorectal cancer cells. Our in vivo experiments indicated that inhibition of miR-4260 reduced colorectal tumor growth in nude mice subcutaneously implanted with HCT116 cells. Significantly, miR-4260 was increased in human colorectal cancer tissues with simultaneous downregulation of MCC and SMAD4, strongly suggesting the clinical relevance of targeting miR-4260 in the treatment of colorectal cancer. In summary, we identified miR-4260 as a novel oncomiR for colorectal cancer that targets MCC and SMAD4. Inhibition of miR-4260 can, therefore, be a potential therapeutic strategy for colorectal cancer.

Ki-67 as a molecular target for therapy in an in vitro three-dimensional model for ovarian cancer.

PubMed

Rahmanzadeh, Ramtin; Rai, Prakash; Celli, Jonathan P; Rizvi, Imran; Baron-Lühr, Bettina; Gerdes, Johannes; Hasan, Tayyaba

2010-11-15

Targeting molecular markers and pathways implicated in cancer cell growth is a promising avenue for developing effective therapies. Although the Ki-67 protein (pKi-67) is a key marker associated with aggressively proliferating cancer cells and poor prognosis, its full potential as a therapeutic target has never before been successfully shown. In this regard, its nuclear localization presents a major hurdle because of the need for intracellular and intranuclear delivery of targeting and therapeutic moieties. Using a liposomally encapsulated construct, we show for the first time the specific delivery of a Ki-67-directed antibody and subsequent light-triggered death in the human ovarian cancer cell line OVCAR-5. Photoimmunoconjugate-encapsulating liposomes (PICEL) were constructed from anti-pKi-67 antibodies conjugated to fluorescein 5(6)-isothiocyanate, as a photoactivatable agent, followed by encapsulation in noncationic liposomes. Nucleolar localization of the PICELs was confirmed by confocal imaging. Photodynamic activation with PICELs specifically killed pKi-67-positive cancer cells both in monolayer and in three-dimensional (3D) cultures of OVCAR-5 cells, with the antibody TuBB-9 targeting a physiologically active form of pKi-67 but not with MIB-1, directed to a different epitope. This is the first demonstration of (a) the exploitation of Ki-67 as a molecular target for therapy and (b) specific delivery of an antibody to the nucleolus in monolayer cancer cells and in an in vitro 3D model system. In view of the ubiquity of pKi-67 in proliferating cells in cancer and the specificity of targeting in 3D multicellular acini, these findings are promising and the approach merits further investigation. Copyright © 2010 AACR.

Ki-67 as a molecular target for therapy in an in vitro 3D model for ovarian cancer

PubMed Central

Rahmanzadeh, Ramtin; Rai, Prakash; Celli, Jonathan P.; Rizvi, Imran; Baron-Lühr, Bettina; Gerdes, Johannes; Hasan, Tayyaba

2010-01-01

Targeting molecular markers and pathways implicated in cancer cell growth is a promising avenue for developing effective therapies. Although the Ki-67 protein (pKi-67) is a key marker associated with aggressively proliferating cancer cells and poor prognosis, its full potential as a therapeutic target has never before been successfully demonstrated. In this regard, its nuclear localization presents a major hurdle because of the need for intracellular and intranuclear delivery of targeting and therapeutic moieties. Using a liposomally encapsulated construct, we demonstrate for the first time, the specific delivery of a Ki-67 directed antibody and subsequent light-triggered death in a human ovarian cancer cell line OVCAR-5. Photoimmunoconjugate encapsulating liposomes (PICELs) were constructed from anti-pKi-67 antibodies conjugated to fluorescein isothiocyanate, as a photoactivatable agent followed by encapsulation in non-cationic liposomes. Nucleolar localization of the PICELs was confirmed by confocal imaging. Photodynamic activation with PICELs specifically killed pKi-67 positive cancer cells both in monolayer and in 3D cultures of OVCAR-5 cells with the antibody TuBB-9 targeting a physiologically active form of pKi-67 but not with MIB-1, directed to a different epitope. This is the first demonstration of: - 1. the exploitation of Ki-67 as a molecular target for therapy and - 2. specific delivery of an antibody to the nucleolus in monolayer cancer cells and in an in vitro 3D model system. In view of the ubiquity of pKi-67 in proliferating cells in cancer and the specificity of targeting in 3D multicellular acini, these findings are promising and the approach merits further investigation. PMID:21045152

RNAi triggered by symmetrically transcribed transgenes in Drosophila melanogaster.

PubMed Central

Giordano, Ennio; Rendina, Rosaria; Peluso, Ivana; Furia, Maria

2002-01-01

Specific silencing of target genes can be induced in a variety of organisms by providing homologous double-stranded RNA molecules. In vivo, these molecules can be generated either by transcription of sequences having an inverted-repeat (IR) configuration or by simultaneous transcription of sense-antisense strands. Since IR constructs are difficult to prepare and can stimulate genomic rearrangements, we investigated the silencing potential of symmetrically transcribed sequences. We report that Drosophila transgenes whose sense-antisense transcription was driven by two convergent arrays of Gal4-dependent UAS sequences can induce specific, dominant, and heritable repression of target genes. This effect is not dependent on a mechanism based on homology-dependent DNA/DNA interactions, but is directly triggered by transcriptional activation and is accompanied by specific depletion of the endogenous target RNA. Tissue-specific induction of these transgenes restricts the target gene silencing to selected body domains, and spreading phenomena described in other cases of post-transcriptional gene silencing (PTGS) were not observed. In addition to providing an additional tool useful for Drosophila functional genomic analysis, these results add further strength to the view that events of sense-antisense transcription may readily account for some, if not all, PTGS-cosuppression phenomena and can potentially play a relevant role in gene regulation. PMID:11861567

The T1R2/T1R3 sweet receptor and TRPM5 ion channel taste targets with therapeutic potential.

PubMed

Sprous, Dennis; Palmer, Kyle R

2010-01-01

Taste signaling is a critical determinant of ingestive behaviors and thereby linked to obesity and related metabolic dysfunctions. Recent evidence of taste signaling pathways in the gut suggests the link to be more direct, raising the possibility that taste receptor systems could be regarded as therapeutic targets. T1R2/T1R3, the G protein coupled receptor that mediates sweet taste, and the TRPM5 ion channel have been the focus of discovery programs seeking novel compounds that could be useful in modifying taste. We review in this chapter the hypothesis of gastrointestinal taste signaling and discuss the potential for T1R2/T1R3 and TRPM5 as targets of therapeutic intervention in obesity and diabetes. Critical to the development of a drug discovery program is the creation of libraries that enhance the likelihood of identifying novel compounds that modulate the target of interest. We advocate a computer-based chemoinformatic approach for assembling natural and synthetic compound libraries as well as for supporting optimization of structure activity relationships. Strategies for discovering modulators of T1R2/T1R3 and TRPM5 using methods of chemoinformatics are presented herein. Copyright 2010 Elsevier Inc. All rights reserved.

The vestibular-related frontal cortex and its role in smooth-pursuit eye movements and vestibular-pursuit interactions

PubMed Central

Fukushima, Junko; Akao, Teppei; Kurkin, Sergei; Kaneko, Chris R.S.; Fukushima, Kikuro

2006-01-01

In order to see clearly when a target is moving slowly, primates with high acuity foveae use smooth-pursuit and vergence eye movements. The former rotates both eyes in the same direction to track target motion in frontal planes, while the latter rotates left and right eyes in opposite directions to track target motion in depth. Together, these two systems pursue targets precisely and maintain their images on the foveae of both eyes. During head movements, both systems must interact with the vestibular system to minimize slip of the retinal images. The primate frontal cortex contains two pursuit-related areas; the caudal part of the frontal eye fields (FEF) and supplementary eye fields (SEF). Evoked potential studies have demonstrated vestibular projections to both areas and pursuit neurons in both areas respond to vestibular stimulation. The majority of FEF pursuit neurons code parameters of pursuit such as pursuit and vergence eye velocity, gaze velocity, and retinal image motion for target velocity in frontal and depth planes. Moreover, vestibular inputs contribute to the predictive pursuit responses of FEF neurons. In contrast, the majority of SEF pursuit neurons do not code pursuit metrics and many SEF neurons are reported to be active in more complex tasks. These results suggest that FEF- and SEF-pursuit neurons are involved in different aspects of vestibular-pursuit interactions and that eye velocity coding of SEF pursuit neurons is specialized for the task condition. PMID:16917164

Tilt anisoplanatism in extended turbulence propagation

NASA Astrophysics Data System (ADS)

Magee, Eric P.; Whiteley, Matthew R.; Das, Shashikala T.; Welsh, Byron M.

2003-04-01

The use of high-energy laser (HEL) weapon systems in tactical air-to-ground target engagements offers great promise for revolutionizing the USAF's war-fighting capabilities. Laser directed-energy systems will enable ultra-precision strike with minimal collateral damage and significant stand-off range for the aerial platform. The tactical directed energy application differs in many crucial ways from the conventional approach used in missile defense. Tactical missions occur at much lower altitudes and involve look-down to low-contrast ground targets instead of a high-contrast boosting missile. At these lower altitudes, the strength of atmospheric turbulence is greatly enhanced. Although the target slant ranges are much shorter, tactical missions may still involve moderate values of the Rytov number (0.1-0.5), and small isoplanatic angles compared to the diffraction angle. With increased density of air in the propagation path, and the potential for slow-moving or stationary ground targets, HEL-induced thermal blooming will certainly be a concern. In order to minimize the errors induced by tracking through thermal blooming, offset aimpoint tracking can be used. However, this will result in significant tilt anisoplanatism, thus degrading beam stabilization on target. In this paper we investigate the effects of extended turbulence on tracking (or tilt) anisoplanatism using theory and wave optics simulations. The simulations show good agreement with geometric optics predictions at angles larger than about 5 micro-radians (asymptotic regime) while at smaller angles the agreement is poor. We present a theoretical basis for this observation.

Confirming therapeutic target of protopine using immobilized β2 -adrenoceptor coupled with site-directed molecular docking and the target-drug interaction by frontal analysis and injection amount-dependent method.

PubMed

Liu, Guangxin; Wang, Pei; Li, Chan; Wang, Jing; Sun, Zhenyu; Zhao, Xinfeng; Zheng, Xiaohui

2017-07-01

Drug-protein interaction analysis is pregnant in designing new leads during drug discovery. We prepared the stationary phase containing immobilized β 2 -adrenoceptor (β 2 -AR) by linkage of the receptor on macroporous silica gel surface through N,N'-carbonyldiimidazole method. The stationary phase was applied in identifying antiasthmatic target of protopine guided by the prediction of site-directed molecular docking. Subsequent application of immobilized β 2 -AR in exploring the binding of protopine to the receptor was realized by frontal analysis and injection amount-dependent method. The association constants of protopine to β 2 -AR by the 2 methods were (1.00 ± 0.06) × 10 5 M -1 and (1.52 ± 0.14) × 10 4 M -1 . The numbers of binding sites were (1.23 ± 0.07) × 10 -7 M and (9.09 ± 0.06) × 10 -7 M, respectively. These results indicated that β 2 -AR is the specific target for therapeutic action of protopine in vivo. The target-drug binding occurred on Ser 169 in crystal structure of the receptor. Compared with frontal analysis, injection amount-dependent method is advantageous to drug saving, improvement of sampling efficiency, and performing speed. It has grave potential in high-throughput drug-receptor interaction analysis. Copyright © 2017 John Wiley & Sons, Ltd.

Impact of GM crops on biodiversity.

PubMed

Carpenter, Janet E

2011-01-01

The potential impact of GM crops on biodiversity has been a topic of interest both in general as well as specifically in the context of the Convention on Biological Diversity. Agricultural biodiversity has been defined at levels from genes to ecosystems that are involved or impacted by agricultural production (www.cbd.int/agro/whatis.shtml). After fifteen years of commercial cultivation, a substantial body of literature now exists addressing the potential impacts of GM crops on the environment. This review takes a biodiversity lens to this literature, considering the impacts at three levels: the crop, farm and landscape scales. Within that framework, this review covers potential impacts of the introduction of genetically engineered crops on: crop diversity, biodiversity of wild relatives, non-target soil organisms, weeds, land use, non-target above-ground organisms, and area-wide pest suppression. The emphasis of the review is peer-reviewed literature that presents direct measures of impacts on biodiversity. In addition, possible impacts of changes in management practises such as tillage and pesticide use are also discussed to complement the literature on direct measures. The focus of the review is on technologies that have been commercialized somewhere in the world, while results may emanate from non-adopting countries and regions. Overall, the review finds that currently commercialized GM crops have reduced the impacts of agriculture on biodiversity, through enhanced adoption of conservation tillage practices, reduction of insecticide use and use of more environmentally benign herbicides and increasing yields to alleviate pressure to convert additional land into agricultural use.

Cancer Treatment Using Peptides: Current Therapies and Future Prospects

PubMed Central

Thundimadathil, Jyothi

2012-01-01

This paper discusses the role of peptides in cancer therapy with special emphasis on peptide drugs which are already approved and those in clinical trials. The potential of peptides in cancer treatment is evident from a variety of different strategies that are available to address the progression of tumor growth and propagation of the disease. Use of peptides that can directly target cancer cells without affecting normal cells (targeted therapy) is evolving as an alternate strategy to conventional chemotherapy. Peptide can be utilized directly as a cytotoxic agent through various mechanisms or can act as a carrier of cytotoxic agents and radioisotopes by specifically targeting cancer cells. Peptide-based hormonal therapy has been extensively studied and utilized for the treatment of breast and prostate cancers. Tremendous amount of clinical data is currently available attesting to the efficiency of peptide-based cancer vaccines. Combination therapy is emerging as an important strategy to achieve synergistic effects in fighting cancer as a single method alone may not be efficient enough to yield positive results. Combining immunotherapy with conventional therapies such as radiation and chemotherapy or combining an anticancer peptide with a nonpeptidic cytotoxic drug is an example of this emerging field. PMID:23316341

Predicting Drug-Target Interactions Based on Small Positive Samples.

PubMed

Hu, Pengwei; Chan, Keith C C; Hu, Yanxing

2018-01-01

A basic task in drug discovery is to find new medication in the form of candidate compounds that act on a target protein. In other words, a drug has to interact with a target and such drug-target interaction (DTI) is not expected to be random. Significant and interesting patterns are expected to be hidden in them. If these patterns can be discovered, new drugs are expected to be more easily discoverable. Currently, a number of computational methods have been proposed to predict DTIs based on their similarity. However, such as approach does not allow biochemical features to be directly considered. As a result, some methods have been proposed to try to discover patterns in physicochemical interactions. Since the number of potential negative DTIs are very high both in absolute terms and in comparison to that of the known ones, these methods are rather computationally expensive and they can only rely on subsets, rather than the full set, of negative DTIs for training and validation. As there is always a relatively high chance for negative DTIs to be falsely identified and as only partial subset of such DTIs is considered, existing approaches can be further improved to better predict DTIs. In this paper, we present a novel approach, called ODT (one class drug target interaction prediction), for such purpose. One main task of ODT is to discover association patterns between interacting drugs and proteins from the chemical structure of the former and the protein sequence network of the latter. ODT does so in two phases. First, the DTI-network is transformed to a representation by structural properties. Second, it applies a oneclass classification algorithm to build a prediction model based only on known positive interactions. We compared the best AUROC scores of the ODT with several state-of-art approaches on Gold standard data. The prediction accuracy of the ODT is superior in comparison with all the other methods at GPCRs dataset and Ion channels dataset. Performance evaluation of ODT shows that it can be potentially useful. It confirms that predicting potential or missing DTIs based on the known interactions is a promising direction to solve problems related to the use of uncertain and unreliable negative samples and those related to the great demand in computational resources. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Command Dysfunction: Minding the Cognitive War

DTIC Science & Technology

1996-06-01

failure sometimes resulted from the physical test of arms in combat, leading to a mortal wound. At other times the fall was psychological , brought...for the attack and protection of command and control. The doctrinal definition follows: C2W is the integrated use of psychological operations (PSYOP... psychological , components of C2W. The problem of emphasizing direct attack C2W targeting is that it potentially underplays the complementary aspect of

Direct Fixed-Bed Biological Perchlorate Destruction Demonstration

DTIC Science & Technology

2008-09-01

1 mg/L)? This issue targets the question of whether the FXB bioreactor system can be applied at a remediation site (i.e., a non-potable...incineration). 11 3. PERFORMANCE OBJECTIVES 3.1 Summary Performance objectives listed in Table 3.1 apply to the complete FXB bioreactor...potential sources of perchlorate. Other areas near Well #2 have been used by a multitude of companies for ordnance and pyrotechnics manufacturing

Beam Research Program

DTIC Science & Technology

1984-04-01

wavelengths. A direct application of such a laser is isotope separation. 2. For a brief status report of the Laboratory’s high- explosive flash...operation in the fall of 1982. in a 50-MeV Advanced Test Accelerator Facility (the ATA)1 that we are con- structing at our high- explosives test loca...chemical explosives in target-damage studies. Potential hazards associated with the ATA experiments were considered in choosing our site. LLNL’s

Using "Functional" Target Coordinates of the Subthalamic Nucleus to Assess the Indirect and Direct Methods of the Preoperative Planning: Do the Anatomical and Functional Targets Coincide?

PubMed

Rabie, Ahmed; Verhagen Metman, Leo; Slavin, Konstantin V

2016-12-21

To answer the question of whether the anatomical center of the subthalamic nucleus (STN), as calculated indirectly from stereotactic atlases or by direct visualization on magnetic resonance imaging (MRI), corresponds to the best functional target. Since the neighboring red nucleus (RN) is well visualized on MRI, we studied the relationships of the final target to its different borders. We analyzed the data of 23 PD patients (46 targets) who underwent bilateral frame-based STN deep brain stimulation (DBS) procedure with microelectrode recording guidance. We calculated coordinates of the active contact on DBS electrode on postoperative MRI, which we referred to as the final "functional/optimal" target. The coordinates calculated by the atlas-based "indirect" and "direct" methods, as well as the coordinates of the different RN borders were compared to these final coordinates. The mean ± SD of the final target coordinates was 11.7 ± 1.5 mm lateral (X), 2.4 ± 1.5 mm posterior (Y), and 6.1 ± 1.7 mm inferior to the mid-commissural point (Z). No significant differences were found between the "indirect" X, Z coordinates and those of the final targets. The "indirect" Y coordinate was significantly posterior to Y of the final target, with mean difference of 0.6 mm ( p = 0.014). No significant differences were found between the "direct" X, Y, and Z coordinates and those of the final targets. The functional STN target is located in direct proximity to its anatomical center. During preoperative targeting, we recommend using the "direct" method, and taking into consideration the relationships of the final target to the mid-commissural point (MCP) and the different RN borders.

The Mawrth Vallis region of Mars: A potential landing site for the Mars Science Laboratory (MSL) mission.

PubMed

Michalski, Joseph R; Jean-PierreBibring; Poulet, François; Loizeau, Damien; Mangold, Nicolas; Dobrea, Eldar Noe; Bishop, Janice L; Wray, James J; McKeown, Nancy K; Parente, Mario; Hauber, Ernst; Altieri, Francesca; Carrozzo, F Giacomo; Niles, Paul B

2010-09-01

The primary objective of NASA's Mars Science Laboratory (MSL) mission, which will launch in 2011, is to characterize the habitability of a site on Mars through detailed analyses of the composition and geological context of surface materials. Within the framework of established mission goals, we have evaluated the value of a possible landing site in the Mawrth Vallis region of Mars that is targeted directly on some of the most geologically and astrobiologically enticing materials in the Solar System. The area around Mawrth Vallis contains a vast (>1 × 10⁶ km²) deposit of phyllosilicate-rich, ancient, layered rocks. A thick (>150 m) stratigraphic section that exhibits spectral evidence for nontronite, montmorillonite, amorphous silica, kaolinite, saponite, other smectite clay minerals, ferrous mica, and sulfate minerals indicates a rich geological history that may have included multiple aqueous environments. Because phyllosilicates are strong indicators of ancient aqueous activity, and the preservation potential of biosignatures within sedimentary clay deposits is high, martian phyllosilicate deposits are desirable astrobiological targets. The proposed MSL landing site at Mawrth Vallis is located directly on the largest and most phyllosilicate-rich deposit on Mars and is therefore an excellent place to explore for evidence of life or habitability.

Microbubble-assisted p53, RB, and p130 gene transfer in combination with radiation therapy in prostate cancer.

PubMed

Nande, Rounak; Greco, Adelaide; Gossman, Michael S; Lopez, Jeffrey P; Claudio, Luigi; Salvatore, Marco; Brunetti, Arturo; Denvir, James; Howard, Candace M; Claudio, Pier Paolo

2013-06-01

Combining radiation therapy and direct intratumoral (IT) injection of adenoviral vectors has been explored as a means to enhance the therapeutic potential of gene transfer. A major challenge for gene transfer is systemic delivery of nucleic acids directly into an affected tissue. Ultrasound (US) contrast agents (microbubbles) are viable candidates to enhance targeted delivery of systemically administered genes. Here we show that p53, pRB, and p130 gene transfer mediated by US cavitation of microbubbles at the tumor site resulted in targeted gene transduction and increased reduction in tumor growth compared to DU-145 prostate cancer cell xenografts treated intratumorally with adenovirus (Ad) or radiation alone. Microbubble-assisted/US-mediated Ad.p53 and Ad.RB treated tumors showed significant reduction in tumor volume compared to Ad.p130 treated tumors (p<0.05). Additionally, US mediated microbubble delivery of p53 and RB combined with external beam radiation resulted in the most profound tumor reduction in DU-145 xenografted nude mice (p<0.05) compared to radiation alone. These findings highlight the potential therapeutic applications of this novel image-guided gene transfer technology in combination with external beam radiation for prostate cancer patients with therapy resistant disease.

Thiol-reactive amphiphilic block copolymer for coating gold nanoparticles with neutral and functionable surfaces

PubMed Central

Chen, Hongwei; Zou, Hao; Paholak, Hayley J.; Ito, Masayuki; Qian, Wei; Che, Yong; Sun, Duxin

2014-01-01

Nanoparticles designed for biomedical applications are often coated with polymers containing reactive functional groups, such as –COOH and –NH2, to conjugate targeting ligands or drugs. However, introducing highly charged surfaces promotes binding of the nanoparticles to biomolecules in biological systems through ionic interactions, causing the nanoparticles to aggregate in biological environments and consequently undergo strong non-specific binding to off-target cells and tissues. Developing a unique polymer with neutral surfaces that can be further functionalized directly would be critical to develop suitable nanomaterials for nanomedicine. Here, we report a thiol-reactive amphiphilic block copolymer poly(ethylene oxide)-block-poly(pyridyldisulfide ethylmeth acrylate) (PEO-b-PPDSM) for coating gold nanoparticles (AuNPs). The resultant polymer-coated AuNPs have almost neutral surfaces with slightly negative zeta potentials from -10 to 0 mV over a wide pH range from 2 to 12. Although the zeta potential is close to zero we show that the PEO-b-PPDSM copolymer-coated AuNPs have both good stability in various physiological conditions and reduced non-specific adsorption of proteins/biomolecules. Because of the multiple pyridyldisulfide groups on the PPDSM block, these individually dispersed nanocomplexes with an overall hydrodynamic size around 43.8 nm can be directly functionalized via disulfide-thiol exchange chemistry. PMID:24729795

Peptide-enhanced mRNA transfection in cultured mouse cardiac fibroblasts and direct reprogramming towards cardiomyocyte-like cells

PubMed Central

Lee, Kunwoo; Yu, Pengzhi; Lingampalli, Nithya; Kim, Hyun Jin; Tang, Richard; Murthy, Niren

2015-01-01

The treatment of myocardial infarction is a major challenge in medicine due to the inability of heart tissue to regenerate. Direct reprogramming of endogenous cardiac fibroblasts into functional cardiomyocytes via the delivery of transcription factor mRNAs has the potential to regenerate cardiac tissue and to treat heart failure. Even though mRNA delivery to cardiac fibroblasts has the therapeutic potential, mRNA transfection in cardiac fibroblasts has been challenging. Herein, we develop an efficient mRNA transfection in cultured mouse cardiac fibroblasts via a polyarginine-fused heart-targeting peptide and lipofectamine complex, termed C-Lipo and demonstrate the partial direct reprogramming of cardiac fibroblasts towards cardiomyocyte cells. C-Lipo enabled the mRNA-induced direct cardiac reprogramming due to its efficient transfection with low toxicity, which allowed for multiple transfections of Gata4, Mef2c, and Tbx5 (GMT) mRNAs for a period of 2 weeks. The induced cardiomyocyte-like cells had α-MHC promoter-driven GFP expression and striated cardiac muscle structure from α-actinin immunohistochemistry. GMT mRNA transfection of cultured mouse cardiac fibroblasts via C-Lipo significantly increased expression of the cardiomyocyte marker genes, Actc1, Actn2, Gja1, Hand2, and Tnnt2, after 2 weeks of transfection. Moreover, this study provides the first direct evidence that the stoichiometry of the GMT reprogramming factors influence the expression of cardiomyocyte marker genes. Our results demonstrate that mRNA delivery is a potential approach for cardiomyocyte generation. PMID:25834424

Preparation and Imaging Investigation of Dual-targeted C3F8-filled PLGA Nanobubbles as a Novel Ultrasound Contrast Agent for Breast Cancer.

PubMed

Du, Jing; Li, Xiao-Yu; Hu, He; Xu, Li; Yang, Shi-Ping; Li, Feng-Hua

2018-03-01

Molecularly-targeted contrast enhanced ultrasound (US) imaging is a promising imaging strategy with large potential for improving diagnostic accuracy of conventional US imaging in breast cancer detection. Therefore, we constructed a novel dual-targeted nanosized US contrast agent (UCA) directed at both vascular endothelial growth factor receptor 2 (VEGFR2) and human epidermal growth factor receptor 2 (HER2) based on perfluoropropane (C 3 F 8 )-filled poly(lactic-co-glycolic acid) (PLGA) (NBs) for breast cancer detection. In vitro, single- or dual-targeted PLGA NBs showed high target specificities and better effects of target enhancement in VEGFR2 or HER2-positive cells. In vivo, US imaging signal in the murine breast cancer model was significantly higher (P < 0.01) for dual-targeted NBs than single-targeted and non-targeted NBs. Small animal fluorescence imaging further confirmed the special affinity of the dual-targeted nanosized contrast agent to both VEGFR2 and HER2. Immunofluorescence and immunohistochemistry staining confirmed the expressions of VEGFR2 and HER2 on tumor neovasculature and tumor cells of breast cancer. In conclusions, the feasibility of using dual-targeted PLGA NBs to enhance ultrasonic images is demonstrated in vitro and in vivo. This may be a promising approach to target biomarkers of breast cancer for two site-specific US molecular imaging.

The Therapeutic Potential of Anti-Inflammatory Exerkines in the Treatment of Atherosclerosis

PubMed Central

Yu, Megan; Tsai, Sheng-Feng; Kuo, Yu-Min

2017-01-01

Although many cardiovascular (CVD) medications, such as antithrombotics, statins, and antihypertensives, have been identified to treat atherosclerosis, at most, many of these therapeutic agents only delay its progression. A growing body of evidence suggests physical exercise could be implemented as a non-pharmacologic treatment due to its pro-metabolic, multisystemic, and anti-inflammatory benefits. Specifically, it has been discovered that certain anti-inflammatory peptides, metabolites, and RNA species (collectively termed “exerkines”) are released in response to exercise that could facilitate these benefits and could serve as potential therapeutic targets for atherosclerosis. However, much of the relationship between exercise and these exerkines remains unanswered, and there are several challenges in the discovery and validation of these exerkines. This review primarily highlights major anti-inflammatory exerkines that could serve as potential therapeutic targets for atherosclerosis. To provide some context and comparison for the therapeutic potential of exerkines, the anti-inflammatory, multisystemic benefits of exercise, the basic mechanisms of atherosclerosis, and the limited efficacies of current anti-inflammatory therapeutics for atherosclerosis are briefly summarized. Finally, key challenges and future directions for exploiting these exerkines in the treatment of atherosclerosis are discussed. PMID:28608819

Naproxen induces cell cycle arrest and apoptosis in human urinary bladder cancer cell lines and chemically induced cancers by targeting PI3-K

PubMed Central

Kim, Mi-Sung; Kim, Jong-Eun; Lim, Do Young; Huang, Zunnan; Chen, Hanyong; Langfald, Alyssa; Lubet, Ronald A.; Grubbs, Clinton J.; Dong, Zigang; Bode, Ann M.

2014-01-01

Naproxen ((S)-6-methoxy-α-methyl-2-naphthaleneacetic acid) is a potent nonsteroidal anti-inflammatory drug that inhibits both COX-1 and COX-2 and is widely used as an over-the-counter medication. Naproxen exhibits analgesic, anti-pyretic, and anti-inflammatory activities. Naproxen, as well as other NSAIDS, has been reported to be effective in the prevention of urinary bladder cancer in rodents. However, potential targets other than the COX isozymes have not been reported. We examined potential additional targets in urinary bladder cancer cells and in rat bladder cancers. Computer kinase profiling results suggested that phosphatidylinositol 3-kinase (PI3-K) is a potential target for naproxen. In vitro kinase assay data revealed that naproxen interacts with PI3-K and inhibits its kinase activity. Pull-down binding assay data confirmed that PI3-K directly binds with naproxen in vitro and ex vivo. Western blot data showed that naproxen decreased phosphorylation of Akt, and subsequently decreased Akt signaling in UM-UC-5 and UMUC-14 urinary bladder cancer cells. Furthermore, naproxen suppressed anchorage-independent cell growth and decreased cell viability by targeting PI3-K in both cell lines. Naproxen caused an accumulation of cells at the G1 phase mediated through CDK4, cyclin D1 and p21. Moreover, naproxen induced significant apoptosis, accompanied with increased levels of cleaved caspase 3, caspase 7, and poly (ADP-ribose) polymerase (PARP) in both cell types. Naproxen-induced cell death was mainly due to apoptosis in which a prominent down-regulation of Bcl-2 and up-regulation of Bax were involved. Naproxen also caused apoptosis and inhibited Akt phosphorylation in rat urinary bladder cancers induced by N-butyl-N-(4-hydroxybutyl)-nitrosamine (OH-BBN). PMID:24327721

Active suppression after involuntary capture of attention.

PubMed

Sawaki, Risa; Luck, Steven J

2013-04-01

After attention has been involuntarily captured by a distractor, how is it reoriented toward a target? One possibility is that attention to the distractor passively fades over time, allowing the target to become attended. Another possibility is that the captured location is actively suppressed so that attention can be directed toward the target location. The present study investigated this issue with event-related potentials (ERPs), focusing on the N2pc component (a neural measure of attentional deployment) and the Pd component (a neural measure of attentional suppression). Observers identified a color-defined target in a search array, which was preceded by a task-irrelevant cue array. When the cue array contained an item that matched the target color, this item captured attention (as measured both behaviorally and with the N2pc component). This capture of attention was followed by active suppression (indexed by the Pd component), and this was then followed by a reorienting of attention toward the target in the search array (indexed by the N2pc component). These findings indicate that the involuntary capture of attention by a distractor is followed by an active suppression process that presumably facilitates the subsequent voluntary orienting of attention to the target.

Advances in identification and validation of protein targets of natural products without chemical modification.

PubMed

Chang, J; Kim, Y; Kwon, H J

2016-05-04

Covering: up to February 2016Identification of the target proteins of natural products is pivotal to understanding the mechanisms of action to develop natural products for use as molecular probes and potential therapeutic drugs. Affinity chromatography of immobilized natural products has been conventionally used to identify target proteins, and has yielded good results. However, this method has limitations, in that labeling or tagging for immobilization and affinity purification often result in reduced or altered activity of the natural product. New strategies have recently been developed and applied to identify the target proteins of natural products and synthetic small molecules without chemical modification of the natural product. These direct and indirect methods for target identification of label-free natural products include drug affinity responsive target stability (DARTS), stability of proteins from rates of oxidation (SPROX), cellular thermal shift assay (CETSA), thermal proteome profiling (TPP), and bioinformatics-based analysis of connectivity. This review focuses on and reports case studies of the latest advances in target protein identification methods for label-free natural products. The integration of newly developed technologies will provide new insights and highlight the value of natural products for use as biological probes and new drug candidates.

Apoptin towards safe and efficient anticancer therapies.

PubMed

Backendorf, Claude; Noteborn, Mathieu H M

2014-01-01

The chicken anemia virus derived protein apoptin harbors cancer-selective cell killing characteristics, essentially based on phosphorylation-mediated nuclear transfer in cancer cells and efficient cytoplasmic degradation in normal cells. Here, we describe a growing set of preclinical experiments underlying the promises of the anti-cancer potential of apoptin. Various non-replicative oncolytic viral vector systems have revealed the safety and efficacy of apoptin. In addition, apoptin enhanced the oncolytic potential of adenovirus, parvovirus and Newcastle disease virus vectors. Intratumoral injection of attenuated Salmonella typhimurium bacterial strains and plasmid-based systems expressing apoptin resulted in significant tumor regression. In-vitro and in-vivo experiments showed that recombinant membrane-transferring PTD4- or TAT-apoptin proteins have potential as a future anticancer therapeutics. In xenografted hepatoma and melanoma mouse models PTD4-apoptin protein entered both cancer and normal cells, but only killed cancer cells. Combinatorial treatment of PTD4-apoptin with various (chemo)therapeutic compounds revealed an additive or even synergistic effect, reducing the side effects of the single (chemo)therapeutic treatment. Degradable polymeric nanocapsules harboring MBP-apoptin fusion-protein induced tumor-selective cell killing in-vitro and in-vivo and revealed the potential of polymer-apoptin protein vehicles as an anticancer agent.Besides its direct use as an anticancer therapeutic, apoptin research has also generated novel possibilities for drug design. The nuclear location domains of apoptin are attractive tools for targeting therapeutic compounds into the nucleus of cancer cells. Identification of cancer-related processes targeted by apoptin can potentially generate novel drug targets. Recent breakthroughs important for clinical applications are reported inferring apoptin-based clinical trials as a feasible reality.

Challenges of coverage policy development for next-generation tumor sequencing panels: experts and payers weigh in.

PubMed

Trosman, Julia R; Weldon, Christine B; Kelley, R Kate; Phillips, Kathryn A

2015-03-01

Next-generation tumor sequencing (NGTS) panels, which include multiple established and novel targets across cancers, are emerging in oncology practice, but lack formal positive coverage by US payers. Lack of coverage may impact access and adoption. This study identified challenges of NGTS coverage by private payers. We conducted semi-structured interviews with 14 NGTS experts on potential NGTS benefits, and with 10 major payers, representing more than 125,000,000 enrollees, on NGTS coverage considerations. We used the framework approach of qualitative research for study design and thematic analyses and simple frequencies to further describe findings. All interviewed payers see potential NGTS benefits, but all noted challenges to formal coverage: 80% state that inherent features of NGTS do not fit the medical necessity definition required for coverage, 70% view NGTS as a bundle of targets versus comprehensive tumor characterization and may evaluate each target individually, and 70% express skepticism regarding new evidence methods proposed for NGTS. Fifty percent of payers expressed sufficient concerns about NGTS adoption and implementation that will preclude their ability to issue positive coverage policies. Payers perceive that NGTS holds significant promise but, in its current form, poses disruptive challenges to coverage policy frameworks. Proactive multidisciplinary efforts to define the direction for NGTS development, evidence generation, and incorporation into coverage policy are necessary to realize its promise and provide patient access. This study contributes to current literature, as possibly the first study to directly interview US payers on NGTS coverage and reimbursement. Copyright © 2015 by the National Comprehensive Cancer Network.

Challenges of Coverage Policy Development for Next-Generation Tumor Sequencing Panels: Experts and Payers Weigh In

PubMed Central

Trosman, Julia R.; Weldon, Christine B.; Kate Kelley, R.; Phillips, Kathryn A.

2015-01-01

Background Next-generation tumor sequencing (NGTS) panels, which include multiple established and novel targets across cancers, are emerging in oncology practice, but lack formal positive coverage by US payers. Lack of coverage may impact access and adoption. This study identified challenges of NGTS coverage by private payers. Methods We conducted semi-structured interviews with 14 NGTS experts on potential NGTS benefits, and with 10 major payers, representing more than 125,000,000 enrollees, on NGTS coverage considerations. We used the framework approach of qualitative research for study design and thematic analyses and simple frequencies to further describe findings. Results All interviewed payers see potential NGTS benefits, but all noted challenges to formal coverage: 80% state that inherent features of NGTS do not fit the medical necessity definition required for coverage, 70% view NGTS as a bundle of targets versus comprehensive tumor characterization and may evaluate each target individually, and 70% express skepticism regarding new evidence methods proposed for NGTS. Fifty percent of payers expressed sufficient concerns about NGTS adoption and implementation that will preclude their ability to issue positive coverage policies. Conclusions Payers perceive that NGTS holds significant promise but, in its current form, poses disruptive challenges to coverage policy frameworks. Proactive multidisciplinary efforts to define the direction for NGTS development, evidence generation, and incorporation into coverage policy are necessary to realize its promise and provide patient access. This study contributes to current literature, as possibly the first study to directly interview US payers on NGTS coverage and reimbursement. PMID:25736008

Direct detection of sub-GeV dark matter with scintillating targets

DOE PAGES

Derenzo, Stephen; Essig, Rouven; Massari, Andrea; ...

2017-07-28

We suggest a novel experimental concept for detecting MeV-to-GeV-mass dark matter, in which the dark matter scatters off electrons in a scintillating target and produces a signal of one or a few photons. New large-area photodetectors are needed to measure the photon signal with negligible dark counts, which could be constructed from transition edge sensor (TES) or microwave kinetic inductance detector (MKID) technology. Alternatively, detecting two photons in coincidence may allow the use of conventional photodetectors like photomultiplier tubes. Here we describe why scintillators may have distinct advantages over other experiments searching for a low ionization signal from sub-GeV darkmore » matter, as there are fewer potential sources of spurious backgrounds. We discuss various target choices, but focus on calculating the expected dark matter-electron scattering rates in three scintillating crystals: sodium iodide (NaI), cesium iodide (CsI), and gallium arsenide (GaAs). Among these, GaAs has the lowest band gap (1.52 eV) compared to NaI (5.9 eV) or CsI (6.4 eV), which in principle allows it to probe dark matter masses as low as ~0.5 MeV, compared to ~1.5 MeV with NaI or CsI. We compare these scattering rates with those expected in silicon (Si) and germanium (Ge). The proposed experimental concept presents an important complementary path to existing efforts, and its potential advantages may make it the most sensitive direct-detection probe of dark matter down to MeV masses.« less

Intranasal brain-targeted clonazepam polymeric micelles for immediate control of status epilepticus: in vitro optimization, ex vivo determination of cytotoxicity, in vivo biodistribution and pharmacodynamics studies.

PubMed

Nour, Samia A; Abdelmalak, Nevine S; Naguib, Marianne J; Rashed, Hassan M; Ibrahim, Ahmed B

2016-11-01

Clonazepam (CZ) is an anti-epileptic drug used mainly in status epilepticus (SE). The drug belongs to Class II according to BCS classification with very limited solubility and high permeability and it suffers from extensive first-pass metabolism. The aim of the present study was to develop CZ-loaded polymeric micelles (PM) for direct brain delivery allowing immediate control of SE. PM were prepared via thin film hydration (TFH) technique adopting a central composite face-centered design (CCFD). The seventeen developed formulae were evaluated in terms of entrapment efficiency (EE), particle size (PS), polydispersity index (PDI), zeta potential (ZP), and in vitro release. For evaluating the in vivo behavior of the optimized formula, both biodistrbution using 99m Tc-radiolabeled CZ and pharmacodynamics studies were done in addition to ex vivo cytotoxicty. At a drug:Pluronic® P123:Pluronic® L121 ratio of 1:20:20 (PM7), a high EE, ZP, Q8h, and a low PDI was achieved. The biodistribution studies revealed that the optimized formula had significantly higher drug targeting efficiency (DTE = 242.3%), drug targeting index (DTI = 144.25), and nose-to-brain direct transport percentage (DTP = 99.30%) and a significant prolongation of protection from seizures in comparison to the intranasally administered solution with minor histopathological changes. The declared results reveal the ability of the developed PM to be a strong potential candidate for the emergency treatment of SE.

Direct detection of sub-GeV dark matter with scintillating targets

DOE Office of Scientific and Technical Information (OSTI.GOV)

Derenzo, Stephen; Essig, Rouven; Massari, Andrea

We suggest a novel experimental concept for detecting MeV-to-GeV-mass dark matter, in which the dark matter scatters off electrons in a scintillating target and produces a signal of one or a few photons. New large-area photodetectors are needed to measure the photon signal with negligible dark counts, which could be constructed from transition edge sensor (TES) or microwave kinetic inductance detector (MKID) technology. Alternatively, detecting two photons in coincidence may allow the use of conventional photodetectors like photomultiplier tubes. Here we describe why scintillators may have distinct advantages over other experiments searching for a low ionization signal from sub-GeV darkmore » matter, as there are fewer potential sources of spurious backgrounds. We discuss various target choices, but focus on calculating the expected dark matter-electron scattering rates in three scintillating crystals: sodium iodide (NaI), cesium iodide (CsI), and gallium arsenide (GaAs). Among these, GaAs has the lowest band gap (1.52 eV) compared to NaI (5.9 eV) or CsI (6.4 eV), which in principle allows it to probe dark matter masses as low as ~0.5 MeV, compared to ~1.5 MeV with NaI or CsI. We compare these scattering rates with those expected in silicon (Si) and germanium (Ge). The proposed experimental concept presents an important complementary path to existing efforts, and its potential advantages may make it the most sensitive direct-detection probe of dark matter down to MeV masses.« less

Diverse correlation patterns between microRNAs and their targets during tomato fruit development indicates different modes of microRNA actions.

PubMed

Lopez-Gomollon, Sara; Mohorianu, Irina; Szittya, Gyorgy; Moulton, Vincent; Dalmay, Tamas

2012-12-01

MicroRNAs negatively regulate the accumulation of mRNAs therefore when they are expressed in the same cells their expression profiles show an inverse correlation. We previously described one positively correlated miRNA/target pair, but it is not known how widespread this phenomenon is. Here, we investigated the correlation between the expression profiles of differentially expressed miRNAs and their targets during tomato fruit development using deep sequencing, Northern blot and RT-qPCR. We found an equal number of positively and negatively correlated miRNA/target pairs indicating that positive correlation is more frequent than previously thought. We also found that the correlation between microRNA and target expression profiles can vary between mRNAs belonging to the same gene family and even for the same target mRNA at different developmental stages. Since microRNAs always negatively regulate their targets, the high number of positively correlated microRNA/target pairs suggests that mutual exclusion could be as widespread as temporal regulation. The change of correlation during development suggests that the type of regulatory circuit directed by a microRNA can change over time and can be different for individual gene family members. Our results also highlight potential problems for expression profiling-based microRNA target identification/validation.

The effect on toxicology, biochemistry and immunology investigations by the use of targeted post-mortem computed tomography angiography.

PubMed

Rutty, G N; Smith, P; Visser, T; Barber, J; Amorosa, J; Morgan, B

2013-02-10

It is recognised in autopsy practice that investigations such as toxicology can be affected by post-mortem change. Post-mortem computed tomography angiography (PMCT-A) involves the injection of contrast agents. This could cause dilution of a biological fluid sample or cause the circulation of blood after death by mechanical pumping, and thus has the potential to affect laboratory investigations. We undertook a small sample study to consider whether targeted PMCT-A had any significant effect on subsequent samples taken for biochemical, toxicological or immunological investigations. Although the results of our study do illustrate differences between the pre and post PMCT-A results, these differences are considered not to be of diagnostic significance and not due to the direct effect of targeted PMCT-A. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Preparation of near-infrared-labeled targeted contrast agents for clinical translation

NASA Astrophysics Data System (ADS)

Olive, D. Michael

2011-03-01

Targeted fluorophore-labeled contrast agents are moving toward translation to human surgical use. To prepare for future clinical use, we examined the performance of potential ligands targeting the epidermal growth factor receptor, α5β3 integrins, and GLUT transporters for their suitability as directed contrast agents. Each agent was labeled with IRDye 800CW, and near-infrared dye with excitation/emission wavelengths of 789/805 nm, which we determined had favorable toxicity characteristics. The probe molecules examined consisted of Affibodies, nanobodies, peptides, and the sugar 2-deoxy-D-glucose. Each probe was tested for specific and non-specific binding in cell based assays. All probe types showed good performance in mouse models for detecting either spontaneous tumors or tumor xenografts in vivo. Each of the probes tested show promise for future human clinical studies.

Coupling systematic planning and expert judgement enhances the efficiency of river restoration.

PubMed

Langhans, Simone D; Gessner, Jörn; Hermoso, Virgilio; Wolter, Christian

2016-08-01

Ineffectiveness of current river restoration practices hinders the achievement of ecological quality targets set by country-specific regulations. Recent advances in river restoration help planning efforts more systematically to reach ecological targets at the least costs. However, such approaches are often desktop-based and overlook real-world constraints. We argue that combining two techniques commonly used in the conservation arena - expert judgement and systematic planning - will deliver cost-effective restoration plans with a high potential for implementation. We tested this idea targeting the restoration of spawning habitat, i.e. gravel bars, for 11 rheophilic fish species along a river system in Germany (Havel-Spree rivers). With a group of local fish experts, we identified the location and extent of potential gravel bars along the rivers and necessary improvements to migration barriers to ensure fish passage. Restoration cost of each gravel bar included the cost of the action itself plus a fraction of the cost necessary to ensure longitudinal connectivity by upgrading or building fish passages located downstream. We set restoration targets according to the EU Water Framework Directive, i.e. relative abundance of 11 fish species in the reference community and optimised a restoration plan by prioritising a subset of restoration sites from the full set of identified sites, using the conservation planning software Marxan. Out of the 66 potential gravel bars, 36 sites which were mainly located in the downstream section of the system were selected, reflecting their cost-effectiveness given that fewer barriers needed intervention. Due to the limited overall number of sites that experts identified as being suitable for restoring spawning habitat, reaching abundance-targets was challenged. We conclude that coupling systematic river restoration planning with expert judgement produces optimised restoration plans that account for on-the-ground implementation constraints. If applied, this approach has a high potential to enhance overall efficiency of future restoration efforts. Copyright © 2016 Elsevier B.V. All rights reserved.

Mitochondrial Approaches to Protect Against Cardiac Ischemia and Reperfusion Injury

PubMed Central

Camara, Amadou K. S.; Bienengraeber, Martin; Stowe, David F.

2011-01-01

The mitochondrion is a vital component in cellular energy metabolism and intracellular signaling processes. Mitochondria are involved in a myriad of complex signaling cascades regulating cell death vs. survival. Importantly, mitochondrial dysfunction and the resulting oxidative and nitrosative stress are central in the pathogenesis of numerous human maladies including cardiovascular diseases, neurodegenerative diseases, diabetes, and retinal diseases, many of which are related. This review will examine the emerging understanding of the role of mitochondria in the etiology and progression of cardiovascular diseases and will explore potential therapeutic benefits of targeting the organelle in attenuating the disease process. Indeed, recent advances in mitochondrial biology have led to selective targeting of drugs designed to modulate or manipulate mitochondrial function, to the use of light therapy directed to the mitochondrial function, and to modification of the mitochondrial genome for potential therapeutic benefit. The approach to rationally treat mitochondrial dysfunction could lead to more effective interventions in cardiovascular diseases that to date have remained elusive. The central premise of this review is that if mitochondrial abnormalities contribute to the etiology of cardiovascular diseases (e.g., ischemic heart disease), alleviating the mitochondrial dysfunction will contribute to mitigating the severity or progression of the disease. To this end, this review will provide an overview of our current understanding of mitochondria function in cardiovascular diseases as well as the potential role for targeting mitochondria with potential drugs or other interventions that lead to protection against cell injury. PMID:21559063

Transient receptor potential cation channels in visceral sensory pathways

PubMed Central

Blackshaw, L Ashley

2014-01-01

The extensive literature on this subject is in direct contrast to the limited range of clinical uses for ligands of the transient receptor potential cation channels (TRPs) in diseases of the viscera. TRPV1 is the most spectacular example of this imbalance, as it is in other systems, but it is nonetheless the only TRP target that is currently targeted clinically in bladder sensory dysfunction. It is not clear why this discrepancy exists, but a likely answer is in the promiscuity of TRPs as sensors and transducers for environmental mechanical and chemical stimuli. This review first describes the different sensory pathways from the viscera, and on which nociceptive and non-nociceptive neurones within these pathways TRPs are expressed. They not only fulfil roles as both mechano-and chemo-sensors on visceral afferents, but also form an effector mechanism for cell activation after activation of GPCR and cytokine receptors. Their role may be markedly changed in diseased states, including chronic pain and inflammation. Pain presents the most obvious potential for further development of therapeutic interventions targeted at TRPs, but forms of inflammation are emerging as likely to benefit also. However, despite much basic research, we are still at the beginning of exploring such potential in visceral sensory pathways. LINKED ARTICLES This article is part of a themed section on the pharmacology of TRP channels. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2014.171.issue-10 PMID:24641218

Mitochondrial-Based Therapeutics for the Treatment of Spinal Cord Injury: Mitochondrial Biogenesis as a Potential Pharmacological Target

PubMed Central

Scholpa, Natalie E.

2017-01-01

Spinal cord injury (SCI) is characterized by an initial trauma followed by a progressive cascade of damage referred to as secondary injury. A hallmark of secondary injury is vascular disruption leading to vasoconstriction and decreased oxygen delivery, which directly reduces the ability of mitochondria to maintain homeostasis and leads to loss of ATP-dependent cellular functions, calcium overload, excitotoxicity, and oxidative stress, further exacerbating injury. Restoration of mitochondria dysfunction during the acute phases of secondary injury after SCI represents a potentially effective therapeutic strategy. This review discusses the past and present pharmacological options for the treatment of SCI as well as current research on mitochondria-targeted approaches. Increased antioxidant activity, inhibition of the mitochondrial permeability transition, alternate energy sources, and manipulation of mitochondrial morphology are among the strategies under investigation. Unfortunately, many of these tactics address single aspects of mitochondrial dysfunction, ultimately proving largely ineffective. Therefore, this review also examines the unexplored therapeutic efficacy of pharmacological enhancement of mitochondrial biogenesis, which has the potential to more comprehensively improve mitochondrial function after SCI. PMID:28935700

Mitochondrial-Based Therapeutics for the Treatment of Spinal Cord Injury: Mitochondrial Biogenesis as a Potential Pharmacological Target.

PubMed

Scholpa, Natalie E; Schnellmann, Rick G

2017-12-01

Spinal cord injury (SCI) is characterized by an initial trauma followed by a progressive cascade of damage referred to as secondary injury. A hallmark of secondary injury is vascular disruption leading to vasoconstriction and decreased oxygen delivery, which directly reduces the ability of mitochondria to maintain homeostasis and leads to loss of ATP-dependent cellular functions, calcium overload, excitotoxicity, and oxidative stress, further exacerbating injury. Restoration of mitochondria dysfunction during the acute phases of secondary injury after SCI represents a potentially effective therapeutic strategy. This review discusses the past and present pharmacological options for the treatment of SCI as well as current research on mitochondria-targeted approaches. Increased antioxidant activity, inhibition of the mitochondrial permeability transition, alternate energy sources, and manipulation of mitochondrial morphology are among the strategies under investigation. Unfortunately, many of these tactics address single aspects of mitochondrial dysfunction, ultimately proving largely ineffective. Therefore, this review also examines the unexplored therapeutic efficacy of pharmacological enhancement of mitochondrial biogenesis, which has the potential to more comprehensively improve mitochondrial function after SCI. U.S. Government work not protected by U.S. copyright.

Insulin-Sensitizers, Polycystic Ovary Syndrome and Gynaecological Cancer Risk

PubMed Central

Lauretta, Rosa; Lanzolla, Giulia; Vici, Patrizia; Mariani, Luciano; Moretti, Costanzo

2016-01-01

Preclinical, early phase clinical trials and epidemiological evidence support the potential role of insulin-sensitizers in cancer prevention and treatment. Insulin-sensitizers improve the metabolic and hormonal profile in PCOS patients and may also act as anticancer agents, especially in cancers associated with hyperinsulinemia and oestrogen dependent cancers. Several lines of evidence support the protection against cancer exerted by dietary inositol, in particular inositol hexaphosphate. Metformin, thiazolidinediones, and myoinositol postreceptor signaling may exhibit direct inhibitory effects on cancer cell growth. AMPK, the main molecular target of metformin, is emerging as a target for cancer prevention and treatment. PCOS may be correlated to an increased risk for developing ovarian and endometrial cancer (up to threefold). Several studies have demonstrated an increase in mortality rate from ovarian cancer among overweight/obese PCOS women compared with normal weight women. Long-term use of metformin has been associated with lower rates of ovarian cancer. Considering the evidence supporting a higher risk of gynaecological cancer in PCOS women, we discuss the potential use of insulin-sensitizers as a potential tool for chemoprevention, hypothesizing a possible rationale through which insulin-sensitizers may inhibit tumourigenesis. PMID:27725832

The effect of saccade metrics on the corollary discharge contribution to perceived eye location

PubMed Central

Bansal, Sonia; Jayet Bray, Laurence C.; Peterson, Matthew S.

2015-01-01

Corollary discharge (CD) is hypothesized to provide the movement information (direction and amplitude) required to compensate for the saccade-induced disruptions to visual input. Here, we investigated to what extent these conveyed metrics influence perceptual stability in human subjects with a target-displacement detection task. Subjects made saccades to targets located at different amplitudes (4°, 6°, or 8°) and directions (horizontal or vertical). During the saccade, the target disappeared and then reappeared at a shifted location either in the same direction or opposite to the movement vector. Subjects reported the target displacement direction, and from these reports we determined the perceptual threshold for shift detection and estimate of target location. Our results indicate that the thresholds for all amplitudes and directions generally scaled with saccade amplitude. Additionally, subjects on average produced hypometric saccades with an estimated CD gain <1. Finally, we examined the contribution of different error signals to perceptual performance, the saccade error (movement-to-movement variability in saccade amplitude) and visual error (distance between the fovea and the shifted target location). Perceptual judgment was not influenced by the fluctuations in movement amplitude, and performance was largely the same across movement directions for different magnitudes of visual error. Importantly, subjects reported the correct direction of target displacement above chance level for very small visual errors (<0.75°), even when these errors were opposite the target-shift direction. Collectively, these results suggest that the CD-based compensatory mechanisms for visual disruptions are highly accurate and comparable for saccades with different metrics. PMID:25761955

Evidence base and future research directions in the management of low back pain

PubMed Central

Abbott, Allan

2016-01-01

Low back pain (LBP) is a prevalent and costly condition. Awareness of valid and reliable patient history taking, physical examination and clinical testing is important for diagnostic accuracy. Stratified care which targets treatment to patient subgroups based on key characteristics is reliant upon accurate diagnostics. Models of stratified care that can potentially improve treatment effects include prognostic risk profiling for persistent LBP, likely response to specific treatment based on clinical prediction models or suspected underlying causal mechanisms. The focus of this editorial is to highlight current research status and future directions for LBP diagnostics and stratified care. PMID:27004162

CNS drug development: part III: future directions.

PubMed

Preskorn, Sheldon H

2011-01-01

This column, the third in a series on central nervous system (CNS) drug development, discusses advances during the first decade of the 21st century and directions the field may take in the next 10 years. By identifying many possible new drug targets, the human genome project has created the potential to develop novel central nervous system (CNS) drugs with new mechanisms of action. At the same time, this proliferation of possible new targets has complicated the drug development process, since research has not yet provided guidance as to which targets may be most fruitful. This and other factors (eg, increasing regulatory requirements) have increased the cost and complexity of the drug development process. In addition, as more is learned about the biology of psychiatric illnesses, syndromes may be subdivided into more specific entities that are better understood from a pathophysiological and pathoetiological perspective. This is likely to lead to development of more targeted treatments focused on underlying causes of illness as well as prevention. The development of drugs for Alzheimer's disease is discussed as a possible model for future CNS drug development. We are at the beginning of an era when it is likely that the way in which CNS drugs are developed will need to be rethought, which will call for flexibility and creativity on the part of both drug developers and clinical researchers.

Differential effects of bifrontal and occipital nerve stimulation on pain and fatigue using transcranial direct current stimulation in fibromyalgia patients.

PubMed

To, Wing Ting; James, Evan; Ost, Jan; Hart, John; De Ridder, Dirk; Vanneste, Sven

2017-07-01

Fibromyalgia is a disorder characterized by widespread musculoskeletal pain frequently accompanied by other symptoms such as fatigue. Moderate improvement from pharmacological and non-pharmacological treatments have proposed non-invasive brain stimulation techniques such as transcranial direct current stimulation (tDCS) to the occipital nerve (more specifically the C2 area) or to the dorsolateral prefrontal cortex (DLPFC) as potential treatments. We aimed to explore the effectiveness of repeated sessions of tDCS (eight sessions) targeting the C2 area and DLPFC in reducing fibromyalgia symptoms, more specifically pain and fatigue. Forty-two fibromyalgia patients received either C2 tDCS, DLPFC tDCS or sham procedure (15 C2 tDCS-11 DLPFC tDCS-16 sham). All groups were treated with eight sessions (two times a week for 4 weeks). Our results show that repeated sessions of C2 tDCS significantly improved pain, but not fatigue, in fibromyalgia patients, whereas repeated sessions of DLPFC tDCS significantly improved pain as well as fatigue. This study shows that eight sessions of tDCS targeting the DLPFC have a more general relief in fibromyalgia patients than when targeting the C2 area, suggesting that stimulating different targets with eight sessions of tDCS can lead to benefits on different symptom dimensions of fibromyalgia.

Emotion and goal-directed behavior: ERP evidence on cognitive and emotional conflict.

PubMed

Zinchenko, Artyom; Kanske, Philipp; Obermeier, Christian; Schröger, Erich; Kotz, Sonja A

2015-11-01

Cognitive control supports goal-directed behavior by resolving conflict among opposing action tendencies. Emotion can trigger cognitive control processes, thus speeding up conflict processing when the target dimension of stimuli is emotional. However, it is unclear what role emotionality of the target dimension plays in the processing of emotional conflict (e.g. in irony). In two EEG experiments, we compared the influence of emotional valence of the target (emotional, neutral) in cognitive and emotional conflict processing. To maximally approximate real-life communication, we used audiovisual stimuli. Participants either categorized spoken vowels (cognitive conflict) or their emotional valence (emotional conflict), while visual information was congruent or incongruent. Emotional target dimension facilitated both cognitive and emotional conflict processing, as shown in a reduced reaction time conflict effect. In contrast, the N100 in the event-related potentials showed a conflict-specific reversal: the conflict effect was larger for emotional compared with neutral trials in cognitive conflict and smaller in emotional conflict. Additionally, domain-general conflict effects were observed in the P200 and N200 responses. The current findings confirm that emotions have a strong influence on cognitive and emotional conflict processing. They also highlight the complexity and heterogeneity of the interaction of emotion with different types of conflict. © The Author (2015). Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com.

Precision Oncology Medicine: The Clinical Relevance of Patient-Specific Biomarkers Used to Optimize Cancer Treatment.

PubMed

Schmidt, Keith T; Chau, Cindy H; Price, Douglas K; Figg, William D

2016-12-01

Precision medicine in oncology is the result of an increasing awareness of patient-specific clinical features coupled with the development of genomic-based diagnostics and targeted therapeutics. Companion diagnostics designed for specific drug-target pairs were the first to widely utilize clinically applicable tumor biomarkers (eg, HER2, EGFR), directing treatment for patients whose tumors exhibit a mutation susceptible to an FDA-approved targeted therapy (eg, trastuzumab, erlotinib). Clinically relevant germline mutations in drug-metabolizing enzymes and transporters (eg, TPMT, DPYD) have been shown to impact drug response, providing a rationale for individualized dosing to optimize treatment. The use of multigene expression-based assays to analyze an array of prognostic biomarkers has been shown to help direct treatment decisions, especially in breast cancer (eg, Oncotype DX). More recently, the use of next-generation sequencing to detect many potential "actionable" cancer molecular alterations is further shifting the 1 gene-1 drug paradigm toward a more comprehensive, multigene approach. Currently, many clinical trials (eg, NCI-MATCH, NCI-MPACT) are assessing novel diagnostic tools with a combination of different targeted therapeutics while also examining tumor biomarkers that were previously unexplored in a variety of cancer histologies. Results from ongoing trials such as the NCI-MATCH will help determine the clinical utility and future development of the precision-medicine approach. © 2016, The American College of Clinical Pharmacology.

Role of microRNA508-3p in melanogenesis by targeting microphthalmia transcription factor in melanocytes of alpaca.

PubMed

Zhang, J; Liu, Y; Zhu, Z; Yang, S; Ji, K; Hu, S; Liu, X; Yao, J; Fan, R; Dong, C

2017-02-01

It has been demonstrated that microRNAs (miRNAs) play important roles in the control of melanogenesis and hair color in mammals. By comparing miRNA expression profiles between brown and white alpaca skin, we previously identified miR508-3p as a differentially expressed miRNA suggesting its potential role in melanogenesis and hair color formation. The present study was conducted to determine the role of miR508-3p in melanogenesis in alpaca melanocytes. In situ hybridization showed that miR508-3p is abundantly present in the cytoplasma of alpaca melanocytes. miR508-3p was predicted to target the gene encoding microphthalmia transcription factor (MITF) and a luciferase reporter assay indicated that miR508-3p regulates MITF expression by directly targeting its 3'UTR. Overexpression of miR508-3p in alpaca melanocytes down-regulated MITF expression both at the messenger RNA and protein level and resulted in decreased expression of key melanogenic genes including tyrosinase and tyrosinase-related protein 2. Overexpression of miR508-3p in melanocytes also resulted in decreased melanin production including total alkali-soluble melanogenesis, eumelanogenesis and pheomelanogenesis. Results support a functional role of miR508-3p in regulating melanogenesis in alpaca melanocytes by directly targeting MITF.

Target- and Effect-Directed Actions towards Temporal Goals: Similar Mechanisms?

ERIC Educational Resources Information Center

Walter, Andrea M.; Rieger, Martina

2012-01-01

The goal of an action can consist of generating a change in the environment (to produce an effect) or changing one's own situation in the environment (to move to a physical target). To investigate whether the mechanisms of effect-directed and target-directed action control are similar, participants performed continuous reversal movements. They…

Interactions between Bilingual Effects and Language Impairment: Exploring Grammatical Markers in Spanish-Speaking Bilingual Children

PubMed Central

Castilla-Earls, Anny P.; Restrepo, María Adelaida; Perez-Leroux, Ana Teresa; Gray, Shelley; Holmes, Paul; Gail, Daniel; Chen, Ziqiang

2015-01-01

This study examines the interaction between language impairment and different levels of bilingual proficiency. Specifically, we explore the potential of articles and direct object pronouns as clinical markers of primary language impairment (PLI) in bilingual Spanish-speaking children. The study compared children with PLI and typically developing children (TD) matched on age, English language proficiency, and mother’s education level. Two types of bilinguals were targeted: Spanish-dominant children with intermediate English proficiency (asymmetrical bilinguals, AsyB), and near-balanced bilinguals (BIL). We measured children’s accuracy in the use of direct object pronouns and articles with an elicited language task. Results from this preliminary study suggest language proficiency affects the patterns of use of direct object pronouns and articles. Across language proficiency groups, we find marked differences between TD and PLI, in the use of both direct object pronouns and articles. However, the magnitude of the difference diminishes in balanced bilinguals. Articles appear more stable in these bilinguals and therefore, seem to have a greater potential to discriminate between TD bilinguals from those with PLI. Future studies using discriminant analyses are needed to assess the clinical impact of these findings. PMID:27570320

Electrical Potential of Leaping Eels

PubMed Central

Catania, Kenneth C.

2017-01-01

When approached by a large, partially submerged conductor, electric eels (Electrophorus electricus) will often defend themselves by leaping from the water to directly shock the threat. Presumably, the conductor is interpreted as an approaching terrestrial or semiaquatic animal. In the course of this defensive behavior, eels first make direct contact with their lower jaw and then rapidly emerge from the water, ascending the conductor while discharging high-voltage volleys. In this study, the equivalent circuit that develops during this behavior was proposed and investigated. First, the electromotive force and internal resistance of four electric eels were determined. These values were then used to estimate the resistance of the water volume between the eel and the conductor by making direct measurements of current with the eel and water in the circuit. The resistance of the return path from the eel's lower jaw to the main body of water was then determined, based on voltage recordings, for each electric eel at the height of the defensive leap. Finally, the addition of a hypothetical target for the leaping defense was considered as part of the circuit. The results suggest the defensive behavior efficiently directs electrical current through the threat, producing an aversive and deterring experience by activating afferents in potential predators. PMID:28651251

Identification of berberine as a direct thrombin inhibitor from traditional Chinese medicine through structural, functional and binding studies

NASA Astrophysics Data System (ADS)

Wang, Xing; Zhang, Yuxin; Yang, Ying; Wu, Xia; Fan, Hantian; Qiao, Yanjiang

2017-03-01

Thrombin acts as a key enzyme in the blood coagulation cascade and represents a potential drug target for the treatment of several cardiovascular diseases. The aim of this study was to identify small-molecule direct thrombin inhibitors from herbs used in traditional Chinese medicine (TCM). A pharmacophore model and molecular docking were utilized to virtually screen a library of chemicals contained in compositions of traditional Chinese herbs, and these analyses were followed by in vitro bioassay validation and binding studies. Berberine (BBR) was first confirmed as a thrombin inhibitor using an enzymatic assay. The BBR IC50 value for thrombin inhibition was 2.92 μM. Direct binding studies using surface plasmon resonance demonstrated that BBR directly interacted with thrombin with a KD value of 16.39 μM. Competitive binding assay indicated that BBR could bind to the same argartroban/thrombin interaction site. A platelet aggregation assay demonstrated that BBR had the ability to inhibit thrombin-induced platelet aggregation in washed platelets samples. This study proved that BBR is a direct thrombin inhibitor that has activity in inhibiting thrombin-induced platelet aggregation. BBR may be a potential candidate for the development of safe and effective thrombin-inhibiting drugs.

Biomolecular damage induced by ionizing radiation: the direct and indirect effects of low-energy electrons on DNA.

PubMed

Alizadeh, Elahe; Orlando, Thomas M; Sanche, Léon

2015-04-01

Many experimental and theoretical advances have recently allowed the study of direct and indirect effects of low-energy electrons (LEEs) on DNA damage. In an effort to explain how LEEs damage the human genome, researchers have focused efforts on LEE interactions with bacterial plasmids, DNA bases, sugar analogs, phosphate groups, and longer DNA moieties. Here, we summarize the current understanding of the fundamental mechanisms involved in LEE-induced damage of DNA and complex biomolecule films. Results obtained by several laboratories on films prepared and analyzed by different methods and irradiated with different electron-beam current densities and fluencies are presented. Despite varied conditions (e.g., film thicknesses and morphologies, intrinsic water content, substrate interactions, and extrinsic atmospheric compositions), comparisons show a striking resemblance in the types of damage produced and their yield functions. The potential of controlling this damage using molecular and nanoparticle targets with high LEE yields in targeted radiation-based cancer therapies is also discussed.

Engineering synthetic vaccines using cues from natural immunity.

PubMed

Irvine, Darrell J; Swartz, Melody A; Szeto, Gregory L

2013-11-01

Vaccines aim to protect against or treat diseases through manipulation of the immune response, promoting either immunity or tolerance. In the former case, vaccines generate antibodies and T cells poised to protect against future pathogen encounter or attack diseased cells such as tumours; in the latter case, which is far less developed, vaccines block pathogenic autoreactive T cells and autoantibodies that target self tissue. Enormous challenges remain, however, as a consequence of our incomplete understanding of human immunity. A rapidly growing field of research is the design of vaccines based on synthetic materials to target organs, tissues, cells or intracellular compartments; to co-deliver immunomodulatory signals that control the quality of the immune response; or to act directly as immune regulators. There exists great potential for well-defined materials to further our understanding of immunity. Here we describe recent advances in the design of synthetic materials to direct immune responses, highlighting successes and challenges in prophylactic, therapeutic and tolerance-inducing vaccines.

Engineering synthetic vaccines using cues from natural immunity

NASA Astrophysics Data System (ADS)

Irvine, Darrell J.; Swartz, Melody A.; Szeto, Gregory L.

2013-11-01

Vaccines aim to protect against or treat diseases through manipulation of the immune response, promoting either immunity or tolerance. In the former case, vaccines generate antibodies and T cells poised to protect against future pathogen encounter or attack diseased cells such as tumours; in the latter case, which is far less developed, vaccines block pathogenic autoreactive T cells and autoantibodies that target self tissue. Enormous challenges remain, however, as a consequence of our incomplete understanding of human immunity. A rapidly growing field of research is the design of vaccines based on synthetic materials to target organs, tissues, cells or intracellular compartments; to co-deliver immunomodulatory signals that control the quality of the immune response; or to act directly as immune regulators. There exists great potential for well-defined materials to further our understanding of immunity. Here we describe recent advances in the design of synthetic materials to direct immune responses, highlighting successes and challenges in prophylactic, therapeutic and tolerance-inducing vaccines.

Multiple Smaller Missions as a Direct Pathway to Mars Sample Return

NASA Technical Reports Server (NTRS)

Niles, P. B.; Draper, D. S.; Evans, C. A.; Gibson, E. K.; Graham, L. D.; Jones, J. H.; Lederer, S. M.; Ming, D.; Seaman, C. H.; Archer, P. D.;

New innovations: therapeutic opportunities for intellectual disabilities.

PubMed

Picker, Jonathan D; Walsh, Christopher A

2013-09-01

Intellectual disability is common and is associated with significant morbidity. Until the latter half of the 20th century, there were no efficacious treatments. Following initial breakthroughs associated with newborn screening and metabolic corrections, little progress was made until recently. With improved understanding of genetic and cellular mechanisms, novel treatment options are beginning to appear for a number of specific conditions. Fragile X and tuberous sclerosis offer paradigms for the development of targeted therapeutics, but advances in understanding of other disorders such as Down syndrome and Rett syndrome, for example, are also resulting in promising treatment directions. In addition, better understanding of the underlying neurobiology is leading to novel developments in enzyme replacement for storage disorders and adjunctive therapies for metabolic disorders, as well as potentially more generalizable approaches that target dysfunctional cell regulation via RNA and chromatin. Physiologic therapies, including deep brain stimulation and transcranial magnetic stimulation, offer yet another direction to enhance cognitive functioning. Current options and evolving opportunities for the intellectually disabled are reviewed and exemplified. Copyright © 2013 American Neurological Association.

Novel anti-inflammatory therapies for the treatment of atherosclerosis.

PubMed

Khan, Razi; Spagnoli, Vincent; Tardif, Jean-Claude; L'Allier, Philippe L

2015-06-01

The underlying role of inflammation in atherosclerosis has been characterized. However, current treatment of coronary artery disease (CAD) predominantly consists of targeted reductions in serum lipoprotein levels rather than combating the deleterious effects of acute and chronic inflammation. Vascular inflammation acts by a number of different molecular and cellular pathways to contribute to atherogenesis. Over the last decades, both basic studies and clinical trials have provided evidence for the potential benefits of treatment of inflammation in CAD. During this period, development of pharmacotherapies directed towards inflammation in atherosclerosis has accelerated quickly. This review will highlight specific therapies targeting interleukin-1β (IL-1β), P-selectin and 5-lipoxygenase (5-LO). It will also aim to examine the anti-inflammatory effects of serpin administration, colchicine and intravenous HDL-directed treatment of CAD. We summarize the mechanistic rationale and evidence for these novel anti-inflammatory treatments at both the experimental and clinical levels. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Gualou Guizhi decoction reverses brain damage with cerebral ischemic stroke, multi-component directed multi-target to screen calcium-overload inhibitors using combination of molecular docking and protein-protein docking.

PubMed

Hu, Juan; Pang, Wen-Sheng; Han, Jing; Zhang, Kuan; Zhang, Ji-Zhou; Chen, Li-Dian

2018-12-01

Stroke is a disease of the leading causes of mortality and disability across the world, but the benefits of drugs curative effects look less compelling, intracellular calcium overload is considered to be a key pathologic factor for ischemic stroke. Gualou Guizhi decoction (GLGZD), a classical Chinese medicine compound prescription, it has been used to human clinical therapy of sequela of cerebral ischemia stroke for 10 years. This work investigated the GLGZD improved prescription against intracellular calcium overload could decreased the concentration of [Ca 2+ ] i in cortex and striatum neurone of MCAO rats. GLGZD contains Trichosanthin and various small molecular that they are the potential active ingredients directed against NR2A, NR2B, FKBP12 and Calnodulin target proteins/enzyme have been screened by computer simulation. "Multicomponent systems" is capable to create pharmacological superposition effects. The Chinese medicine compound prescriptions could be considered as promising sources of candidates for discovery new agents.

Phf8 loss confers resistance to depression-like and anxiety-like behaviors in mice.

PubMed

Walsh, Ryan M; Shen, Erica Y; Bagot, Rosemary C; Anselmo, Anthony; Jiang, Yan; Javidfar, Behnam; Wojtkiewicz, Gregory J; Cloutier, Jennifer; Chen, John W; Sadreyev, Ruslan; Nestler, Eric J; Akbarian, Schahram; Hochedlinger, Konrad

2017-05-09

PHF8 is a histone demethylase with specificity for repressive modifications. While mutations of PHF8 have been associated with cognitive defects and cleft lip/palate, its role in mammalian development and physiology remains unexplored. Here, we have generated a Phf8 knockout allele in mice to examine the consequences of Phf8 loss for development and behaviour. Phf8 deficient mice neither display obvious developmental defects nor signs of cognitive impairment. However, we report a striking resiliency to stress-induced anxiety- and depression-like behaviour on loss of Phf8. We further observe misregulation of serotonin signalling within the prefrontal cortex of Phf8 deficient mice and identify the serotonin receptors Htr1a and Htr2a as direct targets of PHF8. Our results clarify the functional role of Phf8 in mammalian development and behaviour and establish a direct link between Phf8 expression and serotonin signalling, identifying this histone demethylase as a potential target for the treatment of anxiety and depression.

Real-time decoding of the direction of covert visuospatial attention

NASA Astrophysics Data System (ADS)

Andersson, Patrik; Ramsey, Nick F.; Raemaekers, Mathijs; Viergever, Max A.; Pluim, Josien P. W.

2012-08-01

Brain-computer interfaces (BCIs) make it possible to translate a person’s intentions into actions without depending on the muscular system. Brain activity is measured and classified into commands, thereby creating a direct link between the mind and the environment, enabling, e.g., cursor control or navigation of a wheelchair or robot. Most BCI research is conducted with scalp EEG but recent developments move toward intracranial electrodes for paralyzed people. The vast majority of BCI studies focus on the motor system as the appropriate target for recording and decoding movement intentions. However, properties of the visual system may make the visual system an attractive and intuitive alternative. We report on a study investigating feasibility of decoding covert visuospatial attention in real time, exploiting the full potential of a 7 T MRI scanner to obtain the necessary signal quality, capitalizing on earlier fMRI studies indicating that covert visuospatial attention changes activity in the visual areas that respond to stimuli presented in the attended area of the visual field. Healthy volunteers were instructed to shift their attention from the center of the screen to one of four static targets in the periphery, without moving their eyes from the center. During the first part of the fMRI-run, the relevant brain regions were located using incremental statistical analysis. During the second part, the activity in these regions was extracted and classified, and the subject was given visual feedback of the result. Performance was assessed as the number of trials where the real-time classifier correctly identified the direction of attention. On average, 80% of trials were correctly classified (chance level <25%) based on a single image volume, indicating very high decoding performance. While we restricted the experiment to five attention target regions (four peripheral and one central), the number of directions can be higher provided the brain activity patterns can be distinguished. In summary, the visual system promises to be an effective target for BCI control.

Early processing variations in selective attention to the color and direction of moving stimuli during 30 days head-down bed rest

NASA Astrophysics Data System (ADS)

Wang, Lin-Jie; He, Si-Yang; Niu, Dong-Bin; Guo, Jian-Ping; Xu, Yun-Long; Wang, De-Sheng; Cao, Yi; Zhao, Qi; Tan, Cheng; Li, Zhi-Li; Tang, Guo-Hua; Li, Yin-Hui; Bai, Yan-Qiang

2013-11-01

Dynamic variations in early selective attention to the color and direction of moving stimuli were explored during a 30 days period of head-down bed rest. Event-related potentials (ERPs) were recorded at F5, F6, P5, P6 scalp locations in seven male subjects who attended to pairs of bicolored light emitting diodes that flashed sequentially to produce a perception of movement. Subjects were required to attend selectively to a critical feature of the moving target, e.g., color or direction. The tasks included: a no response task, a color selective response task, a moving direction selective response task, and a combined color-direction selective response task. Subjects were asked to perform these four tasks on: the 3rd day before bed rest; the 3rd, 15th and 30th day during the bed rest; and the 5th day after bed rest. Subjects responded quickly to the color than moving direction and combined color-direction response. And they had a longer reaction time during bed rest on the 15th and 30th day during bed rest after a relatively quicker response on the 3rd day. Using brain event-related potentials technique, we found that in the color selective response task, the mean amplitudes of P1 and N1 for target ERPs decreased in the 3rd day during bed rest and 5th day after bed rest in comparison with pre-bed rest, 15th day and 30th day during bed rest. In the combined color-direction selective response task, the P1 latencies for target ERPs on the 3rd and 30th day during bed rest were longer than on the 15th day during bed rest. As 3rd day during bed rest was in the acute adaptation period and 30th day during bed rest was in the relatively adaptation stage of head-down bed rest, the results help to clarify the effects of bed rest on different task loads and patterns of attention. It was suggested that subjects expended more time to give correct decision in the head-down tilt bed rest state. A difficulty in the recruitment of brain resources was found in feature selection task, but no variations were detected in the no response and direction selective response tasks. It is suggested that the negative shift in color selective response task on the 3rd day of bed rest are a result of fluid redistribution. And feature selection was more affected than motion selection in the head down bed rest. The variations in cognitive processing speed observed for the combined color-direction selective response task are suggested to reflect the interaction between top-down mechanisms and hierarchical physiological characteristics during 30 days head-down bed rest.

Effect of Bar-code Technology on the Incidence of Medication Dispensing Errors and Potential Adverse Drug Events in a Hospital Pharmacy

PubMed Central

Poon, Eric G; Cina, Jennifer L; Churchill, William W; Mitton, Patricia; McCrea, Michelle L; Featherstone, Erica; Keohane, Carol A; Rothschild, Jeffrey M; Bates, David W; Gandhi, Tejal K

2005-01-01

We performed a direct observation pre-post study to evaluate the impact of barcode technology on medication dispensing errors and potential adverse drug events in the pharmacy of a tertiary-academic medical center. We found that barcode technology significantly reduced the rate of target dispensing errors leaving the pharmacy by 85%, from 0.37% to 0.06%. The rate of potential adverse drug events (ADEs) due to dispensing errors was also significantly reduced by 63%, from 0.19% to 0.069%. In a 735-bed hospital where 6 million doses of medications are dispensed per year, this technology is expected to prevent about 13,000 dispensing errors and 6,000 potential ADEs per year. PMID:16779372

Computer-aided drug design for AMP-activated protein kinase activators.

PubMed

Wang, Zhanli; Huo, Jianxin; Sun, Lidan; Wang, Yongfu; Jin, Hongwei; Yu, Hui; Zhang, Liangren; Zhou, Lishe

2011-09-01

AMP-activated protein kinase (AMPK) is an important therapeutic target for the potential treatment of metabolic disorders, cardiovascular disease and cancer. Recently, various classes of compounds that activate AMPK by direct or indirect interactions have been reported. The importance of computer-aided drug design approaches in the search for potent activators of AMPK is now established, including structure-based design, ligand-based design, fragment-based design, as well as structural analysis. This review article highlights the computer-aided drug design approaches utilized to discover of activators targeting AMPK. The principles, advantages or limitation of the different methods are also being discussed together with examples of applications taken from the literatures.

Targeting EGFR in lung cancer: Lessons learned and future perspectives

PubMed Central

Steuer, Conor E.; Ramalingam, Suresh S.

2016-01-01

The development of individualized therapies has become the focus of current oncology research. Precision medicine has demonstrated great potential for bringing safe and effective drugs to those patients stricken with cancer, and is becoming a reality as more oncogenic drivers of malignancy are discovered. The discovery of Epidermal Growth Factor Receptor (EGFR) mutations as a driving mutation in non-small cell lung cancer (NSCLC) and the subsequent success of the tyrosine kinase inhibitors (TKI) have led the way for NSCLC to be at the forefront of biomarker-based drug development. However, this direction was not always so clear, and this article describes the lessons learned in targeted therapy development from EGFR in NSCLC. PMID:26022942

Antiparasitic chemotherapy – from genomes to mechanisms

PubMed Central

Horn, David; Duraisingh, Manoj T.

2015-01-01

Due to the absence of antiparistic vaccines, and the constant threat of drug resistance, the development of novel antiparasitic chemotherapies remains of major importance for disease control. A better understanding of drug transport (uptake and efflux), metabolism and the identification of drug targets, as well as potential drug resistance mechanisms would facilitate the development of more effective therapies. Here, we focus on malaria and African tyrpanosaomiasis. We review existing drugs and drug development, emphasizing high-throughput genomic and genetic approaches, which hold great promise for elucidating anti-parasitic mechanisms. We describe the approaches and technologies that have been influential for each parasite and develop some new ideas for future research directions, including strategies for target deconvolution. PMID:24050701

Mitigation of CO2 emissions from the EU-15 building stock: beyond the EU Directive on the Energy Performance of Buildings.

PubMed

Petersdorff, Carsten; Boermans, Thomas; Harnisch, Jochen

2006-09-01

GOAL SCOPE AND BACKGROUND: The European Directive on Energy Performance of Buildings which came into force 16 December 2002 will be implemented in the legislation of Member States by 4 January 2006. In addition to the aim of improving the overall energy efficiency of new buildings, large existing buildings will become a target for improvement, as soon as they undergo significant renovation. The building sector is responsible for about 40% of Europe's total end energy consumption and hence this Directive is an important step for the European Union in order that it should reach the level of saving required by the Kyoto Agreement. In this the EU is committed to reduce CO2 emissions relative to the base year of 1990 by 8 per cent, by 2010. But what will be the impact of the new Directive, how large could be the impacts of extending the obligation for energy efficiency retrofitting towards smaller buildings? Can improvement of the insulation offset or reduce the growing energy consumption from the increasing installation of cooling installations? EURIMA, the European Insulation Manufacturers Association and EuroACE, the European Alliance of Companies for Energy Efficiency in Buildings, asked Ecofys to address these questions. The effect of the EPB Directive on the emissions associated with the heating energy consumption of the total EU 15 building stock has been examined in a model calculation, using the Built Environment Analysis Model (BEAM), which was developed by Ecofys to investigate energy saving measures in the building stock. The great complexity of the EU-15 building stock had to be simplified by examining five standard buildings with eight insulation standards, which are assigned to building age and renovation status. Furthermore, three climatic regions (cold, moderate, warm) were distinguished for the calculation of the heating energy demand. This gave a basic 210 building types for which the heating energy demand and CO2 emissions from heating were calculated according to the principles of the European Norm EN 832. The model calculations demonstrates that the main contributor to the total heating related CO2 emissions of 725 Mt/a from the EU building stock in 2002 is the residential sector (77%) while the remaining 23% originates from non-residential buildings. In the residential sector, single-family houses represent the largest group responsible for 60% of the total CO2 emissions equivalent to 435 Mt/a. THE TECHNICAL POTENTIAL: If all retrofit measures in the scope of the Directive were realised immediately for the complete residential and non-residential building stock the overall CO2 emission savings would add up to 82 Mt/a. An additional saving potential compared to the Directive of 69 Mt/a would be created if the scope of the Directive was extended to cover retrofit measures in multi-family dwellings (200-1000 m2) and non-residential buildings smaller than 1000 m2 used floor space. In addition including the large group of single-family dwellings would lead to a potential for additional CO2 emission reductions compared to the Directive of 316 Mt/a. TEMPORAL MOBILIZATION OF THE POTENTIAL: Calculations based on the building stock as it develops over time with average retrofit rates demonstrated that regulations introduced following the EPB Directive result in a CO2 emissions decrease of 34 Mt/a by the year 2010 compared to the business as usual scenario. Extending the scope of the EPB Directive to all residential buildings (including single and multi-family dwellings), the CO2 emission savings potential over the 'business as usual' scenario could be doubled to 69 Mt/a in the year 2010. This creates an additional saving potential compared to the Directive of 36 Mt/a. COOLING DEMAND: The analysis demonstrated that in warm climatic zones the cooling demand can be reduced drastically by a combination of lowering the internal heat loads and by improved insulation. With the reduction of the heat loads to a moderate level the cooling demand, e.g. of a terraced house located in Madrid, can be reduced by an additional 85% if the insulation level is improved appropriately. This study demonstrates that the European Directive on Energy Performance of Buildings will have a significant impact on the CO2 emissions of the European building stock. The main saving potential lies in insulation of the existing building stock. Beyond this, CO2 emissions could, however, be greatly reduced if the scope of the Directive were to be extended to include retrofit of smaller buildings. The reductions should be seen in relation to the remaining gap of 190 Mt CO2 eq. per annum between the current emission levels of EU-15 and the target under the Kyoto-Protocol for the year 2010. The energy and industrial sector will probably contribute only a fraction of this reduction via the newly established EU emissions trading scheme and connected projects under the flexible mechanism. In addition, the traffic sector is likely to continue its growth path leading to a widening of the gap. Thus, there is likely to be considerable pressure on the EU building sector to contribute to the EU climate targets beyond what will be achieved by means of the current EPB Directive. Legislators on the EU and national level are therefore advised to take accelerated actions to tap the very significant emission reduction potentials available in the EU building stock.

The DNA Replication Checkpoint Directly Regulates MBF-Dependent G1/S Transcription▿

PubMed Central

Dutta, Chaitali; Patel, Prasanta K.; Rosebrock, Adam; Oliva, Anna; Leatherwood, Janet; Rhind, Nicholas

2008-01-01

The DNA replication checkpoint transcriptionally upregulates genes that allow cells to adapt to and survive replication stress. Our results show that, in the fission yeast Schizosaccharomyces pombe, the replication checkpoint regulates the entire G1/S transcriptional program by directly regulating MBF, the G1/S transcription factor. Instead of initiating a checkpoint-specific transcriptional program, the replication checkpoint targets MBF to maintain the normal G1/S transcriptional program during replication stress. We propose a mechanism for this regulation, based on in vitro phosphorylation of the Cdc10 subunit of MBF by the Cds1 replication-checkpoint kinase. Replacement of two potential phosphorylation sites with phosphomimetic amino acids suffices to promote the checkpoint transcriptional program, suggesting that Cds1 phosphorylation directly regulates MBF-dependent transcription. The conservation of MBF between fission and budding yeast, and recent results implicating MBF as a target of the budding yeast replication checkpoint, suggests that checkpoint regulation of the MBF transcription factor is a conserved strategy for coping with replication stress. Furthermore, the structural and regulatory similarity between MBF and E2F, the metazoan G1/S transcription factor, suggests that this checkpoint mechanism may be broadly conserved among eukaryotes. PMID:18662996

Progress in Direct-Drive Inertial Confinement Fusion

DOE Office of Scientific and Technical Information (OSTI.GOV)

McCrory, R.L.; Meyerhofer, D.D.; Betti, R.

Significant progress in direct-drive inertial confinement fusion (ICF) research has been made since the completion of the 60-beam, 30-kJ UV OMEGA Laser System [T. R. Boehly, Opt. Commun. 133, 495 (1997)] in 1995. A theory of ignition requirements, applicable to any ICF concept, has been developed. Detailed understanding of laser-plasma coupling, electron thermal transport, and hot-electron preheating has lead to the measurement of neutron-averaged areal densities of ~200 mg/cm^2 in cryogenic target implosions. These correspond to an estimated peak fuel density in excess of 100 g/cm^3 and are in good agreement with hydrodynamic simulations. The implosions were performed using anmore » 18-kJ drive pulse designed to put the converging fuel on an adiabat of two. The polar-drive concept will allow direct-drive-ignition research on the National Ignition Facility while it is configured for indirect drive. Advanced ICF ignition concepts—fast ignition [Tabak et al., Phys. Plasmas 1, 1626 (1994)] and shock ignition [R. Betti et al., Phys. Rev. Lett. 98, 155001 (2007)]—have the potential to significantly reduce ignition driver energies and/or provide higher target gain.« less

Progress in direct-drive inertial confinement fusion

DOE Office of Scientific and Technical Information (OSTI.GOV)

McCrory, R. L.; Meyerhofer, D. D.; Betti, R.

Significant progress in direct-drive inertial confinement fusion (ICF) research has been made since the completion of the 60-beam, 30-kJ{sub UV} OMEGA Laser System [Boehly, Opt. Commun. 133, 495 (1997)] in 1995. A theory of ignition requirements, applicable to any ICF concept, has been developed. Detailed understanding of laser-plasma coupling, electron thermal transport, and hot-electron preheating has lead to the measurement of neutron-averaged areal densities of {approx}200 mg/cm{sup 2} in cryogenic target implosions. These correspond to an estimated peak fuel density in excess of 100 g/cm{sup 3} and are in good agreement with hydrodynamic simulations. The implosions were performed using anmore » 18-kJ drive pulse designed to put the converging fuel on an adiabat of two. The polar-drive concept will allow direct-drive-ignition research on the National Ignition Facility while it is configured for indirect drive. Advanced ICF ignition concepts - fast ignition [Tabak et al., Phys. Plasmas 1, 1626 (1994)] and shock ignition [Betti et al., Phys. Rev. Lett. 98, 155001 (2007)] - have the potential to significantly reduce ignition driver energies and/or provide higher target gain.« less

Surface invasive cleavage assay on a maskless light-directed diamond DNA microarray for genome-wide human SNP mapping.

PubMed

Nie, Bei; Yang, Min; Fu, Weiling; Liang, Zhiqing

2015-07-07

The surface invasive cleavage assay, because of its innate accuracy and ability for self-signal amplification, provides a potential route for the mapping of hundreds of thousands of human SNP sites. However, its performance on a high density DNA array has not yet been established, due to the unusual "hairpin" probe design on the microarray and the lack of chemical stability of commercially available substrates. Here we present an applicable method to implement a nanocrystalline diamond thin film as an alternative substrate for fabricating an addressable DNA array using maskless light-directed photochemistry, producing the most chemically stable and biocompatible system for genetic analysis and enzymatic reactions. The surface invasive cleavage reaction, followed by degenerated primer ligation and post-rolling circle amplification is consecutively performed on the addressable diamond DNA array, accurately mapping SNP sites from PCR-amplified human genomic target DNA. Furthermore, a specially-designed DNA array containing dual probes in the same pixel is fabricated by following a reverse light-directed DNA synthesis protocol. This essentially enables us to decipher thousands of SNP alleles in a single-pot reaction by the simple addition of enzyme, target and reaction buffers.

Prescription drug coupons: evolution and need for regulation in direct-to-consumer advertising.

PubMed

Mackey, Tim K; Yagi, Nozomi; Liang, Bryan A

2014-01-01

Pharmaceutical marketing in the United States had undergone a shift from largely exclusively targeting physicians to considerable efforts in targeting patients through various forms of direct-to-consumer advertising ("DTCA"). This includes the use of DTCA in prescription drug coupons ("PDCs"), a new form of DTCA that offers discounts and rebates directly to consumers to lower costs of drug purchasing. Our examination of PDCs reveals that the use and types of PDC programs is expanding and includes promotion of the vast majority of top grossing pharmaceuticals. However, controversy regarding this emerging form of DTCA has given rise to health policy concerns about their overall impact on prescription drug expenditures for consumers, payers, and the health care system, and whether they lead to optimal long-term utilization of pharmaceuticals. In response to these concerns and the growing popularity of PDCs, what we propose here are clearer regulation and regulatory guidance for PDC DTCA use. This would include review for appropriate disclosure of marketing claims, increased transparency in PDC use for pharmaceutical pricing, and leveraging potential positive benefits of PDC use for vulnerable or underserved patient populations. Copyright © 2014 Elsevier Inc. All rights reserved.

Dissociable contribution of the parietal and frontal cortex to coding movement direction and amplitude

PubMed Central

Davare, Marco; Zénon, Alexandre; Desmurget, Michel; Olivier, Etienne

2015-01-01

To reach for an object, we must convert its spatial location into an appropriate motor command, merging movement direction and amplitude. In humans, it has been suggested that this visuo-motor transformation occurs in a dorsomedial parieto-frontal pathway, although the causal contribution of the areas constituting the “reaching circuit” remains unknown. Here we used transcranial magnetic stimulation (TMS) in healthy volunteers to disrupt the function of either the medial intraparietal area (mIPS) or dorsal premotor cortex (PMd), in each hemisphere. The task consisted in performing step-tracking movements with the right wrist towards targets located in different directions and eccentricities; targets were either visible for the whole trial (Target-ON) or flashed for 200 ms (Target-OFF). Left and right mIPS disruption led to errors in the initial direction of movements performed towards contralateral targets. These errors were corrected online in the Target-ON condition but when the target was flashed for 200 ms, mIPS TMS manifested as a larger endpoint spreading. In contrast, left PMd virtual lesions led to higher acceleration and velocity peaks—two parameters typically used to probe the planned movement amplitude—irrespective of the target position, hemifield and presentation condition; in the Target-OFF condition, left PMd TMS induced overshooting and increased the endpoint dispersion along the axis of the target direction. These results indicate that left PMd intervenes in coding amplitude during movement preparation. The critical TMS timings leading to errors in direction and amplitude were different, namely 160–100 ms before movement onset for mIPS and 100–40 ms for left PMd. TMS applied over right PMd had no significant effect. These results demonstrate that, during motor preparation, direction and amplitude of goal-directed movements are processed by different cortical areas, at distinct timings, and according to a specific hemispheric organization. PMID:25999837

Synergistic target combination prediction from curated signaling networks: Machine learning meets systems biology and pharmacology.

PubMed

Chua, Huey Eng; Bhowmick, Sourav S; Tucker-Kellogg, Lisa

2017-10-01

Given a signaling network, the target combination prediction problem aims to predict efficacious and safe target combinations for combination therapy. State-of-the-art in silico methods use Monte Carlo simulated annealing (mcsa) to modify a candidate solution stochastically, and use the Metropolis criterion to accept or reject the proposed modifications. However, such stochastic modifications ignore the impact of the choice of targets and their activities on the combination's therapeutic effect and off-target effects, which directly affect the solution quality. In this paper, we present mascot, a method that addresses this limitation by leveraging two additional heuristic criteria to minimize off-target effects and achieve synergy for candidate modification. Specifically, off-target effects measure the unintended response of a signaling network to the target combination and is often associated with toxicity. Synergy occurs when a pair of targets exerts effects that are greater than the sum of their individual effects, and is generally a beneficial strategy for maximizing effect while minimizing toxicity. mascot leverages on a machine learning-based target prioritization method which prioritizes potential targets in a given disease-associated network to select more effective targets (better therapeutic effect and/or lower off-target effects); and on Loewe additivity theory from pharmacology which assesses the non-additive effects in a combination drug treatment to select synergistic target activities. Our experimental study on two disease-related signaling networks demonstrates the superiority of mascot in comparison to existing approaches. Copyright © 2017 Elsevier Inc. All rights reserved.

Assessing the use of immersive virtual reality, mouse and touchscreen in pointing and dragging-and-dropping tasks among young, middle-aged and older adults.

PubMed

Chen, Jiayin; Or, Calvin

2017-11-01

This study assessed the use of an immersive virtual reality (VR), a mouse and a touchscreen for one-directional pointing, multi-directional pointing, and dragging-and-dropping tasks involving targets of smaller and larger widths by young (n = 18; 18-30 years), middle-aged (n = 18; 40-55 years) and older adults (n = 18; 65-75 years). A three-way, mixed-factorial design was used for data collection. The dependent variables were the movement time required and the error rate. Our main findings were that the participants took more time and made more errors in using the VR input interface than in using the mouse or the touchscreen. This pattern applied in all three age groups in all tasks, except for multi-directional pointing with a larger target width among the older group. Overall, older adults took longer to complete the tasks and made more errors than young or middle-aged adults. Larger target widths yielded shorter movement times and lower error rates in pointing tasks, but larger targets yielded higher rates of error in dragging-and-dropping tasks. Our study indicated that any other virtual environments that are similar to those we tested may be more suitable for displaying scenes than for manipulating objects that are small and require fine control. Although interacting with VR is relatively difficult, especially for older adults, there is still potential for older adults to adapt to that interface. Furthermore, adjusting the width of objects according to the type of manipulation required might be an effective way to promote performance. Copyright © 2017 Elsevier Ltd. All rights reserved.

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

PubMed

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

2015-09-01

Tumor microenvironment (TM) is an essential element in prostate cancer (PCA), offering unique opportunities for its prevention. TM includes naïve fibroblasts that are recruited by nascent neoplastic lesion and altered into 'cancer-associated fibroblasts' (CAFs) that promote PCA. A better understanding and targeting of interaction between PCA cells and fibroblasts and inhibiting CAF phenotype through non-toxic agents are novel approaches to prevent PCA progression. One well-studied cancer chemopreventive agent is silibinin, and thus, we examined its efficacy against PCA cells-mediated differentiation of naïve fibroblasts into a myofibroblastic-phenotype similar to that found in CAFs. Silibinin's direct inhibitory effect on the phenotype of CAFs derived directly from PCA patients was also assessed. Human prostate stromal cells (PrSCs) exposed to control conditioned media (CCM) from human PCA PC3 cells showed more invasiveness, with increased alpha-smooth muscle actin (α-SMA) and vimentin expression, and differentiation into a phenotype we identified in CAFs. Importantly, silibinin (at physiologically achievable concentrations) inhibited α-SMA expression and invasiveness in differentiated fibroblasts and prostate CAFs directly, as well as indirectly by targeting PCA cells. The observed increase in α-SMA and CAF-like phenotype was transforming growth factor (TGF) β2 dependent, which was strongly inhibited by silibinin. Furthermore, induction of α-SMA and CAF phenotype by CCM were also strongly inhibited by a TGFβ2-neutralizing antibody. The inhibitory effect of silibinin on TGFβ2 expression and CAF-like biomarkers was also observed in PC3 tumors. Together, these findings highlight the potential usefulness of silibinin in PCA prevention through targeting the CAF phenotype in the prostate TM. © 2014 Wiley Periodicals, Inc.

Biomarkers that currently affect clinical practice: EGFR, ALK, MET, KRAS

PubMed Central

Vincent, M.D.; Kuruvilla, M.S.; Leighl, N.B.; Kamel–Reid, S.

2012-01-01

New drugs such as pemetrexed, the epidermal growth factor receptor (egfr) tyrosine kinase inhibitors, and the Alk inhibitor crizotinib have recently enabled progress in the management of advanced non-small-cell lung cancer (nsclc). More drugs, especially Met inhibitors, will follow. However, the benefits of these agents are not uniform across the spectrum of nsclc, and optimizing their utility requires some degree of subgrouping of nsclc by the presence or absence of certain biomarkers. The biomarkers of current or imminent value are EGFR and KRAS mutational status, ALK rearrangements, and MET immunohistochemistry. As a predictor of benefit for anti-egfr monoclonal antibodies, EGFR immunohistochemistry is also of potential interest. Some of the foregoing biomarkers (EGFR, ALK, MET) are direct drivers of the malignant phenotype. As such, they are, quite rationally, the direct targets of inhibitory drugs. However, KRAS, while definitely a driver, has resisted attempts at direct pharmacologic manipulation, and its main value might lie in its role as part of an efficient testing algorithm, because KRAS mutations appear to exclude EGFR and ALK mutations. The indirect value of KRAS in determining sensitivity to other targeted agents or to pemetrexed remains controversial. The other biomarkers (EGFR, ALK, MET) may also have indirect value as predictors of sensitivity to chemotherapy in general, to pemetrexed specifically, and to radiotherapy and molecularly targeted agents. These biomarkers have all enabled the co-development of new drugs with companion diagnostics, and they illustrate the paradigm that will govern progress in oncology in the immediate future. However, in nsclc, the acquisition of sufficient biopsy material remains a stubborn obstacle to the evolution of novel targeted therapies. PMID:22787409

Direct-to-consumer prescription drug advertising, 1989-1998. A content analysis of conditions, targets, inducements, and appeals.

PubMed

Bell, R A; Kravitz, R L; Wilkes, M S

2000-04-01

We conducted a content analysis of consumer-targeted prescription drug advertisements to explore trends in prevalence, shifts in the medical conditions for which drugs are promoted, reliance on financial and nonmonetary inducements, and appeals used to attract public interest. We collected the drug advertisements appearing in 18 consumer magazines from 1989 through 1998. Two judges independently coded each advertisement and placed it in a category pertaining to the target audience, use of inducements, and product benefits (mean kappa=0.93). We employed descriptive statistics, cross-tabulations, and curve estimation procedures. A total of 320 distinct advertisements were identified, representing 101 brands and 14 medical conditions. New advertisement and brand introductions increased dramatically during this decade. Advertisements for drugs used for dermatologic, human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS), and obstetric/gynecologic conditions were most common. Almost all of the advertisements were aimed at the potential user of the drug, not third-party intermediaries such as parents and spouses. Although most advertisements were gender-neutral, women were more likely to be exclusively targeted. One eighth of the advertisements offered a monetary incentive (eg, a rebate or money-back guarantee), and one third made an offer of additional information in printed or audio/video form. The most common appeals used were effectiveness, symptom control, innovativeness, and convenience. Consumer-directed prescription drug advertising has increased dramatically during the past decade. The pharmaceutical industry is turning to this type of advertising to generate interest in its products. Our data may be useful to physicians who want to stay abreast of the treatments that are being directly marketed to their patients.

Drosophila TRPA1 channel is required to avoid the naturally occurring insect repellent citronellal.

PubMed

Kwon, Young; Kim, Sang Hoon; Ronderos, David S; Lee, Youngseok; Akitake, Bradley; Woodward, Owen M; Guggino, William B; Smith, Dean P; Montell, Craig

2010-09-28

Plants produce insect repellents, such as citronellal, which is the main component of citronellal oil. However, the molecular pathways through which insects sense botanical repellents are unknown. Here, we show that Drosophila use two pathways for direct avoidance of citronellal. The olfactory coreceptor OR83b contributes to citronellal repulsion and is essential for citronellal-evoked action potentials. Mutations affecting the Ca(2+)-permeable cation channel TRPA1 result in a comparable defect in avoiding citronellal vapor. The TRPA1-dependent aversion to citronellal relies on a G protein (Gq)/phospholipase C (PLC) signaling cascade rather than direct detection of citronellal by TRPA1. Loss of TRPA1, Gq, or PLC causes an increase in the frequency of citronellal-evoked action potentials in olfactory receptor neurons. Absence of the Ca(2+)-activated K(+) channel (BK channel) Slowpoke results in a similar impairment in citronellal avoidance and an increase in the frequency of action potentials. These results suggest that TRPA1 is required for activation of a BK channel to modulate citronellal-evoked action potentials and for aversion to citronellal. In contrast to Drosophila TRPA1, Anopheles gambiae TRPA1 is directly and potently activated by citronellal, thereby raising the possibility that mosquito TRPA1 may be a target for developing improved repellents to reduce insect-borne diseases such as malaria. Copyright © 2010 Elsevier Ltd. All rights reserved.

Triple probe interrogation of spokes in a HiPIMS discharge

NASA Astrophysics Data System (ADS)

Lockwood Estrin, F.; Karkari, S. K.; Bradley, J. W.

2017-07-01

Using a triple probe situated above the racetrack and inside the magnetic trap of a magnetron, rotating spoke-like structures have been clearly identified in a single HiPIMS pulse as periodic modulations of the electron temperature T e, electron density n e, ion saturation current I isat, floating potential V f and plasma potential V p. The spokes rotate in the E  ×  B direction with a velocity of ~8.8 km s-1. Defining the spoke shape from the footprint of the ion current, they deliver to flush-mounted probes embedded in the target, each spoke can be characterised by a dense but cool leading edge (n e ~ 2.0  ×  1019 m-3, T e ~ 2.1 eV) and a relatively hotter but more rarefied trailing edge (n e ~ 1  ×  1019 m-3, T e ~ 3.9 eV). Measurements of V p show a potential hump towards the rear of the spoke, separated from regions of the highest density, with plasma potentials up to 8 V more positive than the inter-spoke regions. Azimuthal electric fields of ~1 kV m-1 associated with these structures are calculated. Transforming the triple probe time-traces to functions of the azimuthal angle θ and assuming a Gaussian radial profile for the plasma parameters, 2D spatial maps of n e, T e and V p have been constructed as well as the target ion current density J p from the embedded probes. The phase relationship between T e, V p and n e can be clearly seen using this representation with n e leading T e and V p with a phase shift between them of ~50°. Regions of maximum ion current to the target, delivered by individual spokes, coincide with the overlap of regions of high n e and T e measured above the target at a height of 15 mm. Ions created at elevated positions above the target in the observed dense region will take several micro-seconds to reach that surface, so contributing to the target ion current in the following spokes.

Identification of Keratinocyte Growth Factor as a Target of microRNA-155 in Lung Fibroblasts: Implication in Epithelial-Mesenchymal Interactions

PubMed Central

Chevalier, Benoit; Puisségur, Marie-Pierre; Lebrigand, Kevin; Robbe-Sermesant, Karine; Bertero, Thomas; Lino Cardenas, Christian L.; Courcot, Elisabeth; Rios, Géraldine; Fourre, Sandra; Lo-Guidice, Jean-Marc; Marcet, Brice; Cardinaud, Bruno; Barbry, Pascal; Mari, Bernard

2009-01-01

Background Epithelial-mesenchymal interactions are critical in regulating many aspects of vertebrate embryo development, and for the maintenance of homeostatic equilibrium in adult tissues. The interactions between epithelium and mesenchyme are believed to be mediated by paracrine signals such as cytokines and extracellular matrix components secreted from fibroblasts that affect adjacent epithelia. In this study, we sought to identify the repertoire of microRNAs (miRNAs) in normal lung human fibroblasts and their potential regulation by the cytokines TNF-α, IL-1β and TGF-β. Methodology/Principal Findings MiR-155 was significantly induced by inflammatory cytokines TNF-α and IL-1β while it was down-regulated by TGF-β. Ectopic expression of miR-155 in human fibroblasts induced modulation of a large set of genes related to “cell to cell signalling”, “cell morphology” and “cellular movement”. This was consistent with an induction of caspase-3 activity and with an increase in cell migration in fibroblasts tranfected with miR-155. Using different miRNA bioinformatic target prediction tools, we found a specific enrichment for miR-155 predicted targets among the population of down-regulated transcripts. Among fibroblast-selective targets, one interesting hit was keratinocyte growth factor (KGF, FGF-7), a member of the fibroblast growth factor (FGF) family, which owns two potential binding sites for miR-155 in its 3′-UTR. Luciferase assays experimentally validated that miR-155 can efficiently target KGF 3′-UTR. Site-directed mutagenesis revealed that only one out of the 2 potential sites was truly functional. Functional in vitro assays experimentally validated that miR-155 can efficiently target KGF 3′-UTR. Furthermore, in vivo experiments using a mouse model of lung fibrosis showed that miR-155 expression level was correlated with the degree of lung fibrosis. Conclusions/Significance Our results strongly suggest a physiological function of miR-155 in lung fibroblasts. Altogether, this study implicates this miRNA in the regulation by mesenchymal cells of surrounding lung epithelium, making it a potential key player during tissue injury. PMID:19701459

Targeting synthetic lethality between the SRC kinase and the EPHB6 receptor may benefit cancer treatment.

PubMed

Paul, James M; Toosi, Behzad; Vizeacoumar, Frederick S; Bhanumathy, Kalpana Kalyanasundaram; Li, Yue; Gerger, Courtney; El Zawily, Amr; Freywald, Tanya; Anderson, Deborah H; Mousseau, Darrell; Kanthan, Rani; Zhang, Zhaolei; Vizeacoumar, Franco J; Freywald, Andrew

2016-08-02

Application of tumor genome sequencing has identified numerous loss-of-function alterations in cancer cells. While these alterations are difficult to target using direct interventions, they may be attacked with the help of the synthetic lethality (SL) approach. In this approach, inhibition of one gene causes lethality only when another gene is also completely or partially inactivated. The EPHB6 receptor tyrosine kinase has been shown to have anti-malignant properties and to be downregulated in multiple cancers, which makes it a very attractive target for SL applications. In our work, we used a genome-wide SL screen combined with expression and interaction network analyses, and identified the SRC kinase as a SL partner of EPHB6 in triple-negative breast cancer (TNBC) cells. Our experiments also reveal that this SL interaction can be targeted by small molecule SRC inhibitors, SU6656 and KX2-391, and can be used to improve elimination of human TNBC tumors in a xenograft model. Our observations are of potential practical importance, since TNBC is an aggressive heterogeneous malignancy with a very high rate of patient mortality due to the lack of targeted therapies, and our work indicates that FDA-approved SRC inhibitors may potentially be used in a personalized manner for treating patients with EPHB6-deficient TNBC. Our findings are also of a general interest, as EPHB6 is downregulated in multiple malignancies and our data serve as a proof of principle that EPHB6 deficiency may be targeted by small molecule inhibitors in the SL approach.

Recent Advances in Targeted, Self-Assembling Nanoparticles to Address Vascular Damage Due to Atherosclerosis

PubMed Central

Chung, Eun Ji; Tirrell, Matthew

2016-01-01

Self-assembling nanoparticles functionalized with targeting moieties have significant potential for atherosclerosis nanomedicine. While self-assembly allows for easy construction (and degradation) of nanoparticles with therapeutic or diagnostic functionality, or both, the targeting agent can direct them to a specific molecular marker within a given stage of the disease. Therefore, supramolecular nanoparticles have been investigated in the last decade as molecular imaging agents or explored as nanocarriers that can decrease the systemic toxicity of drugs by producing accumulation predominantly in specific tissues of interest. In this review, we first describe the pathogenesis of atherosclerosis and the damage caused to vascular tissue, as well as the current diagnostic and treatment options. Then we provide an overview of targeted strategies using self-assembling nanoparticles and include liposomes, high density lipoproteins, protein cages, micelles, proticles, and perfluorocarbon nanoparticles. Finally, we elaborate on and provide an overview of current challenges, limitations, and future applications for personalized medicine in the context of atherosclerosis of self-assembling nanoparticles. PMID:26085109

Linker-free conjugation and specific cell targeting of antibody functionalized iron-oxide nanoparticles

PubMed Central

Xu, Yaolin; Baiu, Dana C.; Sherwood, Jennifer A.; McElreath, Meghan R.; Qin, Ying; Lackey, Kimberly H.; Otto, Mario; Bao, Yuping

2015-01-01

Specific targeting is a key step to realize the full potential of iron oxide nanoparticles in biomedical applications, especially tumor-associated diagnosis and therapy. Here, we developed anti-GD2 antibody conjugated iron oxide nanoparticles for highly efficient neuroblastoma cell targeting. The antibody conjugation was achieved through an easy, linker-free method based on catechol reactions. The targeting efficiency and specificity of the antibody-conjugated nanoparticles to GD2-positive neuroblastoma cells were confirmed by flow cytometry, fluorescence microscopy, Prussian blue staining and transmission electron microscopy. These detailed studies indicated that the receptor-recognition capability of the antibody was fully retained after conjugation and the conjugated nanoparticles quickly attached to GD2-positive cells within four hours. Interestingly, longer treatment (12 h) led the cell membrane-bound nanoparticles to be internalized into cytosol, either by directly penetrating the cell membrane or escaping from the endosomes. Last but importantly, the uniquely designed functional surfaces of the nanoparticles allow easy conjugation of other bioactive molecules. PMID:26660881

RNA-dependent RNA targeting by CRISPR-Cas9

DOE Office of Scientific and Technical Information (OSTI.GOV)

Strutt, Steven C.; Torrez, Rachel M.; Kaya, Emine

Double-stranded DNA (dsDNA) binding and cleavage by Cas9 is a hallmark of type II CRISPR-Cas bacterial adaptive immunity. All known Cas9 enzymes are thought to recognize DNA exclusively as a natural substrate, providing protection against DNA phage and plasmids. Here, we show that Cas9 enzymes from both subtypes II-A and II-C can recognize and cleave single-stranded RNA (ssRNA) by an RNA-guided mechanism that is independent of a protospacer-adjacent motif (PAM) sequence in the target RNA. RNA-guided RNA cleavage is programmable and site-specific, and we find that this activity can be exploited to reduce infection by single-stranded RNA phage in vivo.more » We also demonstrate that Cas9 can direct PAM-independent repression of gene expression in bacteria. In conclusion, these results indicate that a subset of Cas9 enzymes have the ability to act on both DNA and RNA target sequences, and suggest the potential for use in programmable RNA targeting applications.« less

RNA-dependent RNA targeting by CRISPR-Cas9

DOE PAGES

Strutt, Steven C.; Torrez, Rachel M.; Kaya, Emine; ...

2018-01-05

Double-stranded DNA (dsDNA) binding and cleavage by Cas9 is a hallmark of type II CRISPR-Cas bacterial adaptive immunity. All known Cas9 enzymes are thought to recognize DNA exclusively as a natural substrate, providing protection against DNA phage and plasmids. Here, we show that Cas9 enzymes from both subtypes II-A and II-C can recognize and cleave single-stranded RNA (ssRNA) by an RNA-guided mechanism that is independent of a protospacer-adjacent motif (PAM) sequence in the target RNA. RNA-guided RNA cleavage is programmable and site-specific, and we find that this activity can be exploited to reduce infection by single-stranded RNA phage in vivo.more » We also demonstrate that Cas9 can direct PAM-independent repression of gene expression in bacteria. In conclusion, these results indicate that a subset of Cas9 enzymes have the ability to act on both DNA and RNA target sequences, and suggest the potential for use in programmable RNA targeting applications.« less

Cell Membrane-formed Nanovesicles for Disease-Targeted Delivery

PubMed Central

Gao, Jin; Chu, Dafeng; Wang, Zhenjia

2016-01-01

Vascular inflammation is underlying components of most diseases. To target inflamed vasculature, nanoparticles are commonly engineered by conjugating antibody to the nanoparticle surface, but this bottom-up approach could affect nanoparticle targeting and therapeutic efficacy in complex, physiologically related systems. During vascular inflammation endothelium via the NF-κB pathway instantly upregulates intercellular adhesion molecule 1 (ICAM-1) which binds integrin β2 on neutrophil membrane. Inspired by this interaction, we created a nanovesicle-based drug delivery system using nitrogen cavitation which rapidly disrupts activated neutrophils to make cell membrane nanovesicles. Studies using intravital microscopy of live mouse cremaster venules showed that these vesicles can selectively bind inflamed vasculature because they possess intact targeting molecules of integrin β2. Administering of nanovesicles loaded with TPCA-1 (a NF-κB inhibitor) markedly mitigated mouse acute lung inflammation. Our studies reveal a new top-down strategy for directly employing a diseased tissue to produce biofunctional nanovesicle-based drug delivery systems potentially applied to treat various diseases. PMID:26778696

RNA-dependent RNA targeting by CRISPR-Cas9

PubMed Central

Strutt, Steven C; Torrez, Rachel M; Kaya, Emine; Negrete, Oscar A

2018-01-01

Double-stranded DNA (dsDNA) binding and cleavage by Cas9 is a hallmark of type II CRISPR-Cas bacterial adaptive immunity. All known Cas9 enzymes are thought to recognize DNA exclusively as a natural substrate, providing protection against DNA phage and plasmids. Here, we show that Cas9 enzymes from both subtypes II-A and II-C can recognize and cleave single-stranded RNA (ssRNA) by an RNA-guided mechanism that is independent of a protospacer-adjacent motif (PAM) sequence in the target RNA. RNA-guided RNA cleavage is programmable and site-specific, and we find that this activity can be exploited to reduce infection by single-stranded RNA phage in vivo. We also demonstrate that Cas9 can direct PAM-independent repression of gene expression in bacteria. These results indicate that a subset of Cas9 enzymes have the ability to act on both DNA and RNA target sequences, and suggest the potential for use in programmable RNA targeting applications. PMID:29303478

Targeting monoamine oxidases with multipotent ligands: an emerging strategy in the search of new drugs against neurodegenerative diseases.

PubMed

Pisani, L; Catto, M; Leonetti, F; Nicolotti, O; Stefanachi, A; Campagna, F; Carotti, A

2011-01-01

The socioeconomic burden of multi-factorial pathologies, such as neurodegenerative diseases (NDs), is enormous worldwide. Unfortunately, no proven disease-modifying therapy is available yet and in most cases (e.g., Alzheimer's and Parkinson's disease) the approved drugs exert only palliative and symptomatic effects. Nowadays, an emerging strategy for the discovery of disease-modifying drugs is based on the multi-target directed ligand (MTDL) design, an innovative shift from the traditional approach one-drug-one-target to the more ambitious one-drug-more-targets goal. Herein, we review the discovery strategy, the mechanism of action and the biopharmacological evaluation of multipotent ligands exhibiting monoamine oxidase (MAO) inhibition as the core activity with a potential for the treatment of NDs. In particular, MAO inhibitors exhibiting additional acetylcholinesterase (AChE) or nitric oxide synthase (NOS) inhibition, or ion chelation/antioxidant-radical scavenging/anti-inflammatory/A2A receptor antagonist/APP processing modulating activities have been thoroughly examined.

Mass Spectrometry Based Ultrasensitive DNA Methylation Profiling Using Target Fragmentation Assay.

PubMed

Lin, Xiang-Cheng; Zhang, Ting; Liu, Lan; Tang, Hao; Yu, Ru-Qin; Jiang, Jian-Hui

2016-01-19

Efficient tools for profiling DNA methylation in specific genes are essential for epigenetics and clinical diagnostics. Current DNA methylation profiling techniques have been limited by inconvenient implementation, requirements of specific reagents, and inferior accuracy in quantifying methylation degree. We develop a novel mass spectrometry method, target fragmentation assay (TFA), which enable to profile methylation in specific sequences. This method combines selective capture of DNA target from restricted cleavage of genomic DNA using magnetic separation with MS detection of the nonenzymatic hydrolysates of target DNA. This method is shown to be highly sensitive with a detection limit as low as 0.056 amol, allowing direct profiling of methylation using genome DNA without preamplification. Moreover, this method offers a unique advantage in accurately determining DNA methylation level. The clinical applicability was demonstrated by DNA methylation analysis using prostate tissue samples, implying the potential of this method as a useful tool for DNA methylation profiling in early detection of related diseases.

Discovery and Development of Kelch-like ECH-Associated Protein 1. Nuclear Factor Erythroid 2-Related Factor 2 (KEAP1:NRF2) Protein-Protein Interaction Inhibitors: Achievements, Challenges, and Future Directions.

PubMed

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

2016-12-22

The transcription factor Nrf2 is the primary regulator of the cellular defense system, and enhancing Nrf2 activity has potential usages in various diseases, especially chronic age-related and inflammatory diseases. Recently, directly targeting Keap1-Nrf2 protein-protein interaction (PPI) has been an emerging strategy to selectively and effectively activate Nrf2. This Perspective summarizes the progress in the discovery and development of Keap1-Nrf2 PPI inhibitors, including the Keap1-Nrf2 regulatory mechanisms, biochemical techniques for inhibitor identification, and approaches for identifying peptide and small-molecule inhibitors, as well as discusses privileged structures and future directions for further development of Keap1-Nrf2 PPI inhibitors.

Current ethical and legal issues in health-related direct-to-consumer genetic testing.

PubMed

Niemiec, Emilia; Kalokairinou, Louiza; Howard, Heidi Carmen

2017-09-01

A variety of health-related genetic testing is currently advertized directly to consumers. This article provides a timely overview of direct-to-consumer genetic testing (DTC GT) and salient ethical issues, as well as an analysis of the impact of the recently adopted regulation on in vitro diagnostic medical devices on DTC GT. DTC GT companies currently employ new testing approaches, report on a wide spectrum of conditions and target new groups of consumers. Such activities raise ethical issues including the questionable analytic and clinical validity of tests, the adequacy of informed consent, potentially misleading advertizing, testing in children, research uses and commercialization of genomic data. The recently adopted regulation on in vitro diagnostic medical devices may limit the offers of predisposition DTC GT in the EU market.

Cortical sources of ERP in prosaccade and antisaccade eye movements using realistic source models

PubMed Central

Richards, John E.

2013-01-01

The cortical sources of event-related-potentials (ERP) using realistic source models were examined in a prosaccade and antisaccade procedure. College-age participants were presented with a preparatory interval and a target that indicated the direction of the eye movement that was to be made. In some blocks a cue was given in the peripheral location where the target was to be presented and in other blocks no cue was given. In Experiment 1 the prosaccade and antisaccade trials were presented randomly within a block; in Experiment 2 procedures were compared in which either prosaccade and antisaccade trials were mixed in the same block, or trials were presented in separate blocks with only one type of eye movement. There was a central negative slow wave occurring prior to the target, a slow positive wave over the parietal scalp prior to the saccade, and a parietal spike potential immediately prior to saccade onset. Cortical source analysis of these ERP components showed a common set of sources in the ventral anterior cingulate and orbital frontal gyrus for the presaccadic positive slow wave and the spike potential. In Experiment 2 the same cued- and non-cued blocks were used, but prosaccade and antisaccade trials were presented in separate blocks. This resulted in a smaller difference in reaction time between prosaccade and antisaccade trials. Unlike the first experiment, the central negative slow wave was larger on antisaccade than on prosaccade trials, and this effect on the ERP component had its cortical source primarily in the parietal and mid-central cortical areas contralateral to the direction of the eye movement. These results suggest that blocked prosaccade and antisaccade trials results in preparatory or set effects that decreases reaction time, eliminates some cueing effects, and is based on contralateral parietal-central brain areas. PMID:23847476

Characterization of the Discoidin Domain Receptor 2 Kinase as a Novel Therapeutic Target for Squamous Cell Lung Cancer

DTIC Science & Technology

2012-09-01

for patients with squamous cell lung cancer we have observed substantial fatigue as well as pleural effusions in two patients, a potentially very...treatment-induced airspace disease and pleural effusions . We performed directed sequencing of DDR2 in a pretreat- ment tumor specimen derived from...34). Dasatinib treatment is associated with toxicity in patients, including myelosuppression and the development of pleural and pericardial

Continued Development of the AF/SGR Tricorder Program for Homeland Security, Military, Public Health, and Medical Operations

DTIC Science & Technology

2012-05-15

Method for Ubiquitous Robots Based on Wireless Sensor Networks , in 1st European Conference on Smart Sensing and Context2006, Springer: Enschede, The...SUBJECT TERMS Directed Energy, Lasers, Networking , Wireless , Threat, Remote, Sensors , Database, Targets, Security, Transmit, Mobile, Unmanned...the researchers explore the potential for a network that could transport any type of sensor data now or in the future. 29 3. Methods , Assumptions

Generation of Constructs for DNA-Directed RNA Interference of Venezuelan Equine Encephalitis Virus Genes

DTIC Science & Technology

2006-12-01

Defence Research and Recherche et developpement Development Canada pour la defense Canada DEFENCE I I! / DEFENSE Generation of Constructs for DNA... research into specific antiviral strategies. One such strategy is RNA interference. RNA interference involves the targeted silencing of a gene using...of an effective vaccine or therapeutic for VEE, a highly infectious virus, underscores the need for research in this area. In addition, the potential

Collaborative Enhancement of Endothelial Targeting of Nanocarriers by Modulating Platelet-Endothelial Cell Adhesion Molecule-1/CD31 Epitope Engagement.

PubMed

Chacko, Ann-Marie; Han, Jingyan; Greineder, Colin F; Zern, Blaine J; Mikitsh, John L; Nayak, Madhura; Menon, Divya; Johnston, Ian H; Poncz, Mortimer; Eckmann, David M; Davies, Peter F; Muzykantov, Vladimir R

2015-07-28

Nanocarriers (NCs) coated with antibodies (Abs) to extracellular epitopes of the transmembrane glycoprotein PECAM (platelet endothelial cell adhesion molecule-1/CD31) enable targeted drug delivery to vascular endothelial cells. Recent studies revealed that paired Abs directed to adjacent, yet distinct epitopes of PECAM stimulate each other's binding to endothelial cells in vitro and in vivo ("collaborative enhancement"). This phenomenon improves targeting of therapeutic fusion proteins, yet its potential role in targeting multivalent NCs has not been addressed. Herein, we studied the effects of Ab-mediated collaborative enhancement on multivalent NC spheres coated with PECAM Abs (Ab/NC, ∼180 nm diameter). We found that PECAM Abs do mutually enhance endothelial cell binding of Ab/NC coated by paired, but not "self" Ab. In vitro, collaborative enhancement of endothelial binding of Ab/NC by paired Abs is modulated by Ab/NC avidity, epitope selection, and flow. Cell fixation, but not blocking of endocytosis, obliterated collaborative enhancement of Ab/NC binding, indicating that the effect is mediated by molecular reorganization of PECAM molecules in the endothelial plasmalemma. The collaborative enhancement of Ab/NC binding was affirmed in vivo. Intravascular injection of paired Abs enhanced targeting of Ab/NC to pulmonary vasculature in mice by an order of magnitude. This stimulatory effect greatly exceeded enhancement of Ab targeting by paired Abs, indicating that '"collaborative enhancement"' effect is even more pronounced for relatively large multivalent carriers versus free Abs, likely due to more profound consequences of positive alteration of epitope accessibility. This phenomenon provides a potential paradigm for optimizing the endothelial-targeted nanocarrier delivery of therapeutic agents.

Original Research: miR-194 inhibits proliferation and invasion and promotes apoptosis by targeting KDM5B in esophageal squamous cell carcinoma cells.

PubMed

Cui, Guanghui; Liu, Donglei; Li, Weihao; Li, Yuhang; Liang, Youguang; Shi, Wensong; Zhao, Song

2017-01-01

Increasing evidence suggests that miR-194 is down-regulated in esophageal squamous cell carcinoma tumor tissue. However, the role and underlying mechanism of miR-194 in esophageal squamous cell carcinoma have not been well defined. We used DIANA, TargetScan and miRanda to perform target prediction analysis and found KDM5B is a potential target of miR-194. Based on these findings, we speculated that miR-194 might play a role in esophageal squamous cell carcinoma development and progression by regulation the expression of KDM5B. We detected the expression of miR-194 and KDM5B by quantitative real-time reverse transcription PCR (qRT-PCR) and Western blot assays, respectively, and found down-regulation of miR-194 and up-regulation of KDM5B existed in esophageal squamous cell carcinoma cell lines. By detecting proliferation, invasion and apoptosis of TE6 and TE14 cells transfected with miR-194 mimics or mimic control, miR-194 was found to inhibit proliferation and invasion and promote apoptosis of esophageal squamous cell carcinoma cells. miR-194 was further verified to regulate proliferation, apoptosis and invasion of esophageal squamous cell carcinoma cells by directly targeting KDM5B. Furthermore, animal studies were performed and showed that overexpression of miR-194 inhibited the growth of esophageal squamous cell carcinoma tumors in vivo. These results confirmed our speculation that miR-194 targets KDM5B to inhibit esophageal squamous cell carcinoma development and progression. These findings offer new clues for esophageal squamous cell carcinoma development and progression and novel potential therapeutic targets for esophageal squamous cell carcinoma. © 2016 by the Society for Experimental Biology and Medicine.

Imaging analysis of nuclear antiviral factors through direct detection of incoming adenovirus genome complexes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Komatsu, Tetsuro; Department of Infection Biology, Faculty of Medicine, University of Tsukuba, Tsukuba 305-8575; Will, Hans

2016-04-22

Recent studies involving several viral systems have highlighted the importance of cellular intrinsic defense mechanisms through nuclear antiviral proteins that restrict viral propagation. These factors include among others components of PML nuclear bodies, the nuclear DNA sensor IFI16, and a potential restriction factor PHF13/SPOC1. For several nuclear replicating DNA viruses, it was shown that these factors sense and target viral genomes immediately upon nuclear import. In contrast to the anticipated view, we recently found that incoming adenoviral genomes are not targeted by PML nuclear bodies. Here we further explored cellular responses against adenoviral infection by focusing on specific conditions asmore » well as additional nuclear antiviral factors. In line with our previous findings, we show that neither interferon treatment nor the use of specific isoforms of PML nuclear body components results in co-localization between incoming adenoviral genomes and the subnuclear domains. Furthermore, our imaging analyses indicated that neither IFI16 nor PHF13/SPOC1 are likely to target incoming adenoviral genomes. Thus our findings suggest that incoming adenoviral genomes may be able to escape from a large repertoire of nuclear antiviral mechanisms, providing a rationale for the efficient initiation of lytic replication cycle. - Highlights: • Host nuclear antiviral factors were analyzed upon adenovirus genome delivery. • Interferon treatments fail to permit PML nuclear bodies to target adenoviral genomes. • Neither Sp100A nor B targets adenoviral genomes despite potentially opposite roles. • The nuclear DNA sensor IFI16 does not target incoming adenoviral genomes. • PHF13/SPOC1 targets neither incoming adenoviral genomes nor genome-bound protein VII.« less

Amyloid-ß-directed immunotherapy for Alzheimer's disease

PubMed Central

Lannfelt, L; Relkin, N R; Siemers, E R

2014-01-01

Lannfelt L, Relkin NR, Siemers ER (Uppsala University, Uppsala, Sweden; Weill Cornell Medical College, New York, NY; and Eli Lilly and Co., Indianapolis, IN, USA). Amyloid-ß-directed immunotherapy for Alzheimer’s disease. (Key Symposium). J Intern Med 2014; 275: 284–295. Current treatment options for Alzheimer's disease (AD) are limited to medications that reduce dementia symptoms. Given the rapidly ageing populations in most areas of the world, new therapeutic interventions for AD are urgently needed. In recent years, a number of drug candidates targeting the amyloid-ß (Aß) peptide have advanced into clinical trials; however, most have failed because of safety issues or lack of efficacy. The Aß peptide is central to the pathogenesis, and immunotherapy against Aß has attracted considerable interest. It offers the possibility to reach the target with highly specific drugs. Active immunization and passive immunization have been the most widely studied approaches to immunotherapy of AD. A favourable aspect of active immunization is the capacity for a small number of vaccinations to generate a prolonged antibody response. A potential disadvantage is the variability in the antibody response across patients. The potential advantages of passive immunotherapy include the reproducible delivery of a known amount of therapeutic antibodies to the patient and rapid clearance of those antibodies if side effects develop. A disadvantage is the requirement for repeated infusions of antibodies over time. After more than a decade of research, anti-amyloid immunotherapy remains one of the most promising emerging strategies for developing disease-modifying treatments for AD. In this review, we examine the presently ongoing Aß-directed immunotherapies that have passed clinical development Phase IIa. PMID:24605809

Conjugation of antibodies to gold nanorods through Fc portion: synthesis and molecular specific imaging

PubMed Central

Joshi, Pratixa P.; Yoon, Soon Joon; Hardin, William G.; Emelianov, Stanislav; Sokolov, Konstantin V.

2013-01-01

Anisotropic gold nanorods provide a convenient combination of properties, such as tunability of plasmon resonances and strong extinction cross-sections in the near-infrared to red spectral region. These properties have created significant interest in the development of antibody conjugation methods for synthesis of targeted nanorods for a number of biomedical applications, including molecular specific imaging and therapy. Previously published conjugation approaches have achieved molecular specificity. However, the current conjugation methods have several downsides including low stability and potential cytotoxicity of bioconjugates that are produced by electrostatic interactions as well as lack of control over antibody orientation during covalent conjugation. Here we addressed these shortcomings by introducing directional antibody conjugation to the gold nanorod surface. The directional conjugation is achieved through the carbohydrate moiety, which is located on one of the heavy chains of the Fc portion of most antibodies. The carbohydrate is oxidized under mild conditions to a hydrazide reactive aldehyde group. Then, a heterofunctional linker with hydrazide and dithiol groups is used to attach antibodies to gold nanorods. The directional conjugation approach was characterized using electron microscopy, zeta potential and extinction spectra. We also determined spectral changes associated with nanorod aggregation; these spectral changes can be used as a convenient quality control of nanorod bioconjugates. Molecular specificity of the synthesized antibody targeted nanorods was demonstrated using hyperspectral optical and photoacoustic imaging of cancer cell culture models. Additionally, we observed characteristic changes in optical spectra of molecular specific nanorods after their interactions with cancer cells; the observed spectral signatures can be explored for sensitive cancer detection. PMID:23631707

Active Electro-Location of Objects in the Underwater Environment Based on the Mixed Polarization Multiple Signal Classification Algorithm

PubMed Central

Guo, Lili; Qi, Junwei; Xue, Wei

2018-01-01

This article proposes a novel active localization method based on the mixed polarization multiple signal classification (MP-MUSIC) algorithm for positioning a metal target or an insulator target in the underwater environment by using a uniform circular antenna (UCA). The boundary element method (BEM) is introduced to analyze the boundary of the target by use of a matrix equation. In this method, an electric dipole source as a part of the locating system is set perpendicularly to the plane of the UCA. As a result, the UCA can only receive the induction field of the target. The potential of each electrode of the UCA is used as spatial-temporal localization data, and it does not need to obtain the field component in each direction compared with the conventional fields-based localization method, which can be easily implemented in practical engineering applications. A simulation model and a physical experiment are constructed. The simulation and the experiment results provide accurate positioning performance, with the help of verifying the effectiveness of the proposed localization method in underwater target locating. PMID:29439495

LHRH-Targeted Drug Delivery Systems for Cancer Therapy.

PubMed

Li, Xiaoning; Taratula, Oleh; Taratula, Olena; Schumann, Canan; Minko, Tamara

2017-01-01

Targeted delivery of therapeutic and diagnostic agents to cancer sites has significant potential to improve the therapeutic outcome of treatment while minimizing severe side effects. It is widely accepted that decoration of the drug delivery systems with targeting ligands that bind specifically to the receptors on the cancer cells is a promising strategy that may substantially enhance accumulation of anticancer agents in the tumors. Due to the transformed cellular nature, cancer cells exhibit a variety of overexpressed cell surface receptors for peptides, hormones, and essential nutrients, providing a significant number of target candidates for selective drug delivery. Among others, luteinizing hormonereleasing hormone (LHRH) receptors are overexpressed in the majority of cancers, while their expression in healthy tissues, apart from pituitary cells, is limited. The recent studies indicate that LHRH peptides can be employed to efficiently guide anticancer and imaging agents directly to cancerous cells, thereby increasing the amount of these substances in tumor tissue and preventing normal cells from unnecessary exposure. This manuscript provides an overview of the targeted drug delivery platforms that take advantage of the LHRH receptors overexpression by cancer cells.

DNA-PKcs, a novel functional target of acriflavine, mediates acriflavine's p53-dependent synergistic anti-tumor efficiency with melphalan.

PubMed

Cao, Ji; Lin, Guanyu; Gong, Yanling; Pan, Peichen; Ma, Yaxi; Huang, Ping; Ying, Meidan; Hou, Tingjun; He, Qiaojun; Yang, Bo

2016-12-01

Acriflavine (ACF), a known antibacterial drug, has recently been recognized as a suitable candidate for cancer chemotherapy. However, the molecular target of ACF is not fully understood, which limits its application in cancer therapy. In this study, we established a structure-specific probe-based pull-down approach to comprehensively profile the potential target of ACF, and we identified DNA dependent protein kinase catalytic subunit (DNA-PKcs) as the direct target of ACF. Since DNA-PKcs facilitates the repair process following DNA double-strand breaks, we further developed a drug combination strategy that combined ACF with the bifunctional alkylating agent melphalan, which exerted a p53-dependent synergistic efficacy against human cancer cells both in vitro and in vivo. With these findings, our study demonstrated that structure-specific probe-based pull-down approaches can be used to identify new functional target of drug, and provided novel opportunities for the development of ACF-based antitumor chemotherapies. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

miR-133 regulates Evi1 expression in AML cells as a potential therapeutic target.

PubMed

Yamamoto, Haruna; Lu, Jun; Oba, Shigeyoshi; Kawamata, Toyotaka; Yoshimi, Akihide; Kurosaki, Natsumi; Yokoyama, Kazuaki; Matsushita, Hiromichi; Kurokawa, Mineo; Tojo, Arinobu; Ando, Kiyoshi; Morishita, Kazuhiro; Katagiri, Koko; Kotani, Ai

2016-01-12

The Ecotropic viral integration site 1 (Evi1) is a zinc finger transcription factor, which is located on chromosome 3q26, over-expression in some acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Elevated Evi1 expression in AML is associated with unfavorable prognosis. Therefore, Evi1 is one of the strong candidate in molecular target therapy for the leukemia. MicroRNAs (miRNAs) are small non-coding RNAs, vital to many cell functions that negatively regulate gene expression by translation or inducing sequence-specific degradation of target mRNAs. As a novel biologics, miRNAs is a promising therapeutic target due to its low toxicity and low cost. We screened miRNAs which down-regulate Evi1. miR-133 was identified to directly bind to Evi1 to regulate it. miR-133 increases drug sensitivity specifically in Evi1 expressing leukemic cells, but not in Evi1-non-expressing cells The results suggest that miR-133 can be promising therapeutic target for the Evi1 dysregulated poor prognostic leukemia.

FGFR a promising druggable target in cancer: Molecular biology and new drugs.

PubMed

Porta, Rut; Borea, Roberto; Coelho, Andreia; Khan, Shahanavaj; Araújo, António; Reclusa, Pablo; Franchina, Tindara; Van Der Steen, Nele; Van Dam, Peter; Ferri, Jose; Sirera, Rafael; Naing, Aung; Hong, David; Rolfo, Christian

2017-05-01

The Fibroblast Growth Factor Receptor (FGFR) family consists of Tyrosine Kinase Receptors (TKR) involved in several biological functions. Recently, alterations of FGFR have been reported to be important for progression and development of several cancers. In this setting, different studies are trying to evaluate the efficacy of different therapies targeting FGFR. This review summarizes the current status of treatments targeting FGFR, focusing on the trials that are evaluating the FGFR profile as inclusion criteria: Multi-Target, Pan-FGFR Inhibitors and anti-FGF (Fibroblast Growth Factor)/FGFR Monoclonal Antibodies. Most of the TKR share intracellular signaling pathways; therefore, cancer cells tend to overcome the inhibition of one tyrosine kinase receptor by activating another. The future of TKI (Tyrosine Kinase Inhibitor) therapy will potentially come from multi-targeted TKIs that target different TKR simultaneously. It is crucial to understand the interaction of the FGF-FGFR axis with other known driver TKRs. Based on this, it is possible to develop therapeutic strategies targeting multiple connected TKRs at once. One correct step in this direction is the reassessment of multi target inhibitors considering the FGFR status of the tumor. Another opportunity arises from assessing the use of FGFR TKI on patients harboring FGFR alterations. Copyright © 2017 Elsevier B.V. All rights reserved.

Robot-assisted adaptive training: custom force fields for teaching movement patterns.

PubMed

Patton, James L; Mussa-Ivaldi, Ferdinando A

2004-04-01

Based on recent studies of neuro-adaptive control, we tested a new iterative algorithm to generate custom training forces to "trick" subjects into altering their target-directed reaching movements to a prechosen movement as an after-effect of adaptation. The prechosen movement goal, a sinusoidal-shaped path from start to end point, was never explicitly conveyed to the subject. We hypothesized that the adaptation would cause an alteration in the feedforward command that would result in the prechosen movement. Our results showed that when forces were suddenly removed after a training period of 330 movements, trajectories were significantly shifted toward the prechosen movement. However, de-adaptation occurred (i.e., the after-effect "washed out") in the 50-75 movements that followed the removal of the training forces. A second experiment suppressed vision of hand location and found a detectable reduction in the washout of after-effects, suggesting that visual feedback of error critically influences learning. A final experiment demonstrated that after-effects were also present in the neighborhood of training--44% of original directional shift was seen in adjacent, unpracticed movement directions to targets that were 60 degrees different from the targets used for training. These results demonstrate the potential for these methods for teaching motor skills and for neuro-rehabilitation of brain-injured patients. This is a form of "implicit learning," because unlike explicit training methods, subjects learn movements with minimal instructions, no knowledge of, and little attention to the trajectory.

Potential primary and secondary hazards of avicides

USGS Publications Warehouse

Schafer, E.W.; Clark, Dell O.

1984-01-01

There are six chemicals or groups of chemicals that are currently registered as avicides that can be used in some or all of the U.S. Most of these chemicals, because of their diverse chemical composition and innate toxicological effects, present somewhat different primary and secondary hazards to avian and mammalian predators and scavengers. Of the chemicals reviewed, all appear to present some degree of primary hazard to non-target birds and mammals; however, PA-14, the Starlicide family of chemicals and fenthion appear to be the least hazardous when used according to use directions. 4-Aminopyridine, endrin and strychnine, because of their high acute toxicity and lack of selectivity, must be considered potentially more hazardous. With respect to secondary hazards, the ranking of chemicals changes considerably and only PA-14 appears to present a negligible hazard. The Starlicide family of chemicals presents negligible hazards to most animal species under currently registered uses, but may be potentially hazardous to cats and owls under specific use conditions. Two chemicals, 4-aminopyridine and strychnine, are potentially more hazardous to predatory and scavenger animals due to their highly toxic nature and rapid lethal effects in target species, leaving unassimilated chemical in the gastrointestinal tract. The remaining chemicals, endrin and fenthion, have been shown to possess the potential for more significant secondary poisoning; however, because of restrictive uses, most of the potential hazards have been avoided in operational use.

MicroRNA-429 induces tumorigenesis of human non-small cell lung cancer cells and targets multiple tumor suppressor genes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lang, Yaoguo; Xu, Shidong; Ma, Jianqun

2014-07-18

Highlights: • MiR-429 expression is upregulated in non-small cell lung cancer (NSCLC). • MiR-429 inhibits PTEN, RASSF8 and TIMP2 expression. • MiR-429 promotes metastasis and proliferation. • We report important regulatory mechanisms involved in NSCLC progression. • MiR-429 is a potential therapeutic target and diagnostic marker. - Abstract: Lung cancer is the major cause of cancer death globally. MicroRNAs are evolutionally conserved small noncoding RNAs that are critical for the regulation of gene expression. Aberrant expression of microRNA (miRNA) has been implicated in cancer initiation and progression. In this study, we demonstrated that the expression of miR-429 are often upregulatedmore » in non-small cell lung cancer (NSCLC) compared with normal lung tissues, and its expression level is also increased in NSCLC cell lines compared with normal lung cells. Overexpression of miR-429 in A549 NSCLC cells significantly promoted cell proliferation, migration and invasion, whereas inhibition of miR-429 inhibits these effects. Furthermore, we demonstrated that miR-429 down-regulates PTEN, RASSF8 and TIMP2 expression by directly targeting the 3′-untranslated region of these target genes. Taken together, our results suggest that miR-429 plays an important role in promoting the proliferation and metastasis of NSCLC cells and is a potential target for NSCLC therapy.« less

Identification of Reprogrammed Myeloid Cell Transcriptomes in NSCLC

PubMed Central

Gupta, Ravi; Fischer, Kari R.; Choi, Hyejin; El Rayes, Tina; Ryu, Seongho; Nasar, Abu; Spinelli, Cathy F.; Andrews, Weston; Elemento, Olivier; Nolan, Daniel; Stiles, Brendon; Rafii, Shahin; Narula, Navneet; Davuluri, Ramana; Altorki, Nasser K.; Mittal, Vivek

2015-01-01

Lung cancer is the leading cause of cancer related mortality worldwide, with non-small cell lung cancer (NSCLC) as the most prevalent form. Despite advances in treatment options including minimally invasive surgery, CT-guided radiation, novel chemotherapeutic regimens, and targeted therapeutics, prognosis remains dismal. Therefore, further molecular analysis of NSCLC is necessary to identify novel molecular targets that impact prognosis and the design of new-targeted therapies. In recent years, tumor “activated/reprogrammed” stromal cells that promote carcinogenesis have emerged as potential therapeutic targets. However, the contribution of stromal cells to NSCLC is poorly understood. Here, we show increased numbers of bone marrow (BM)-derived hematopoietic cells in the tumor parenchyma of NSCLC patients compared with matched adjacent non-neoplastic lung tissue. By sorting specific cellular fractions from lung cancer patients, we compared the transcriptomes of intratumoral myeloid compartments within the tumor bed with their counterparts within adjacent non-neoplastic tissue from NSCLC patients. The RNA sequencing of specific myeloid compartments (immature monocytic myeloid cells and polymorphonuclear neutrophils) identified differentially regulated genes and mRNA isoforms, which were inconspicuous in whole tumor analysis. Genes encoding secreted factors, including osteopontin (OPN), chemokine (C-C motif) ligand 7 (CCL7) and thrombospondin 1 (TSP1) were identified, which enhanced tumorigenic properties of lung cancer cells indicative of their potential as targets for therapy. This study demonstrates that analysis of homogeneous stromal populations isolated directly from fresh clinical specimens can detect important stromal genes of therapeutic value. PMID:26046767