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Sample records for internal targeting signal

  1. Internal targets for LEAR

    International Nuclear Information System (INIS)

    Kilian, K.; Gspann, J.; Mohl, D.; Poth, H.

    1984-01-01

    This chapter considers the use of thin internal targets in conjunction with phase-space cooling at the Low-Energy Antiproton Ring (LEAR). Topics considered include the merits of internal target operation; the most efficient use of antiprotons and of proton synchrotron (PS) protons, highest center-of-mass (c.m.) energy resolution; highest angular resolution and access to extreme angles; the transparent environment for all reaction products; a windowless source and pure targets; highest luminosity and count rates; access to lowest energies with increasing resolution; internal target thickness and vacuum requirements; required cooling performance; and modes of operation. It is demonstrated that an internal target in conjunction with phase-space cooling has the potential of better performance in terms of the economic use of antiprotons and consequently of PS protons; energy resolution; angular resolution; maximum reaction rate capability (statistical precision); efficient parasitic operation; transparency of the target for reaction products; access to low energies; and the ease of polarized target experiments. It is concluded that all p - experiments which need high statistics and high p - flux, such as studies of rare channels or broad, weak resonance structures, would profit from internal targets

  2. STANFORD: Internal targets

    Energy Technology Data Exchange (ETDEWEB)

    Riordan, Michael

    1989-05-15

    Of burgeoning interest to many nuclear and particle physicists is a storage ring technique for fixed target experiments. It hinges on the use of gas-jet targets, shooting a narrow stream of atoms through a circulating beam of electrons or protons. Pioneered at CERN and the Soviet Novosibirsk Laboratory, more such 'internal targets' are being built or contemplated for storage rings in Europe, the Soviet Union, and the United States. From 9-12 January, physicists from around the world met at the Stanford Linear Accelerator Center (SLAC) to discuss prospects and problems in this expanding field.

  3. Dopamine signaling: target in glioblastoma

    Czech Academy of Sciences Publication Activity Database

    Bartek, Jiří; Hodný, Zdeněk

    2014-01-01

    Roč. 5, č. 5 (2014), 1116-1117 ISSN 1949-2553 Institutional support: RVO:68378050 Keywords : Dopamine signaling * glioblastoma * MAPK Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 6.359, year: 2014

  4. Internal magnetic target of proton synchrotron

    International Nuclear Information System (INIS)

    Gachurin, V.V.; Kats, M.M.; Kondrat'ev, L.N.; Rogal', A.D.; Rusinov, V.Yu.

    1988-01-01

    Proton extraction from a synchrotron by means of an internal target of magnetized iron is described. The particles that are aimed at the target pass directly through it and are deflected by the internal magnetic field of the target in the extraction direction. The general properties of magnetic targets are examined theoretically and a specific devices and results of its testing are described

  5. Targeting Apoptosis Signaling in Pancreatic Cancer

    International Nuclear Information System (INIS)

    Fulda, Simone

    2011-01-01

    The ability to escape apoptosis or programmed cell death is a hallmark of human cancers, for example pancreatic cancer. This can promote tumorigenesis, since too little cell death by apoptosis disturbs tissue homeostasis. Additionally, defective apoptosis signaling is the underlying cause of failure to respond to current treatment approaches, since therapy-mediated antitumor activity requires the intactness of apoptosis signaling pathways in cancer cells. Thus, the elucidation of defects in the regulation of apoptosis in pancreatic carcinoma can result in the identification of novel targets for therapeutic interference and for exploitation for cancer drug discovery

  6. Targeting Apoptosis Signaling in Pancreatic Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Fulda, Simone [Institute for Experimental Cancer Research in Pediatrics, Goethe-University Frankfurt, Komturstr. 3a, 60528 Frankfurt (Germany)

    2011-01-11

    The ability to escape apoptosis or programmed cell death is a hallmark of human cancers, for example pancreatic cancer. This can promote tumorigenesis, since too little cell death by apoptosis disturbs tissue homeostasis. Additionally, defective apoptosis signaling is the underlying cause of failure to respond to current treatment approaches, since therapy-mediated antitumor activity requires the intactness of apoptosis signaling pathways in cancer cells. Thus, the elucidation of defects in the regulation of apoptosis in pancreatic carcinoma can result in the identification of novel targets for therapeutic interference and for exploitation for cancer drug discovery.

  7. Targeting Apoptosis Signaling Pathways for Anticancer Therapy

    Energy Technology Data Exchange (ETDEWEB)

    Fulda, Simone, E-mail: simone.fulda@kgu.de [Institute for Experimental Cancer Research in Pediatrics, Goethe-University, Frankfurt (Germany)

    2011-08-29

    Treatment approaches for cancer, for example chemotherapy, radiotherapy, or immunotherapy, primarily act by inducing cell death in cancer cells. Consequently, the inability to trigger cell death pathways or alternatively, evasion of cancer cells to the induction of cell death pathways can result in resistance of cancers to current treatment protocols. Therefore, in order to overcome treatment resistance a better understanding of the underlying mechanisms that regulate cell death and survival pathways in cancers and in response to cancer therapy is necessary to develop molecular-targeted therapies. This strategy should lead to more effective and individualized treatment strategies that selectively target deregulated signaling pathways in a tumor type- and patient-specific manner.

  8. Targeting Apoptosis Signaling Pathways for Anticancer Therapy

    International Nuclear Information System (INIS)

    Fulda, Simone

    2011-01-01

    Treatment approaches for cancer, for example chemotherapy, radiotherapy, or immunotherapy, primarily act by inducing cell death in cancer cells. Consequently, the inability to trigger cell death pathways or alternatively, evasion of cancer cells to the induction of cell death pathways can result in resistance of cancers to current treatment protocols. Therefore, in order to overcome treatment resistance a better understanding of the underlying mechanisms that regulate cell death and survival pathways in cancers and in response to cancer therapy is necessary to develop molecular-targeted therapies. This strategy should lead to more effective and individualized treatment strategies that selectively target deregulated signaling pathways in a tumor type- and patient-specific manner.

  9. HIRFL–CSR internal cluster target

    International Nuclear Information System (INIS)

    Shao, Caojie; Lu, Rongchun; Cai, Xiaohong; Yu, Deyang; Ruan, Fangfang; Xue, Yingli; Zhang, Jianming; Torpokov, D.K.; Nikolenko, D.

    2013-01-01

    Highlights: • An internal cluster target was built and installed at HIRFL–CSR. • The target thickness for H 2 amounts up to 6.6 × 10 12 atoms/cm 2 . • The feasibility and stability of the internal cluster target were verified by on-line experiments. -- Abstract: Since HIRFL–CSR internal cluster target was built, it has played a key role in in-ring experiments at HIRFL–CSR. So far it have been operated with five gas species as targets for scattering experiments, i.e. hydrogen, nitrogen, argon, neon, and krypton. The obtained highest thickness for hydrogen target amounts up to 10 12 atoms/cm 2 , and those of other targets are larger than 10 13 atoms/cm 2 with the background pressure of 10 −11 mbar in CSR. The target thickness can be varied by regulating the nozzle temperature and pressure of the inlet gas. The first online internal target experiment dedicated to investigate radioactive electron capture (REC) process with Xe 54+ ions colliding with the nitrogen target demonstrated the stability and reliability of the internal target system. In addition, hydrogen and krypton were also tested online in recent experiments, which indicate the target system can meet experimental requirements for the thickness of target, pressure in scattering chamber, and long-term stability

  10. Target cells in internal dosimetry

    Energy Technology Data Exchange (ETDEWEB)

    Goessner, W

    2003-07-01

    Data related to radium induced bone sarcomas in humans are used as a model for defining target cells on bone surfaces and in the bone marrow. The differential distribution of radiation induced bone sarcoma types with a high ratio of non-bone producing, mainly fibroblastic tumours, challenges the ICRP concept that the bone lining cells are target cells. Multipotential mesenchymal stem cells are located within the range of alpha particles, and are the most likely target cells for the fibroblastic type of bone sarcoma. The histogenesis of bone sarcomas after irradiation with alpha emitters shows that their final histopathology is not dependent on a single target cell. Each target cell has a microenvironment, which has to be regarded as a synergistic morpho-functional tissue unit. For this the concept of 'histion', a term used in general pathology, is proposed. Interactions between target cells that have been hit by alpha-particles, leading to lethal, mutational or transformation events with all components of a 'histion', will prove critical to understanding the pathogenesis of both deterministic and stochastic late effects. (author)

  11. Target cells in internal dosimetry

    International Nuclear Information System (INIS)

    Goessner, W.

    2003-01-01

    Data related to radium induced bone sarcomas in humans are used as a model for defining target cells on bone surfaces and in the bone marrow. The differential distribution of radiation induced bone sarcoma types with a high ratio of non-bone producing, mainly fibroblastic tumours, challenges the ICRP concept that the bone lining cells are target cells. Multipotential mesenchymal stem cells are located within the range of alpha particles, and are the most likely target cells for the fibroblastic type of bone sarcoma. The histogenesis of bone sarcomas after irradiation with alpha emitters shows that their final histopathology is not dependent on a single target cell. Each target cell has a microenvironment, which has to be regarded as a synergistic morpho-functional tissue unit. For this the concept of 'histion', a term used in general pathology, is proposed. Interactions between target cells that have been hit by alpha-particles, leading to lethal, mutational or transformation events with all components of a 'histion', will prove critical to understanding the pathogenesis of both deterministic and stochastic late effects. (author)

  12. Targeting embryonic signaling pathways in cancer therapy.

    Science.gov (United States)

    Harris, Pamela Jo; Speranza, Giovanna; Dansky Ullmann, Claudio

    2012-01-01

    The embryonic signaling pathways (ESP), Hedgehog, Notch and Wnt, are critical for the regulation of normal stem cells and cellular development processes. They are also activated in the majority of cancers. ESP are operational in putative cancer stem cells (CSC), which drive initial tumorigenesis and sustain cancer progression and recurrence in non-CSC bulk subpopulations. ESP represent novel therapeutic targets. A variety of inhibitors and targeting strategies are being developed. This review discusses the rationale for targeting ESP for cancer treatment, as well as specific inhibitors under development; mainly focusing on those approaching clinical use and the challenges that lie ahead. The data sources utilized are several database search engines (PubMed, Google, Clinicaltrials.gov), and the authors' involvement in the field. CSC research is rapidly evolving. Expectations regarding their therapeutic targeting are rising quickly. Further definition of what constitutes a true CSC, proper validation of CSC markers, a better understanding of cross-talk among ESP and other pathways, and interactions with tumor non-CSC and the tumor microenvironment are needed. The appropriate patient population, the right clinical setting and combination strategies to test these therapies, as well as the proper pharmacodynamic markers to measure, need to be further established.

  13. Polarized internal targets for electronuclear experiments

    International Nuclear Information System (INIS)

    van den Brand, J.F.J.

    1993-01-01

    Polarized internal gas targets represent a unique opportunity for the measurement of spin observables in electro-nuclear physics. Two measurements will be discussed. First, spin observables have been measured in elastic and quasi-free scattering of 45, 200, 300, and 415 MeV polarized protons from a polarized 3 He internal gas target at the Indiana University Cyclotron Facility Cooler Ring. The data obtained constitute the first measurement of spin correlation parameters using a storage ring with polarized beam and polarized internal gas target. Second, a quasi-free (e,e'p) experiment using tensor polarized deuterium will be discussed. Here, the goal is the measurement of the S- and D-state parts of the proton spectral function by scattering 700 MeV electrons from an atomic beam source. Large acceptance detectors have been used in both experiments. The internal-target technique has broad applicability in nuclear and particle physics

  14. Polarization measurement for internal polarized gaseous targets

    International Nuclear Information System (INIS)

    Ye Zhenyu; Ye Yunxiu; Lv Haijiang; Mao Yajun

    2004-01-01

    The authors present an introduction to internal polarized gaseous targets, polarization method, polarization measurement method and procedure. To get the total nuclear polarization of hydrogen atoms (including the polarization of the recombined hydrogen molecules) in the target cell, authors have measured the parameters relating to atomic polarization and polarized hydrogen atoms and molecules. The total polarization of the target during our measurement is P T =0.853 ± 0.036. (authors)

  15. Internal Targeting and External Control: Phototriggered Targeting in Nanomedicine.

    Science.gov (United States)

    Arrue, Lily; Ratjen, Lars

    2017-12-07

    The photochemical control of structure and reactivity bears great potential for chemistry, biology, and life sciences. A key feature of photochemistry is the spatiotemporal control over secondary events. Well-established applications of photochemistry in medicine are photodynamic therapy (PDT) and photopharmacology (PP). However, although both are highly localizable through the application of light, they lack cell- and tissue-specificity. The combination of nanomaterial-based drug delivery and targeting has the potential to overcome limitations for many established therapy concepts. Even more privileged seems the merger of nanomedicine and cell-specific targeting (internal targeting) controlled by light (external control), as it can potentially be applied to many different areas of medicine and pharmaceutical research, including the aforementioned PDT and PP. In this review a survey of the interface of photochemistry, medicine and targeted drug delivery is given, especially focusing on phototriggered targeting in nanomedicine. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  16. Targeting NRF2 signaling for cancer chemoprevention

    International Nuclear Information System (INIS)

    Kwak, Mi-Kyoung; Kensler, Thomas W.

    2010-01-01

    Modulation of the metabolism and disposition of carcinogens through induction of cytoprotective enzymes is one of several promising strategies to prevent cancer. Chemopreventive efficacies of inducers such as dithiolethiones and sulforaphane have been extensively studied in animals as well as in humans. The KEAP1-NRF2 system is a key, but not unilateral, molecular target for these chemopreventive agents. The transcription factor NRF2 (NF-E2-related factor 2) is a master regulator of the expression of a subset of genes, which produce proteins responsible for the detoxication of electrophiles and reactive oxygen species as well as the removal or repair of some of their damage products. It is believed that chemopreventive enzyme inducers affect the interaction between KEAP1 and NRF2 through either mediating conformational changes of the KEAP1 protein or activating phosphorylation cascades targeting the KEAP1-NRF2 complex. These events in turn affect NRF2 stability and trafficking. Recent advances elucidating the underlying structural biology of KEAP1-NRF2 signaling and identification of the gene clusters under the transcriptional control of NRF2 are facilitating understanding of the potential pleiotropic effects of NRF2 activators and discovery of novel classes of potent chemopreventive agents such as the triterpenoids. Although there is appropriately a concern regarding a deleterious role of the KEAP1-NRF2 system in cancer cell biology, especially as the pathway affects cell survival and drug resistance, the development and the use of NRF2 activators as chemopreventive agents still holds a great promise for protection of normal cells from a diversity of environmental stresses that contribute to the burden of cancer and other chronic, degenerative diseases.

  17. Storage rings, internal targets and PEP

    International Nuclear Information System (INIS)

    Spencer, J.E.

    1986-11-01

    Storage rings with internal targets are described, using PEP as an example. The difference between electrons and heavier particles such as protons, antiprotons, and heavy ions is also discussed because it raises possibilities of bypass insertions for more exotic experiments. PEP is compared to other rings in various contexts to verify the assertion that it is an ideal ring for many fundamental and practical applications that can be carried on simultaneously

  18. Targeting Signaling Pathways in Epithelial Ovarian Cancer

    Directory of Open Access Journals (Sweden)

    Johannes Haybaeck

    2013-05-01

    Full Text Available Ovarian carcinoma (OC is the most lethal gynecological malignancy. Response to platinum-based chemotherapy is poor in some patients and, thus, current research is focusing on new therapy options. The various histological types of OC are characterized by distinctive molecular genetic alterations that are relevant for ovarian tumorigenesis. The understanding of these molecular pathways is essential for the development of novel therapeutic strategies. Purpose: We want to give an overview on the molecular genetic changes of the histopathological types of OC and their role as putative therapeutic targets. In Depth Review of Existing Data: In 2012, the vascular endothelial growth factor (VEGF inhibitor, bevacizumab, was approved for OC treatment. Bevacizumab has shown promising results as single agent and in combination with conventional chemotherapy, but its target is not distinctive when analyzed before treatment. At present, mammalian target of rapamycin (mTOR inhibitors, poly-ADP-ribose polymerase (PARP inhibitors and components of the EGFR pathway are in the focus of clinical research. Interestingly, some phytochemical substances show good synergistic effects when used in combination with chemotherapy. Conclusion: Ongoing studies of targeted agents in conjunction with chemotherapy will show whether there are alternative options to bevacizumab available for OC patients. Novel targets which can be assessed before therapy to predict efficacy are needed. The assessment of therapeutic targets is continuously improved by molecular pathological analyses on tumor tissue. A careful selection of patients for personalized treatment will help to reduce putative side effects and toxicity.

  19. Targeting and localized signalling by small GTPases

    NARCIS (Netherlands)

    ten Klooster, Jean Paul; Hordijk, Peter L.

    2007-01-01

    Polarized cellular responses, for example, cell migration, require the co-ordinated assembly of signalling complexes at a particular subcellular location, such as the leading edge of cells. Small GTPases of the Ras superfamily play central roles in many (polarized) responses to growth factors,

  20. [Target volume margins for lung cancer: internal target volume/clinical target volume].

    Science.gov (United States)

    Jouin, A; Pourel, N

    2013-10-01

    The aim of this study was to carry out a review of margins that should be used for the delineation of target volumes in lung cancer, with a focus on margins from gross tumour volume (GTV) to clinical target volume (CTV) and internal target volume (ITV) delineation. Our review was based on a PubMed literature search with, as a cornerstone, the 2010 European Organisation for Research and Treatment of Cancer (EORTC) recommandations by De Ruysscher et al. The keywords used for the search were: radiotherapy, lung cancer, clinical target volume, internal target volume. The relevant information was categorized under the following headings: gross tumour volume definition (GTV), CTV-GTV margin (first tumoural CTV then nodal CTV definition), in field versus elective nodal irradiation, metabolic imaging role through the input of the PET scanner for tumour target volume and limitations of PET-CT imaging for nodal target volume definition, postoperative radiotherapy target volume definition, delineation of target volumes after induction chemotherapy; then the internal target volume is specified as well as tumoural mobility for lung cancer and respiratory gating techniques. Finally, a chapter is dedicated to planning target volume definition and another to small cell lung cancer. For each heading, the most relevant and recent clinical trials and publications are mentioned. Copyright © 2013. Published by Elsevier SAS.

  1. Nuclear physics with internal targets in electron storage rings

    International Nuclear Information System (INIS)

    Holt, R.J.

    1986-01-01

    Two key experiments in nuclear physics will be discussed in order to illustrate the advantages of the internal target method and demonstrate the power of polarization techniques in electron scattering studies. The progress of internal target experiments will be discussed and the technology of internal polarized target development will be reviewed. 43 refs., 11 figs

  2. MPD model for radar echo signal of hypersonic targets

    Directory of Open Access Journals (Sweden)

    Xu Xuefei

    2014-08-01

    Full Text Available The stop-and-go (SAG model is typically used for echo signal received by the radar using linear frequency modulation pulse compression. In this study, the authors demonstrate that this model is not applicable to hypersonic targets. Instead of SAG model, they present a more realistic echo signal model (moving-in-pulse duration (MPD for hypersonic targets. Following that, they evaluate the performances of pulse compression under the SAG and MPD models by theoretical analysis and simulations. They found that the pulse compression gain has an increase of 3 dB by using the MPD model compared with the SAG model in typical cases.

  3. IEEE International Workshop on Machine Learning for Signal Processing: Preface

    DEFF Research Database (Denmark)

    Tao, Jianhua

    The 21st IEEE International Workshop on Machine Learning for Signal Processing will be held in Beijing, China, on September 18–21, 2011. The workshop series is the major annual technical event of the IEEE Signal Processing Society's Technical Committee on Machine Learning for Signal Processing...

  4. The Nuclotron internal target control and data acquisition system

    Energy Technology Data Exchange (ETDEWEB)

    Isupov, A.Yu., E-mail: isupov@moonhe.jinr.ru [Joint Institute for Nuclear Research, Dubna 141980 (Russian Federation); Krasnov, V.A.; Ladygin, V.P.; Piyadin, S.M.; Reznikov, S.G. [Joint Institute for Nuclear Research, Dubna 141980 (Russian Federation)

    2013-01-11

    The new control system of the Nuclotron (JINR, Dubna) internal target is described in both hardware and software aspects. The CAMAC hardware is based on the use of the standard CAMAC modules developed and manufactured at JINR. The internal target control and data acquisition (IntTarg CDAQ) system software is implemented using the ngdp framework under the Unix-like operating system (OS) FreeBSD to allow easy network distribution of the online data collected from internal target and accompanying detectors, as well as the internal target remote control.

  5. GPR Signal Denoising and Target Extraction With the CEEMD Method

    KAUST Repository

    Li, Jing

    2015-04-17

    In this letter, we apply a time and frequency analysis method based on the complete ensemble empirical mode decomposition (CEEMD) method in ground-penetrating radar (GPR) signal processing. It decomposes the GPR signal into a sum of oscillatory components, with guaranteed positive and smoothly varying instantaneous frequencies. The key idea of this method relies on averaging the modes obtained by empirical mode decomposition (EMD) applied to several realizations of Gaussian white noise added to the original signal. It can solve the mode-mixing problem in the EMD method and improve the resolution of ensemble EMD (EEMD) when the signal has a low signal-to-noise ratio. First, we analyze the difference between the basic theory of EMD, EEMD, and CEEMD. Then, we compare the time and frequency analysis with Hilbert-Huang transform to test the results of different methods. The synthetic and real GPR data demonstrate that CEEMD promises higher spectral-spatial resolution than the other two EMD methods in GPR signal denoising and target extraction. Its decomposition is complete, with a numerically negligible error.

  6. The Rac1 hypervariable region in targeting and signaling

    Science.gov (United States)

    Lam, B. Daniel; Hordijk, Peter L.

    2013-01-01

    Cellular signaling by small GTPases is critically dependent on proper spatio-temporal orchestration of activation and output. In addition to their core G (guanine nucleotide binding)-domain, small GTPases comprise a hypervariable region (HVR) and a lipid anchor that are generally accepted to control subcellullar localization. The HVR encodes in many small GTPases a polybasic region (PBR) that permits charge-mediated association to the inner leaflet of the plasma membrane or to intracellular organelles. Over the past 15–20 years, evidence has accumulated for specific protein–protein interactions, mediated by the HVR, that control both targeting and signaling specificity of small GTPases. Using the RhoGTPase Rac1 as a paradigm we here review a series of protein partners that require the Rac1 HVR for association and that control various aspects of localized Rac1 signaling. Some of these proteins represent Rac1 activators, whereas others mediate Rac1 inactivation and degradation and yet others potentiate Rac1 downstream signaling. Finally, evidence is discussed which shows that the HVR of Rac1 also contributes to effector interactions, co-operating with the N-terminal effector domain. The complexity of localized Rac1 signaling, reviewed here, is most likely exemplary for many other small GTPases as well, representing a challenge to identify and define similar mechanisms controlling the specific signaling induced by small GTPases. PMID:23354415

  7. mTOR Signaling Confers Resistance to Targeted Cancer Drugs.

    Science.gov (United States)

    Guri, Yakir; Hall, Michael N

    2016-11-01

    Cancer is a complex disease and a leading cause of death worldwide. Extensive research over decades has led to the development of therapies that target cancer-specific signaling pathways. However, the clinical benefits of such drugs are at best transient due to tumors displaying intrinsic or adaptive resistance. The underlying compensatory pathways that allow cancer cells to circumvent a drug blockade are poorly understood. We review here recent studies suggesting that mammalian TOR (mTOR) signaling is a major compensatory pathway conferring resistance to many cancer drugs. mTOR-mediated resistance can be cell-autonomous or non-cell-autonomous. These findings suggest that mTOR signaling should be monitored routinely in tumors and that an mTOR inhibitor should be considered as a co-therapy. Copyright © 2016 Elsevier Inc. All rights reserved.

  8. Chemokine Signaling in Allergic Contact Dermatitis: Toward Targeted Therapies.

    Science.gov (United States)

    Smith, Jeffrey S; Rajagopal, Sudarshan; Atwater, Amber Reck

    2018-06-22

    Allergic contact dermatitis (ACD) is a common skin disease that results in significant cost and morbidity. Despite its high prevalence, therapeutic options are limited. Allergic contact dermatitis is regulated primarily by T cells within the adaptive immune system, but also by natural killer and innate lymphoid cells within the innate immune system. The chemokine receptor system, consisting of chemokine peptides and chemokine G protein-coupled receptors, is a critical regulator of inflammatory processes such as ACD. Specific chemokine signaling pathways are selectively up-regulated in ACD, most prominently CXCR3 and its endogenous chemokines CXCL9, CXCL10, and CXCL11. Recent research demonstrates that these 3 chemokines are not redundant and indeed activate distinct intracellular signaling profiles such as those activated by heterotrimeric G proteins and β-arrestin adapter proteins. Such differential signaling provides an attractive therapeutic target for novel ACD therapies and other inflammatory diseases.

  9. Labor Inhibits Placental Mechanistic Target of Rapamycin Complex 1 Signaling

    Science.gov (United States)

    LAGER, Susanne; AYE, Irving L.M.H.; GACCIOLI, Francesca; RAMIREZ, Vanessa I.; JANSSON, Thomas; POWELL, Theresa L.

    2014-01-01

    Introduction Labor induces a myriad of changes in placental gene expression. These changes may represent a physiological adaptation inhibiting placental cellular processes associated with a high demand for oxygen and energy (e.g., protein synthesis and active transport) thereby promoting oxygen and glucose transfer to the fetus. We hypothesized that mechanistic target of rapamycin complex 1 (mTORC1) signaling, a positive regulator of trophoblast protein synthesis and amino acid transport, is inhibited by labor. Methods Placental tissue was collected from healthy, term pregnancies (n=15 no-labor; n=12 labor). Activation of Caspase-1, IRS1/Akt, STAT, mTOR, and inflammatory signaling pathways was determined by Western blot. NFκB p65 and PPARγ DNA binding activity was measured in isolated nuclei. Results Labor increased Caspase-1 activation and mTOR complex 2 signaling, as measured by phosphorylation of Akt (S473). However, mTORC1 signaling was inhibited in response to labor as evidenced by decreased phosphorylation of mTOR (S2448) and 4EBP1 (T37/46 and T70). Labor also decreased NFκB and PPARγ DNA binding activity, while having no effect on IRS1 or STAT signaling pathway. Discussion and conclusion Several placental signaling pathways are affected by labor, which has implications for experimental design in studies of placental signaling. Inhibition of placental mTORC1 signaling in response to labor may serve to down-regulate protein synthesis and amino acid transport, processes that account for a large share of placental oxygen and glucose consumption. We speculate that this response preserves glucose and oxygen for transfer to the fetus during the stressful events of labor. PMID:25454472

  10. Targeting fibroblast growth factor receptor signaling inhibits prostate cancer progression.

    Science.gov (United States)

    Feng, Shu; Shao, Longjiang; Yu, Wendong; Gavine, Paul; Ittmann, Michael

    2012-07-15

    Extensive correlative studies in human prostate cancer as well as studies in vitro and in mouse models indicate that fibroblast growth factor receptor (FGFR) signaling plays an important role in prostate cancer progression. In this study, we used a probe compound for an FGFR inhibitor, which potently inhibits FGFR-1-3 and significantly inhibits FGFR-4. The purpose of this study is to determine whether targeting FGFR signaling from all four FGFRs will have in vitro activities consistent with inhibition of tumor progression and will inhibit tumor progression in vivo. Effects of AZ8010 on FGFR signaling and invasion were analyzed using immortalized normal prostate epithelial (PNT1a) cells and PNT1a overexpressing FGFR-1 or FGFR-4. The effect of AZ8010 on invasion and proliferation in vitro was also evaluated in prostate cancer cell lines. Finally, the impact of AZ8010 on tumor progression in vivo was evaluated using a VCaP xenograft model. AZ8010 completely inhibits FGFR-1 and significantly inhibits FGFR-4 signaling at 100 nmol/L, which is an achievable in vivo concentration. This results in marked inhibition of extracellular signal-regulated kinase (ERK) phosphorylation and invasion in PNT1a cells expressing FGFR-1 and FGFR-4 and all prostate cancer cell lines tested. Treatment in vivo completely inhibited VCaP tumor growth and significantly inhibited angiogenesis and proliferation and increased cell death in treated tumors. This was associated with marked inhibition of ERK phosphorylation in treated tumors. Targeting FGFR signaling is a promising new approach to treating aggressive prostate cancer.

  11. Physics and technology of superthin internal targets in storage rings

    International Nuclear Information System (INIS)

    Popov, S.G.

    1989-01-01

    The new generation of accelerators for coincidence electronuclear investigations is discussed. The luminosity and beam parameters are calculated for an electron storage ring with an internal target operating in the superthin regime. The advantages and disadvantages in comparison with conventional operation using an external beam and target are described. The intermediate results for 2 GeV electron scattering on polarized internal deuterium target are given (joint Novosibirsk-Argonne experiment). 32 refs.; 5 figs

  12. Target acquisition performance : Effects of target aspect angle, dynamic imaging and signal processing

    NARCIS (Netherlands)

    Beintema, J.A.; Bijl, P.; Hogervorst, M.A.; Dijk, J.

    2008-01-01

    In an extensive Target Acquisition (TA) performance study, we recorded static and dynamic imagery of a set of military and civilian two-handheld objects at a range of distances and aspect angles with an under-sampled uncooled thermal imager. Next, we applied signal processing techniques including

  13. A polarized sup 3 He internal target for storage rings

    CERN Document Server

    Poolman, H R; Bulten, H J; Doets, M; Ent, R; Ferro-Luzzi, M; Geurts, D G; Harvey, M; Mul, F A

    2000-01-01

    A polarized sup 3 He internal target was employed at the internal target facility of the Amsterdam electron Pulse Stretcher and Storage ring (AmPS) at the Dutch National Institute for Nuclear and High-Energy Physics (NIKHEF). The unique features of internal targets such as chemical and isotopic purity, high and rapidly reversible polarization, and the ability to manipulate the target spin orientation were successfully demonstrated. A nuclear polarization of 0.50 (0.42) at a sup 3 He gas flow of 1.0 (2.0)x10 sup 1 sup 7 at s sup - sup 1 could be obtained. Operation at a nominal flow of 1x10 sup 1 sup 7 at s sup - sup 1 resulted in a target thickness of 0.7x10 sup 1 sup 5 at cm sup - sup 2 at a target temperature of 17 K.

  14. HER3 signaling and targeted therapy in cancer

    Directory of Open Access Journals (Sweden)

    Rosalin Mishra

    2018-05-01

    Full Text Available ERBB family members including epidermal growth factor receptor (EGFR also known as HER1, ERBB2/HER2/Neu, ERBB3/HER3 and ERBB4/HER4 are aberrantly activated in multiple cancers and hence serve as drug targets and biomarkers in modern precision therapy. The therapeutic potential of HER3 has long been underappreciated, due to impaired kinase activity and relatively low expression in tumors. However, HER3 has received attention in recent years as it is a crucial heterodimeric partner for other EGFR family members and has the potential to regulate EGFR/HER2-mediated resistance. Upregulation of HER3 is associated with several malignancies where it fosters tumor progression via interaction with different receptor tyrosine kinases (RTKs. Studies also implicate HER3 contributing significantly to treatment failure, mostly through the activation of PI3K/AKT, MAPK/ERK and JAK/STAT pathways. Moreover, activating mutations in HER3 have highlighted the role of HER3 as a direct therapeutic target. Therapeutic targeting of HER3 includes abrogating its dimerization partners’ kinase activity using small molecule inhibitors (lapatinib, erlotinib, gefitinib, afatinib, neratinib or direct targeting of its extracellular domain. In this review, we focus on HER3-mediated signaling, its role in drug resistance and discuss the latest advances to overcome resistance by targeting HER3 using mono- and bispecific antibodies and small molecule inhibitors.

  15. 4D MR imaging using robust internal respiratory signal

    International Nuclear Information System (INIS)

    Hui, CheukKai; Wen, Zhifei; Beddar, Sam; Stemkens, Bjorn; Tijssen, R H N; Van den Berg, C A T; Hwang, Ken-Pin

    2016-01-01

    The purpose of this study is to investigate the feasibility of using internal respiratory (IR) surrogates to sort four-dimensional (4D) magnetic resonance (MR) images. The 4D MR images were constructed by acquiring fast 2D cine MR images sequentially, with each slice scanned for more than one breathing cycle. The 4D volume was then sorted retrospectively using the IR signal. In this study, we propose to use multiple low-frequency components in the Fourier space as well as the anterior body boundary as potential IR surrogates. From these potential IR surrogates, we used a clustering algorithm to identify those that best represented the respiratory pattern to derive the IR signal. A study with healthy volunteers was performed to assess the feasibility of the proposed IR signal. We compared this proposed IR signal with the respiratory signal obtained using respiratory bellows. Overall, 99% of the IR signals matched the bellows signals. The average difference between the end inspiration times in the IR signal and bellows signal was 0.18 s in this cohort of matching signals. For the acquired images corresponding to the other 1% of non-matching signal pairs, the respiratory motion shown in the images was coherent with the respiratory phases determined by the IR signal, but not the bellows signal. This suggested that the IR signal determined by the proposed method could potentially correct the faulty bellows signal. The sorted 4D images showed minimal mismatched artefacts and potential clinical applicability. The proposed IR signal therefore provides a feasible alternative to effectively sort MR images in 4D. (paper)

  16. India advancing as international exploration target

    International Nuclear Information System (INIS)

    Anon.

    1994-01-01

    Mighty as it is in terms of sedimentary area, hydrocarbon potential, and sheer market size, India does not occupy a position of like stature on the international oil explorer's chart. Yet Indian government policy initiatives during the past 3 years have thrown the country open to foreign investment upstream and downstream. Strapped for cash, hounded by declining production and reserves, the government is leaving higher cost and higher risk exploration to foreign and domestic private sector companies. Furthermore, India has approved majority capital holdings in the downstream sector, invited bids on field reactivation schemes and speculative seismic surveys, and adopted attractive and flexible production sharing contracts to govern these agreements. A strong tradition upholding sanctity of law provides a solid guarantee that such contracts will not be broken or modified. The paper discusses India's restructuring, the bidding rounds, the growing interest of foreign companies, downstream and gas deals, acreage and terms being offered, and other projects

  17. Targeting GPCR-Gβγ-GRK2 signaling as a novel strategy for treating cardiorenal pathologies.

    Science.gov (United States)

    Rudomanova, Valeria; Blaxall, Burns C

    2017-08-01

    The pathologic crosstalk between the heart and kidney is known as cardiorenal syndrome (CRS). While the specific mechanisms underlying this crosstalk remain poorly understood, CRS is associated with exacerbated dysfunction of either or both organs and reduced survival. Maladaptive fibrotic remodeling is a key component of both heart and kidney failure pathogenesis and progression. G-protein coupled receptor (GPCR) signaling is a crucial regulator of cardiovascular and renal function. Chronic/pathologic GPCR signaling elicits the interaction of the G-protein Gβγ subunit with GPCR kinase 2 (GRK2), targeting the receptor for internalization, scaffolding to pathologic signals, and receptor degradation. Targeting this pathologic Gβγ-GRK2 interaction has been suggested as a possible strategy for the treatment of HF. In the current review, we discuss recent updates in understanding the role of GPCR-Gβγ-GRK2 signaling as a crucial mediator of maladaptive organ remodeling detected in HF and kidney dysfunction, with specific attention to small molecule-mediated inhibition of pathologic Gβγ-GRK2 interactions. Further, we explore the potential of GPCR-Gβγ-GRK2 signaling as a possible therapeutic target for cardiorenal pathologies. Copyright © 2017 Elsevier B.V. All rights reserved.

  18. Ganoderma lucidum targeting lung cancer signaling: A review.

    Science.gov (United States)

    Gill, Balraj Singh; Navgeet; Kumar, Sanjeev

    2017-06-01

    Lung cancer causes huge mortality to population, and pharmaceutical companies require new drugs as an alternative either synthetic or natural targeting lung cancer. The conventional therapies cause side effects, and therefore, natural products are used as a therapeutic candidate in lung cancer. Chemical diversity among natural products highlights the impact of evolution and survival of fittest. One such neglected natural product is Ganoderma lucidum used for promoting health and longevity for a longer time. The major bioconstituents of G. lucidum are mainly terpenes, polysaccharides, and proteins, which were explored for various activities ranging from apoptosis to autophagy. The bioconstituents of G. lucidum activate plasma membrane receptors and initiate various downstream signaling leading to nuclear factor-κB, phosphoinositide 3-kinase, Akt, and mammalian target of rapamycin in cancer. The bioconstituents regulate the expression of various genes involved in cell cycle, immune response, apoptosis, and autophagy in lung cancer. This review highlights the inextricable role of G. lucidum and its bioconstituents in lung cancer signaling for the first time.

  19. 4th International Conference on Communications, Signal Processing, and Systems

    CERN Document Server

    Mu, Jiasong; Wang, Wei; Zhang, Baoju

    2016-01-01

    This book brings together papers presented at the 4th International Conference on Communications, Signal Processing, and Systems, which provides a venue to disseminate the latest developments and to discuss the interactions and links between these multidisciplinary fields. Spanning topics ranging from Communications, Signal Processing and Systems, this book is aimed at undergraduate and graduate students in Electrical Engineering, Computer Science and Mathematics, researchers and engineers from academia and industry as well as government employees (such as NSF, DOD, DOE, etc).

  20. Therapeutically targeting mitochondrial redox signalling alleviates endothelial dysfunction in preeclampsia.

    Science.gov (United States)

    McCarthy, Cathal; Kenny, Louise C

    2016-09-08

    Aberrant placentation generating placental oxidative stress is proposed to play a critical role in the pathophysiology of preeclampsia. Unfortunately, therapeutic trials of antioxidants have been uniformly disappointing. There is provisional evidence implicating mitochondrial dysfunction as a source of oxidative stress in preeclampsia. Here we provide evidence that mitochondrial reactive oxygen species mediates endothelial dysfunction and establish that directly targeting mitochondrial scavenging may provide a protective role. Human umbilical vein endothelial cells exposed to 3% plasma from women with pregnancies complicated by preeclampsia resulted in a significant decrease in mitochondrial function with a subsequent significant increase in mitochondrial superoxide generation compared to cells exposed to plasma from women with uncomplicated pregnancies. Real-time PCR analysis showed increased expression of inflammatory markers TNF-α, TLR-9 and ICAM-1 respectively in endothelial cells treated with preeclampsia plasma. MitoTempo is a mitochondrial-targeted antioxidant, pre-treatment of cells with MitoTempo protected against hydrogen peroxide-induced cell death. Furthermore MitoTempo significantly reduced mitochondrial superoxide production in cells exposed to preeclampsia plasma by normalising mitochondrial metabolism. MitoTempo significantly altered the inflammatory profile of plasma treated cells. These novel data support a functional role for mitochondrial redox signaling in modulating the pathogenesis of preeclampsia and identifies mitochondrial-targeted antioxidants as potential therapeutic candidates.

  1. Leptin signaling molecular actions and drug target in hepatocellular carcinoma

    Directory of Open Access Journals (Sweden)

    Jiang N

    2014-11-01

    Full Text Available Nan Jiang,1,* Rongtong Sun,2,* Qing Sun3 1Shandong University School of Medicine, Jinan, Shandong Province, People’s Republic of China; 2Weihai Municipal Hospital, Weihai, Shandong Province, People’s Republic of China; 3Department of Pathology, QianFoShan Hospital Affiliated to Shandong University, Jinan, Shandong Province, People’s Republic of China *These authors contributed equally to this work Abstract: Previous reports indicate that over 13 different tumors, including hepatocellular carcinoma (HCC, are related to obesity. Obesity-associated inflammatory, metabolic, and endocrine mediators, as well as the functioning of the gut microbiota, are suspected to contribute to tumorigenesis. In obese people, proinflammatory cytokines/chemokines including tumor necrosis factor-alpha, interleukin (IL-1 and IL-6, insulin and insulin-like growth factors, adipokines, plasminogen activator inhibitor-1, adiponectin, and leptin are found to play crucial roles in the initiation and development of cancer. The cytokines induced by leptin in adipose tissue or tumor cells have been intensely studied. Leptin-induced signaling pathways are critical for biological functions such as adiposity, energy balance, endocrine function, immune reaction, and angiogenesis as well as oncogenesis. Leptin is an activator of cell proliferation and anti-apoptosis in several cell types, and an inducer of cancer stem cells; its critical roles in tumorigenesis are based on its oncogenic, mitogenic, proinflammatory, and pro-angiogenic actions. This review provides an update of the pathological effects of leptin signaling with special emphasis on potential molecular mechanisms and therapeutic targeting, which could potentially be used in future clinical settings. In addition, leptin-induced angiogenic ability and molecular mechanisms in HCC are discussed. The stringent binding affinity of leptin and its receptor Ob-R, as well as the highly upregulated expression of both

  2. Slow extraction from the IHEP accelerator by internal target scattering

    International Nuclear Information System (INIS)

    Maksimov, A.V.

    1994-01-01

    The existing slow extraction system is not able to satisfy the required quality of the beam time structure in the intensity region 10 10 - 10 11 ppp. Calculations on simulation of slow extraction by internal target scattering are presented. Two regime of slow extraction are analysed: nonresonant and resonant extraction by target scattering. Resonant extraction by target scattering is able to ensure intensity of extracted beam up to 10 11 . The agreement between calculations and experimental data is good enough. The calculation of extraction possibility by thin W-target scattering are also presented. In this case the extraction efficiency is about 85%. 15 refs., 6 figs

  3. Workshop on electronuclear physics with internal targets: Proceedings

    International Nuclear Information System (INIS)

    Arnold, R.G.; Minehart, R.C.

    1987-05-01

    The Workshop on Electronuclear Physics with Internal Targets was held at SLAC on January 5-8, 1987. The idea for this workshop grew out of interest among physicists at SLAC and MIT/Bates who have been exploring the possibilities for internal targets in the PEP ring at SLAC and in a proposed stretcher ring at MIT/Bates. The aim of the workshop was to bring together physicists from these groups and from other laboratories and universities to discuss the new physics that could be made accessible with internal targets, and to share information on recent developments in internal target technology, on the impact of internal targets on ring operation, and on the detector requirements. The workshop was sponsored by NPAS, the program of Nuclear Physics at SLAC, and it was attended by more than 100 physicists from the US, Canada, Europe, and Japan. The workshop sessions began with two days of invited talks followed by two days of shorter presentations organized by the chairmen of four Working Groups. Written versions of all the plenary talks and all but four of the Working Group talks are presented here

  4. Workshop on electronuclear physics with internal targets: Proceedings

    Energy Technology Data Exchange (ETDEWEB)

    Arnold, R.G.; Minehart, R.C. (eds.)

    1987-05-01

    The Workshop on Electronuclear Physics with Internal Targets was held at SLAC on January 5-8, 1987. The idea for this workshop grew out of interest among physicists at SLAC and MIT/Bates who have been exploring the possibilities for internal targets in the PEP ring at SLAC and in a proposed stretcher ring at MIT/Bates. The aim of the workshop was to bring together physicists from these groups and from other laboratories and universities to discuss the new physics that could be made accessible with internal targets, and to share information on recent developments in internal target technology, on the impact of internal targets on ring operation, and on the detector requirements. The workshop was sponsored by NPAS, the program of Nuclear Physics at SLAC, and it was attended by more than 100 physicists from the US, Canada, Europe, and Japan. The workshop sessions began with two days of invited talks followed by two days of shorter presentations organized by the chairmen of four Working Groups. Written versions of all the plenary talks and all but four of the Working Group talks are presented here.

  5. Romidepsin targets multiple survival signaling pathways in malignant T cells

    International Nuclear Information System (INIS)

    Valdez, B C; Brammer, J E; Li, Y; Murray, D; Liu, Y; Hosing, C; Nieto, Y; Champlin, R E; Andersson, B S

    2015-01-01

    Romidepsin is a cyclic molecule that inhibits histone deacetylases. It is Food and Drug Administration-approved for treatment of cutaneous and peripheral T-cell lymphoma, but its precise mechanism of action against malignant T cells is unknown. To better understand the biological effects of romidepsin in these cells, we exposed PEER and SUPT1 T-cell lines, and a primary sample from T-cell lymphoma patient (Patient J) to romidepsin. We then examined the consequences in some key oncogenic signaling pathways. Romidepsin displayed IC 50 values of 10.8, 7.9 and 7.0 nm in PEER, SUPT1 and Patient J cells, respectively. Strong inhibition of histone deacetylases and demethylases, increased production of reactive oxygen species and decreased mitochondrial membrane potential were observed, which may contribute to the observed DNA-damage response and apoptosis. The stress-activated protein kinase/c-Jun N-terminal kinase signaling pathway and unfolded protein response in the endoplasmic reticulum were activated, whereas the phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin (PI3K/AKT/mTOR) and β-catenin pro-survival pathways were inhibited. The decreased level of β-catenin correlated with the upregulation of its inhibitor SFRP1 through romidepsin-mediated hypomethylation of its gene promoter. Our results provide new insights into how romidepsin invokes malignant T-cell killing, show evidence of its associated DNA hypomethylating activity and offer a rationale for the development of romidepsin-containing combination therapies

  6. Internal target effects in ion storage rings with beam cooling

    International Nuclear Information System (INIS)

    Gostishchev, Vitaly

    2008-06-01

    The accurate description of internal target effects is important for the prediction of operation conditions which are required for experiments in the planned storage rings of the FAIR facility. The BETACOOL code developed by the Dubna group has been used to evaluate beam dynamics in ion storage rings, where electron cooling in combination with an internal target is applied. Systematic benchmarking experiments of this code were carried out at the ESR storage ring at GSI. A mode with vanishing dispersion in the target position was applied to evaluate the influence of the dispersion function on the parameters when the target is heating the beam. The influence of the internal target on the beam parameters is demonstrated in the present work. A comparison of experimental results with simple models describing the energy loss of the beam particles in the target as well as with more sophisticated simulations with the BETACOOL code is given. In order to study the conditions which can be achieved in the proposed experiments the simulation results were quantitatively compared with experimental results and simulations for the ESR. The results of this comparison are discussed in the present thesis. BETACOOL simulations of target effects were performed for the NESR and the HESR of the future FAIR facility in order to predict the beam parameters for the planned experiments. (orig.)

  7. Internal target effects in ion storage rings with beam cooling

    Energy Technology Data Exchange (ETDEWEB)

    Gostishchev, Vitaly

    2008-06-15

    The accurate description of internal target effects is important for the prediction of operation conditions which are required for experiments in the planned storage rings of the FAIR facility. The BETACOOL code developed by the Dubna group has been used to evaluate beam dynamics in ion storage rings, where electron cooling in combination with an internal target is applied. Systematic benchmarking experiments of this code were carried out at the ESR storage ring at GSI. A mode with vanishing dispersion in the target position was applied to evaluate the influence of the dispersion function on the parameters when the target is heating the beam. The influence of the internal target on the beam parameters is demonstrated in the present work. A comparison of experimental results with simple models describing the energy loss of the beam particles in the target as well as with more sophisticated simulations with the BETACOOL code is given. In order to study the conditions which can be achieved in the proposed experiments the simulation results were quantitatively compared with experimental results and simulations for the ESR. The results of this comparison are discussed in the present thesis. BETACOOL simulations of target effects were performed for the NESR and the HESR of the future FAIR facility in order to predict the beam parameters for the planned experiments. (orig.)

  8. Signal Transduction and Molecular Targets of Selected Flavonoids

    Science.gov (United States)

    Bode, Ann M.

    2013-01-01

    Abstract Significance: Diet exerts a major influence on the risk for developing cancer and heart disease. Food factors such as flavonoids are alleged to protect cells from premature aging and disease by shielding DNA, proteins, and lipids from oxidative damage. Recent Advances: Our work has focused on clarifying the effects of dietary components on cancer cell proliferation and tumor growth, discovering mechanisms to explain the effects, and identifying the specific molecular targets of these compounds. Our strategy for identifying specific molecular targets of phytochemicals involves the use of supercomputer technology combined with protein crystallography, molecular biology, and experimental laboratory verification. Critical Issues: One of the greatest challenges for scientists is to reduce the accumulation of distortion and half truths reported in the popular media regarding the health benefits of certain foods or food supplements. The use of these is not new, but interest has increased dramatically because of perceived health benefits that are presumably acquired without unpleasant side effects. Flavonoids are touted to exert many beneficial effects in vitro. However, whether they can produce these effects in vivo is disputed. Future Directions: The World Health Organization indicates that one third of all cancer deaths are preventable and that diet is closely linked to prevention. Based on this idea and epidemiological findings, attention has centered on dietary phytochemicals as an effective intervention in cancer development. However, an unequivocal link between diet and cancer has not been established. Thus, identifying cancer preventive dietary agents with specific molecular targets is essential to move forward toward successful cancer prevention. Antioxid. Redox Signal. 19, 163–180. PMID:23458437

  9. Car Motivations in the Young Target Group: An International Perspective

    Directory of Open Access Journals (Sweden)

    Michael Bahles

    2017-10-01

    Full Text Available Globally, there are many profound changes going on within the automotive sector. There are new technological developments like e-mobility and autonomous cars, as well as new business models such as car sharing that may make purchasing a car obsolete for the younger, international target group. The intention of this paper is to identify the role and importance of cars in the young target group internationally and to explore current motives for buying an automobile. To this end, the authors conducted a psychological research study on a diverse group of upper division undergraduate and master’s degree level students originating from more than twenty different nations. Research methods used include structured one-on-one interviews and in-depth focus groups. The study’s results are useful for international marketing practitioners as they contribute to understanding the relevance and importance of automobiles for the international youth target market as well as identification of motives regarding car purchase across various countries. The results have implications for international managers within the automotive industry for the development of new mobility concepts as well as for international marketing communications within the automotive sector.

  10. Potentialities of the internal target station at the Nuclotron

    Energy Technology Data Exchange (ETDEWEB)

    Malakhov, A.I.; Afanasiev, S.V.; Anisimov, Yu.S.; Artiomov, A.S.; Bazilev, S.N.; Khrenov, A.N.; Kliman, J.; Krasnov, V.A.; Matousek, V.; Morhac, M. E-mail: fyzimiro@savba.sk; Starikov, A.Yu.; Shabunov, A.V.; Slepnev, V.M.; Turzo, I

    2000-02-01

    The potentialities of the internal target station used in physics experiments at the Nuclotron, as well as its construction, hardware and software configurations are described. The remote control of the station is performed by means of a PC and is based on operative presentation of the magnetic field cycle, the beam parameters and the target position on screen. Consequently, the space-time trajectory of motion of a chosen target can be determined in an interactive way by an operator. During the accelerator operation the motion is carried out by means of a stepper motor.

  11. 1st International Conference on Signal, Networks, Computing, and Systems

    CERN Document Server

    Mohapatra, Durga; Nagar, Atulya; Sahoo, Manmath

    2016-01-01

    The book is a collection of high-quality peer-reviewed research papers presented in the first International Conference on Signal, Networks, Computing, and Systems (ICSNCS 2016) held at Jawaharlal Nehru University, New Delhi, India during February 25–27, 2016. The book is organized in to two volumes and primarily focuses on theory and applications in the broad areas of communication technology, computer science and information security. The book aims to bring together the latest scientific research works of academic scientists, professors, research scholars and students in the areas of signal, networks, computing and systems detailing the practical challenges encountered and the solutions adopted.

  12. Targeting AMPK Signaling as a Neuroprotective Strategy in Parkinson's Disease.

    Science.gov (United States)

    Curry, Daniel W; Stutz, Bernardo; Andrews, Zane B; Elsworth, John D

    2018-03-26

    Parkinson's disease (PD) is the second most common neurodegenerative disorder. It is characterized by the accumulation of intracellular α-synuclein aggregates and the degeneration of nigrostriatal dopaminergic neurons. While no treatment strategy has been proven to slow or halt the progression of the disease, there is mounting evidence from preclinical PD models that activation of 5'-AMP-activated protein kinase (AMPK) may have broad neuroprotective effects. Numerous dietary supplements and pharmaceuticals (e.g., metformin) that increase AMPK activity are available for use in humans, but clinical studies of their effects in PD patients are limited. AMPK is an evolutionarily conserved serine/threonine kinase that is activated by falling energy levels and functions to restore cellular energy balance. However, in response to certain cellular stressors, AMPK activation may exacerbate neuronal atrophy and cell death. This review describes the regulation and functions of AMPK, evaluates the controversies in the field, and assesses the potential of targeting AMPK signaling as a neuroprotective treatment for PD.

  13. 2015 International Conference on Machine Learning and Signal Processing

    CERN Document Server

    Woo, Wai; Sulaiman, Hamzah; Othman, Mohd; Saat, Mohd

    2016-01-01

    This book presents important research findings and recent innovations in the field of machine learning and signal processing. A wide range of topics relating to machine learning and signal processing techniques and their applications are addressed in order to provide both researchers and practitioners with a valuable resource documenting the latest advances and trends. The book comprises a careful selection of the papers submitted to the 2015 International Conference on Machine Learning and Signal Processing (MALSIP 2015), which was held on 15–17 December 2015 in Ho Chi Minh City, Vietnam with the aim of offering researchers, academicians, and practitioners an ideal opportunity to disseminate their findings and achievements. All of the included contributions were chosen by expert peer reviewers from across the world on the basis of their interest to the community. In addition to presenting the latest in design, development, and research, the book provides access to numerous new algorithms for machine learni...

  14. Target Canada: Lesson from Failure of International Entry

    Directory of Open Access Journals (Sweden)

    Nikolay Megits

    2015-10-01

    Full Text Available Target Corporation, the second largest retailing company in the United States, is well known for their value to guests (customers, continuous innovation, and exceptional guest experience. With a desire of international expansion, Target announced their Foreign Direct Investment (FDI plans for Target Canada in January 2011.  In August 2012, headquarters opened in Mississauga with 124 store openings following throughout 2013. Two years later an unsuccessful attempt at entering the Canadian retail market resulted in a loss of over $5.4B. Target Canada rushed into its expansion into the Canadian foreign market and corporation was unable to repeat the successful US concept in Canada for several factors. Target’s scale was too large, the timeline was too aggressive, and the entrance method was attractive from a price perspective.  As a consequence, Target was unable to efficiently manage the whole supply-chain, resulting in an unpleasant shopping experience for the customers.  Finally, the incapability to differentiate itself from other retailers led to an unsuccessful attempt at gaining greater market share from the competition. Despite the fact that Target does not have a plan to enter back into Canada, this case offers suggestions for Target’s location strategy and plausible alternatives when revisiting potential re-entry into the international retail market. Recommendations are given based on what they learned from their first attempt at failed expansion.

  15. Test of internal halo targets in the HERA proton ring

    International Nuclear Information System (INIS)

    Hast, C.; Hofmann, W.; Khan, S.; Knoepfle, K.T.; Reber, M.; Rieling, J.; Spahn, M.; Spengler, J.; Lohse, T.; Pugatch, V.

    1995-01-01

    Internal wire targets in the halo of stored proton beams provide a line source of proton-nucleus interactions for highest-rate fixed target experiments. We have studied such internal halo targets at the 820 GeV proton ring of the HERA ep collider. The tests showed that most of the protons in the beam halo - which would otherwise hit the collimators - can be brought to interaction in a relatively thin target wire at distances of 7 to 8 beam widths from the center of the beam. At less than 10% of the HERA total design current, and less than 20% of the current per bunch, interaction rates up to 8 MHz were observed, corresponding to more than 2 interactions per bunch crossing. The halo targets were used in parallel to the HERA luminosity operation; no significant disturbances of the HERA ep experiments, of the machine stability or beam quality were observed. We present data on the steady-state and transient behaviour of interaction rates and discuss the interpretation in terms of a simple beam dynamics model. Issues of short-, medium- and long-term rate fluctuations and of rate stabilization by feedback are addressed. ((orig.))

  16. Test of internal halo targets in the HERA proton ring

    International Nuclear Information System (INIS)

    Hast, C.; Hofmann, W.; Khan, S.; Knoepfle, K.T.; Reber, M.; Rieling, J.; Spahn, M.; Spengler, J.; Lohse, T.; Pugatch, V.

    1994-07-01

    Internal wire targets in the halo of stored proton beams provide a line source of proton-nucleus interactions for highest-rate fixed target experiments. We have studied such internal halo targets at the 820 GeV proton ring of the HERA ep collider. The tests showed that most of the protons in the beam halo - which would otherwise hit the collimators - can be brought to interaction in a relatively thin target wire at distances of 7 to 8 beam widths from the center of the beam. At less than 10% of the HERA total design current, and less than 20% of the current per bunch, interaction rates up to 8 MHz were observed, corresponding to more than 2 interactions per bunch crossing. The halo targets were used in parallel to the HERA luminosity operation; no significant disturbances of the HERA ep experiments, of the machine stability or beam quality were observed. We present data on the steady-state and transient behaviour of interaction rates and discuss the interpretation in terms of a simple beam dynamics model. Issues of short-, medium- and long-term rate fluctuations and of rate stabilization by feedback are addressed. (orig.)

  17. Signal Detection, Target Tracking and Differential Geometry Applications to Statistical Inference

    National Research Council Canada - National Science Library

    Rao, C

    1997-01-01

    Signal detection and target tracking. A novel method known as polynomial rooting approach is proposed to obtain estimates of frequencies, amplitudes and noise variance of two-dimensional exponential signals...

  18. National environmental targets and international emission reduction instruments

    International Nuclear Information System (INIS)

    Morthorst, P.E.

    2003-01-01

    According to the agreed burden sharing within the European Union the overall EU emission reduction target as agreed by in the Kyoto protocol is converted into national greenhouse gas reduction-targets for each of the member states. In parallel with national emission reduction initiatives common EU policies for emission reductions are considered. Currently discussed is the introduction of a market for tradable permits for CO 2 -emissions to achieve emission reductions within the power industry and other energy intensive industries. In parallel with this markets for green certificates to deploy renewable energy technologies seem to be appearing in a number of countries, among these Denmark, Italy, Sweden, Belgium (Flanders), England and Australia. Although these national initiatives for a green certificate market are fairly different, they could be a starting point for establishing a common EU certificate market. But interactions between national targets for greenhouse gas emissions and these international instruments for emission reduction are not a trivial matter, especially not seen in relation to the possible contributions of these instruments in achieving national GHG-reduction targets. The paper is split into three parts all taking a liberalised power market as starting point: The first part discusses the consequences of a general deployment of renewable energy technologies, using planning initiatives or national promotion schemes (feed-in tariffs). In the second part an international green certificate market is introduced into the liberalised power market context, substituting other national promotion schemes. Finally, in the third part a combination of an international green certificate market (TGC) and an international emission-trading scheme for CO 2 is analysed within the liberalised international power market set-up. The main conclusion is that neither the use of national renewable support schemes nor the introduction of a TGC-market into a liberalised

  19. A generalizable platform for interrogating target- and signal-specific consequences of electrophilic modifications in redox-dependent cell signaling.

    Science.gov (United States)

    Lin, Hong-Yu; Haegele, Joseph A; Disare, Michael T; Lin, Qishan; Aye, Yimon

    2015-05-20

    Despite the known propensity of small-molecule electrophiles to react with numerous cysteine-active proteins, biological actions of individual signal inducers have emerged to be chemotype-specific. To pinpoint and quantify the impacts of modifying one target out of the whole proteome, we develop a target-protein-personalized "electrophile toolbox" with which specific intracellular targets can be selectively modified at a precise time by specific reactive signals. This general methodology, T-REX (targetable reactive electrophiles and oxidants), is established by (1) constructing a platform that can deliver a range of electronic and sterically different bioactive lipid-derived signaling electrophiles to specific proteins in cells; (2) probing the kinetics of targeted delivery concept, which revealed that targeting efficiency in cells is largely driven by initial on-rate of alkylation; and (3) evaluating the consequences of protein-target- and small-molecule-signal-specific modifications on the strength of downstream signaling. These data show that T-REX allows quantitative interrogations into the extent to which the Nrf2 transcription factor-dependent antioxidant response element (ARE) signaling is activated by selective electrophilic modifications on Keap1 protein, one of several redox-sensitive regulators of the Nrf2-ARE axis. The results document Keap1 as a promiscuous electrophile-responsive sensor able to respond with similar efficiencies to discrete electrophilic signals, promoting comparable strength of Nrf2-ARE induction. T-REX is also able to elicit cell activation in cases in which whole-cell electrophile flooding fails to stimulate ARE induction prior to causing cytotoxicity. The platform presents a previously unavailable opportunity to elucidate the functional consequences of small-molecule-signal- and protein-target-specific electrophilic modifications in an otherwise unaffected cellular background.

  20. Modernization of internal target assembly for AIC-144 cyclotron - proposal

    International Nuclear Information System (INIS)

    Petelenz, B.; Szalkowski, M.

    2007-01-01

    The report describes a prototype of the remotely controlled internal target assembly, designed and built in the Institute of Nuclear Physics. After a series of technical tests, the machine was used in 2006 to produce 73 As from proton bombarded germanium targets. Before this, distribution of the proton beam on the target was checked by autoradiography of irradiated copper foils exposed on large area thermoluminescence detectors. Since the experiments exhibited some severe drawbacks of the machine, the report gives hints how to get rid of them, which is the answer to the question asked by the Deputy Director of the Institute on the topic. The construction parts of the assembly are listed in the Chapter 10. (author)

  1. New method to extract radial acceleration of target from short-duration signal at low SNR

    Institute of Scientific and Technical Information of China (English)

    2008-01-01

    In order to extract target radial acceleration from radar echo signal at low SNR (signal-to-noise), this paper employed FRFT (fractional Fourier transformation) to analyze short-duration radar echo and studied the relations between signal convergence peaks in matched transformation domain and signal duration and modu- lated frequency of signal. When signal duration is specified, the method of multi- plying sampled signal by the known frequency modulated signal to alter modulated frequency was presented, which generated the new signal with larger convergence peaks than the initial signal in matched transformation domain. Thus, it could successfully estimate the radial acceleration of radar target at low SNR. Simulations were conducted to show the feasibility and effectiveness of the method.

  2. Laser-driven nuclear-polarized hydrogen internal gas target

    International Nuclear Information System (INIS)

    Seely, J.; Crawford, C.; Clasie, B.; Xu, W.; Dutta, D.; Gao, H.

    2006-01-01

    We report the performance of a laser-driven polarized internal hydrogen gas target (LDT) in a configuration similar to that used in scattering experiments. This target used the technique of spin-exchange optical pumping to produce nuclear spin polarized hydrogen gas that was fed into a cylindrical storage (target) cell. We present in this paper the performance of the target, methods that were tried to improve the figure-of-merit (FOM) of the target, and a Monte Carlo simulation of spin-exchange optical pumping. The dimensions of the apparatus were optimized using the simulation and the experimental results were in good agreement with the results from the simulation. The best experimental result achieved was at a hydrogen flow rate of 1.1x10 18 atoms/s, where the sample beam exiting the storage cell had 58.2% degree of dissociation and 50.5% polarization. Based on this measurement, the atomic fraction in the storage cell was 49.6% and the density averaged nuclear polarization was 25.0%. This represents the highest FOM for hydrogen from an LDT and is higher than the best FOM reported by atomic beam sources that used storage cells

  3. Internal high linear energy transfer (LET) targeted radiotherapy for cancer

    International Nuclear Information System (INIS)

    Allen, Barry J

    2006-01-01

    High linear energy transfer (LET) radiation for internal targeted therapy has been a long time coming on to the medical therapy scene. While fundamental principles were established many decades ago, the clinical implementation has been slow. Localized neutron capture therapy, and more recently systemic targeted alpha therapy, are at the clinical trial stage. What are the attributes of these therapies that have led a band of scientists and clinicians to dedicate so much of their careers? High LET means high energy density, causing double strand breaks in DNA, and short-range radiation, sparing adjacent normal tissues. This targeted approach complements conventional radiotherapy and chemotherapy. Such therapies fail on several fronts. Foremost is the complete lack of progress for the control of primary GBM, the holy grail for cancer therapies. Next is the inability to regress metastatic cancer on a systemic basis. This has been the task of chemotherapy, but palliation is the major application. Finally, there is the inability to inhibit the development of lethal metastatic cancer after successful treatment of the primary cancer. This review charts, from an Australian perspective, the developing role of local and systemic high LET, internal radiation therapy. (review)

  4. Using NEG-pumping near a high density internal target

    International Nuclear Information System (INIS)

    Gruber, A.; Marton, J.; Widmann, E.; Zmeskal, J.; Orth, H.

    2008-01-01

    Full text: The Stefan Meyer Institut (SMI) is part of the international PANDA collaboration. The universal detector will be constructed at the future high-energy antiproton storage ring HESR at FAIR (Facility for Antiproton and Ion Research, GSI/Darmstadt). PANDA will use antiproton beams (1.5 to 15 GeV/c) for hadron physics in the charmonium region. SMI contributes to major parts of the PANDA detector like the hydrogen cluster-jet target and the vacuum system of the antiproton - target interaction zone. To ensure low background, the residual gas load in the interaction zone and in the antiproton beam-pipe has to be minimized. Most of the gas load, of course will come from the high density internal hydrogen target. Since the PANDA detector will cover almost the full solid angle, the installation of pumps near the interaction zone is impossible. Therefore, the use of NEG (non-evaporative-getter) coated beam pipes has been considered as an alternative. Two setups with NEG coated tubes have been installed at SMI as prototypes of the PANDA interaction zone. The outgassing behavior, the pumping speed and the pumping capacity for hydrogen have been tested. The status of the studies of the interaction region will be presented. (author)

  5. Imaging of persistent cAMP signaling by internalized G protein-coupled receptors.

    Science.gov (United States)

    Calebiro, Davide; Nikolaev, Viacheslav O; Lohse, Martin J

    2010-07-01

    G protein-coupled receptors (GPCRs) are the largest family of plasma membrane receptors. They mediate the effects of several endogenous cues and serve as important pharmacological targets. Although many biochemical events involved in GPCR signaling have been characterized in great detail, little is known about their spatiotemporal dynamics in living cells. The recent advent of optical methods based on fluorescent resonance energy transfer allows, for the first time, to directly monitor GPCR signaling in living cells. Utilizing these methods, it has been recently possible to show that the receptors for two protein/peptide hormones, the TSH and the parathyroid hormone, continue signaling to cAMP after their internalization into endosomes. This type of intracellular signaling is persistent and apparently triggers specific cellular outcomes. Here, we review these recent data and explain the optical methods used for such studies. Based on these findings, we propose a revision of the current model of the GPCR-cAMP signaling pathway to accommodate receptor signaling at endosomes.

  6. International law implications of the detection of extraterrestrial intelligent signals

    Science.gov (United States)

    Kopal, Vladimir

    This paper first considers whether the present law of outer space, as it has been enshrined in five United Nations treaties and other legal documents concerning outer space, provides a satisfactory basis for SETI/CETI activities. In the author's opinion, these activities may serve "the common interest of all mankind in the progress of the exploration and use of outer space for peaceful purposes," as recognized in the 1967 Outer Space Treaty. The use of the radio frequency spectrum for SETI/CETI purposes should be in conformity with the legal principles governing this valuable natural resource, as expressed in the International Telecommunication Convention and related documents, and with allocations of the relevant segments of the spectrum by the competent bodies of the International Telecommunication Union. In the second part the author examines the impact that the detection of extraterrestrial intelligent signals may have on the present body of space law. A possible role for the United Nations in this respect is also explored and a timely interest of the world body in discussing questions relating to this subject is recommended. Consideration of these questions could become a tool helping to concentrate the attention of the world community on problems of common concern and thus to strengthen international cooperation. However, the author believes that a law-making process that would aim at elaborating a special regulation of activities in this field would be premature at this stage. It should be initiated only when the boundary between possibilities and realities is crossed. Finally, the paper outlines some likely transformation in our space law thinking that would be the consequence of the detection of extraterrestrial intelligent signals. Elaboration of the principles and norms to govern relations between the international community of our own planet and other intelligent communities in the universe would add a new dimension to the present body of outer space

  7. Analysis and Simulation of Multi-target Echo Signals from a Phased Array Radar

    OpenAIRE

    Jia Zhen; Zhou Rui

    2017-01-01

    The construction of digital radar simulation systems has been a research hotspot of the radar field. This paper focuses on theoretical analysis and simulation of multi-target echo signals produced in a phased array radar system, and constructs an array antenna element and a signal generation environment. The antenna element is able to simulate planar arrays and optimizes these arrays by adding window functions. And the signal environment can model and simulate radar transmission signals, rada...

  8. Convergent transmission of RNAi guide-target mismatch information across Argonaute internal allosteric network.

    Science.gov (United States)

    Joseph, Thomas T; Osman, Roman

    2012-01-01

    In RNA interference, a guide strand derived from a short dsRNA such as a microRNA (miRNA) is loaded into Argonaute, the central protein in the RNA Induced Silencing Complex (RISC) that silences messenger RNAs on a sequence-specific basis. The positions of any mismatched base pairs in an miRNA determine which Argonaute subtype is used. Subsequently, the Argonaute-guide complex binds and silences complementary target mRNAs; certain Argonautes cleave the target. Mismatches between guide strand and the target mRNA decrease cleavage efficiency. Thus, loading and silencing both require that signals about the presence of a mismatched base pair are communicated from the mismatch site to effector sites. These effector sites include the active site, to prevent target cleavage; the binding groove, to modify nucleic acid binding affinity; and surface allosteric sites, to control recruitment of additional proteins to form the RISC. To examine how such signals may be propagated, we analyzed the network of internal allosteric pathways in Argonaute exhibited through correlations of residue-residue interactions. The emerging network can be described as a set of pathways emanating from the core of the protein near the active site, distributed into the bulk of the protein, and converging upon a distributed cluster of surface residues. Nucleotides in the guide strand "seed region" have a stronger relationship with the protein than other nucleotides, concordant with their importance in sequence selectivity. Finally, any of several seed region guide-target mismatches cause certain Argonaute residues to have modified correlations with the rest of the protein. This arises from the aggregation of relatively small interaction correlation changes distributed across a large subset of residues. These residues are in effector sites: the active site, binding groove, and surface, implying that direct functional consequences of guide-target mismatches are mediated through the cumulative effects of

  9. Convergent transmission of RNAi guide-target mismatch information across Argonaute internal allosteric network.

    Directory of Open Access Journals (Sweden)

    Thomas T Joseph

    Full Text Available In RNA interference, a guide strand derived from a short dsRNA such as a microRNA (miRNA is loaded into Argonaute, the central protein in the RNA Induced Silencing Complex (RISC that silences messenger RNAs on a sequence-specific basis. The positions of any mismatched base pairs in an miRNA determine which Argonaute subtype is used. Subsequently, the Argonaute-guide complex binds and silences complementary target mRNAs; certain Argonautes cleave the target. Mismatches between guide strand and the target mRNA decrease cleavage efficiency. Thus, loading and silencing both require that signals about the presence of a mismatched base pair are communicated from the mismatch site to effector sites. These effector sites include the active site, to prevent target cleavage; the binding groove, to modify nucleic acid binding affinity; and surface allosteric sites, to control recruitment of additional proteins to form the RISC. To examine how such signals may be propagated, we analyzed the network of internal allosteric pathways in Argonaute exhibited through correlations of residue-residue interactions. The emerging network can be described as a set of pathways emanating from the core of the protein near the active site, distributed into the bulk of the protein, and converging upon a distributed cluster of surface residues. Nucleotides in the guide strand "seed region" have a stronger relationship with the protein than other nucleotides, concordant with their importance in sequence selectivity. Finally, any of several seed region guide-target mismatches cause certain Argonaute residues to have modified correlations with the rest of the protein. This arises from the aggregation of relatively small interaction correlation changes distributed across a large subset of residues. These residues are in effector sites: the active site, binding groove, and surface, implying that direct functional consequences of guide-target mismatches are mediated through the

  10. Therapeutic Targeting of the IL-6 Trans-Signaling/Mechanistic Target of Rapamycin Complex 1 Axis in Pulmonary Emphysema.

    Science.gov (United States)

    Ruwanpura, Saleela M; McLeod, Louise; Dousha, Lovisa F; Seow, Huei J; Alhayyani, Sultan; Tate, Michelle D; Deswaerte, Virginie; Brooks, Gavin D; Bozinovski, Steven; MacDonald, Martin; Garbers, Christoph; King, Paul T; Bardin, Philip G; Vlahos, Ross; Rose-John, Stefan; Anderson, Gary P; Jenkins, Brendan J

    2016-12-15

    The potent immunomodulatory cytokine IL-6 is consistently up-regulated in human lungs with emphysema and in mouse emphysema models; however, the mechanisms by which IL-6 promotes emphysema remain obscure. IL-6 signals using two distinct modes: classical signaling via its membrane-bound IL-6 receptor (IL-6R), and trans-signaling via a naturally occurring soluble IL-6R. To identify whether IL-6 trans-signaling and/or classical signaling contribute to the pathogenesis of emphysema. We used the gp130 F/F genetic mouse model for spontaneous emphysema and cigarette smoke-induced emphysema models. Emphysema in mice was quantified by various methods including in vivo lung function and stereology, and terminal deoxynucleotidyl transferase dUTP nick end labeling assay was used to assess alveolar cell apoptosis. In mouse and human lung tissues, the expression level and location of IL-6 signaling-related genes and proteins were measured, and the levels of IL-6 and related proteins in sera from emphysematous mice and patients were also assessed. Lung tissues from patients with emphysema, and from spontaneous and cigarette smoke-induced emphysema mouse models, were characterized by excessive production of soluble IL-6R. Genetic blockade of IL-6 trans-signaling in emphysema mouse models and therapy with the IL-6 trans-signaling antagonist sgp130Fc ameliorated emphysema by suppressing augmented alveolar type II cell apoptosis. Furthermore, IL-6 trans-signaling-driven emphysematous changes in the lung correlated with mechanistic target of rapamycin complex 1 hyperactivation, and treatment of emphysema mouse models with the mechanistic target of rapamycin complex 1 inhibitor rapamycin attenuated emphysematous changes. Collectively, our data reveal that specific targeting of IL-6 trans-signaling may represent a novel treatment strategy for emphysema.

  11. Targeting Signaling to YAP for the Therapy of NF2

    Science.gov (United States)

    2016-12-01

    nucleus, thus activating YAP-driven transcription and oncogenesis. Genetic epistasis experiments provided evidence that this oncogenic pathway...which loss of Merlin activates mitogenic signaling by using somatic cell genetics and biochemistry. In addition, we have initiated high-throughput...which represents the ultimate long term goal of this grant. Although our studies have identified a critical role for nuclear Merlin in inhibition of

  12. Rac1 in human diseases: The therapeutic potential of targeting Rac1 signaling regulatory mechanisms.

    Science.gov (United States)

    Marei, Hadir; Malliri, Angeliki

    2017-07-03

    Abnormal Rac1 signaling is linked to a number of debilitating human diseases, including cancer, cardiovascular diseases and neurodegenerative disorders. As such, Rac1 represents an attractive therapeutic target, yet the search for effective Rac1 inhibitors is still underway. Given the adverse effects associated with Rac1 signaling perturbation, cells have evolved several mechanisms to ensure the tight regulation of Rac1 signaling. Thus, characterizing these mechanisms can provide invaluable information regarding major cellular events that lead to aberrant Rac1 signaling. Importantly, this information can be utilized to further facilitate the development of effective pharmacological modulators that can restore normal Rac1 signaling. In this review, we focus on the pathological role of Rac1 signaling, highlighting the benefits and potential drawbacks of targeting Rac1 in a clinical setting. Additionally, we provide an overview of available compounds that target key Rac1 regulatory mechanisms and discuss future therapeutic avenues arising from our understanding of these mechanisms.

  13. Laser-driven polarized hydrogen and deuterium internal targets

    International Nuclear Information System (INIS)

    Jones, C.E.; Fedchak, J.A.; Kowalczyk, R.S.

    1995-01-01

    After completing comprehensive tests of the performance of the source with both hydrogen and deuterium gas, we began tests of a realistic polarized deuterium internal target. These tests involve characterizing the atomic polarization and dissociation fraction of atoms in a storage cell as a function of flow and magnetic field, and making direct measurements of the average nuclear tensor polarization of deuterium atoms in the storage cell. Transfer of polarization from the atomic electron to the nucleus as a result of D-D spin-exchange collisions was observed in deuterium, verifying calculations suggesting that high vector polarization in both hydrogen and deuterium can be obtained in a gas in spin temperature equilibrium without inducing RF transitions between the magnetic substates. In order to improve the durability of the system, the source glassware was redesigned to simplify construction and installation and eliminate stress points that led to frequent breakage. Improvements made to the nuclear polarimeter, which used the low energy 3 H(d,n) 4 He reaction to analyze the tensor polarization of the deuterium, included installing acceleration lenses constructed of wire mesh to improve pumping conductance, construction of a new holding field coil, and elimination of the Wien filter from the setup. These changes substantially simplified operation of the polarimeter and should have reduced depolarization in collisions with the wall. However, when a number of tests failed to show an improvement of the nuclear polarization, it was discovered that extended operation of the system with a section of teflon as a getter for potassium caused the dissociation fraction to decline with time under realistic operating conditions, suggesting that teflon may not be a suitable material to eliminate potassium from the target. We are replacing the teflon surfaces with drifilm-coated ones and plan to continue tests of the polarized internal target in this configuration

  14. Using NEG-pumping near a high density internal target

    Energy Technology Data Exchange (ETDEWEB)

    Gruber, Alexander; Marton, Johann; Widmann, Eberhard; Zmeskal, Johann [Stefan Meyer Institut fuer Subatomare Physik, OeAW (Germany); Orth, Herbert [GSI, Helmholtzzentrum fuer Schwerionenforschung, Darmstadt (Germany)

    2009-07-01

    The universal detector PANDA will be constructed at the future high-energy antiproton storage ring HESR at FAIR (Facility for Antiproton and Ion Research, GSI/Darmstadt). It will use antiproton beams (1.5 to 15 GeV/c) for hadron physics in the charmonium region. The Stefan Meyer Institut (SMI) contributes to major parts of the PANDA detector like the hydrogen cluster-jet target and the vacuum system of the antiproton - target interaction zone. To ensure low background, the residual gas load in the interaction zone and in the antiproton beam-pipe has to be minimised. Most of the gas load will come from the high density internal hydrogen target. As the detector will cover almost the full solid angle, the installation of pumps near the interaction zone is impossible. Therefore the use of NEG (non-evaporative-getter) coated beam pipes has been considered as an alternative. Two setups with NEG coated tubes have been installed at SMI as prototypes of the PANDA interaction zone. General parameters of the NEG-film, its outgassing behaviour, the pumping speed and the pumping capacity for hydrogen have been tested. The results of the studies on the PANDA-interaction region are presented.

  15. Signalling in international environmental agreements. Using pre-agreement emission level as a signalling device

    Energy Technology Data Exchange (ETDEWEB)

    Steiner, U.

    1997-12-31

    This paper addresses the question about strategic incentives in international environmental agreements and tries to give a positive description of how the design of the agreement influences the strategic behaviour of potential participants before they enter the treaty. A common feature of the design of agreements is that the reduction obligations (RO) are made contingent on a pre-agreement or baseline emission. As it is assumed that countries posses better information about their reduction costs than does the international body in charge of deciding the RO, countries might have incentives to signal higher costs by increasing their baseline emission, and thereby reducing the costs of entering the agreement. The appropriate analytical framework is to use a signalling game approach, where the pre-agreement emission level conveys information about the privately informed country`s reduction cost. In this paper two types of agreement design are considered, one with uniform obligations, and one with differentiated obligations. This enables us to make a comparison between two different reduction regimes. The result is that the predicted outcomes vary with regard to both the environmental effectiveness and the associated expected costs for the participating countries. This means that when private information is considered, the anticipation of a given institutional framework has significant impact on the resulting distortion of the total emission level, highlighting the necessity of taking this into consideration when future designs are proposed. (au)

  16. Signalling in international environmental agreements: Using pre-agreement emission level as a signalling device

    International Nuclear Information System (INIS)

    Steiner, U.

    1997-01-01

    This paper addresses the question about strategic incentives in international environmental agreements and tries to give a positive description of how the design of the agreement influences the strategic behaviour of potential participants before they enter the treaty. A common feature of the design of agreements is that the reduction obligations (RO) are made contingent on a pre-agreement or baseline emission. As it is assumed that countries posses better information about their reduction costs than does the international body in charge of deciding the RO, countries might have incentives to signal higher costs by increasing their baseline emission, and thereby reducing the costs of entering the agreement. The appropriate analytical framework is to use a signalling game approach, where the pre-agreement emission level conveys information about the privately informed country's reduction cost. In this paper two types of agreement design are considered, one with uniform obligations, and one with differentiated obligations. This enables us to make a comparison between two different reduction regimes. The result is that the predicted outcomes vary with regard to both the environmental effectiveness and the associated expected costs for the participating countries. This means that when private information is considered, the anticipation of a given institutional framework has significant impact on the resulting distortion of the total emission level, highlighting the necessity of taking this into consideration when future designs are proposed. (au)

  17. Targeting Signaling to YAP for the Therapy of NF2

    Science.gov (United States)

    2015-10-01

    which encodes the FERM domain-containing protein Merlin. Children and young adults, who inherit an NF2 mutation, develop Schwannomas, usually of the...targeted therapy in the same way Chronic Myelogenous Leukemia is cured by Gleevec. The prospect of resistance is minimal, as Schwannoma cells do not seem to... treatment with Verteporfin, suggesting that this reporter system is not sensitive enough in physiopathologically relevant cell types. In parallel, it

  18. Direct targets of pSTAT5 signalling in erythropoiesis.

    Directory of Open Access Journals (Sweden)

    Kevin R Gillinder

    Full Text Available Erythropoietin (EPO acts through the dimeric erythropoietin receptor to stimulate proliferation, survival, differentiation and enucleation of erythroid progenitor cells. We undertook two complimentary approaches to find EPO-dependent pSTAT5 target genes in murine erythroid cells: RNA-seq of newly transcribed (4sU-labelled RNA, and ChIP-seq for pSTAT5 30 minutes after EPO stimulation. We found 302 pSTAT5-occupied sites: ~15% of these reside in promoters while the rest reside within intronic enhancers or intergenic regions, some >100kb from the nearest TSS. The majority of pSTAT5 peaks contain a central palindromic GAS element, TTCYXRGAA. There was significant enrichment for GATA motifs and CACCC-box motifs within the neighbourhood of pSTAT5-bound peaks, and GATA1 and/or KLF1 co-occupancy at many sites. Using 4sU-RNA-seq we determined the EPO-induced transcriptome and validated differentially expressed genes using dynamic CAGE data and qRT-PCR. We identified known direct pSTAT5 target genes such as Bcl2l1, Pim1 and Cish, and many new targets likely to be involved in driving erythroid cell differentiation including those involved in mRNA splicing (Rbm25, epigenetic regulation (Suv420h2, and EpoR turnover (Clint1/EpsinR. Some of these new EpoR-JAK2-pSTAT5 target genes could be used as biomarkers for monitoring disease activity in polycythaemia vera, and for monitoring responses to JAK inhibitors.

  19. Cancer Cell Signaling Pathways Targeted by Spice-Derived Nutraceuticals

    Science.gov (United States)

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

    2012-01-01

    Extensive research within the last half a century has revealed that cancer is caused by dysregulation of as many as 500 different gene products. Most natural products target multiple gene products and thus are ideally suited for prevention and treatment of various chronic diseases, including cancer. Dietary agents such as spices have been used extensively in the Eastern world for a variety of ailments for millennia, and five centuries ago they took a golden journey to the Western world. Various spice-derived nutraceuticals, including 1′-acetoxychavicol acetate, anethole, capsaicin, car-damonin, curcumin, dibenzoylmethane, diosgenin, eugenol, gambogic acid, gingerol, thymoquinone, ursolic acid, xanthohumol, and zerumbone derived from galangal, anise, red chili, black cardamom, turmeric, licorice, fenugreek, clove, kokum, ginger, black cumin, rosemary, hop, and pinecone ginger, respectively, are the focus of this review. The modulation of various transcription factors, growth factors, protein kinases, and inflammatory mediators by these spice-derived nutraceuticals are described. The anticancer potential through the modulation of various targets is also the subject of this review. Although they have always been used to improve taste and color and as a preservative, they are now also used for prevention and treatment of a wide variety of chronic inflammatory diseases, including cancer. PMID:22149093

  20. Charomers-Interleukin-6 Receptor Specific Aptamers for Cellular Internalization and Targeted Drug Delivery.

    Science.gov (United States)

    Hahn, Ulrich

    2017-12-06

    Interleukin-6 (IL-6) is a key player in inflammation and the main factor for the induction of acute phase protein biosynthesis. Further to its central role in many aspects of the immune system, IL-6 regulates a variety of homeostatic processes. To interfere with IL-6 dependent diseases, such as various autoimmune diseases or certain cancers like multiple myeloma or hepatocellular carcinoma associated with chronic inflammation, it might be a sensible strategy to target human IL-6 receptor (hIL-6R) presenting cells with aptamers. We therefore have selected and characterized different DNA and RNA aptamers specifically binding IL-6R. These IL-6R aptamers, however, do not interfere with the IL-6 signaling pathway but are internalized with the receptor and thus can serve as vehicles for the delivery of different cargo molecules like therapeutics. We succeeded in the construction of a chlorin e6 derivatized aptamer to be delivered for targeted photodynamic therapy (PDT). Furthermore, we were able to synthesize an aptamer intrinsically comprising the cytostatic 5-Fluoro-2'-deoxy-uridine for targeted chemotherapy. The α6β4 integrin specific DNA aptamer IDA, also selected in our laboratory is internalized, too. All these aptamers can serve as vehicles for targeted drug delivery into cells. We call them charomers-in memory of Charon, the ferryman in Greek mythology, who ferried the deceased into the underworld.

  1. Charomers—Interleukin-6 Receptor Specific Aptamers for Cellular Internalization and Targeted Drug Delivery

    Science.gov (United States)

    2017-01-01

    Interleukin-6 (IL-6) is a key player in inflammation and the main factor for the induction of acute phase protein biosynthesis. Further to its central role in many aspects of the immune system, IL-6 regulates a variety of homeostatic processes. To interfere with IL-6 dependent diseases, such as various autoimmune diseases or certain cancers like multiple myeloma or hepatocellular carcinoma associated with chronic inflammation, it might be a sensible strategy to target human IL-6 receptor (hIL-6R) presenting cells with aptamers. We therefore have selected and characterized different DNA and RNA aptamers specifically binding IL-6R. These IL-6R aptamers, however, do not interfere with the IL-6 signaling pathway but are internalized with the receptor and thus can serve as vehicles for the delivery of different cargo molecules like therapeutics. We succeeded in the construction of a chlorin e6 derivatized aptamer to be delivered for targeted photodynamic therapy (PDT). Furthermore, we were able to synthesize an aptamer intrinsically comprising the cytostatic 5-Fluoro-2′-deoxy-uridine for targeted chemotherapy. The α6β4 integrin specific DNA aptamer IDA, also selected in our laboratory is internalized, too. All these aptamers can serve as vehicles for targeted drug delivery into cells. We call them charomers—in memory of Charon, the ferryman in Greek mythology, who ferried the deceased into the underworld. PMID:29211023

  2. Charomers—Interleukin-6 Receptor Specific Aptamers for Cellular Internalization and Targeted Drug Delivery

    Directory of Open Access Journals (Sweden)

    Ulrich Hahn

    2017-12-01

    Full Text Available Interleukin-6 (IL-6 is a key player in inflammation and the main factor for the induction of acute phase protein biosynthesis. Further to its central role in many aspects of the immune system, IL-6 regulates a variety of homeostatic processes. To interfere with IL-6 dependent diseases, such as various autoimmune diseases or certain cancers like multiple myeloma or hepatocellular carcinoma associated with chronic inflammation, it might be a sensible strategy to target human IL-6 receptor (hIL-6R presenting cells with aptamers. We therefore have selected and characterized different DNA and RNA aptamers specifically binding IL-6R. These IL-6R aptamers, however, do not interfere with the IL-6 signaling pathway but are internalized with the receptor and thus can serve as vehicles for the delivery of different cargo molecules like therapeutics. We succeeded in the construction of a chlorin e6 derivatized aptamer to be delivered for targeted photodynamic therapy (PDT. Furthermore, we were able to synthesize an aptamer intrinsically comprising the cytostatic 5-Fluoro-2′-deoxy-uridine for targeted chemotherapy. The α6β4 integrin specific DNA aptamer IDA, also selected in our laboratory is internalized, too. All these aptamers can serve as vehicles for targeted drug delivery into cells. We call them charomers—in memory of Charon, the ferryman in Greek mythology, who ferried the deceased into the underworld.

  3. Targeting mammalian organelles with internalizing phage (iPhage) libraries

    Science.gov (United States)

    Rangel, Roberto; Dobroff, Andrey S.; Guzman-Rojas, Liliana; Salmeron, Carolina C.; Gelovani, Juri G.; Sidman, Richard L.; Pasqualini, Renata; Arap, Wadih

    2015-01-01

    Techniques largely used for protein interaction studies and discovery of intracellular receptors, such as affinity capture complex purification and yeast two-hybrid, may produce inaccurate datasets due to protein insolubility, transient or weak protein interactions, or irrelevant intracellular context. A versatile tool to overcome these limitations as well as to potentially create vaccines and engineer peptides and antibodies as targeted diagnostic and therapeutic agents, is the phage display technique. We have recently developed a new technology for screening internalizing phage (iPhage) vectors and libraries utilizing a ligand/receptor-independent mechanism to penetrate eukaryotic cells. iPhage particles provide a unique discovery platform for combinatorial intracellular targeting of organelle ligands along with their corresponding receptors and to fingerprint functional protein domains in living cells. Here we explain the design, cloning, construction, and production of iPhage-based vectors and libraries, along with basic ligand-receptor identification and validation methodologies for organelle receptors. An iPhage library screening can be performed in ~8 weeks. PMID:24030441

  4. Anti-vascular internal high LET targeted radiotherapy for cancer

    International Nuclear Information System (INIS)

    Allen, Barry J.

    2006-01-01

    Targeted alpha therapy (TAT) is an emerging therapeutic modality, thought to be best suited to cancers such as leukaemia and cancer micrometastases, but not solid tumours. However, several subjects in our phase 1 clinical trial of systemic TAT for melanoma experienced marked regression of subcutaneous and internal tumours. The MCSP receptor is expressed on both tumour capillary pericytes and melanoma cells, and is targeted by the 9.2.27 monoclonal antibody. When this is labelled with the alpha-emitting radioisotope Bi-213, the resulting alpha-immunoconjugate can extravasate through capillary fenestrations and selectively kill these cells, as well as the contiguous endothelial cells in the capillaries, causing capillary closure and subsequent tumour regression. These results suggest that tumours can be regressed by a process called tumour anti-vascular alpha therapy (TAVAT). By analogy, tumour regression in boron neutron capture therapy could be achieved by similar means, where in the alpha and Li-7 ions emitted by boron-10 neutron capture events in cancer cells contiguous to the endothelial cells could shut down tumour capillaries by a process of tumour anti-vascular neutron capture therapy (TAVNCT). (author)

  5. Target sites for chemical regulation of strigolactone signaling

    Directory of Open Access Journals (Sweden)

    Hidemitsu eNakamura

    2014-11-01

    Full Text Available Demands for plant growth regulators (chemicals that control plant growth are increasing globally, especially in developing countries. Both positive and negative plant growth regulators are widely used to enhance crop production and to suppress unwanted shoot growth, respectively. Strigolactones (SLs are multifunctional molecules that function as phytohormones, inhibiting shoot branching and also functioning in the rhizospheric communication with symbiotic fungi and parasitic weeds. Therefore, it is anticipated that chemicals that regulate the functions of SLs will be widely used in agricultural applications. Although the SL biosynthetic pathway is not fully understood, it has been demonstrated that beta-carotene isomerases, carotenoid cleavage dioxygenases (CCDs, and a cytochrome P450 monooxygenase are involved in strigolactone biosynthesis. A CCD inhibitor, abamine, which is also an inhibitor of abscisic acid biosynthesis, reduces the levels of SL in several plant species and reduces the germination rate of Orobanche minor seeds grown with tobacco. On the basis of the structure of abamine, several chemicals have been designed to specifically inhibit CCDs during SL synthesis. Cytochrome P450 monooxygenase is another target enzyme in the development of SL biosynthesis inhibitors, and the triazole-derived TIS series of chemicals is known to include SL biosynthesis inhibitors, although their target enzyme has not been identified. Recently, DWARF14 (D14 has been shown to be a receptor for SLs, and the D-ring moiety of SL is essential for its recognition by D14. A variety of SL agonists are currently under development and most agonists commonly contain the D-ring or a D-ring-like moiety. Several research groups have also resolved the crystal structure of D14 in the last two years. It is expected that this information on the D14 structure will be invaluable not only for developing SL agonists with novel structures but also in the design of inhibitors

  6. Amphetamine activates Rho GTPase signaling to mediate dopamine transporter internalization and acute behavioral effects of amphetamine

    Science.gov (United States)

    Wheeler, David S.; Underhill, Suzanne M.; Stolz, Donna B.; Murdoch, Geoffrey H.; Thiels, Edda; Romero, Guillermo; Amara, Susan G.

    2015-01-01

    Acute amphetamine (AMPH) exposure elevates extracellular dopamine through a variety of mechanisms that include inhibition of dopamine reuptake, depletion of vesicular stores, and facilitation of dopamine efflux across the plasma membrane. Recent work has shown that the DAT substrate AMPH, unlike cocaine and other nontransported blockers, can also stimulate endocytosis of the plasma membrane dopamine transporter (DAT). Here, we show that when AMPH enters the cytoplasm it rapidly stimulates DAT internalization through a dynamin-dependent, clathrin-independent process. This effect, which can be observed in transfected cells, cultured dopamine neurons, and midbrain slices, is mediated by activation of the small GTPase RhoA. Inhibition of RhoA activity with C3 exotoxin or a dominant-negative RhoA blocks AMPH-induced DAT internalization. These actions depend on AMPH entry into the cell and are blocked by the DAT inhibitor cocaine. AMPH also stimulates cAMP accumulation and PKA-dependent inactivation of RhoA, thus providing a mechanism whereby PKA- and RhoA-dependent signaling pathways can interact to regulate the timing and robustness of AMPH’s effects on DAT internalization. Consistent with this model, the activation of D1/D5 receptors that couple to PKA in dopamine neurons antagonizes RhoA activation, DAT internalization, and hyperlocomotion observed in mice after AMPH treatment. These observations support the existence of an unanticipated intracellular target that mediates the effects of AMPH on RhoA and cAMP signaling and suggest new pathways to target to disrupt AMPH action. PMID:26553986

  7. Targeting FLT3 Signaling in Childhood Acute Myeloid Leukemia

    Directory of Open Access Journals (Sweden)

    Amy N. Sexauer

    2017-11-01

    Full Text Available Acute myeloid leukemia (AML is the second most common leukemia of childhood and is associated with high rates of chemotherapy resistance and relapse. Clinical outcomes for children with AML treated with maximally intensive multi-agent chemotherapy lag far behind those of children with the more common acute lymphoblastic leukemia, demonstrating continued need for new therapeutic approaches to decrease relapse risk and improve long-term survival. Mutations in the FMS-like tyrosine kinase-3 receptor gene (FLT3 occur in approximately 25% of children and adults with AML and are associated with particularly poor prognoses. Identification and development of targeted FLT3 inhibitors represents a major precision medicine paradigm shift in the treatment of patients with AML. While further development of many first-generation FLT3 inhibitors was hampered by limited potency and significant toxicity due to effects upon other kinases, the more selective second- and third-generation FLT3 inhibitors have demonstrated excellent tolerability and remarkable efficacy in the relapsed/refractory and now de novo FLT3-mutated AML settings. While these newest and most promising inhibitors have largely been studied in the adult population, pediatric investigation of FLT3 inhibitors with chemotherapy is relatively recently ongoing or planned. Successful development of FLT3 inhibitor-based therapies will be essential to improve outcomes in children with this high-risk subtype of AML.

  8. Preparation of 199Tl using the electroplating gold targets on the internal target installation of cyclotron

    International Nuclear Information System (INIS)

    Zhou Dehai; Xie Degao; Chao Yangshu; Liao Fuquan; Zhang Youfa; Wang Zefu

    1992-01-01

    The separative conditions of 199 Tl from Cu, Au and Ga by reaction 197 Au(α, 2n) 199 Tl on the internal target installation of cyclotron is studied. The α-particle energy is selected in the range of 24-15 MeV. The cumulative current intensities of such α-particle beams bombarding the gold target at 150-200 μA are 1200 μA · h and 1500 μA · h respectively. The radiochemical separation of 199 Tl is carried out with isopropyl ether extraction and anions exchange from the irradiated gold targets. The radioactivities of 199 Tl and 200 Tl are 2.3 x 10 5 Bq and 7.1 x 10 2 Bq, and 200 Tl makes up 0.29% of the total radioactivity. The impurity elements contained 1 ml of 199 TlCl injection solution are Au 199 TlCl has been used in clinical experiments in vivo and relatively good results have been obtained

  9. Synergistic target combination prediction from curated signaling networks: Machine learning meets systems biology and pharmacology.

    Science.gov (United States)

    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.

  10. Survival signalling and apoptosis resistance in glioblastomas: opportunities for targeted therapeutics

    Directory of Open Access Journals (Sweden)

    Krakstad Camilla

    2010-06-01

    Full Text Available Abstract Glioblastoma multiforme (GBM is the most common primary brain tumour in adults and one of the most aggressive cancers in man. Despite technological advances in surgical management, combined regimens of radiotherapy with new generation chemotherapy, the median survival for these patients is 14.6 months. This is largely due to a highly deregulated tumour genome with opportunistic deletion of tumour suppressor genes, amplification and/or mutational hyper-activation of receptor tyrosine kinase receptors. The net result of these genetic changes is augmented survival pathways and systematic defects in the apoptosis signalling machinery. The only randomised, controlled phase II trial conducted targeting the epidermal growth factor receptor (EGFR signalling with the small molecule inhibitor, erlotinib, has showed no therapeutic benefit. Survival signalling and apoptosis resistance in GBMs can be viewed as two sides of the same coin. Targeting increased survival is unlikely to be efficacious without at the same time targeting apoptosis resistance. We have critically reviewed the literature regarding survival and apoptosis signalling in GBM, and highlighted experimental, preclinical and recent clinical trials attempting to target these pathways. Combined therapies simultaneously targeting apoptosis and survival signalling defects might shift the balance from tumour growth stasis to cytotoxic therapeutic responses that might be associated with greater therapeutic benefits.

  11. Sensitivity analysis of intracellular signaling pathway kinetics predicts targets for stem cell fate control.

    Directory of Open Access Journals (Sweden)

    Alborz Mahdavi

    2007-07-01

    Full Text Available Directing stem cell fate requires knowledge of how signaling networks integrate temporally and spatially segregated stimuli. We developed and validated a computational model of signal transducer and activator of transcription-3 (Stat3 pathway kinetics, a signaling network involved in embryonic stem cell (ESC self-renewal. Our analysis identified novel pathway responses; for example, overexpression of the receptor glycoprotein-130 results in reduced pathway activation and increased ESC differentiation. We used a systematic in silico screen to identify novel targets and protein interactions involved in Stat3 activation. Our analysis demonstrates that signaling activation and desensitization (the inability to respond to ligand restimulation is regulated by balancing the activation state of a distributed set of parameters including nuclear export of Stat3, nuclear phosphatase activity, inhibition by suppressor of cytokine signaling, and receptor trafficking. This knowledge was used to devise a temporally modulated ligand delivery strategy that maximizes signaling activation and leads to enhanced ESC self-renewal.

  12. Fractal properties of background noise and target signal enhancement using CSEM data

    Science.gov (United States)

    Benavides, Alfonso; Everett, Mark E.; Pierce, Carl; Nguyen, Cam

    2003-09-01

    Controlled-source electromagnetic (CSEM) spatial profiles and 2-D conductivity maps were obtained on the Brazos Valley, TX floodplain to study the fractal statistics of geological signals and effects of man-made conductive targets using Geonics EM34, EM31 and EM63. Using target-free areas, a consistent power-law power spectrum (|A(k)| ~ k ^-β) for the profiles was found with β values typical of fractional Brownian motion (fBm). This means that the spatial variation of conductivity does not correspond to Gaussian statistics, where there are spatial correlations at different scales. The presence of targets tends to flatten the power-law power spectrum (PS) at small wavenumbers. Detection and localization of targets can be achieved using short-time Fourier transform (STFT). The presence of targets is enhanced because the signal energy is spread to higher wavenumbers (small scale numbers) in the positions occupied by the targets. In the case of poor spatial sampling or small amount of data, the information available from the power spectrum is not enough to separate spatial correlations from target signatures. Advantages are gained by using the spatial correlations of the fBm in order to reject the background response, and to enhance the signals from highly conductive targets. This approach was tested for the EM31 using a pre-processing step that combines apparent conductivity readings from two perpendicular transmitter-receiver orientations at each station. The response obtained using time-domain CSEM is influence to a lesser degree by geological noise and the target response can be processed to recover target features. The homotopy method is proposed to solve the inverse problem using a set of possible target models and a dynamic library of responses used to optimize the starting model.

  13. Fibers as solid, internal targets for storage rings

    International Nuclear Information System (INIS)

    Przewoski, B.v.

    1994-01-01

    It has been demonstrated that fibers or micro ribbons provide the possibility to expose solid targets to a stored ion beam. Compared to gas targets or micro particle targets fiber targets require a relatively small technical effort, since differential pumping systems are not necessary to maintain the ring vacuum. Since stationary fibers are often too thick to allow for long enough lifetimes of the stored beam to be useful for experiments, a methods has been developed to move the fiber periodically through the beam. That way, the time averaged target thickness is small compared to the thickness the same fiber would have, if it were stationary in the path of the beam. In addition, the time averaged thickness can be adjusted if the amplitude of the fiber motion is increased or decreased to obtain a thinner or thicker target respectively. Measurements that compare the lifetime of the stored beam in the presence of a fiber target with the lifetime of a stored beam in the presence of a gas target show that a fiber target of a certain time averaged target thickness is equivalent to a homogeneous target of the same thickness. The data are in good agreement with Monte Carlo calculations

  14. A single peroxisomal targeting signal mediates matrix protein import in diatoms.

    Directory of Open Access Journals (Sweden)

    Nicola H Gonzalez

    Full Text Available Peroxisomes are single membrane bound compartments. They are thought to be present in almost all eukaryotic cells, although the bulk of our knowledge about peroxisomes has been generated from only a handful of model organisms. Peroxisomal matrix proteins are synthesized cytosolically and posttranslationally imported into the peroxisomal matrix. The import is generally thought to be mediated by two different targeting signals. These are respectively recognized by the two import receptor proteins Pex5 and Pex7, which facilitate transport across the peroxisomal membrane. Here, we show the first in vivo localization studies of peroxisomes in a representative organism of the ecologically relevant group of diatoms using fluorescence and transmission electron microscopy. By expression of various homologous and heterologous fusion proteins we demonstrate that targeting of Phaeodactylum tricornutum peroxisomal matrix proteins is mediated only by PTS1 targeting signals, also for proteins that are in other systems imported via a PTS2 mode of action. Additional in silico analyses suggest this surprising finding may also apply to further diatoms. Our data suggest that loss of the PTS2 peroxisomal import signal is not reserved to Caenorhabditis elegans as a single exception, but has also occurred in evolutionary divergent organisms. Obviously, targeting switching from PTS2 to PTS1 across different major eukaryotic groups might have occurred for different reasons. Thus, our findings question the widespread assumption that import of peroxisomal matrix proteins is generally mediated by two different targeting signals. Our results implicate that there apparently must have been an event causing the loss of one targeting signal even in the group of diatoms. Different possibilities are discussed that indicate multiple reasons for the detected targeting switching from PTS2 to PTS1.

  15. The Role of Cyclic Nucleotide Signaling Pathways in Cancer: Targets for Prevention and Treatment

    Energy Technology Data Exchange (ETDEWEB)

    Fajardo, Alexandra M.; Piazza, Gary A. [Drug Discovery Research Center, Mitchell Cancer Institute, University of South Alabama, 1660 Springhill Ave, Suite 3029, Mobile, AL 36604 (United States); Tinsley, Heather N., E-mail: htinsley@montevallo.edu [Department of Biology, Chemistry, and Mathematics, University of Montevallo, Station 6480, Montevallo, AL 35115 (United States)

    2014-02-26

    For more than four decades, the cyclic nucleotides cyclic AMP (cAMP) and cyclic GMP (cGMP) have been recognized as important signaling molecules within cells. Under normal physiological conditions, cyclic nucleotides regulate a myriad of biological processes such as cell growth and adhesion, energy homeostasis, neuronal signaling, and muscle relaxation. In addition, altered cyclic nucleotide signaling has been observed in a number of pathophysiological conditions, including cancer. While the distinct molecular alterations responsible for these effects vary depending on the specific cancer type, several studies have demonstrated that activation of cyclic nucleotide signaling through one of three mechanisms—induction of cyclic nucleotide synthesis, inhibition of cyclic nucleotide degradation, or activation of cyclic nucleotide receptors—is sufficient to inhibit proliferation and activate apoptosis in many types of cancer cells. These findings suggest that targeting cyclic nucleotide signaling can provide a strategy for the discovery of novel agents for the prevention and/or treatment of selected cancers.

  16. 2012 Proceedings of the International Conference on Communications, Signal Processing, and Systems

    CERN Document Server

    Wang, Wei; Mu, Jiasong; Liang, Jing; Zhang, Baoju; Pi, Yiming; Zhao, Chenglin

    2012-01-01

    Communications, Signal Processing, and Systems is a collection of contributions coming out of the International Conference on Communications, Signal Processing, and Systems (CSPS) held October 2012. This book provides the state-of-art developments of Communications, Signal Processing, and Systems, and their interactions in multidisciplinary fields, such as Smart Grid. The book also examines Radar Systems, Sensor Networks, Radar Signal Processing, Design and Implementation of Signal Processing Systems and Applications. Written by experts and students in the fields of Communications, Signal Processing, and Systems.

  17. Delineating neurotrophin-3 dependent signaling pathways underlying sympathetic axon growth along intermediate targets.

    Science.gov (United States)

    Keeler, Austin B; Suo, Dong; Park, Juyeon; Deppmann, Christopher D

    2017-07-01

    Postganglionic sympathetic neurons detect vascular derived neurotrophin 3 (NT3) via the axonally expressed receptor tyrosine kinase, TrkA, to promote chemo-attraction along intermediate targets. Once axons arrive to their final target, a structurally related neurotrophic factor, nerve growth factor (NGF), also acts through TrkA to promote final target innervation. Does TrkA signal differently at these different locales? We previously found that Coronin-1 is upregulated in sympathetic neurons upon exposure to NGF, thereby endowing the NGF-TrkA complex with new signaling capabilities (i.e. calcium signaling), which dampens axon growth and branching. Based on the notion that axons do not express functional levels of Coronin-1 prior to final target innervation, we developed an in vitro model for axon growth and branching along intermediate targets using Coro1a -/- neurons grown in NT3. We found that, similar to NGF-TrkA, NT3-TrkA is capable of inducing MAPK and PI3K in the presence or absence of Coronin-1. However, unlike NGF, NT3 does not induce calcium release from intracellular stores. Using a combination of pharmacology, knockout neurons and in vitro functional assays, we suggest that the NT3-TrkA complex uses Ras/MAPK and/or PI3K-AKT signaling to induce axon growth and inhibit axon branching along intermediate targets. However, in the presence of Coronin-1, these signaling pathways lose their ability to impact NT3 dependent axon growth or branching. This is consistent with a role for Coronin-1 as a molecular switch for axon behavior and suggests that Coronin-1 suppresses NT3 dependent axon behavior. Copyright © 2017 Elsevier Inc. All rights reserved.

  18. International Nuclear Target Development Society workshop 1983: proceedings

    Energy Technology Data Exchange (ETDEWEB)

    Thomas, G. (ed.)

    1983-01-01

    Separate abstracts were prepared for 11 of the 19 papers presented. Eight papers were previously included in the data base. Discussion group session papers on carbon stripper foils, problems in producing heavy-ion targets, and problems in producing general type targets are included. (WHK)

  19. International Nuclear Target Development Society workshop 1983: proceedings

    International Nuclear Information System (INIS)

    Thomas, G.

    1983-01-01

    Separate abstracts were prepared for 11 of the 19 papers presented. Eight papers were previously included in the data base. Discussion group session papers on carbon stripper foils, problems in producing heavy-ion targets, and problems in producing general type targets are included

  20. Overlapping activities of TGF-β and Hedgehog signaling in cancer: therapeutic targets for cancer treatment.

    Science.gov (United States)

    Perrot, Carole Y; Javelaud, Delphine; Mauviel, Alain

    2013-02-01

    Recent advances in the field of cancer therapeutics come from the development of drugs that specifically recognize validated oncogenic or pro-metastatic targets. The latter may be mutated proteins with altered function, such as kinases that become constitutively active, or critical components of growth factor signaling pathways, whose deregulation leads to aberrant malignant cell proliferation and dissemination to metastatic sites. We herein focus on the description of the overlapping activities of two important developmental pathways often exacerbated in cancer, namely Transforming Growth Factor-β (TGF-β) and Hedgehog (HH) signaling, with a special emphasis on the unifying oncogenic role played by GLI1/2 transcription factors. The latter are the main effectors of the canonical HH pathway, yet are direct target genes of TGF-β/SMAD signal transduction. While tumor-suppressor in healthy and pre-malignant tissues, TGF-β is often expressed at high levels in tumors and contributes to tumor growth, escape from immune surveillance, invasion and metastasis. HH signaling regulates cell proliferation, differentiation and apoptosis, and aberrant HH signaling is found in a variety of cancers. We discuss the current knowledge on HH and TGF-β implication in cancer including cancer stem cell biology, as well as the current state, both successes and failures, of targeted therapeutics aimed at blocking either of these pathways in the pre-clinical and clinical settings. Copyright © 2012 Elsevier Inc. All rights reserved.

  1. MicroRNA-145 suppresses hepatocellular carcinoma by targeting IRS1 and its downstream Akt signaling

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Yelin [Department of Anesthesiology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou (China); Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou (China); Hu, Chen; Cheng, Jun [Department of Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou (China); Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou (China); Chen, Binquan [Department of Anesthesiology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou (China); Ke, Qinghong; Lv, Zhen; Wu, Jian [Department of Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou (China); Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou (China); Zhou, Yanfeng, E-mail: zyfhdj@yahoo.com [Department of Anesthesiology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou (China)

    2014-04-18

    Highlights: • MiR-145 expression is down-regulated in HCC tissues and inversely related with IRS1 levels. • MiR-145 directly targets IRS1 in HCC cells. • Restored expression of miR-145 suppressed HCC cell proliferation and growth. • MiR-145 induced IRS1 under-expression potentially reduced downstream AKT signaling. - Abstract: Accumulating evidences have proved that dysregulation of microRNAs (miRNAs) is involved in cancer initiation and progression. In this study, we showed that miRNA-145 level was significantly decreased in hepatocellular cancer (HCC) tissues and cell lines, and its low expression was inversely associated with the abundance of insulin receptor substrate 1 (IRS1), a key mediator in oncogenic insulin-like growth factor (IGF) signaling. We verified IRS1 as a direct target of miR-145 using Western blotting and luciferase reporter assay. Further, the restoration of miR-145 in HCC cell lines suppressed cancer cell growth, owing to down-regulated IRS1 expression and its downstream Akt/FOXO1 signaling. Our results demonstrated that miR-145 could inhibit HCC through targeting IRS1 and its downstream signaling, implicating the loss of miR-145 regulation may be a potential molecular mechanism causing aberrant oncogenic signaling in HCC.

  2. In Vivo Phosphoproteomics Analysis Reveals the Cardiac Targets of β-Adrenergic Receptor Signaling

    DEFF Research Database (Denmark)

    Lundby, Alicia; Andersen, Martin N; Steffensen, Annette B

    2013-01-01

    β-Blockers are widely used to prevent cardiac arrhythmias and to treat hypertension by inhibiting β-adrenergic receptors (βARs) and thus decreasing contractility and heart rate. βARs initiate phosphorylation-dependent signaling cascades, but only a small number of the target proteins are known. We...

  3. Fluorescence analysis of the Hansenula polymorpha peroxisomal targeting signal-1 receptor, Pex5p

    NARCIS (Netherlands)

    Boteva, R.; Koek, A.; Visser, N.V.; Visser, A.J.W.G.; Krieger, E.; Zlateva, T.; Veenhuis, M.; Klei, van der I.

    2003-01-01

    Correct sorting of newly synthesized peroxisomal matrix proteins is dependent on a peroxisomal targeting signal (PTS). So far two PTSs are known. PTS1 consists of a tripeptide that is located at the extreme C terminus of matrix proteins and is specifically recognized by the PTS1-receptor Pex5p. We

  4. Homogeneous electrochemical aptamer-based ATP assay with signal amplification by exonuclease III assisted target recycling.

    Science.gov (United States)

    Liu, Shufeng; Wang, Ying; Zhang, Chengxin; Lin, Ying; Li, Feng

    2013-03-21

    A novel and homogeneous electrochemical aptamer-based adenosine triphosphate (ATP) assay was demonstrated with signal amplification by exonuclease III-assisted target recycling. A superior detection limit of 1 nM toward ATP with an excellent selectivity could be achieved.

  5. Signal integration: a framework for understanding the efficacy of therapeutics targeting the human EGFR family

    Science.gov (United States)

    Shepard, H. Michael; Brdlik, Cathleen M.; Schreiber, Hans

    2008-01-01

    The human EGFR (HER) family is essential for communication between many epithelial cancer cell types and the tumor microenvironment. Therapeutics targeting the HER family have demonstrated clinical success in the treatment of diverse epithelial cancers. Here we propose that the success of HER family–targeted monoclonal antibodies in cancer results from their ability to interfere with HER family consolidation of signals initiated by a multitude of other receptor systems. Ligand/receptor systems that initiate these signals include cytokine receptors, chemokine receptors, TLRs, GPCRs, and integrins. We further extrapolate that improvements in cancer therapeutics targeting the HER family are likely to incorporate mechanisms that block or reverse stromal support of malignant progression by isolating the HER family from autocrine and stromal influences. PMID:18982164

  6. Requirements on internal targets for the Aladdin storage ring

    International Nuclear Information System (INIS)

    Holt, R.J.

    1984-01-01

    The feasibility of performing electron scattering experiments with polarized targets in electron storage rings is explored by considering an electron-deuteron scattering experiment at the Aladdin storage ring. It is noted that this new method is compatible with recent proposals for linac-stretcher-ring accelerator designs. A new method for producing a polarized hydrogen or deuterium target is proposed and some preliminary results are described. 21 references, 6 figures, 1 table

  7. New software of the control and data acquisition system for the Nuclotron internal target station

    International Nuclear Information System (INIS)

    Isupov, A.Yu.

    2012-01-01

    The control and data acquisition system for the Internal Target Station (ITS) of the Nuclotron (LHEP, JINR) is implemented. The new software is based on the ngdp framework under the Unix-like operating system FreeBSD to allow easy network distribution of the on-line data collected from ITS, as well as the internal target remote control

  8. A Large-Acceptance Detector System for Electron Scattering from Polarized Internal targets.

    NARCIS (Netherlands)

    Passchier, E.; Bouwhuis, M.; Choi, S.; Zhou, Z.L.; Alarcon, R.; Anghinolfi, M.; Botto, T.; van den Brand, J.F.J.; Bulten, H.J.; Dimitroyannis, D.; Doets, M.; Ent, R.; Ferro Luzzi, M.M.E.; Higinbotham, D.W.; de Jager, C.W.; Lang, J.; de Lange, D.J.; Nikolenko, D.; Nooren, G.J.; Papadakis, N.; Passchier, I.; Popov, S.G.; Rachek, I.; Ripani, M.; Steijger, J.J.M.; Taiuti, M.; Vodinas, N.; de Vries, H.

    1997-01-01

    The design and the performance of a non-magnetic detector setup for internal target physics at the NIKHEF electron-scattering facility is described. The detector setup, used in the first internal-target experiment at the AmPS ring, measures the spin dependence in the elastic and break-up reaction

  9. International Conference on Ultrawideband and Ultrashort Impulse Signals (5th)

    Science.gov (United States)

    2010-09-10

    COOPERATION WITH National Antenna Association of Ukraine Kharkiv National University of Radio Electronics Radio Astronomy Institute of NASU...WELCOME Dear colleagues, We are happy to welcome all our participants in the beautiful Crimea city of great ancient history – Sevastopol, which...input signal on an axis of time in synchronism zones. Will disas- semble more in detail, in what physical zones this phe- nomenon and in what it results

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

    Science.gov (United States)

    Wang, Sheng; Huang, Peng; Chen, Xiaoyuan

    2016-09-01

    Targeted delivery of therapeutic agents is an important way to improve the therapeutic index and reduce side effects. To design nanoparticles for targeted delivery, both enhanced tumor tissue accumulation/retention and enhanced cellular internalization should be considered simultaneously. So far, there have been very few nanoparticles with immutable structures that can achieve this goal efficiently. Hierarchical targeting, a novel targeting strategy based on stimuli responsiveness, shows good potential to enhance both tumor tissue accumulation/retention and cellular internalization. Here, the recent design and development of hierarchical targeting nanoplatforms, based on changeable particle sizes, switchable surface charges and activatable surface ligands, will be introduced. In general, the targeting moieties in these nanoplatforms are not activated during blood circulation for efficient tumor tissue accumulation, but re-activated by certain internal or external stimuli in the tumor microenvironment for enhanced cellular internalization. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  11. An internal superconducting ''holding-coil'' for frozen spin targets

    International Nuclear Information System (INIS)

    Dutz, H.; Gehring, R.; Goertz, S.; Kraemer, D.; Meyer, W.; Reicherz, G.; Thomas, A.

    1995-01-01

    A new concept of a small superconducting holding magnet, placed inside a polarizing refrigerator, has been developed for frozen spin targets. The superconducting wire has been wound on the inner cooling shield of the vertical dilution refrigerator of the Bonn frozen spin target. The maximum field of the magnet is 0.35 T. The total thickness of the superconducting coil consisting of the wire and the copper carrier is of the order of 500 μm. Based on this concept, a frozen spin target is under construction for the measurement of the Gerasimov-Drell-Hearn sum rule with polarized real photons at the Mainz microtron MAMI and the Bonn electron stretcher accelerator ELSA. ((orig.))

  12. An internal superconducting ``holding-coil`` for frozen spin targets

    Energy Technology Data Exchange (ETDEWEB)

    Dutz, H. [Bonn Univ. (Germany). Physikalisches Inst.; Gehring, R. [Bonn Univ. (Germany). Physikalisches Inst.; Goertz, S. [Bonn Univ. (Germany). Physikalisches Inst.; Kraemer, D. [Bonn Univ. (Germany). Physikalisches Inst.; Meyer, W. [Bonn Univ. (Germany). Physikalisches Inst.; Reicherz, G. [Bonn Univ. (Germany). Physikalisches Inst.; Thomas, A. [Bonn Univ. (Germany). Physikalisches Inst.

    1995-03-01

    A new concept of a small superconducting holding magnet, placed inside a polarizing refrigerator, has been developed for frozen spin targets. The superconducting wire has been wound on the inner cooling shield of the vertical dilution refrigerator of the Bonn frozen spin target. The maximum field of the magnet is 0.35 T. The total thickness of the superconducting coil consisting of the wire and the copper carrier is of the order of 500 {mu}m. Based on this concept, a frozen spin target is under construction for the measurement of the Gerasimov-Drell-Hearn sum rule with polarized real photons at the Mainz microtron MAMI and the Bonn electron stretcher accelerator ELSA. ((orig.))

  13. Identification of the feedforward component in manual control with predictable target signals.

    Science.gov (United States)

    Drop, Frank M; Pool, Daan M; Damveld, Herman J; van Paassen, Marinus M; Mulder, Max

    2013-12-01

    In the manual control of a dynamic system, the human controller (HC) often follows a visible and predictable reference path. Compared with a purely feedback control strategy, performance can be improved by making use of this knowledge of the reference. The operator could effectively introduce feedforward control in conjunction with a feedback path to compensate for errors, as hypothesized in literature. However, feedforward behavior has never been identified from experimental data, nor have the hypothesized models been validated. This paper investigates human control behavior in pursuit tracking of a predictable reference signal while being perturbed by a quasi-random multisine disturbance signal. An experiment was done in which the relative strength of the target and disturbance signals were systematically varied. The anticipated changes in control behavior were studied by means of an ARX model analysis and by fitting three parametric HC models: two different feedback models and a combined feedforward and feedback model. The ARX analysis shows that the experiment participants employed control action on both the error and the target signal. The control action on the target was similar to the inverse of the system dynamics. Model fits show that this behavior can be modeled best by the combined feedforward and feedback model.

  14. Uterine progesterone signaling is a target for metformin therapy in PCOS-like rats.

    Science.gov (United States)

    Hu, Min; Zhang, Yuehui; Feng, Jiaxing; Xu, Xue; Zhang, Jiao; Zhao, Wei; Guo, Xiaozhu; Li, Juan; Vestin, Edvin; Cui, Peng; Li, Xin; Wu, Xiao-Ke; Brännström, Mats; Shao, Linus R; Billig, Håkan

    2018-05-01

    Impaired progesterone (P4) signaling is linked to endometrial dysfunction and infertility in women with polycystic ovary syndrome (PCOS). Here, we report for the first time that elevated expression of progesterone receptor (PGR) isoforms A and B parallels increased estrogen receptor (ER) expression in PCOS-like rat uteri. The aberrant PGR-targeted gene expression in PCOS-like rats before and after implantation overlaps with dysregulated expression of Fkbp52 and Ncoa2 , two genes that contribute to the development of uterine P4 resistance. In vivo and in vitro studies of the effects of metformin on the regulation of the uterine P4 signaling pathway under PCOS conditions showed that metformin directly inhibits the expression of PGR and ER along with the regulation of several genes that are targeted dependently or independently of PGR-mediated uterine implantation. Functionally, metformin treatment corrected the abnormal expression of cell-specific PGR and ER and some PGR-target genes in PCOS-like rats with implantation. Additionally, we documented how metformin contributes to the regulation of the PGR-associated MAPK/ERK/p38 signaling pathway in the PCOS-like rat uterus. Our data provide novel insights into how metformin therapy regulates uterine P4 signaling molecules under PCOS conditions. © 2018 Society for Endocrinology.

  15. To fingolimod and beyond: The rich pipeline of drug candidates that target S1P signaling.

    Science.gov (United States)

    Chew, Wee Siong; Wang, Wei; Herr, Deron R

    2016-11-01

    Sphingosine 1-phosphate (S1P) is an extracellular lipid signaling molecule that acts as a selective, high-affinity ligand for a family of five G protein-coupled receptors. This signaling system was first identified twenty years ago, and has since been shown to regulate a diverse range of physiological processes and disease states, such as cardiovascular development, immune function, hypoxic responses, and cancer. The therapeutic potential of targeting this system took center stage when it was demonstrated that the immune modulator, fingolimod (FTY720/Gilenya), exerts it lymphopenic effect by acting on S1P receptors, primarily on S1P receptor 1 (S1P 1 ). In 2010, fingolimod became the first oral medication approved for the treatment of multiple sclerosis (MS). Since then, second-generation S1P receptor modulators have been under development in an effort to provide improved safety and efficacy profiles for MS, and to broaden their use to other autoimmune indications. Beyond the development of S1P 1 -modulators, there has been considerable effort in targeting other components of the S1P signaling pathway for the treatment of other diseases, such as cardiovascular disease, sepsis, and cancer. This manuscript provides an overview of the clinical and preclinical development of drugs targeting S1P signaling. Copyright © 2016 Elsevier Ltd. All rights reserved.

  16. The influence of signal type on the internal auditory representation of a room

    Science.gov (United States)

    Teret, Elizabeth

    Currently, architectural acousticians make no real distinction between a room impulse response and the auditory system's internal representation of a room. With this lack of a good model for the auditory representation of a room, it is indirectly assumed that our internal representation of a room is independent of the sound source needed to make the room characteristics audible. The extent to which this assumption holds true is examined with perceptual tests. Listeners are presented with various pairs of signals (music, speech, and noise) convolved with synthesized impulse responses of different reverberation times. They are asked to adjust the reverberation of one of the signals to match the other. Analysis of the data show that the source signal significantly influences perceived reverberance. Listeners are less accurate when matching reverberation times of varied signals than they are with identical signals. Additional testing shows that perception of reverberation can be linked to the existence of transients in the signal.

  17. Targeting CB2-GPR55 Receptor Heteromers Modulates Cancer Cell Signaling*

    Science.gov (United States)

    Moreno, Estefanía; Andradas, Clara; Medrano, Mireia; Caffarel, María M.; Pérez-Gómez, Eduardo; Blasco-Benito, Sandra; Gómez-Cañas, María; Pazos, M. Ruth; Irving, Andrew J.; Lluís, Carme; Canela, Enric I.; Fernández-Ruiz, Javier; Guzmán, Manuel; McCormick, Peter J.; Sánchez, Cristina

    2014-01-01

    The G protein-coupled receptors CB2 (CB2R) and GPR55 are overexpressed in cancer cells and human tumors. Because a modulation of GPR55 activity by cannabinoids has been suggested, we analyzed whether this receptor participates in cannabinoid effects on cancer cells. Here we show that CB2R and GPR55 form heteromers in cancer cells, that these structures possess unique signaling properties, and that modulation of these heteromers can modify the antitumoral activity of cannabinoids in vivo. These findings unveil the existence of previously unknown signaling platforms that help explain the complex behavior of cannabinoids and may constitute new targets for therapeutic intervention in oncology. PMID:24942731

  18. GCN5 Regulates FGF Signaling and Activates Selective MYC Target Genes during Early Embryoid Body Differentiation

    Directory of Open Access Journals (Sweden)

    Li Wang

    2018-01-01

    Full Text Available Precise control of gene expression during development is orchestrated by transcription factors and co-regulators including chromatin modifiers. How particular chromatin-modifying enzymes affect specific developmental processes is not well defined. Here, we report that GCN5, a histone acetyltransferase essential for embryonic development, is required for proper expression of multiple genes encoding components of the fibroblast growth factor (FGF signaling pathway in early embryoid bodies (EBs. Gcn5−/− EBs display deficient activation of ERK and p38, mislocalization of cytoskeletal components, and compromised capacity to differentiate toward mesodermal lineage. Genomic analyses identified seven genes as putative direct targets of GCN5 during early differentiation, four of which are cMYC targets. These findings established a link between GCN5 and the FGF signaling pathway and highlighted specific GCN5-MYC partnerships in gene regulation during early differentiation.

  19. cGMP signaling as a target for the prevention and treatment of breast cancer.

    Science.gov (United States)

    Windham, Perrin F; Tinsley, Heather N

    2015-04-01

    One in eight women in the United States will be diagnosed with invasive breast cancer in her lifetime. Advances in therapeutic strategies, diagnosis, and improved awareness have resulted in a significant reduction in breast cancer related mortality. However, there is a continued need for more effective and less toxic drugs for both the prevention and the treatment of breast cancer in order to see a continued decline in the morbidity and mortality associated with this disease. Recent studies suggest that the cGMP signaling pathway may be aberrantly regulated in breast cancer. As such, this pathway may serve as a source of novel targets for future breast cancer drug discovery efforts. This review provides an overview of cGMP signaling in normal physiology and in breast cancer as well as current strategies being investigated for targeting this pathway in breast cancer. Copyright © 2014 Elsevier Ltd. All rights reserved.

  20. Lithium inhibits tumorigenic potential of PDA cells through targeting hedgehog-GLI signaling pathway.

    Directory of Open Access Journals (Sweden)

    Zhonglu Peng

    Full Text Available Hedgehog signaling pathway plays a critical role in the initiation and development of pancreatic ductal adenocarcinoma (PDA and represents an attractive target for PDA treatment. Lithium, a clinical mood stabilizer for mental disorders, potently inhibits the activity of glycogen synthase kinase 3β (GSK3β that promotes the ubiquitin-dependent proteasome degradation of GLI1, an important downstream component of hedgehog signaling. Herein, we report that lithium inhibits cell proliferation, blocks G1/S cell-cycle progression, induces cell apoptosis and suppresses tumorigenic potential of PDA cells through down-regulation of the expression and activity of GLI1. Moreover, lithium synergistically enhances the anti-cancer effect of gemcitabine. These findings further our knowledge of mechanisms of action for lithium and provide a potentially new therapeutic strategy for PDA through targeting GLI1.

  1. TARGETING THE HUMAN DOMAIN: REACHING INTERNAL, JOINT, AND ADVERSARIAL AUDIENCES

    Science.gov (United States)

    2017-04-06

    86th Medical Support Squadron, Ramstein Air Base, Germany . In this capacity, she commanded a 197-person unit providing health care support services to...religion, illustrated via such military- specific rites as the Uniformed Code of Military Justice as a moral compass. This holds for smaller groupings...within a service, as well as for larger joint and international allied warfighting. Correspondingly, service history , rhetoric and literature must focus

  2. Automatic detection of the unknown number point targets in FMICW radar signals

    Czech Academy of Sciences Publication Activity Database

    Rejfek, L.; Mošna, Zbyšek; Beran, L.; Fišer, O.; Dobrovolný, M.

    2017-01-01

    Roč. 4, č. 11 (2017), s. 116-120 ISSN 2313-626X R&D Projects: GA ČR(CZ) GA15-24688S Institutional support: RVO:68378289 Keywords : FMICW radar * 2D FFT * signal filtration * taraget detection * target parameter estimation Subject RIV: DG - Athmosphere Sciences, Meteorology OBOR OECD: Meteorology and atmospheric sciences http://science-gate.com/IJAAS/Articles/2017-4-11/18%202017-4-11-pp.116-120.pdf

  3. NMR signal analysis in the large COMPASS $^{14}$NH$_{3}$ target

    CERN Document Server

    Koivuniemi, J; Hess, C; Kisselev, Y U; Meyer, W; Radtke, E; Reicherz, G; Doshita, N; Iwata, T; Kondo, K; Michigami, T

    2009-01-01

    In the large COMPASS polarized proton target the 1508 cm$^{3}$ of irradiated granular ammonia is polarized with dynamic nuclear polarization method using 4 mm microwaves in 2.5 T eld. The nuclear polarization up to 90 - 93 % is determined with cw NMR. The properties of the observed ammonia proton signals are described and spin thermodynamics in high elds is presented. Also the second moment of the NMR line is estimated.

  4. Alteration of SHP-1/p-STAT3 Signaling: A Potential Target for Anticancer Therapy

    Directory of Open Access Journals (Sweden)

    Tzu-Ting Huang

    2017-06-01

    Full Text Available The Src homology 2 (SH2 domain-containing protein tyrosine phosphatase 1 (SHP-1, a non-receptor protein tyrosine phosphatase, has been reported as a negative regulator of phosphorylated signal transducer and activator of transcription 3 (STAT3 and linked to tumor development. In this present review, we will discuss the importance and function of SHP-1/p-STAT3 signaling in nonmalignant conditions as well as malignancies, its cross-talk with other pathways, the current clinical development and the potential role of inhibitors of this pathway in anticancer therapy and clinical relevance of SHP-1/p-STAT3 in cancers. Lastly, we will summarize and highlight work involving novel drugs/compounds targeting SHP-1/p-STAT3 signaling and combined strategies that were/are discovered in our and our colleagues’ laboratories.

  5. Non-genomic actions of aldosterone: From receptors and signals to membrane targets.

    LENUS (Irish Health Repository)

    2012-02-01

    In tissues which express the mineralocorticoid receptor (MR), aldosterone modulates the expression of membrane targets such as the subunits of the epithelial Na(+) channel, in combination with important signalling intermediates such as serum and glucocorticoid-regulated kinase-1. In addition, the rapid \\'non-genomic\\' activation of protein kinases and secondary messenger signalling cascades has also been detected in aldosterone-sensitive tissues of the nephron, distal colon and cardiovascular system. These rapid actions are variously described as being coupled to MR or to an as yet unidentified, membrane-associated aldosterone receptor. The rapidly activated signalling cascades add a level of fine-tuning to the activity of aldosterone-responsive membrane transporters and also modulate the aldosterone-induced changes in gene expression through receptor and transcription factor phosphorylation.

  6. Non-genomic actions of aldosterone: From receptors and signals to membrane targets.

    LENUS (Irish Health Repository)

    Dooley, Ruth

    2011-07-26

    In tissues which express the mineralocorticoid receptor (MR), aldosterone modulates the expression of membrane targets such as the subunits of the epithelial Na(+) channel, in combination with important signalling intermediates such as serum and glucocorticoid-regulated kinase-1. In addition, the rapid \\'non-genomic\\' activation of protein kinases and secondary messenger signalling cascades has also been detected in aldosterone-sensitive tissues of the nephron, distal colon and cardiovascular system. These rapid actions are variously described as being coupled to MR or to an as yet unidentified, membrane-associated aldosterone receptor. The rapidly activated signalling cascades add a level of fine-tuning to the activity of aldosterone-responsive membrane transporters and also modulate the aldosterone-induced changes in gene expression through receptor and transcription factor phosphorylation.

  7. Gating based on internal/external signals with dynamic correlation updates

    International Nuclear Information System (INIS)

    Wu Huanmei; Zhao Qingya; Berbeco, Ross I; Nishioka, Seiko; Shirato, Hiroki; Jiang, Steve B

    2008-01-01

    Precise localization of mobile tumor positions in real time is critical to the success of gated radiotherapy. Tumor positions are usually derived from either internal or external surrogates. Fluoroscopic gating based on internal surrogates, such as implanted fiducial markers, is accurate however requiring a large amount of imaging dose. Gating based on external surrogates, such as patient abdominal surface motion, is non-invasive however less accurate due to the uncertainty in the correlation between tumor location and external surrogates. To address these complications, we propose to investigate an approach based on hybrid gating with dynamic internal/external correlation updates. In this approach, the external signal is acquired at high frequency (such as 30 Hz) while the internal signal is sparsely acquired (such as 0.5 Hz or less). The internal signal is used to validate and update the internal/external correlation during treatment. Tumor positions are derived from the external signal based on the newly updated correlation. Two dynamic correlation updating algorithms are introduced. One is based on the motion amplitude and the other is based on the motion phase. Nine patients with synchronized internal/external motion signals are simulated retrospectively to evaluate the effectiveness of hybrid gating. The influences of different clinical conditions on hybrid gating, such as the size of gating windows, the optimal timing for internal signal acquisition and the acquisition frequency are investigated. The results demonstrate that dynamically updating the internal/external correlation in or around the gating window will reduce false positive with relatively diminished treatment efficiency. This improvement will benefit patients with mobile tumors, especially greater for early stage lung cancers, for which the tumors are less attached or freely floating in the lung.

  8. Gating based on internal/external signals with dynamic correlation updates

    Energy Technology Data Exchange (ETDEWEB)

    Wu Huanmei [Purdue School of Engineering and Technology, Indiana University School of Informatics, IUPUI, Indianapolis, IN (United States); Zhao Qingya [School of Health Sciences, Purdue University, West Lafayette, IN (United States); Berbeco, Ross I [Department of Radiation Oncology, Dana-Farber/Brigham and Womens Cancer Center and Harvard Medical School, Boston, MA (United States); Nishioka, Seiko [NTT East-Japan Sapporo Hospital, Sapporo (Japan); Shirato, Hiroki [Hokkaido University Graduate School of Medicine, Sapporo (Japan); Jiang, Steve B [Department of Radiation Oncology, School of Medicine, University of California, San Diego, CA (United States)], E-mail: hw9@iupui.edu, E-mail: sbjiang@ucsd.edu

    2008-12-21

    Precise localization of mobile tumor positions in real time is critical to the success of gated radiotherapy. Tumor positions are usually derived from either internal or external surrogates. Fluoroscopic gating based on internal surrogates, such as implanted fiducial markers, is accurate however requiring a large amount of imaging dose. Gating based on external surrogates, such as patient abdominal surface motion, is non-invasive however less accurate due to the uncertainty in the correlation between tumor location and external surrogates. To address these complications, we propose to investigate an approach based on hybrid gating with dynamic internal/external correlation updates. In this approach, the external signal is acquired at high frequency (such as 30 Hz) while the internal signal is sparsely acquired (such as 0.5 Hz or less). The internal signal is used to validate and update the internal/external correlation during treatment. Tumor positions are derived from the external signal based on the newly updated correlation. Two dynamic correlation updating algorithms are introduced. One is based on the motion amplitude and the other is based on the motion phase. Nine patients with synchronized internal/external motion signals are simulated retrospectively to evaluate the effectiveness of hybrid gating. The influences of different clinical conditions on hybrid gating, such as the size of gating windows, the optimal timing for internal signal acquisition and the acquisition frequency are investigated. The results demonstrate that dynamically updating the internal/external correlation in or around the gating window will reduce false positive with relatively diminished treatment efficiency. This improvement will benefit patients with mobile tumors, especially greater for early stage lung cancers, for which the tumors are less attached or freely floating in the lung.

  9. The antidepressant sertraline inhibits translation initiation by curtailing mammalian target of rapamycin signaling.

    Science.gov (United States)

    Lin, Chen-Ju; Robert, Francis; Sukarieh, Rami; Michnick, Stephen; Pelletier, Jerry

    2010-04-15

    Sertraline, a selective serotonin reuptake inhibitor, is a widely used antidepressant agent. Here, we show that sertraline also exhibits antiproliferative activity. Exposure to sertraline leads to a concentration-dependent decrease in protein synthesis. Moreover, polysome profile analysis of sertraline-treated cells shows a reduction in polysome content and a concomitant increase in 80S ribosomes. The inhibition in translation caused by sertraline is associated with decreased levels of the eukaryotic initiation factor (eIF) 4F complex, altered localization of eIF4E, and increased eIF2alpha phosphorylation. The latter event leads to increased REDD1 expression, which in turn impinges on the mammalian target of rapamycin (mTOR) pathway by affecting TSC1/2 signaling. Sertraline also independently targets the mTOR signaling pathway downstream of Rheb. In the Emu-myc murine lymphoma model where carcinogenesis is driven by phosphatase and tensin homologue (PTEN) inactivation, sertraline is able to enhance chemosensitivity to doxorubicin. Our results indicate that sertraline exerts antiproliferative activity by targeting the mTOR signaling pathway in a REDD1-dependent manner. (c) 2010 AACR.

  10. Monte Carlo Simulation of the Echo Signals from Low-Flying Targets for Airborne Radar

    Directory of Open Access Journals (Sweden)

    Mingyuan Man

    2014-01-01

    Full Text Available A demonstrated hybrid method based on the combination of half-space physical optics method (PO, graphical-electromagnetic computing (GRECO, and Monte Carlo method on echo signals from low-flying targets based on actual environment for airborne radar is presented in this paper. The half-space physical optics method , combined with the graphical-electromagnetic computing (GRECO method to eliminate the shadow regions quickly and rebuild the target automatically, is employed to calculate the radar cross section (RCS of the conductive targets in half space fast and accurately. The direct echo is computed based on the radar equation. The reflected paths from sea or ground surface cause multipath effects. In order to accurately obtain the echo signals, the phase factors are modified for fluctuations in multipath, and the statistical average value of the echo signals is obtained using the Monte Carlo method. A typical simulation is performed, and the numerical results show the accuracy of the proposed method.

  11. Effect of microbubble ligation to cells on ultrasound signal enhancement: implications for targeted imaging.

    Science.gov (United States)

    Lankford, Miles; Behm, Carolyn Z; Yeh, James; Klibanov, Alexander L; Robinson, Peter; Lindner, Jonathan R

    2006-10-01

    Molecular imaging with contrast-enhanced ultrasound (CEU) relies on the detection of microbubbles retained in regions of disease. The aim of this study was to determine whether microbubble attachment to cells influences their acoustic signal generation and stability. Biotinylated microbubbles were attached to streptavidin-coated plates to derive density versus intensity relations during low- and high-power imaging. To assess damping from microbubble attachment to solid or cell surfaces, in vitro imaging was performed for microbubbles charge-coupled to methacrylate spheres and for vascular cell adhesion molecule-1-targeted microbubbles attached to endothelial cells. Signal enhancement on plates increased according to acoustic power and microbubble site density up to 300 mm. Microbubble signal was reduced by attachment to solid spheres during high- and low-power imaging but was minimally reduced by attachment to endothelial cells and only at low power. Attachment of targeted microbubbles to rigid surfaces results in damping and a reduction of their acoustic signal, which is not seen when microbubbles are attached to cells. A reliable concentration versus intensity relationship can be expected from microbubble attachment to 2-dimensional surfaces until a very high site density is reached.

  12. Target of Rapamycin (TOR) Regulates Growth in Response to Nutritional Signals.

    Science.gov (United States)

    Weisman, Ronit

    2016-10-01

    All organisms can respond to the availability of nutrients by regulating their metabolism, growth, and cell division. Central to the regulation of growth in response to nutrient availability is the target of rapamycin (TOR) signaling that is composed of two structurally distinct complexes: TOR complex 1 (TORC1) and TOR complex 2 (TORC2). The TOR genes were first identified in yeast as target of rapamycin, a natural product of a soil bacterium, which proved beneficial as an immunosuppressive and anticancer drug and is currently being tested for a handful of other pathological conditions including diabetes, neurodegeneration, and age-related diseases. Studies of the TOR pathway unraveled a complex growth-regulating network. TOR regulates nutrient uptake, transcription, protein synthesis and degradation, as well as metabolic pathways, in a coordinated manner that ensures that cells grow or cease growth in response to nutrient availability. The identification of specific signals and mechanisms that stimulate TOR signaling is an active and exciting field of research that has already identified nitrogen and amino acids as key regulators of TORC1 activity. The signals, as well as the cellular functions of TORC2, are far less well understood. Additional open questions in the field concern the relationships between TORC1 and TORC2, as well as the links with other nutrient-responsive pathways. Here I review the main features of TORC1 and TORC2, with a particular focus on yeasts as model organisms.

  13. MicroRNA-99 family targets AKT/mTOR signaling pathway in dermal wound healing.

    Science.gov (United States)

    Jin, Yi; Tymen, Stéphanie D; Chen, Dan; Fang, Zong Juan; Zhao, Yan; Dragas, Dragan; Dai, Yang; Marucha, Phillip T; Zhou, Xiaofeng

    2013-01-01

    Recent studies suggest that microRNAs play important roles in dermal wound healing and microRNA deregulation has been linked with impaired wound repair. Here, using a mouse experimental wound healing model, we identified a panel of 63 differentially expressed microRNAs during dermal wound healing, including members of miR-99 family (miR-99a, miR-99b, miR-100). We further demonstrated that miR-99 family members regulate cell proliferation, cell migration, and AKT/mTOR signaling. Combined experimental and bioinformatics analyses revealed that miR-99 family members regulate AKT/mTOR signaling by targeting multiple genes, including known target genes (e.g., IGF1R, mTOR) and a new target (AKT1). The effects of miR-99 family members on the expression of IGF1R, mTOR and AKT1 were validated at both the mRNA and protein levels. Two adjacent miR-99 family targeting sites were identified in the 3'-UTR of the AKT1 mRNA. The direct interaction of miR-100 with these targeting sites was confirmed using luciferase reporter assays. The microRNA-100-directed recruitment of AKT1 mRNA to the RNAi-induced silencing complex (RISC) was confirmed by a ribonucleoprotein-IP assay. In summary, we identified a panel of differentially expressed microRNAs which may play important roles in wound healing. We provide evidence that miR-99 family members contribute to wound healing by regulating the AKT/mTOR signaling.

  14. B cell antigen receptor signaling and internalization are mutually exclusive events.

    Directory of Open Access Journals (Sweden)

    Ping Hou

    2006-07-01

    Full Text Available Engagement of the B cell antigen receptor initiates two concurrent processes, signaling and receptor internalization. While both are required for normal humoral immune responses, the relationship between these two processes is unknown. Herein, we demonstrate that following receptor ligation, a small subpopulation of B cell antigen receptors are inductively phosphorylated and selectively retained at the cell surface where they can serve as scaffolds for the assembly of signaling molecules. In contrast, the larger population of non-phosphorylated receptors is rapidly endocytosed. Each receptor can undergo only one of two mutually exclusive fates because the tyrosine-based motifs that mediate signaling when phosphorylated mediate internalization when not phosphorylated. Mathematical modeling indicates that the observed competition between receptor phosphorylation and internalization enhances signaling responses to low avidity ligands.

  15. MicroRNA expression, target genes, and signaling pathways in infants with a ventricular septal defect.

    Science.gov (United States)

    Chai, Hui; Yan, Zhaoyuan; Huang, Ke; Jiang, Yuanqing; Zhang, Lin

    2018-02-01

    This study aimed to systematically investigate the relationship between miRNA expression and the occurrence of ventricular septal defect (VSD), and characterize the miRNA target genes and pathways that can lead to VSD. The miRNAs that were differentially expressed in blood samples from VSD and normal infants were screened and validated by implementing miRNA microarrays and qRT-PCR. The target genes regulated by differentially expressed miRNAs were predicted using three target gene databases. The functions and signaling pathways of the target genes were enriched using the GO database and KEGG database, respectively. The transcription and protein expression of specific target genes in critical pathways were compared in the VSD and normal control groups using qRT-PCR and western blotting, respectively. Compared with the normal control group, the VSD group had 22 differentially expressed miRNAs; 19 were downregulated and three were upregulated. The 10,677 predicted target genes participated in many biological functions related to cardiac development and morphogenesis. Four target genes (mGLUR, Gq, PLC, and PKC) were involved in the PKC pathway and four (ECM, FAK, PI3 K, and PDK1) were involved in the PI3 K-Akt pathway. The transcription and protein expression of these eight target genes were significantly upregulated in the VSD group. The 22 miRNAs that were dysregulated in the VSD group were mainly downregulated, which may result in the dysregulation of several key genes and biological functions related to cardiac development. These effects could also be exerted via the upregulation of eight specific target genes, the subsequent over-activation of the PKC and PI3 K-Akt pathways, and the eventual abnormal cardiac development and VSD.

  16. MicroRNA-467g inhibits new bone regeneration by targeting Ihh/Runx-2 signaling.

    Science.gov (United States)

    Kureel, Jyoti; John, Aijaz A; Dixit, Manisha; Singh, Divya

    2017-04-01

    MicroRNAs are important post transcriptional regulators of gene expression and play critical role in osteoblast differentiation. In this study we report miR-467g, an uncharacterized novel miRNA, in regulation of osteoblast functions. Over-expression of miR-467g inhibited osteoblast differentiation. Target prediction analysis tools and experimental validation by luciferase 3' UTR reporter assay identified Runx-2 as a direct target of miR-467g. Over expression of miR-467g in osteoblasts down regulated Runx-2 and Ihh signaling components. Furthermore, silencing of miR-467g was done to see its role in Ihh and Runx-2 mediated bone healing and regeneration in a drill hole injury model in BALB/c mice. Silencing of miR-467g led to significant increase in new bone regeneration and Ihh and Runx-2 localization at injury site in a day dependent manner. In conclusion, miR-467g negatively regulates osteogenesis by targeting Ihh/Runx-2 signaling. We, thus, propose that therapeutic approaches targeting miR-467g could be useful in enhancing the new bone formation. Copyright © 2017 Elsevier Ltd. All rights reserved.

  17. Cellular Signaling Pathway Alterations and Potential Targeted Therapies for Medullary Thyroid Carcinoma

    Directory of Open Access Journals (Sweden)

    Serena Giunti

    2013-01-01

    Full Text Available Parafollicular C-cell-derived medullary thyroid cancer (MTC comprises 3% to 4% of all thyroid cancers. While cytotoxic treatments have been shown to have limited efficacy, targeted molecular therapies that inhibit rearranged during transfection (RET and other tyrosine kinase receptors that are mainly involved in angiogenesis have shown great promise in the treatment of metastatic or locally advanced MTC. Multi-tyrosine kinase inhibitors such as vandetanib, which is already approved for the treatment of progressive MTC, and cabozantinib have shown distinct advantages with regard to rates of disease response and control. However, these types of tyrosine kinase inhibitor compounds are able to concurrently block several types of targets, which limits the understanding of RET as a specific target. Moreover, important resistances to tyrosine kinase inhibitors can occur, which limit the long-term efficacy of these treatments. Deregulated cellular signaling pathways and genetic alterations in MTC, particularly the activation of the RAS/mammalian target of rapamycin (mTOR cascades and RET crosstalk signaling, are now emerging as novel and potentially promising therapeutic treatments for aggressive MTC.

  18. Targeting cytokine signaling checkpoint CIS activates NK cells to protect from tumor initiation and metastasis

    Science.gov (United States)

    Putz, Eva M.; Guillerey, Camille; Kos, Kevin; Stannard, Kimberley; Miles, Kim; Delconte, Rebecca B.; Nicholson, Sandra E.; Huntington, Nicholas D.; Smyth, Mark J.

    2017-01-01

    ABSTRACT The cytokine-induced SH2-containing protein CIS belongs to the suppressor of cytokine signaling (SOCS) protein family. Here, we show the critical role of CIS in suppressing natural killer (NK) cell control of tumor initiation and metastasis. Cish-deficient mice were highly resistant to methylcholanthrene-induced sarcoma formation and protected from lung metastasis of B16F10 melanoma and RM-1 prostate carcinoma cells. In contrast, the growth of primary subcutaneous tumors, including those expressing the foreign antigen OVA, was unchanged in Cish-deficient mice. The combination of Cish deficiency and relevant targeted and immuno-therapies such as combined BRAF and MEK inhibitors, immune checkpoint blockade antibodies, IL-2 and type I interferon revealed further improved control of metastasis. The data clearly indicate that targeting CIS promotes NK cell antitumor functions and CIS holds great promise as a novel target in NK cell immunotherapy. PMID:28344878

  19. Flavored alcoholic beverages: an international marketing campaign that targets youth.

    Science.gov (United States)

    Mosher, James F; Johnsson, Diane

    2005-09-01

    Flavored alcoholic beverages (FABs) were first introduced into the alcohol market in the early I980s in the form of wine coolers. FABs are sweet, relatively low alcohol content beverages that are designed for "entry-level" drinkers. The alcohol industry has introduced new products and production methods to expand the category's popularity. Research suggests that they are popular with underage drinkers, particularly teenage girls, and that the industry uses marketing practices that appear to target youth. FABs are now marketed globally, and their production and marketing vary by country based on national regulatory restraints. In the United States, industry representations that the products are malt beverages for regulatory purposes appears to violate many state laws because the alcohol in the FABs is derived from distilled spirits. Recommendations for regulatory reform, including new legal definitions of FABs, increased taxes, and restrictions on availability, are applicable at both national and state levels.

  20. Identification of potential pathway mediation targets in Toll-like receptor signaling.

    Directory of Open Access Journals (Sweden)

    Fan Li

    2009-02-01

    Full Text Available Recent advances in reconstruction and analytical methods for signaling networks have spurred the development of large-scale models that incorporate fully functional and biologically relevant features. An extended reconstruction of the human Toll-like receptor signaling network is presented herein. This reconstruction contains an extensive complement of kinases, phosphatases, and other associated proteins that mediate the signaling cascade along with a delineation of their associated chemical reactions. A computational framework based on the methods of large-scale convex analysis was developed and applied to this network to characterize input-output relationships. The input-output relationships enabled significant modularization of the network into ten pathways. The analysis identified potential candidates for inhibitory mediation of TLR signaling with respect to their specificity and potency. Subsequently, we were able to identify eight novel inhibition targets through constraint-based modeling methods. The results of this study are expected to yield meaningful avenues for further research in the task of mediating the Toll-like receptor signaling network and its effects.

  1. Sonic Hedgehog Signaling Drives Proliferation of Synoviocytes in Rheumatoid Arthritis: A Possible Novel Therapeutic Target

    Directory of Open Access Journals (Sweden)

    Mingxia Wang

    2014-01-01

    Full Text Available Sonic hedgehog (Shh signaling controls many aspects of human development, regulates cell growth and differentiation in adult tissues, and is activated in a number of malignancies. Rheumatoid arthritis (RA is characterized by chronic synovitis and pannus formation associated with activation of fibroblast-like synoviocytes (FLS. We investigated whether Shh signaling plays a role in the proliferation of FLS in RA. Expression of Shh signaling related components (Shh, Ptch1, Smo, and Gli1 in RA synovial tissues was examined by immunohistochemistry (IHC and in FLS by IHC, immunofluorescence (IF, quantitative RT-PCR, and western blotting. Expression of Shh, Smo, and Gli1 in RA synovial tissue was higher than that in control tissue (P<0.05. Cyclopamine (a specific inhibitor of Shh signaling decreased mRNA expression of Shh, Ptch1, Smo, and Gli1 in cultured RA FLS, Shh, and Smo protein expression, and significantly decreased FLS proliferation. Flow cytometry analysis suggested that cyclopamine treatment resulted in cell cycle arrest of FLS in G1 phase. Our data show that Shh signaling is activated in synovium of RA patients in vivo and in cultured FLS form RA patients in vitro, suggesting a role in the proliferation of FLS in RA. It may therefore be a novel therapeutic target in RA.

  2. Effect of an internal target on the beam behaviour in a storage ring

    International Nuclear Information System (INIS)

    Diehl, N.

    1988-04-01

    For the study of the effects of an internal target on the beam behaviour in a storage ring a Monte Carlo simulation program was developed. Special importance was attached to the ranges of validity of the used models. The dominating effects are the Coulomb scattering of the projectiles on the target nuclei, which lead to an angular dispersion, and the collisions of the projectiles on the electrons of the target atoms which cause an energy loss. The target effects are regarded in the simulation program. The simulation calculations for the storage ring COSY give cause for the hope that experiments with internal targets because of high luminosity represent an interesting alternative in spite of thin targets. (orig./HSI) [de

  3. PC-based control of the internal target station at the Nuclotron

    Energy Technology Data Exchange (ETDEWEB)

    Kilman, J [and others

    1996-12-31

    A PC-based control system of the internal target at the Nuclotron is described. The system is based on CAMAC-control of the step motor of the station and screen representation of information about needed beam parameters and space-time position of targets relative to a beam. 6 refs.; 4 figs.

  4. First Nuclear Reaction Experiment with Stored Radioactive 56Ni Beam and Internal Hydrogen and Helium Targets

    NARCIS (Netherlands)

    Egelhof, P.; Bagchi, Soumya; Csatlós, M.; Dillmann, I.; Dimopoulou, C.; Furuno, T; Geissel, H.; Gernhauser, R.; Kalantar-Nayestanaki, Nasser; Kuilman, M.; Mahjour-Shafiei, M.; Najafi, M.A.; Rigollet, C.; Streicher, B.

    2014-01-01

    The investigation of light-ion induced direct reactions using stored and cooled radioactive beams, interacting with internal targets of storage rings, can lead to substantial advantages over external target experiments, in particular for direct reaction experiments in inverse kinematics at very low

  5. Performance of a Polarized Deuterium Internal Target in a Medium-Energy Electron Storage Ring.

    NARCIS (Netherlands)

    Zhou, Z.L.; Ferro Luzzi, M.M.E.; van den Brand, J.F.J.; Bulten, H.J.; Alarcon, R.; van Bommel, R.; Botto, T.; Bouwhuis, M.; Buchholz, M.; Choi, S.; Comfort, J.; Doets, M.; Dolfini, S.; Ent, R.; Gaulard, C.; de Jager, C.W.; Lang, J.; de Lange, D.J.; Miller, M.A.; Passchier, E.; Passchier, I.; Poolman, H.R.; Six, E.; Steijger, J.J.M.; Unal, O.; de Vries, H.

    1996-01-01

    A polarized deuterium target internal to a medium-energy electron storage ring is described in the context of spindependent (e, e′d) and (e ,e′p) experiments. Tensor polarized deuterium was produced in an atomic beam source and injected into a storage cell target. A Breit-Rabi polarimeter was used

  6. 16th International Workshop on Polarized Sources, Targets, and Polarimetry (PSTP 2015)

    CERN Document Server

    2015-01-01

    The Workshop on Polarized Sources, Targets and Polarimetry has been a tradition for more than 20 years, moving between Europe, USA and Japan. The XVIth International Workshop on Polarized Sources, Targets and Polarimetry (PSTP 2015) will take place at the Ruhr-University of Bochum, Germany. The workshop addresses the physics and technological challenges related to polarized gas/solid targets, polarized electron/positron/ion/neutron sources, polarimetry and their applications. will be published in Proceedings of Science

  7. Targeting Sonic Hedgehog Signaling by Compounds and Derivatives from Natural Products

    Directory of Open Access Journals (Sweden)

    Yu-Chuen Huang

    2013-01-01

    Full Text Available Cancer stem cells (CSCs are a major cause of cancer treatment failure, relapse, and drug resistance and are known to be responsible for cancer cell invasion and metastasis. The Sonic hedgehog (Shh signaling pathway is crucial to embryonic development. Intriguingly, the aberrant activation of the Shh pathway plays critical roles in developing CSCs and leads to angiogenesis, migration, invasion, and metastasis. Natural compounds and chemical structure modified derivatives from complementary and alternative medicine have received increasing attention as cancer chemopreventives, and their antitumor effects have been demonstrated both in vitro and in vivo. However, reports for their bioactivity against CSCs and specifically targeting Shh signaling remain limited. In this review, we summarize investigations of the compounds cyclopamine, curcumin, epigallocatechin-3-gallate, genistein, resveratrol, zerumbone, norcantharidin, and arsenic trioxide, with a focus on Shh signaling blockade. Given that Shh signaling antagonism has been clinically proven as effective strategy against CSCs, this review may be exploitable for development of novel anticancer agents from complementary and alternative medicine.

  8. [Cell signaling pathways interaction in cellular proliferation: Potential target for therapeutic interventionism].

    Science.gov (United States)

    Valdespino-Gómez, Víctor Manuel; Valdespino-Castillo, Patricia Margarita; Valdespino-Castillo, Víctor Edmundo

    2015-01-01

    Nowadays, cellular physiology is best understood by analysing their interacting molecular components. Proteins are the major components of the cells. Different proteins are organised in the form of functional clusters, pathways or networks. These molecules are ordered in clusters of receptor molecules of extracellular signals, transducers, sensors and biological response effectors. The identification of these intracellular signaling pathways in different cellular types has required a long journey of experimental work. More than 300 intracellular signaling pathways have been identified in human cells. They participate in cell homeostasis processes for structural and functional maintenance. Some of them participate simultaneously or in a nearly-consecutive progression to generate a cellular phenotypic change. In this review, an analysis is performed on the main intracellular signaling pathways that take part in the cellular proliferation process, and the potential use of some components of these pathways as target for therapeutic interventionism are also underlined. Copyright © 2015 Academia Mexicana de Cirugía A.C. Published by Masson Doyma México S.A. All rights reserved.

  9. Targeting sTNF/TNFR1 Signaling as a New Therapeutic Strategy

    Directory of Open Access Journals (Sweden)

    Roman Fischer

    2015-03-01

    Full Text Available Deregulation of the tumor necrosis factor (TNF plays an important role in the initiation and perpetuation of chronic inflammation and has been implicated in the development of various autoimmune diseases. Accordingly, TNF-inhibitors are successfully used for the treatment of several diseases, such as rheumatoid arthritis, inflammatory bowel disease, and psoriasis. However, total inhibition of TNF can cause severe side effects such as an increased risk of inflammation and reactivation of tuberculosis. This is likely due to the different actions of the two TNF receptors. Whereas TNFR1 predominantly promotes inflammatory signaling pathways, TNFR2 mediates immune modulatory functions and promotes tissue homeostasis and regeneration. Therefore, the specific blockage of TNFR1 signaling, either by direct inhibition with TNFR1-selective antagonists or by targeting soluble TNF, which predominantly activates TNFR1, may prevent the detrimental effects associated with total TNF-inhibitors and constitute a next-generation approach to interfere with TNF.

  10. Low-Z internal target from a cryogenically cooled liquid microjet source

    Energy Technology Data Exchange (ETDEWEB)

    Kuehnel, M.; Petridis, N. [Institut fuer Kernphysik, J.W. Goethe-Universitaet, Max-von-Laue-Str. 1, 60438 Frankfurt (Germany); Winters, D.F.A. [GSI, Planckstr. 1, 64291 (Germany); Physikalisches Institut, Ruprecht-Karls-Universitaet, Philosophenweg 12, 69120 Heidelberg (Germany); Popp, U. [GSI, Planckstr. 1, 64291 (Germany); Doerner, R. [Institut fuer Kernphysik, J.W. Goethe-Universitaet, Max-von-Laue-Str. 1, 60438 Frankfurt a. M. (Germany); Stoehlker, Th. [GSI, Planckstr. 1, 64291 (Germany); Physikalisches Institut, Ruprecht-Karls-Universitaet, Philosophenweg 12, 69120 Heidelberg (Germany); Grisenti, R.E. [Institut fuer Kernphysik, J.W. Goethe-Universitaet, Max-von-Laue-Str. 1, 60438 Frankfurt (Germany); GSI, Planckstr. 1, 64291 (Germany)], E-mail: grisenti@atom.uni-frankfurt.de

    2009-04-21

    We carried out an extensive investigation on the production of cryogenically cooled liquid hydrogen and helium droplet beams at the experimental storage ring at GSI with the goal to achieve high area densities for these low-Z internal targets. Our results show that an area density of up to 10{sup 14}cm{sup -2} is achieved for both light gases by expanding the liquid through sub-10 {mu}m diameter nozzles. The achieved area density is comparable with the previous results for the hydrogen internal target and represents an improvement by about four orders of magnitude for the helium target.

  11. Low-Z internal target from a cryogenically cooled liquid microjet source

    International Nuclear Information System (INIS)

    Kuehnel, M.; Petridis, N.; Winters, D.F.A.; Popp, U.; Doerner, R.; Stoehlker, Th.; Grisenti, R.E.

    2009-01-01

    We carried out an extensive investigation on the production of cryogenically cooled liquid hydrogen and helium droplet beams at the experimental storage ring at GSI with the goal to achieve high area densities for these low-Z internal targets. Our results show that an area density of up to 10 14 cm -2 is achieved for both light gases by expanding the liquid through sub-10 μm diameter nozzles. The achieved area density is comparable with the previous results for the hydrogen internal target and represents an improvement by about four orders of magnitude for the helium target.

  12. Internalization of targeted quantum dots by brain capillary endothelial cells in vivo.

    Science.gov (United States)

    Paris-Robidas, Sarah; Brouard, Danny; Emond, Vincent; Parent, Martin; Calon, Frédéric

    2016-04-01

    Receptors located on brain capillary endothelial cells forming the blood-brain barrier are the target of most brain drug delivery approaches. Yet, direct subcellular evidence of vectorized transport of nanoformulations into the brain is lacking. To resolve this question, quantum dots were conjugated to monoclonal antibodies (Ri7) targeting the murine transferrin receptor. Specific transferrin receptor-mediated endocytosis of Ri7-quantum dots was first confirmed in N2A and bEnd5 cells. After intravenous injection in mice, Ri7-quantum dots exhibited a fourfold higher volume of distribution in brain tissues, compared to controls. Immunofluorescence analysis showed that Ri7-quantum dots were sequestered throughout the cerebral vasculature 30 min, 1 h, and 4 h post injection, with a decline of signal intensity after 24 h. Transmission electron microscopic studies confirmed that Ri7-quantum dots were massively internalized by brain capillary endothelial cells, averaging 37 ± 4 Ri7-quantum dots/cell 1 h after injection. Most quantum dots within brain capillary endothelial cells were observed in small vesicles (58%), with a smaller proportion detected in tubular structures or in multivesicular bodies. Parenchymal penetration of Ri7-quantum dots was extremely low and comparable to control IgG. Our results show that systemically administered Ri7-quantum dots complexes undergo extensive endocytosis by brain capillary endothelial cells and open the door for novel therapeutic approaches based on brain endothelial cell drug delivery. © The Author(s) 2015.

  13. Magnolin inhibits cell migration and invasion by targeting the ERKs/RSK2 signaling pathway

    International Nuclear Information System (INIS)

    Lee, Cheol-Jung; Lee, Mee-Hyun; Yoo, Sun-Mi; Choi, Kyung-Il; Song, Ji-Hong; Jang, Jeong-Hoon; Oh, Sei-Ryang; Ryu, Hyung-Won; Lee, Hye-Suk; Surh, Young-Joon; Cho, Yong-Yeon

    2015-01-01

    Magnolin is a natural compound abundantly found in Magnolia flos, which has been traditionally used in oriental medicine to treat headaches, nasal congestion and anti-inflammatory reactions. Our recent results have demonstrated that magnolin targets the active pockets of ERK1 and ERK2, which are important signaling molecules in cancer cell metastasis. The aim of this study is to evaluate the effects of magnolin on cell migration and to further explore the molecular mechanisms involved. Magnolin-mediated signaling inhibition was confirmed by Western blotting using RSK2 +/+ and RSK2 −/− MEFs, A549 and NCI-H1975 lung cancer cells, and by NF-κB and Cox-2 promoter luciferase reporter assays. Inhibition of cell migration by magnolin was examined by wound healing and/or Boyden Chamber assays using JB6 Cl41 and A549 human lung cancer cells. The molecular mechanisms involved in cell migration and epithelial-to-mesenchymal transition were determined by zymography, Western blotting, real-time PCR and immunocytofluorescence. Magnolin inhibited NF-κB transactivation activity by suppressing the ERKs/RSK2 signaling pathway. Moreover, magnolin abrogated the increase in EGF-induced COX-2 protein levels and wound healing. In human lung cancer cells such as A549 and NCI-H1975, which harbor constitutive active Ras and EGFR mutants, respectively, magnolin suppressed wound healing and cell invasion as seen by a Boyden chamber assay. In addition, it was observed that magnolin inhibited MMP-2 and −9 gene expression and activity. The knockdown or knockout of RSK2 in A549 lung cancer cells or MEFs revealed that magnolin targeting ERKs/RSK2 signaling suppressed epithelial-to-mesenchymal transition by modulating EMT marker proteins such as N-cadherin, E-cadherin, Snail, Vimentin and MMPs. These results demonstrate that magnolin inhibits cell migration and invasion by targeting the ERKs/RSK2 signaling pathway. The online version of this article (doi:10.1186/s12885-015-1580-7) contains

  14. MGAT1 is a novel transcriptional target of Wnt/β-catenin signaling pathway.

    Science.gov (United States)

    Akiva, Izzet; Birgül Iyison, Necla

    2018-01-08

    The Wnt/β-catenin signaling pathway is an evolutionary conserved pathway, which has important functions in vertebrate early development, axis formation, cellular proliferation and morphogenesis. Additionally, Wnt/β-catenin signaling pathway is one of the most important intracellular pathways that controls cancer progression. To date most of the identified targets of this pathway are shown to harbor tumorigenic properties. We previously showed that Mannosyl glycoprotein acetylglucosaminyl-transferase (MGAT1) enzyme is among the Wnt/β-catenin signaling putative target genes in hepatocellular carcinoma cell lines (Huh7). MGAT1 protein levels were determined by Western Blotting from Huh7 cell lines in which Wnt/β-catenin pathway was activated by means of different approaches such as LiCl treatment and mutant β-catenin overexpression. Luciferase reporter assay was used to analyze the promoter activity of MGAT1. The mRNA levels of MGAT1 were determined by quantitative real-time PCR from Huh7 cells that were treated with either Wnt agonist or GSK-3β inhibitor. Wound healing and XTT cell proliferation assays were performed in order to determine the proliferation and migration capacities of MGAT1 overexpressing stable Huh7 cells. Finally, xenograft experiments were carried out to measure the tumor formation capacities in vivo. In this study we showed that the activation of Wnt/β-catenin pathway culminates in the upregulation of MGAT1 enzyme both at transcriptional and post-transcriptional levels. We also showed that overexpression of the β-catenin gene (CTNNB1) increased the promoter activity of MGAT1. We applied a set of complementary approaches to elucidate the functional importance of MGAT1 as a vital target of Wnt/β-catenin signaling in Huh7 cells. Our analyses related to cell proliferation and migration assays showed that in comparison to the control cells, MGAT1 expressing Huh7 cells have greater proliferative and invasive capabilities. Furthermore, the

  15. Targeting dysfunctional beta-cell signaling for the potential treatment of type 1 diabetes mellitus.

    Science.gov (United States)

    Fenske, Rachel J; Kimple, Michelle E

    2018-03-01

    Since its discovery and purification by Frederick Banting in 1921, exogenous insulin has remained almost the sole therapy for type 1 diabetes mellitus. While insulin alleviates the primary dysfunction of the disease, many other aspects of the pathophysiology of type 1 diabetes mellitus are unaffected. Research aimed towards the discovery of novel type 1 diabetes mellitus therapeutics targeting different cell signaling pathways is gaining momentum. The focus of these efforts has been almost entirely on the impact of immunomodulatory drugs, particularly those that have already received FDA-approval for other autoimmune diseases. However, these drugs can often have severe side effects, while also putting already immunocompromised individuals at an increased risk for other infections. Potential therapeutic targets in the insulin-producing beta-cell have been largely ignored by the type 1 diabetes mellitus field, save the glucagon-like peptide 1 receptor. While there is preliminary evidence to support the clinical exploration of glucagon-like peptide 1 receptor-based drugs as type 1 diabetes mellitus adjuvant therapeutics, there is a vast space for other putative therapeutic targets to be explored. The alpha subunit of the heterotrimeric G z protein (Gα z ) has been shown to promote beta-cell inflammation, dysfunction, death, and failure to replicate in the context of diabetes in a number of mouse models. Genetic loss of Gα z or inhibition of the Gα z signaling pathway through dietary interventions is protective against the development of insulitis and hyperglycemia. The multifaceted effects of Gα z in regards to beta-cell health in the context of diabetes make it an ideal therapeutic target for further study. It is our belief that a low-risk, effective therapy for type 1 diabetes mellitus will involve a multidimensional approach targeting a number of regulatory systems, not the least of which is the insulin-producing beta-cell. Impact statement The expanding

  16. 2nd International Symposium on Signal Processing and Intelligent Recognition Systems

    CERN Document Server

    Bandyopadhyay, Sanghamitra; Krishnan, Sri; Li, Kuan-Ching; Mosin, Sergey; Ma, Maode

    2016-01-01

    This Edited Volume contains a selection of refereed and revised papers originally presented at the second International Symposium on Signal Processing and Intelligent Recognition Systems (SIRS-2015), December 16-19, 2015, Trivandrum, India. The program committee received 175 submissions. Each paper was peer reviewed by at least three or more independent referees of the program committee and the 59 papers were finally selected. The papers offer stimulating insights into biometrics, digital watermarking, recognition systems, image and video processing, signal and speech processing, pattern recognition, machine learning and knowledge-based systems. The book is directed to the researchers and scientists engaged in various field of signal processing and related areas. .

  17. Rapamycin and Glucose-Target of Rapamycin (TOR) Protein Signaling in Plants*

    Science.gov (United States)

    Xiong, Yan; Sheen, Jen

    2012-01-01

    Target of rapamycin (TOR) kinase is an evolutionarily conserved master regulator that integrates energy, nutrients, growth factors, and stress signals to promote survival and growth in all eukaryotes. The reported land plant resistance to rapamycin and the embryo lethality of the Arabidopsis tor mutants have hindered functional dissection of TOR signaling in plants. We developed sensitive cellular and seedling assays to monitor endogenous Arabidopsis TOR activity based on its conserved S6 kinase (S6K) phosphorylation. Surprisingly, rapamycin effectively inhibits Arabidopsis TOR-S6K1 signaling and retards glucose-mediated root and leaf growth, mimicking estradiol-inducible tor mutants. Rapamycin inhibition is relieved in transgenic plants deficient in Arabidopsis FK506-binding protein 12 (FKP12), whereas FKP12 overexpression dramatically enhances rapamycin sensitivity. The role of Arabidopsis FKP12 is highly specific as overexpression of seven closely related FKP proteins fails to increase rapamycin sensitivity. Rapamycin exerts TOR inhibition by inducing direct interaction between the TOR-FRB (FKP-rapamycin binding) domain and FKP12 in plant cells. We suggest that variable endogenous FKP12 protein levels may underlie the molecular explanation for longstanding enigmatic observations on inconsistent rapamycin resistance in plants and in various mammalian cell lines or diverse animal cell types. Integrative analyses with rapamycin and conditional tor and fkp12 mutants also reveal a central role of glucose-TOR signaling in root hair formation. Our studies demonstrate the power of chemical genetic approaches in the discovery of previously unknown and pivotal functions of glucose-TOR signaling in governing the growth of cotyledons, true leaves, petioles, and primary and secondary roots and root hairs. PMID:22134914

  18. Target-assistant Zn2+-dependent DNAzyme for signal-on electrochemiluminescent biosensing

    International Nuclear Information System (INIS)

    Huang, Yin; Lei, Jianping; Cheng, Yan; Ju, Huangxian

    2015-01-01

    Highlights: • The sensing strategy is based on cleavage reaction of target-assistant Zn 2+ -dependent DNAzyme. • A dual quenching mechanism of ECL is identified. • A sensitive and selective ECL sensor is constructed for detection of ATP. • The biosensor can detect ATP in serum samples with good accuracy. - Abstract: A signal-on electrochemiluminescent (ECL) approach for ultrasensitive ATP detection was developed using target-assistant Zn 2+ -dependent DNAzyme via a dual quenching pathway between quantum dots (QDs) and Au nanoclusters (Au NCs). The facile ECL biosensor was constructed by covalent assembly of Au NCs-labeled hairpin DNA on QDs modified glassy carbon electrode. A dual quenching ECL mechanism was identified to be via resonance energy transfer between QDs and Au NCs and electrocatalytic reduction of coreactant oxygen by Au NCs. With the assistance of two help DNAs, the G-quadruplex structure of ATP aptamer was formed, and thus narrowed the two fragments of Zn 2+ -dependent DNAzyme. In the presence of Zn 2+ , Zn 2+ -dependent DNAzyme can be generated in situ on the biosensor's surface. The as-prepared DNAzyme can cleave the substrate strand, and release the Au NCs from the electrode, resulting in the signal-on ECL state. This biosensor showed good analytical performance with 4 orders magnitude linear range, excellent specificity, and acceptable stability. The biosensor had been applied in detection of ATP in real serum sample and provided significant potential application in clinical analysis

  19. Targeting loss of the Hippo signaling pathway in NF2-deficient papillary kidney cancers

    Science.gov (United States)

    Ricketts, Christopher J.; Wei, Darmood; Yang, Youfeng; Baranes, Sarah M.; Gibbs, Benjamin K.; Ohanjanian, Lernik; Spencer Krane, L.; Scroggins, Bradley T.; Keith Killian, J.; Wei, Ming-Hui; Kijima, Toshiki; Meltzer, Paul S.; Citrin, Deborah E.; Neckers, Len; Vocke, Cathy D.; Marston Linehan, W.

    2018-01-01

    Papillary renal cell carcinomas (PRCC) are a histologically and genetically heterogeneous group of tumors that represent 15–20% of all kidney neoplasms and may require diverse therapeutic approaches. Alteration of the NF2 tumor suppressor gene, encoding a key regulator of the Hippo signaling pathway, is observed in 22.5% of PRCC. The Hippo signaling pathway controls cell proliferation by regulating the transcriptional activity of Yes-Associated Protein, YAP1. Loss of NF2 results in aberrant YAP1 activation. The Src family kinase member Yes also regulates YAP1 transcriptional activity. This study investigated the importance of YAP and Yes activity in three NF2-deficient PRCC cell lines. NF2-deficency correlated with increased expression of YAP1 transcriptional targets and siRNA-based knockdown of YAP1 and Yes1 downregulated this pathway and dramatically reduced cell viability. Dasatinib and saracatinib have potent inhibitory effects on Yes and treatment with either resulted in downregulation of YAP1 transcription targets, reduced cell viability, and G0-G1 cell cycle arrest. Xenograft models for NF2-deficient PRCC also demonstrated reduced tumor growth in response to dasatinib. Thus, inhibiting Yes and the subsequent transcriptional activity of YAP1 had a substantial anti-tumor cell effect both in vitro and in vivo and may provide a viable therapeutic approach for patients with NF2-deficient PRCC. PMID:29535838

  20. Investigations of internal noise levels for different target sizes, contrasts, and noise structures

    Science.gov (United States)

    Han, Minah; Choi, Shinkook; Baek, Jongduk

    2014-03-01

    To describe internal noise levels for different target sizes, contrasts, and noise structures, Gaussian targets with four different sizes (i.e., standard deviation of 2,4,6 and 8) and three different noise structures(i.e., white, low-pass, and highpass) were generated. The generated noise images were scaled to have standard deviation of 0.15. For each noise type, target contrasts were adjusted to have the same detectability based on NPW, and the detectability of CHO was calculated accordingly. For human observer study, 3 trained observers performed 2AFC detection tasks, and correction rate, Pc, was calculated for each task. By adding proper internal noise level to numerical observer (i.e., NPW and CHO), detectability of human observer was matched with that of numerical observers. Even though target contrasts were adjusted to have the same detectability of NPW observer, detectability of human observer decreases as the target size increases. The internal noise level varies for different target sizes, contrasts, and noise structures, demonstrating different internal noise levels should be considered in numerical observer to predict the detection performance of human observer.

  1. New Challenges in Targeting Signaling Pathways in Acute Lymphoblastic Leukemia by NGS Approaches: An Update

    Science.gov (United States)

    Hernández-Rivas, Jesús María

    2018-01-01

    The identification and study of genetic alterations involved in various signaling pathways associated with the pathogenesis of acute lymphoblastic leukemia (ALL) and the application of recent next-generation sequencing (NGS) in the identification of these lesions not only broaden our understanding of the involvement of various genetic alterations in the pathogenesis of the disease but also identify new therapeutic targets for future clinical trials. The present review describes the main deletions, amplifications, sequence mutations, epigenetic lesions, and new structural DNA rearrangements detected by NGS in B-ALL and T-ALL and their clinical importance for therapeutic procedures. We reviewed the molecular basis of pathways including transcriptional regulation, lymphoid differentiation and development, TP53 and the cell cycle, RAS signaling, JAK/STAT, NOTCH, PI3K/AKT/mTOR, Wnt/β-catenin signaling, chromatin structure modifiers, and epigenetic regulators. The implementation of NGS strategies has enabled important mutated genes in each pathway, their associations with the genetic subtypes of ALL, and their outcomes, which will be described further. We also discuss classic and new cryptic DNA rearrangements in ALL identified by mRNA-seq strategies. Novel cooperative abnormalities in ALL could be key prognostic and/or predictive biomarkers for selecting the best frontline treatment and for developing therapies after the first relapse or refractory disease. PMID:29642462

  2. Monoglyceride lipase as a drug target: At the crossroads of arachidonic acid metabolism and endocannabinoid signaling.

    Science.gov (United States)

    Grabner, Gernot F; Zimmermann, Robert; Schicho, Rudolf; Taschler, Ulrike

    2017-07-01

    Monoglyerides (MGs) are short-lived, intermediary lipids deriving from the degradation of phospho- and neutral lipids, and monoglyceride lipase (MGL), also designated as monoacylglycerol lipase (MAGL), is the major enzyme catalyzing the hydrolysis of MGs into glycerol and fatty acids. This distinct function enables MGL to regulate a number of physiological and pathophysiological processes since both MGs and fatty acids can act as signaling lipids or precursors thereof. The most prominent MG species acting as signaling lipid is 2-arachidonoyl glycerol (2-AG) which is the most abundant endogenous agonist of cannabinoid receptors in the body. Importantly, recent observations demonstrate that 2-AG represents a quantitatively important source for arachidonic acid, the precursor of prostaglandins and other inflammatory mediators. Accordingly, MGL-mediated 2-AG degradation affects lipid signaling by cannabinoid receptor-dependent and independent mechanisms. Recent genetic and pharmacological studies gave important insights into MGL's role in (patho-)physiological processes, and the enzyme is now considered as a promising drug target for a number of disorders including cancer, neurodegenerative and inflammatory diseases. This review summarizes the basics of MG (2-AG) metabolism and provides an overview on the therapeutic potential of MGL. Copyright © 2017 Elsevier Inc. All rights reserved.

  3. Targeting of macrophage galactose-type C-type lectin (MGL) induces DC signaling and activation

    DEFF Research Database (Denmark)

    Napoletano, Chiara; Zizzari, Ilaria G; Rughetti, Aurelia

    2012-01-01

    NAc or Tn)-carrying tumor-associated antigens to improve DC performance. MGL expressed by ex vivo-generated iDCs from healthy donors was engaged by a 60-mer MUC1(9Tn) -glycopeptide as a Tn-carrying tumor-associated antigen, and an anti-MGL antibody, as a specific MGL binder. We demonstrated that MGL......Dendritic cells (DCs) sense the microenvironment through several types of receptors recognizing pathogen-associated molecular patterns. In particular, C-type lectins, expressed by distinct subsets of DCs, recognize and internalize specific carbohydrate antigen in a Ca(2+) -dependent manner....... Targeting of these receptors is becoming an efficient strategy of delivering antigens in DC-based anticancer immunotherapy. Here we investigated the role of the macrophage galactose type C-lectin receptor (MGL), expressed by immature DCs (iDCs), as a molecular target for a-N-acetylgalactosamine (Gal...

  4. Myeloproliferative neoplasms: JAK2 signaling pathway as a central target for therapy.

    Science.gov (United States)

    Pasquier, Florence; Cabagnols, Xenia; Secardin, Lise; Plo, Isabelle; Vainchenker, William

    2014-09-01

    The discovery of the JAK2V617F mutation followed by the discovery of other genetic abnormalities allowed important progress in the understanding of the pathogenesis and management of myeloproliferative neoplasms (MPN)s. Classical Breakpoint cluster region-Abelson (BCR-ABL)-negative neoplasms include 3 main disorders: essential thrombocythemia (ET), polycythemia vera (PV), and primary myelofibrosis (PMF). Genomic studies have shown that these disorders are more heterogeneous than previously thought with 3 main entities corresponding to different gene mutations: the JAK2 disorder, essentially due to JAK2V617F mutation, which includes nearly all PVs and a majority of ETs and PMFs with a continuum between these diseases and the myeloproliferative leukemia (MPL) and calreticulin (CALR) disorders, which include a fraction of ET and PMF. All of these mutations lead to a JAK2 constitutive activation. Murine models either with JAK2V617F or MPLW515L, but also with JAK2 or MPL germ line mutations found in hereditary thrombocytosis, have demonstrated that they are drivers of myeloproliferation. However, the myeloproliferative driver mutation is still unknown in approximately 15% of ET and PMF, but appears to also target the JAK/Signal Transducer and Activator of Transcription (STAT) pathway. However, other mutations in genes involved in epigenetics or splicing also can be present and can predate or follow mutations in signaling. They are involved either in clonal dominance or in phenotypic changes, more particularly in PMF. They can be associated with leukemic progression and might have an important prognostic value such as additional sex comb-like 1 mutations. Despite this heterogeneity, it is tempting to target JAK2 and its signaling for therapy. However in PMF, Adenosine Tri-Phosphate (ATP)-competitive JAK2 inhibitors have shown their interest, but also their important limitations. Thus, other approaches are required, which are discussed in this review. Copyright © 2014

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

    Science.gov (United States)

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

    2015-01-01

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

  6. Arcing and rf signal generation during target irradiation by a high-energy, pulsed neutral particle beam

    International Nuclear Information System (INIS)

    Robiscoe, R.T.

    1988-02-01

    We present a theory describing the dynamics of arc discharges in bulk dielectric materials on board space-based vehicles. Such ''punch-through'' arcs can occur in target satellites irradiated by high-energy (250 MeV), pulsed (100 mA x 10 ms) neutral particle beams. We treat the arc as a capacitively limited avalanche current in the target dielectric material, and we find expressions for the arc duration, charge transport, currents, and discharge energy. These quantities are adjusted to be consistent with known scaling laws for the area of charge depleted by the arc. After a brief account of the statistical distribution of voltages at which the arc starts and stops, we calculate the signal strength and frequency spectrum of the electromagnetic radiation broadcast by the arc. We find that arcs from thick (/similar to/1 cm) targets can generate rf signals detectable up to 1000 km from the target, bu a radio receiver operating at frequency 80 MHz, bandwidth 100 kHz, and detection threshold -105 dBm. These thick-target arc signals are 10 to 20 dB above ambient noise at the receiver, and they provide target hit assessment if the signal spectrum can be sampled at several frequencies in the nominal range 30-200 MHz. Thin-target (/similar to/1 mm) arc signals are much weaker, but when they are detecable in conjunction with thick-target signals, target discrimination is possible by comparing the signal frequency spectra. 24 refs., 12 figs

  7. 12th International Conference on Intelligent Information Hiding and Multimedia Signal Processing

    CERN Document Server

    Tsai, Pei-Wei; Huang, Hsiang-Cheh

    2017-01-01

    This volume of Smart Innovation, Systems and Technologies contains accepted papers presented in IIH-MSP-2016, the 12th International Conference on Intelligent Information Hiding and Multimedia Signal Processing. The conference this year was technically co-sponsored by Tainan Chapter of IEEE Signal Processing Society, Fujian University of Technology, Chaoyang University of Technology, Taiwan Association for Web Intelligence Consortium, Fujian Provincial Key Laboratory of Big Data Mining and Applications (Fujian University of Technology), and Harbin Institute of Technology Shenzhen Graduate School. IIH-MSP 2016 is held in 21-23, November, 2016 in Kaohsiung, Taiwan. The conference is an international forum for the researchers and professionals in all areas of information hiding and multimedia signal processing. .

  8. Target of rapamycin signalling mediates the lifespan-extending effects of dietary restriction by essential amino acid alteration

    NARCIS (Netherlands)

    Emran, S.; Yang, M.Y.; He, X.L.; Zandveld, J.; Piper, M.D.W.

    2014-01-01

    Dietary restriction (DR), defined as a moderate reduction in food intake short of malnutrition, has been shown to extend healthy lifespan in a diverse range of organisms, from yeast to primates. Reduced signalling through the insulin/IGF-like (IIS) and Target of Rapamycin (TOR) signalling pathways

  9. Antisense Oligonucleotides Internally Labeled with Peptides Show Improved Target Recognition and Stability to Enzymatic Degradation

    DEFF Research Database (Denmark)

    Taskova, Maria; Madsen, Charlotte S.; Jensen, Knud J.

    2017-01-01

    Specific target binding and stability in diverse biological media is of crucial importance for applications of synthetic oligonucleotides as diagnostic and therapeutic tools. So far, these issues have been addressed by chemical modification of oligonucleotides and by conjugation with a peptide, m...... and makes internally labeled POCs an exciting object of study, i.e., showing high target specificity and simultaneous stability in biological media.......Specific target binding and stability in diverse biological media is of crucial importance for applications of synthetic oligonucleotides as diagnostic and therapeutic tools. So far, these issues have been addressed by chemical modification of oligonucleotides and by conjugation with a peptide......, most often at the terminal position of the oligonucleotide. Herein, we for the first time systematically investigate the influence of internally attached short peptides on the properties of antisense oligonucleotides. We report the synthesis and internal double labeling of 21-mer oligonucleotides...

  10. Motion-specific internal target volumes for FDG-avid mediastinal and hilar lymph nodes

    International Nuclear Information System (INIS)

    Lamb, James M.; Robinson, Clifford G.; Bradley, Jeffrey D.; Low, Daniel A.

    2013-01-01

    Background and purpose: To quantify the benefit of motion-specific internal target volumes for FDG-avid mediastinal and hilar lymph nodes generated using 4D-PET, vs. conventional internal target volumes generated using non-respiratory gated PET and 4D-CT scans. Materials and methods: Five patients with FDG-avid tumors metastatic to 11 hilar or mediastinal lymph nodes were imaged with respiratory-correlated FDG-PET (4D-PET) and 4D-CT. FDG-avid nodes were contoured by a radiation oncologist in two ways. Standard-of-care volumes were contoured using conventional un-gated PET, 4D-CT, and breath-hold CT. A second, motion-specific, set of volumes were contoured using 4D-PET.Contours based on 4D-PET corresponded directly to an internal target volume (ITV 4D ), whereas contours based on un-gated PET were expanded by a series of exploratory isotropic margins (from 5 to 13 mm) based on literature recommendations on lymph node motion to form internal target volumes (ITV 3D ). Results: A 13 mm expansion of the un-gated PET nodal volume was needed to cover the ITV 4D for 10 of 11 nodes studied. The ITV 3D based on a 13 mm expansion included on average 45 cm 3 of tissue that was not included in the ITV 4D . Conclusions: Motion-specific lymph-node internal target volumes generated from 4D-PET imaging could be used to improve accuracy and/or reduce normal-tissue irradiation compared to the standard-of-care un-gated PET based internal target volumes

  11. Commissioning experiment of the polarized internal gas target with deuterium at ANKE/COSY

    Energy Technology Data Exchange (ETDEWEB)

    Gou, Boxing [Institut fuer Kernphysik, Forschungszentrum Juelich (Germany); Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou (China); Collaboration: ANKE-Collaboration

    2012-07-01

    In order to conduct the production experiments with polarized deuterium target and (un)polarized proton beam at ANKE/COSY, a commissioning experiment of the polarized internal target with deuterium is imperative. The commissioning experiment includes the measurements of both the vector (Q{sub y}) and tensor (Q{sub yy}) polarization of the deuterium gas target through the nuclear reactions with large and well known analyzing powers, which can be detected in ANKE. The dependence of the polarizations along the storage cell is also determined. The poster presents the physics case for the experiments with deuterium polarized internal target and the apparatus needed for the commissioning experiment, as well as the procedure of extraction for spin observables.

  12. A highly polarized hydrogen/deuterium internal gas target embedded in a toroidal magnetic spectrometer

    International Nuclear Information System (INIS)

    Cheever, D.; Ihloff, E.; Kelsey, J.; Kolster, H.; Meitanis, N.; Milner, R.; Shinozaki, A.; Tsentalovich, E.; Zwart, T.; Ziskin, V.; Xiao, Y.; Zhang, C.

    2006-01-01

    A polarized hydrogen/deuterium internal gas target has been constructed and operated at the internal target region of the South Hall Ring (SHR) of the MIT-Bates Linear Accelerator Center to carry out measurements of spin-dependent electron scattering at 850MeV. The target used an Atomic Beam Source (ABS) to inject a flux of highly polarized atoms into a thin-walled, coated storage cell. The polarization of the electron beam was determined using a Compton laser backscattering polarimeter. The target polarization was determined using well-known nuclear reactions. The ABS and storage cell were embedded in the Bates Large Acceptance Toroidal Spectrometer (BLAST), which was used to detect scattered particles from the electron-target interactions. The target has been designed to rapidly (∼8h) switch operation from hydrogen to deuterium. Further, this target was the first to be operated inside a magnetic spectrometer in the presence of a magnetic field exceeding 2kG. An ABS intensity 2.5x10 16 at/s and a high polarization (∼70%) inside the storage cell have been achieved. The details of the target design and construction are described here and the performance over an 18 month period is reported

  13. Enhanced targeting of triple-negative breast carcinoma and malignant melanoma by photochemical internalization of CSPG4-targeting immunotoxins.

    Science.gov (United States)

    Eng, M S; Kaur, J; Prasmickaite, L; Engesæter, B Ø; Weyergang, A; Skarpen, E; Berg, K; Rosenblum, M G; Mælandsmo, G M; Høgset, A; Ferrone, S; Selbo, P K

    2018-05-16

    Triple-negative breast cancer (TNBC) and malignant melanoma are highly aggressive cancers that widely express the cell surface chondroitin sulfate proteoglycan 4 (CSPG4/NG2). CSPG4 plays an important role in tumor cell growth and survival and promotes chemo- and radiotherapy resistance, suggesting that CSPG4 is an attractive target in cancer therapy. In the present work, we applied the drug delivery technology photochemical internalization (PCI) in combination with the novel CSPG4-targeting immunotoxin 225.28-saporin as an efficient and specific strategy to kill aggressive TNBC and amelanotic melanoma cells. Light-activation of the clinically relevant photosensitizer TPCS2a (fimaporfin) and 225.28-saporin was found to act in a synergistic manner, and was superior to both PCI of saporin and PCI-no-drug (TPCS2a + light only) in three TNBC cell lines (MDA-MB-231, MDA-MB-435 and SUM149) and two BRAFV600E mutated malignant melanoma cell lines (Melmet 1 and Melmet 5). The cytotoxic effect was highly dependent on the light dose and expression of CSPG4 since no enhanced cytotoxicity of PCI of 225.28-saporin compared to PCI of saporin was observed in the CSPG4-negative MCF-7 cells. The PCI of a smaller, and clinically relevant CSPG4-targeting toxin (scFvMEL-rGel) validated the CSPG4-targeting concept in vitro and induced a strong inhibition of tumor growth in the amelanotic melanoma xenograft A-375 model. In conclusion, the combination of the drug delivery technology PCI and CSPG4-targeting immunotoxins is an efficient, specific and light-controlled strategy for the elimination of aggressive cells of TNBC and malignant melanoma origin. This study lays the foundation for further preclinical evaluation of PCI in combination with CSPG4-targeting.

  14. Internal combustion engine run on biogas is a potential solution to meet Indonesia emission target

    Science.gov (United States)

    Ambarita, Himsar

    2017-09-01

    Indonesia has released two different Greenhouse Gas (GHG) emissions reduction targets. The first target, released in 2009, is reduction GHG emissions 26% from Business-as-Usual (BAU) level using own budget and up 41% if supported international aids by 2020. The second target is reduction 29% and 41% from BAU by 2030 using own budget and with international support, respectively. In this paper, the BAU emissions and emissions reduction target of these two targets are elaborated. In addition, the characteristics of emissions from transportation sector are discussed. One of the potential mitigation actions is switching fuel in transportation sector. The results the most promising mitigation action in the transportation is switching oil fuel with biofuel. The Government of Indonesia (GoI) focuses on using biodiesel and bioethanol to run internal combustion engine in transportation sector and biogas is aimed to fuel power plant unit. However, there is very limited of success stories on using biogas in the power plant. The barriers and challenges will be discussed here. It is suggested to run internal combustion engine with biogas.

  15. Signal and data processing of small targets 1992; Proceedings of the Meeting, Orlando, FL, Apr. 20-22, 1992

    Science.gov (United States)

    Drummond, Oliver E.

    This volume on signal and data processing of small targets contains chapters devoted to signal processing, low observable detection, systems and simulations, association and filtering in tracking, multiple sensor processing and fusion, and data processing. Papers included are on multisensor predetection fusion, adaptive whitening filters for small target detection, unified framework for IR target detection and tracking, and target detection from image sequences using pixel-based decision criterion. Attention is also given to automatic acquisition and tracking of rounds and targets for electrooptic fire control, advanced surveillance testbed and background modeling, an interacting-multiple-model algorithm for tracking targets that maneuver through coordinated turns, and angular momentum and ballistic tracking. Other papers are on a data integration (fusion) tree paradigm, single-scan tracking using N IR sensors, and track monitoring with single and multiple 2D passive sensors. (No individual items are abstracted in this volume)

  16. Molecular Pathways: Cachexia Signaling-A Targeted Approach to Cancer Treatment.

    Science.gov (United States)

    Miyamoto, Yuji; Hanna, Diana L; Zhang, Wu; Baba, Hideo; Lenz, Heinz-Josef

    2016-08-15

    Cancer cachexia is a multifactorial syndrome characterized by an ongoing loss of skeletal muscle mass, which negatively affects quality of life and portends a poor prognosis. Numerous molecular substrates and mechanisms underlie the dysregulation of skeletal muscle synthesis and degradation observed in cancer cachexia, including proinflammatory cytokines (TNFα, IL1, and IL6), and the NF-κB, IGF1/AKT/mTOR, and myostatin/activin-SMAD pathways. Recent preclinical and clinical studies have demonstrated that anti-cachexia drugs (such as MABp1 and soluble receptor antagonist of myostatin/activin) not only prevent muscle wasting but also may prolong overall survival. In this review, we focus on the significance of cachexia signaling in patients with cancer and highlight promising drugs targeting tumor cachexia in clinical development. Clin Cancer Res; 22(16); 3999-4004. ©2016 AACR. ©2016 American Association for Cancer Research.

  17. Bmi-1-targeting suppresses osteosarcoma aggressiveness through the NF-κB signaling pathway

    Science.gov (United States)

    Liu, Jiaguo; Luo, Bin; Zhao, Meng

    2017-01-01

    Bone cancer is one of the most lethal malignancies and the specific causes of tumor initiation are not well understood. B-cell-specific Moloney murine leukemia virus integration site 1 protein (Bmi-1) has been reported to be associated with the initiation and progression of osteosarcoma, and as a prognostic indicator in the clinic. In the current study, a full-length antibody targeting Bmi-1 (AbBmi-1) was produced and the preclinical value of Bmi-1-targeted therapy was evaluated in bone carcinoma cells and tumor xenograft mice. The results indicated that the Bmi-1 expression level was markedly upregulated in bone cancer cell lines, and inhibition of Bmi-1 by AbBmi-1 reduced the invasiveness and migration of osteosarcoma cells. Overexpression of Bmi-1 promoted proliferation and angiogenesis, and increased apoptosis resistance induced by cisplatin via the nuclear factor-κB (NF-κB) signal pathway. In addition, AbBmi-1 treatment inhibited the tumorigenicity of osteosarcoma cells in vivo. Furthermore, AbBmi-1 blocked NF-κB signaling and reduced MMP-9 expression. Furthermore, Bmi-1 promoted osteosarcoma tumor growth, whereas AbBmi-1 significantly inhibited osteosarcoma tumor growth in vitro and in vivo. Notably, AbBmi-1 decreased the percentages of Ki67-positive cells and terminal deoxynucleotidyl transferase dUTP nick end labeling-positive cells in tumors compared with Bmi-1-treated and PBS controls. Notably, MMP-9 and NF-κB expression were downregulated by treatment with AbBmi-1 in MG-63 osteosarcoma cells. In conclusion, the data provides evidence that AbBmi-1 inhibited the progression of osteosarcoma, suggesting that AbBmi-1 may be a novel anti-cancer agent through the inhibition of Bmi-1 via activating the NF-κB pathway in osteosarcoma. PMID:28983587

  18. Andrographolide suppresses TRIF-dependent signaling of toll-like receptors by targeting TBK1.

    Science.gov (United States)

    Kim, Ah-Yeon; Shim, Hyun-Jin; Shin, Hyeon-Myeong; Lee, Yoo Jung; Nam, Hyeonjeong; Kim, Su Yeon; Youn, Hyung-Sun

    2018-04-01

    Toll-like receptors (TLRs) play a crucial role in danger recognition and induction of innate immune response against bacterial and viral infections. The TLR adaptor molecule, toll-interleukin-1 receptor domain-containing adapter inducing interferon-β (TRIF), facilitates TLR3 and TLR4 signaling, leading to the activation of the transcription factor, NF-κB and interferon regulatory factor 3 (IRF3). Andrographolide, the active component of Andrographis paniculata, exerts anti-inflammatory effects; however, the principal molecular mechanisms remain unclear. The objective of this study was to investigate the role of andrographolide in TLR signaling pathways. Andrographolide suppressed NF-κB activation as well as COX-2 expression induced by TLR3 or TLR4 agonists. Andrographolide also suppressed the activation of IRF3 and the expression of interferon inducible protein-10 (IP-10) induced by TLR3 or TLR4 agonists. Andrographolide attenuated ligand-independent activation of IRF3 following overexpression of TRIF, TBK1, or IRF3. Furthermore, andrographolide inhibited TBK1 kinase activity in vitro. These results indicate that andrographolide modulates the TRIF-dependent pathway of TLRs by targeting TBK1 and represents a potential new anti-inflammatory candidate. Copyright © 2018 Elsevier B.V. All rights reserved.

  19. Quorum sensing communication between bacteria and human cells: signals, targets and functions

    Directory of Open Access Journals (Sweden)

    Angelika eHolm

    2014-06-01

    Full Text Available Both direct and long-range interactions between pathogenic Pseudomonas aeruginosa bacteria and their eukaryotic hosts are important in the outcome of infections. For cell-to-cell communication, these bacteria employ the quorum sensing (QS system to pass on information of the density of the bacterial population and collectively switch on virulence factor production, biofilm formation and resistance development. Thus, QS allows bacteria to behave as a community to perform tasks which would be impossible for individual cells, e.g. to overcome defense and immune systems and establish infections in higher organisms. This review highlights these aspects of QS and our own recent research on how P.aeruginosa communicates with human cells using the small QS signal molecules N-acyl homoserine lactones (AHL. We focus on how this conversation changes the behavior and function of neutrophils, macrophages and epithelial cells and on how the signaling machinery in human cells responsible for the recognition of AHL. Understanding the bacteria-host relationships at both cellular and molecular levels is essential for the identification of new targets and for the development of novel strategies to fight bacterial infections in the future.

  20. ATP as a Multi-target Danger Signal in the Brain

    Directory of Open Access Journals (Sweden)

    Ricardo J Rodrigues

    2015-04-01

    Full Text Available ATP is released in an activity-dependent manner from different cell types in the brain, fulfilling different roles as a neurotransmitter, neuromodulator, astrocyte-to-neuron communication, propagating astrocytic responses and formatting microglia responses. This involves the activation of different ATP P2 receptors (P2R as well as adenosine receptors upon extracellular ATP catabolism by ecto-nucleotidases. Notably, brain noxious stimuli trigger a sustained increase of extracellular ATP, which plays a key role as danger signal in the brain. This involves a combined action of extracellular ATP in different cell types, namely increasing the susceptibility of neurons to damage, promoting astrogliosis and recruiting and formatting microglia to mount neuroinflammatory responses. Such actions involve the activation of different receptors, as heralded by neuroprotective effects resulting from blockade mainly of P2X7R, P2Y1R and adenosine A2A receptors (A2AR, which hierarchy, cooperation and/or redundancy is still not resolved. These pleiotropic functions of ATP as a danger signal in brain damage prompt a therapeutic interest to multi-target different purinergic receptors to provide maximal opportunities for neuroprotection.

  1. Therapeutic Targeting of Redox Signaling in Myofibroblast Differentiation and Age-Related Fibrotic Disease

    Directory of Open Access Journals (Sweden)

    Natalie Sampson

    2012-01-01

    Full Text Available Myofibroblast activation plays a central role during normal wound healing. Whereas insufficient myofibroblast activation impairs wound healing, excessive myofibroblast activation promotes fibrosis in diverse tissues (including benign prostatic hyperplasia, BPH leading to organ dysfunction and also promotes a stromal response that supports tumor progression. The incidence of impaired wound healing, tissue fibrosis, BPH, and certain cancers strongly increases with age. This paper summarizes findings from in vitro fibroblast-to-myofibroblast differentiation systems that serve as cellular models to study fibrogenesis of diverse tissues. Supported by substantial in vivo data, a large body of evidence indicates that myofibroblast differentiation induced by the profibrotic cytokine transforming growth factor beta is driven by a prooxidant shift in redox homeostasis due to elevated production of NADPH oxidase 4 (NOX4-derived hydrogen peroxide and supported by concomitant decreases in nitric oxide/cGMP signaling and reactive oxygen species (ROS scavenging enzymes. Fibroblast-to-myofibroblast differentiation can be inhibited and reversed by restoring redox homeostasis using antioxidants or NOX4 inactivation as well as enhancing nitric oxide/cGMP signaling via activation of soluble guanylyl cyclases or inhibition of phosphodiesterases. Current evidence indicates the therapeutic potential of targeting the prooxidant shift in redox homeostasis for the treatment of age-related diseases associated with myofibroblast dysregulation.

  2. Pengaruh Pengendalian Intern Terhadap Efektivitas Target Produksi PT. Lucas Djaja Pharmaceutical Industry Bandung Jawa Barat

    Directory of Open Access Journals (Sweden)

    Bulan Tati Fitria

    2013-04-01

    Full Text Available The achievement of operational targets is expected by each organization / company. Due to the achievement of the target, it can be judged that the performance of the company very well. Therefore, if it is not achieved it is necessary to study the factors that influence it. For then do repairs on these factors. In the achievement of the target company, it takes a process associated with the target to be achieved. In order to achieve maximum results and effective it is necessary to an adequate internal control structure, which aims to regulate the operational steps the company to run an organized and effective.The study was conducted at PT. Lucas Djaja Pharmaceutical Industry, located in Bandung, is to know how the implementation of internal controls and how they affect the effectiveness of the production targets, in particular the production of injection of 1 (one milliliter. This research used descriptive analysis with research techniques such as interviews, observations, questionnaires and literature study. Based on the results of this study concluded that the implementation of internal control at PT. Lucas Djaja is sufficient, this can be seen from the data obtained from the questionnaire filled out by the respondents, which is related to the control environment, risk assessment, information and communication, control activities, and monitoring. Meanwhile that of the effectiveness of the production target is still this can be seen from the data obtained from the questionnaire filled out by the respondents, ranging from productivity, quality, efficiency, flexibility, excellence, development, and satisfaction. And the obtained results of the research stating that the internal control effect on effectiveness production targets with determination coefficient of 56.01% and the remaining 43.99% influenced by other factors.

  3. 9th International Conference on Robotics, Vision, Signal Processing & Power Applications

    CERN Document Server

    Iqbal, Shahid; Teoh, Soo; Mustaffa, Mohd

    2017-01-01

     The proceeding is a collection of research papers presented, at the 9th International Conference on Robotics, Vision, Signal Processing & Power Applications (ROVISP 2016), by researchers, scientists, engineers, academicians as well as industrial professionals from all around the globe to present their research results and development activities for oral or poster presentations. The topics of interest are as follows but are not limited to:   • Robotics, Control, Mechatronics and Automation • Vision, Image, and Signal Processing • Artificial Intelligence and Computer Applications • Electronic Design and Applications • Telecommunication Systems and Applications • Power System and Industrial Applications • Engineering Education.

  4. 8th International Conference on Robotic, Vision, Signal Processing & Power Applications

    CERN Document Server

    Mustaffa, Mohd

    2014-01-01

    The proceeding is a collection of research papers presented, at the 8th International Conference on Robotics, Vision, Signal Processing and Power Applications (ROVISP 2013), by researchers, scientists, engineers, academicians as well as industrial professionals from all around the globe. The topics of interest are as follows but are not limited to: • Robotics, Control, Mechatronics and Automation • Vision, Image, and Signal Processing • Artificial Intelligence and Computer Applications • Electronic Design and Applications • Telecommunication Systems and Applications • Power System and Industrial Applications  

  5. Targeting Glutamatergic Signaling and the PI3 Kinase Pathway to Halt Melanoma Progression

    Directory of Open Access Journals (Sweden)

    Stephen A. Rosenberg

    2015-02-01

    Full Text Available Our group has previously reported that the majority of human melanomas (>60% express the metabotropic glutamate receptor 1 (GRM1 and that the glutamate release inhibitor riluzole, a drug currently used to treat amyotrophic lateral sclerosis, can induce apoptosis in GRM1-expressing melanoma cells. Our group previously reported that in vitro riluzole treatment reduces cell growth in three-dimensional (3D soft agar colony assays by 80% in cells with wildtype phosphoinositide 3-kinase (PI3K pathway activation. However, melanoma cell lines harboring constitutive activating mutations of the PI3K pathway (PTEN and NRAS mutations showed only a 35% to 40% decrease in colony formation in soft agar in the presence of riluzole. In this study, we have continued our preclinical studies of riluzole and its effect on melanoma cells alone and in combination with inhibitors of the PI3 kinase pathway: the AKT inhibitor, API-2, and the mammalian target of rapamycin (mTOR inhibitor, rapamycin. We modeled these combinatorial therapies on various melanoma cell lines in 3D and 2D systems and in vivo. Riluzole combined with mTOR inhibition is more effective at halting melanoma anchorage-independent growth and xenograft tumor progression than either agent alone. PI3K signaling changes associated with this combinatorial treatment shows that 3D (nanoculture modeling of cell signaling more closely resembles in vivo signaling than monolayer models. Riluzole combined with mTOR inhibition is effective at halting tumor cell progression independent of BRAF mutational status. This makes this combinatorial therapy a potentially viable alternative for metastatic melanoma patients who are BRAF WT and are therefore ineligible for vemurafenib therapy.

  6. Targeting the NFκB signaling pathways for breast cancer prevention and therapy.

    Science.gov (United States)

    Wang, Wei; Nag, Subhasree A; Zhang, Ruiwen

    2015-01-01

    The activation of nuclear factor-kappaB (NFκB), a proinflammatory transcription factor, is a commonly observed phenomenon in breast cancer. It facilitates the development of a hormone-independent, invasive, high-grade, and late-stage tumor phenotype. Moreover, the commonly used cancer chemotherapy and radiotherapy approaches activate NFκB, leading to the development of invasive breast cancers that show resistance to chemotherapy, radiotherapy, and endocrine therapy. Inhibition of NFκB results in an increase in the sensitivity of cancer cells to the apoptotic effects of chemotherapeutic agents and radiation and restoring hormone sensitivity, which is correlated with increased disease-free survival in patients with breast cancer. In this review article, we focus on the role of the NFκB signaling pathways in the development and progression of breast cancer and the validity of NFκB as a potential target for breast cancer prevention and therapy. We also discuss the recent findings that NFκB may have tumor suppressing activity in certain cancer types. Finally, this review also covers the state-of-the-art development of NFκB inhibitors for cancer therapy and prevention, the challenges in targeting validation, and pharmacology and toxicology evaluations of these agents from the bench to the bedside.

  7. Control of the beam-internal target interaction at the nuclotron by means of light radiation

    Energy Technology Data Exchange (ETDEWEB)

    Artiomov, A.S. [Laboratory of High Energies, Joint Institute for Nuclear Research, Dubna 141980 (Russian Federation)]. E-mail: artiomov@moonhe.jinr.ru; Anisimov, Yu.S. [Laboratory of High Energies, Joint Institute for Nuclear Research, Dubna 141980 (Russian Federation); Afanasiev, S.V. [Laboratory of High Energies, Joint Institute for Nuclear Research, Dubna 141980 (Russian Federation); Bazilev, S.N. [Laboratory of High Energies, Joint Institute for Nuclear Research, Dubna 141980 (Russian Federation); Zolin, L.S. [Laboratory of High Energies, Joint Institute for Nuclear Research, Dubna 141980 (Russian Federation); Issinsky, I.B. [Laboratory of High Energies, Joint Institute for Nuclear Research, Dubna 141980 (Russian Federation); Kliman, J. [Laboratory of High Energies, Joint Institute for Nuclear Research, Dubna 141980 (Russian Federation); Institute of Physics, Slovak Academy of Sciences, Bratislava (Slovakia); Malakhov, A.I. [Laboratory of High Energies, Joint Institute for Nuclear Research, Dubna 141980 (Russian Federation); Matousek, V. [Institute of Physics, Slovak Academy of Sciences, Bratislava (Slovakia); Morhac, M. [Laboratory of High Energies, Joint Institute for Nuclear Research, Dubna 141980 (Russian Federation); Institute of Physics, Slovak Academy of Sciences, Bratislava (Slovakia); Nikitin, V.A. [Laboratory of High Energies, Joint Institute for Nuclear Research, Dubna 141980 (Russian Federation); Nikiforov, A.S. [Laboratory of High Energies, Joint Institute for Nuclear Research, Dubna 141980 (Russian Federation); Nomokonov, P.V. [Laboratory of High Energies, Joint Institute for Nuclear Research, Dubna 141980 (Russian Federation); Pilyar, A.V. [Laboratory of High Energies, Joint Institute for Nuclear Research, Dubna 141980 (Russian Federation); Turzo, I. [Institute of Physics, Slovak Academy of Sciences, Bratislava (Slovakia)

    2005-02-11

    The light radiation from various internal targets at the nuclotron can be utilized for the operative control and time optimization of the interaction intensity of the beam. The examples presented in the paper illustrate information about the space characteristics of the circulating beam during one cycle of the accelerator run at the stages of injection, acceleration and during the physical experiments, respectively.

  8. A review of the report ''IAEA safety targets and probabilistic risk assessment'' prepared for Greenpeace International

    International Nuclear Information System (INIS)

    1991-01-01

    At the request of the Director General, INSAG reviewed the report ''IAEA Safety Targets and Probabilistic Risk Assessment'' prepared for Greenpeace International by the Gesellschaft fuer Oekologische Forschung und Beratung mbH, Hannover, Germany. The conclusions of the report as well as the review results of INSAG experts are reproduced in this document

  9. Moeller polarimeter for VEPP-3 storage ring based on internal polarized gas jet target

    International Nuclear Information System (INIS)

    Dyug, M.V.; Grigoriev, A.V.; Kiselev, V.A.; Lazarenko, B.A.; Levichev, E.B.; Mikaiylov, A.I.; Mishnev, S.I.; Nikitin, S.A.; Nikolenko, D.M.; Rachek, I.A.; Shestakov, Yu.V.; Toporkov, D.K.; Zevakov, S.A.; Zhilich, V.N.

    2005-01-01

    A new method to determine the polarization of an electron beam circulating in a storage ring by a non-destructive way, based on measuring the asymmetry in scattering of beam electrons on electrons of the internal polarized gas jet target, has been developed and tested at the VEPP-3 storage ring

  10. International Test Comparisons: Reviewing Translation Error in Different Source Language-Target Language Combinations

    Science.gov (United States)

    Zhao, Xueyu; Solano-Flores, Guillermo; Qian, Ming

    2018-01-01

    This article addresses test translation review in international test comparisons. We investigated the applicability of the theory of test translation error--a theory of the multidimensionality and inevitability of test translation error--across source language-target language combinations in the translation of PISA (Programme of International…

  11. The 270 MeV deuteron beam polarimeter at the Nuclotron Internal Target Station

    Energy Technology Data Exchange (ETDEWEB)

    Kurilkin, P.K. [Joint Institute for Nuclear Research, Dubna (Russian Federation); Moscow State Institute of Radio-engineering Electronics and Automation (Technical University), Moscow (Russian Federation); Ladygin, V.P., E-mail: vladygin@jinr.ru [Joint Institute for Nuclear Research, Dubna (Russian Federation); Moscow State Institute of Radio-engineering Electronics and Automation (Technical University), Moscow (Russian Federation); Uesaka, T. [Center for Nuclear Study, University of Tokyo, Tokyo 113-0033 (Japan); Suda, K. [RIKEN Nishina Center, Saitama (Japan); Gurchin, Yu.V.; Isupov, A.Yu. [Joint Institute for Nuclear Research, Dubna (Russian Federation); Itoh, K. [Department of Physics, Saitama University, Saitama (Japan); Janek, M. [Joint Institute for Nuclear Research, Dubna (Russian Federation); Physics Department, University of Zilina, 010 26 Zilina (Slovakia); Karachuk, J.-T. [Joint Institute for Nuclear Research, Dubna (Russian Federation); Advanced Research Institute for Electrical Engineering, Bucharest (Romania); Kawabata, T. [Center for Nuclear Study, University of Tokyo, Tokyo 113-0033 (Japan); Khrenov, A.N.; Kiselev, A.S.; Kizka, V.A. [Joint Institute for Nuclear Research, Dubna (Russian Federation); Kliman, J. [Institute of Physics of Slovak Academy of Sciences, Bratislava (Slovakia); Krasnov, V.A.; Livanov, A.N. [Joint Institute for Nuclear Research, Dubna (Russian Federation); Institute for Nuclear Research, Moscow (Russian Federation); Maeda, Y. [Kyushi University, Hakozaki (Japan); Malakhov, A.I. [Joint Institute for Nuclear Research, Dubna (Russian Federation); Matousek, V.; Morhach, M. [Institute of Physics of Slovak Academy of Sciences, Bratislava (Slovakia)

    2011-06-21

    A deuteron beam polarimeter has been constructed at the Internal Target Station at the Nuclotron of JINR. The polarimeter is based on spin-asymmetry measurements in the d-p elastic scattering at large angles and the deuteron kinetic energy of 270 MeV. It allows to measure vector and tensor components of the deuteron beam polarization simultaneously.

  12. Internal and External Triggering Mechanism of "Smart" Nanoparticle-Based DDSs in Targeted Tumor Therapy.

    Science.gov (United States)

    Qiana, Xian-Ling; Li, Jun; Wei, Ran; Lin, Hui; Xiong, Li-Xia

    2018-05-09

    Anticancer chemotherapeutics have a lot of problems via conventional drug delivery systems (DDSs), including non-specificity, burst release, severe side-effects, and damage to normal cells. Owing to its potential to circumventing these problems, nanotechnology has gained increasing attention in targeted tumor therapy. Chemotherapeutic drugs or genes encapsulated in nanoparticles could be used to target therapies to the tumor site in three ways: "passive", "active", and "smart" targeting. To summarize the mechanisms of various internal and external "smart" stimulating factors on the basis of findings from in vivo and in vitro studies. A thorough search of PubMed was conducted in order to identify the majority of trials, studies and novel articles related to the subject. Activated by internal triggering factors (pH, redox, enzyme, hypoxia, etc.) or external triggering factors (temperature, light of different wavelengths, ultrasound, magnetic fields, etc.), "smart" DDSs exhibit targeted delivery to the tumor site, and controlled release of chemotherapeutic drugs or genes. In this review article, we summarize and classify the internal and external triggering mechanism of "smart" nanoparticle-based DDSs in targeted tumor therapy, and the most recent research advances are illustrated for better understanding. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  13. Targeting Wnt signaling in colorectal cancer. A Review in the Theme: Cell Signaling: Proteins, Pathways and Mechanisms

    Science.gov (United States)

    Novellasdemunt, Laura; Antas, Pedro

    2015-01-01

    The evolutionarily conserved Wnt signaling pathway plays essential roles during embryonic development and tissue homeostasis. Notably, comprehensive genetic studies in Drosophila and mice in the past decades have demonstrated the crucial role of Wnt signaling in intestinal stem cell maintenance by regulating proliferation, differentiation, and cell-fate decisions. Wnt signaling has also been implicated in a variety of cancers and other diseases. Loss of the Wnt pathway negative regulator adenomatous polyposis coli (APC) is the hallmark of human colorectal cancers (CRC). Recent advances in high-throughput sequencing further reveal many novel recurrent Wnt pathway mutations in addition to the well-characterized APC and β-catenin mutations in CRC. Despite attractive strategies to develop drugs for Wnt signaling, major hurdles in therapeutic intervention of the pathway persist. Here we discuss the Wnt-activating mechanisms in CRC and review the current advances and challenges in drug discovery. PMID:26289750

  14. International Conference on VLSI, Communication, Advanced Devices, Signals & Systems and Networking

    CERN Document Server

    Shirur, Yasha; Prasad, Rekha

    2013-01-01

    This book is a collection of papers presented by renowned researchers, keynote speakers and academicians in the International Conference on VLSI, Communication, Analog Designs, Signals and Systems, and Networking (VCASAN-2013), organized by B.N.M. Institute of Technology, Bangalore, India during July 17-19, 2013. The book provides global trends in cutting-edge technologies in electronics and communication engineering. The content of the book is useful to engineers, researchers and academicians as well as industry professionals.

  15. Discovery of a Novel Inhibitor of the Hedgehog Signaling Pathway through Cell-based Compound Discovery and Target Prediction.

    Science.gov (United States)

    Kremer, Lea; Schultz-Fademrecht, Carsten; Baumann, Matthias; Habenberger, Peter; Choidas, Axel; Klebl, Bert; Kordes, Susanne; Schöler, Hans R; Sterneckert, Jared; Ziegler, Slava; Schneider, Gisbert; Waldmann, Herbert

    2017-10-09

    Cell-based assays enable monitoring of small-molecule bioactivity in a target-agnostic manner and help uncover new biological mechanisms. Subsequent identification and validation of the small-molecule targets, typically employing proteomics techniques, is very challenging and limited, in particular if the targets are membrane proteins. Herein, we demonstrate that the combination of cell-based bioactive-compound discovery with cheminformatic target prediction may provide an efficient approach to accelerate the process and render target identification and validation more efficient. Using a cell-based assay, we identified the pyrazolo-imidazole smoothib as a new inhibitor of hedgehog (Hh) signaling and an antagonist of the protein smoothened (SMO) with a novel chemotype. Smoothib targets the heptahelical bundle of SMO, prevents its ciliary localization, reduces the expression of Hh target genes, and suppresses the growth of Ptch +/- medulloblastoma cells. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  16. TRAIL, Wnt, Sonic Hedgehog, TGFβ, and miRNA Signalings Are Potential Targets for Oral Cancer Therapy.

    Science.gov (United States)

    Farooqi, Ammad Ahmad; Shu, Chih-Wen; Huang, Hurng-Wern; Wang, Hui-Ru; Chang, Yung-Ting; Fayyaz, Sundas; Yuan, Shyng-Shiou F; Tang, Jen-Yang; Chang, Hsueh-Wei

    2017-07-14

    Clinical studies and cancer cell models emphasize the importance of targeting therapies for oral cancer. The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is highly expressed in cancer, and is a selective killing ligand for oral cancer. Signaling proteins in the wingless-type mouse mammary tumor virus (MMTV) integration site family (Wnt), Sonic hedgehog (SHH), and transforming growth factor β (TGFβ) pathways may regulate cell proliferation, migration, and apoptosis. Accordingly, the genes encoding these signaling proteins are potential targets for oral cancer therapy. In this review, we focus on recent advances in targeting therapies for oral cancer and discuss the gene targets within TRAIL, Wnt, SHH, and TGFβ signaling for oral cancer therapies. Oncogenic microRNAs (miRNAs) and tumor suppressor miRNAs targeting the genes encoding these signaling proteins are summarized, and the interactions between Wnt, SHH, TGFβ, and miRNAs are interpreted. With suitable combination treatments, synergistic effects are expected to improve targeting therapies for oral cancer.

  17. TRAIL, Wnt, Sonic Hedgehog, TGFβ, and miRNA Signalings Are Potential Targets for Oral Cancer Therapy

    Science.gov (United States)

    Farooqi, Ammad Ahmad; Shu, Chih-Wen; Huang, Hurng-Wern; Wang, Hui-Ru; Chang, Yung-Ting; Fayyaz, Sundas; Yuan, Shyng-Shiou F.; Tang, Jen-Yang

    2017-01-01

    Clinical studies and cancer cell models emphasize the importance of targeting therapies for oral cancer. The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is highly expressed in cancer, and is a selective killing ligand for oral cancer. Signaling proteins in the wingless-type mouse mammary tumor virus (MMTV) integration site family (Wnt), Sonic hedgehog (SHH), and transforming growth factor β (TGFβ) pathways may regulate cell proliferation, migration, and apoptosis. Accordingly, the genes encoding these signaling proteins are potential targets for oral cancer therapy. In this review, we focus on recent advances in targeting therapies for oral cancer and discuss the gene targets within TRAIL, Wnt, SHH, and TGFβ signaling for oral cancer therapies. Oncogenic microRNAs (miRNAs) and tumor suppressor miRNAs targeting the genes encoding these signaling proteins are summarized, and the interactions between Wnt, SHH, TGFβ, and miRNAs are interpreted. With suitable combination treatments, synergistic effects are expected to improve targeting therapies for oral cancer. PMID:28708091

  18. Cooling equilibrium and beam loss with internal targets in high energy storage rings

    International Nuclear Information System (INIS)

    Boine-Frankenheim, O.; Hasse, R.; Hinterberger, F.; Lehrach, A.; Zenkevich, P.

    2006-01-01

    The beam cooling equilibrium with internal target interaction is analyzed for parameters relevant to the proposed High Energy Storage Ring (HESR). For the proposed experiments with anti-protons high luminosities together with low momentum spreads are required. Rate equations are used to predict the rms equilibrium beam parameters. The cooling and IBS rate coefficients are obtained from simplified models. Energy loss straggling in the target and the associated beam loss are analyzed analytically assuming a thin target. A longitudinal kinetic simulation code is used to study the evolution of the momentum distribution in coasting and bunched beams. Analytic expressions for the target induced momentum tail are found in good agreement with the simulation results

  19. Summary of the XIII International Workshop on Polarized Sources, Targets and Polarimetry

    Science.gov (United States)

    Rathmann, F.

    2011-01-01

    The workshops on polarized sources, targets, and polarimetry are held every two years. The present meeting took place in Ferrara, Italy, and was organized by the University of Ferrara. Sessions on Polarized Proton and Deuterium Sources, Polarized Electron Sources, Polarimetry, Polarized Solid Targets, and Polarized Internal Targets, highlighted topics, recent developments, and progress in the field. A session decicated to Future Facilities provided an overview of a number of new activities in the spin-physics sector at facilities that are currently in the planning stage. Besides presenting a broad overview of polarized ion sources, electron sources, solid and gaseous targets, and their neighboring fields, the workshop also addressed the application of polarized atoms in applied sciences and medicine that is becoming increasingly important.

  20. PST 2009: XIII International Workshop on Polarized Sources Targets and Polarimetry

    Science.gov (United States)

    Lenisa, Paolo

    2011-05-01

    The workshops on polarized sources, targets, and polarimetry are held every two years. In 2009 the meeting took place in Ferrara, Italy, and was organized by the University of Ferrara and INFN. Sessions on Polarized Proton and Deuterium Sources, Polarized Electron Sources, Polarimetry, Polarized Solid Targets, and Polarized Internal Targets, highlighted topics, recent developments, and progress in the field. A session dedicated to Future Facilities provided an overview of a number of new activities in the spin-physics sector at facilities that are currently in the planning stage. Besides presenting a broad overview of polarized ion sources, electron sources, solid and gaseous targets, and their neighbouring fields, the workshop also addressed the application of polarized atoms in applied sciences and medicine that is becoming increasingly important.

  1. Signal and data processing of small targets 1991; Proceedings of the Meeting, Orlando, FL, Apr. 1-3, 1991

    Science.gov (United States)

    Drummond, Oliver E.

    Attention is given to signal processing; track-before-detect; systems and simulations; association and filtering in tracking; and data processing. Particular attention is given to a linear modeling algorithm for tracking time-varying signals, an optoelectric Gabor detector for transient signals, small-target acquisition and typing by AASAP, model-based analysis of 3D spatial-temporal IR clutter suppression filtering, algorithms and architectures for implementing large-velocity filter banks, an end-to-end scenario-generating model for IRST performance analysis, detection and tracking of small targets in persistence, an incremental model for target maneuver estimation, implementation of an angle-only tracking filter, a global modeling approach for multisensor problems, passive-sensor data fusion, midcourse multitarget racking using continuous representation, neural data association, and statistical initial orbit determination. (For individual items see A93-26797 to A93-26799)

  2. Dovitinib Acts As a Novel Radiosensitizer in Hepatocellular Carcinoma by Targeting SHP-1/STAT3 Signaling

    Energy Technology Data Exchange (ETDEWEB)

    Huang, Chao-Yuan [Department of Oncology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan (China); Department of Radiological Technology, Yuanpei University, Hsinchu, Taiwan (China); Tai, Wei-Tien [Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan (China); National Center of Excellence for Clinical Trial and Research, National Taiwan University Hospital, Taipei, Taiwan (China); Wu, Szu-Yuan [Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan (China); Department of Radiation Oncology, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan (China); Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan (China); Department of Biotechnology, Hungkuang University, Taichung, Taiwan (China); Shih, Chih-Ting; Chen, Min-Hsuan; Tsai, Ming-Hsien [Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan (China); Kuo, Chiung-Wen [Department of Medical Imaging and Radiological Technology, Yuanpei University of Medical Technology, Hsinchu, Taiwan (China); Shiau, Chung-Wai [Institute of Biopharmaceutical Sciences, National Yang-Ming University, Taipei, Taiwan (China); Hung, Man-Hsin, E-mail: cindybeaty@gmail.com [Division of Medical Oncology, Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan (China); Division of Hematology and Oncology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan (China); Program in Molecular Medicine, School of Life Science, National Yang-Ming University, Taipei, Taiwan (China); School of Medicine, National Yang-Ming University, Taipei, Taiwan (China); Chen, Kuen-Feng, E-mail: kfchen1970@ntu.edu.tw [Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan (China); National Center of Excellence for Clinical Trial and Research, National Taiwan University Hospital, Taipei, Taiwan (China)

    2016-06-01

    Purpose: Hepatocellular carcinoma (HCC) is among the most lethal human malignancies, and curative therapy is not an option for most patients. There is growing interest in the potential benefit of combining targeted therapies with radiation therapy (RT). This study aimed to characterize the efficacy and mechanism of an investigational drug, dovitinib, used in combination with RT. Methods and Materials: HCC cell lines (PLC5, Hep3B, SK-Hep1, HA59T, and Huh-7) were treated with dovitinib, RT, or both, and apoptosis and signal transduction were analyzed. Results: Dovitinib treatment resulted in Src homology region 2 (SH2) domain-containing phosphatase 1 (SHP-1)-mediated downregulation of p-STAT3 and promoted potent apoptosis of HCC cells. Ectopic expression of STAT3, or inhibition of SHP-1, diminished the effects of dovitinib on HCC cells. By ectopic expression and purified recombinant proteins of various mutant forms of SHP-1, the N-SH2 domain of SHP-1 was found to be required for dovitinib treatment. Overexpression of STAT3 or catalytic-dead mutant SHP-1 restored RT-induced reduction of HCC cell survival. Conversely, ectopic expression of SHP-1 or activation of SHP-1 by dovitinib enhanced the effects of RT against HCC in vitro and in vivo. Conclusions: SHP-1/STAT3 signaling is critically associated with the radiosensitivity of HCC cells. Combination therapy with RT and the SHP-1 agonist, such as dovitinib, resulted in enhanced in vitro and in vivo anti-HCC effects.

  3. Targeting Cannabinoid Signaling in the Immune System: “High”-ly Exciting Questions, Possibilities, and Challenges

    Directory of Open Access Journals (Sweden)

    Attila Oláh

    2017-11-01

    Full Text Available It is well known that certain active ingredients of the plants of Cannabis genus, i.e., the “phytocannabinoids” [pCBs; e.g., (−-trans-Δ9-tetrahydrocannabinol (THC, (−-cannabidiol, etc.] can influence a wide array of biological processes, and the human body is able to produce endogenous analogs of these substances [“endocannabinoids” (eCB, e.g., arachidonoylethanolamine (anandamide, AEA, 2-arachidonoylglycerol (2-AG, etc.]. These ligands, together with multiple receptors (e.g., CB1 and CB2 cannabinoid receptors, etc., and a complex enzyme and transporter apparatus involved in the synthesis and degradation of the ligands constitute the endocannabinoid system (ECS, a recently emerging regulator of several physiological processes. The ECS is widely expressed in the human body, including several members of the innate and adaptive immune system, where eCBs, as well as several pCBs were shown to deeply influence immune functions thereby regulating inflammation, autoimmunity, antitumor, as well as antipathogen immune responses, etc. Based on this knowledge, many in vitro and in vivo studies aimed at exploiting the putative therapeutic potential of cannabinoid signaling in inflammation-accompanied diseases (e.g., multiple sclerosis or in organ transplantation, and to dissect the complex immunological effects of medical and “recreational” marijuana consumption. Thus, the objective of the current article is (i to summarize the most recent findings of the field; (ii to highlight the putative therapeutic potential of targeting cannabinoid signaling; (iii to identify open questions and key challenges; and (iv to suggest promising future directions for cannabinoid-based drug development.

  4. Dovitinib Acts As a Novel Radiosensitizer in Hepatocellular Carcinoma by Targeting SHP-1/STAT3 Signaling

    International Nuclear Information System (INIS)

    Huang, Chao-Yuan; Tai, Wei-Tien; Wu, Szu-Yuan; Shih, Chih-Ting; Chen, Min-Hsuan; Tsai, Ming-Hsien; Kuo, Chiung-Wen; Shiau, Chung-Wai; Hung, Man-Hsin; Chen, Kuen-Feng

    2016-01-01

    Purpose: Hepatocellular carcinoma (HCC) is among the most lethal human malignancies, and curative therapy is not an option for most patients. There is growing interest in the potential benefit of combining targeted therapies with radiation therapy (RT). This study aimed to characterize the efficacy and mechanism of an investigational drug, dovitinib, used in combination with RT. Methods and Materials: HCC cell lines (PLC5, Hep3B, SK-Hep1, HA59T, and Huh-7) were treated with dovitinib, RT, or both, and apoptosis and signal transduction were analyzed. Results: Dovitinib treatment resulted in Src homology region 2 (SH2) domain-containing phosphatase 1 (SHP-1)-mediated downregulation of p-STAT3 and promoted potent apoptosis of HCC cells. Ectopic expression of STAT3, or inhibition of SHP-1, diminished the effects of dovitinib on HCC cells. By ectopic expression and purified recombinant proteins of various mutant forms of SHP-1, the N-SH2 domain of SHP-1 was found to be required for dovitinib treatment. Overexpression of STAT3 or catalytic-dead mutant SHP-1 restored RT-induced reduction of HCC cell survival. Conversely, ectopic expression of SHP-1 or activation of SHP-1 by dovitinib enhanced the effects of RT against HCC in vitro and in vivo. Conclusions: SHP-1/STAT3 signaling is critically associated with the radiosensitivity of HCC cells. Combination therapy with RT and the SHP-1 agonist, such as dovitinib, resulted in enhanced in vitro and in vivo anti-HCC effects.

  5. Role of adenosine 5'-monophosphate-activated protein kinase subunits in skeletal muscle mammalian target of rapamycin signaling

    DEFF Research Database (Denmark)

    Deshmukh, Atul S.; Treebak, Jonas Thue; Long, Yun Chau

    2008-01-01

    AMP-activated protein kinase (AMPK) is an important energy-sensing protein in skeletal muscle. Mammalian target of rapamycin (mTOR) mediates translation initiation and protein synthesis through ribosomal S6 kinase 1 (S6K1) and eukaryotic initiation factor 4E-binding protein 1 (4E-BP1). AMPK...... activation reduces muscle protein synthesis by down-regulating mTOR signaling, whereas insulin mediates mTOR signaling via Akt activation. We hypothesized that AMPK-mediated inhibitory effects on mTOR signaling depend on catalytic alpha2 and regulatory gamma3 subunits. Extensor digitorum longus muscle from...... (Thr37/46) (P mTOR targets, suggesting mTOR signaling is blocked by prior AMPK activation. The AICAR-induced inhibition was partly rescued...

  6. Pressure control of a proton beam-irradiated water target through an internal flow channel-induced thermosyphon.

    Science.gov (United States)

    Hong, Bong Hwan; Jung, In Su

    2017-07-01

    A water target was designed to enhance cooling efficiency using a thermosyphon, which is a system that uses natural convection to induce heat exchange. Two water targets were fabricated: a square target without any flow channel and a target with a flow channel design to induce a thermosyphon mechanism. These two targets had the same internal volume of 8 ml. First, visualization experiments were performed to observe the internal flow by natural convection. Subsequently, an experiment was conducted to compare the cooling performance of both water targets by measuring the temperature and pressure. A 30-MeV proton beam with a beam current of 20 μA was used to irradiate both targets. Consequently, the target with an internal flow channel had a lower mean temperature and a 50% pressure drop compared to the target without a flow channel during proton beam irradiation. Copyright © 2017 Elsevier Ltd. All rights reserved.

  7. Randomized controlled trial of internal and external targeted temperature management methods in post- cardiac arrest patients.

    Science.gov (United States)

    Look, Xinqi; Li, Huihua; Ng, Mingwei; Lim, Eric Tien Siang; Pothiawala, Sohil; Tan, Kenneth Boon Kiat; Sewa, Duu Wen; Shahidah, Nur; Pek, Pin Pin; Ong, Marcus Eng Hock

    2018-01-01

    Targeted temperature management post-cardiac arrest is currently implemented using various methods, broadly categorized as internal and external. This study aimed to evaluate survival-to-hospital discharge and neurological outcomes (Glasgow-Pittsburgh Score) of post-cardiac arrest patients undergoing internal cooling verses external cooling. A randomized controlled trial of post-resuscitation cardiac arrest patients was conducted from October 2008-September 2014. Patients were randomized to either internal or external cooling methods. Historical controls were selected matched by age and gender. Analysis using SPSS version 21.0 presented descriptive statistics and frequencies while univariate logistic regression was done using R 3.1.3. 23 patients were randomized to internal cooling and 22 patients to external cooling and 42 matched controls were selected. No significant difference was seen between internal and external cooling in terms of survival, neurological outcomes and complications. However in the internal cooling arm, there was lower risk of developing overcooling (p=0.01) and rebound hyperthermia (p=0.02). Compared to normothermia, internal cooling had higher survival (OR=3.36, 95% CI=(1.130, 10.412), and lower risk of developing cardiac arrhythmias (OR=0.18, 95% CI=(0.04, 0.63)). Subgroup analysis showed those with cardiac cause of arrest (OR=4.29, 95% CI=(1.26, 15.80)) and sustained ROSC (OR=5.50, 95% CI=(1.64, 20.39)) had better survival with internal cooling compared to normothermia. Cooling curves showed tighter temperature control for internal compared to external cooling. Internal cooling showed tighter temperature control compared to external cooling. Internal cooling can potentially provide better survival-to-hospital discharge outcomes and reduce cardiac arrhythmia complications in carefully selected patients as compared to normothermia. Copyright © 2017. Published by Elsevier Inc.

  8. Elimination of head and neck cancer initiating cells through targeting glucose regulated protein78 signaling

    Directory of Open Access Journals (Sweden)

    Huang Chih-Yang

    2010-10-01

    Full Text Available Abstract Background Head and neck squamous cell carcinoma (HNSCC is a highly lethal cancer that contains cellular and functional heterogeneity. Previously, we enriched a subpopulation of highly tumorigenic head and neck cancer initiating cells (HN-CICs from HNSCC. However, the molecular mechanisms by which to govern the characteristics of HN-CICs remain unclear. GRP78, a stress-inducible endoplasmic reticulum chaperone, has been reported to play a crucial role in the maintenance of embryonic stem cells, but the role of GRP78 in CICs has not been elucidated. Results Initially, we recognized GRP78 as a putative candidate on mediating the stemness and tumorigenic properties of HN-CICs by differential systemic analyses. Subsequently, cells with GRP78 anchored at the plasma membrane (memGRP78+ exerted cancer stemness properties of self-renewal, differentiation and radioresistance. Of note, xenotransplantation assay indicated merely 100 memGRP78+ HNSCCs resulted in tumor growth. Moreover, knockdown of GRP78 significantly reduced the self-renewal ability, side population cells and expression of stemness genes, but inversely promoted cell differentiation and apoptosis in HN-CICs. Targeting GRP78 also lessened tumorigenicity of HN-CICs both in vitro and in vivo. Clinically, co-expression of GRP78 and Nanog predicted the worse survival prognosis of HNSCC patients by immunohistochemical analyses. Finally, depletion of GRP78 in HN-CICs induced the expression of Bax, Caspase 3, and PTEN. Conclusions In summary, memGRP78 should be a novel surface marker for isolation of HN-CICs, and targeting GRP78 signaling might be a potential therapeutic strategy for HNSCC through eliminating HN-CICs.

  9. Targeted Gene-Silencing Reveals the Functional Significance of Myocardin Signaling in the Failing Heart

    Science.gov (United States)

    Torrado, Mario; Iglesias, Raquel; Centeno, Alberto; López, Eduardo; Mikhailov, Alexander T.

    2011-01-01

    Background Myocardin (MYOCD), a potent transcriptional coactivator of smooth muscle (SM) and cardiac genes, is upregulated in failing myocardium in animal models and human end-stage heart failure (HF). However, the molecular and functional consequences of myocd upregulation in HF are still unclear. Methodology/Principal Findings The goal of the present study was to investigate if targeted inhibition of upregulated expression of myocd could influence failing heart gene expression and function. To this end, we used the doxorubicin (Dox)-induced diastolic HF (DHF) model in neonatal piglets, in which, as we show, not only myocd but also myocd-dependent SM-marker genes are highly activated in failing left ventricular (LV) myocardium. In this model, intra-myocardial delivery of short-hairpin RNAs, designed to target myocd variants expressed in porcine heart, leads on day 2 post-delivery to: (1) a decrease in the activated expression of myocd and myocd-dependent SM-marker genes in failing myocardium to levels seen in healthy control animals, (2) amelioration of impaired diastolic dysfunction, and (3) higher survival rates of DHF piglets. The posterior restoration of elevated myocd expression (on day 7 post-delivery) led to overexpression of myocd-dependent SM-marker genes in failing LV-myocardium that was associated with a return to altered diastolic function. Conclusions/Significance These data provide the first evidence that a moderate inhibition (e.g., normalization) of the activated MYOCD signaling in the diseased heart may be promising from a therapeutic point of view. PMID:22028870

  10. Targeted gene-silencing reveals the functional significance of myocardin signaling in the failing heart.

    Directory of Open Access Journals (Sweden)

    Mario Torrado

    Full Text Available BACKGROUND: Myocardin (MYOCD, a potent transcriptional coactivator of smooth muscle (SM and cardiac genes, is upregulated in failing myocardium in animal models and human end-stage heart failure (HF. However, the molecular and functional consequences of myocd upregulation in HF are still unclear. METHODOLOGY/PRINCIPAL FINDINGS: The goal of the present study was to investigate if targeted inhibition of upregulated expression of myocd could influence failing heart gene expression and function. To this end, we used the doxorubicin (Dox-induced diastolic HF (DHF model in neonatal piglets, in which, as we show, not only myocd but also myocd-dependent SM-marker genes are highly activated in failing left ventricular (LV myocardium. In this model, intra-myocardial delivery of short-hairpin RNAs, designed to target myocd variants expressed in porcine heart, leads on day 2 post-delivery to: (1 a decrease in the activated expression of myocd and myocd-dependent SM-marker genes in failing myocardium to levels seen in healthy control animals, (2 amelioration of impaired diastolic dysfunction, and (3 higher survival rates of DHF piglets. The posterior restoration of elevated myocd expression (on day 7 post-delivery led to overexpression of myocd-dependent SM-marker genes in failing LV-myocardium that was associated with a return to altered diastolic function. CONCLUSIONS/SIGNIFICANCE: These data provide the first evidence that a moderate inhibition (e.g., normalization of the activated MYOCD signaling in the diseased heart may be promising from a therapeutic point of view.

  11. Cone-Beam CT Localization of Internal Target Volumes for Stereotactic Body Radiotherapy of Lung Lesions

    International Nuclear Information System (INIS)

    Wang Zhiheng; Wu, Q. Jackie; Marks, Lawrence B.; Larrier, Nicole; Yin Fangfang

    2007-01-01

    Purpose: In this study, we investigate a technique of matching internal target volumes (ITVs) in four-dimensional (4D) simulation computed tomography (CT) to the composite target volume in free-breathing on-board cone-beam (CB) CT. The technique is illustrated by using both phantom and patient cases. Methods and Materials: A dynamic phantom with a target ball simulating respiratory motion with various amplitude and cycle times was used to verify localization accuracy. The dynamic phantom was scanned using simulation CT with a phase-based retrospective sorting technique. The ITV was then determined based on 10 sets of sorted images. The size and epicenter of the ITV identified from 4D simulation CT images and the composite target volume identified from on-board CBCT images were compared to assess localization accuracy. Similarly, for two clinical cases of patients with lung cancer, ITVs defined from 4D simulation CT images and CBCT images were compared. Results: For the phantom, localization accuracy between the ITV in 4D simulation CT and the composite target volume in CBCT was within 1 mm, and ITV was within 8.7%. For patient cases, ITVs on simulation CT and CBCT were within 8.0%. Conclusion: This study shows that CBCT is a useful tool to localize ITV for targets affected by respiratory motion. Verification of the ITV from 4D simulation CT using on-board free-breathing CBCT is feasible for the target localization of lung tumors

  12. Signal and data processing of small targets 1989; Proceedings of the Meeting, Orlando, FL, Mar. 27-29, 1989

    Science.gov (United States)

    Drummond, Oliver E. (Editor)

    1989-01-01

    The present conference on digital signal processing, association and filtering techniques, and multiple-sensor/multiple-tracking techniques, discusses single-frame velocity estimation, efficient target extraction for laser radar imagery, precision target tracking for small extended objects, IR clutter partitioning for matched filter design, the maximum-likelihood approach to gamma circumvention, position estimation for optical point targets using staring detector arrays, and a multiple-scan signal processing technique for area-moving target indication. Also discussed are a proportional integral estimator, the prediction of track purity in tracking performance evaluations, synchronization and fault-tolerance in a distributed tracker, the benefits of soft sensors and probabilistic fusion, and testing track initiation algorithms fusing two-dimensional tracks.

  13. Mycobacterium tuberculosis Controls Phagosomal Acidification by Targeting CISH-Mediated Signaling.

    Science.gov (United States)

    Queval, Christophe J; Song, Ok-Ryul; Carralot, Jean-Philippe; Saliou, Jean-Michel; Bongiovanni, Antonino; Deloison, Gaspard; Deboosère, Nathalie; Jouny, Samuel; Iantomasi, Raffaella; Delorme, Vincent; Debrie, Anne-Sophie; Park, Sei-Jin; Gouveia, Joana Costa; Tomavo, Stanislas; Brosch, Roland; Yoshimura, Akihiko; Yeramian, Edouard; Brodin, Priscille

    2017-09-26

    Pathogens have evolved a range of mechanisms to counteract host defenses, notably to survive harsh acidic conditions in phagosomes. In the case of Mycobacterium tuberculosis, it has been shown that regulation of phagosome acidification could be achieved by interfering with the retention of the V-ATPase complexes at the vacuole. Here, we present evidence that M. tuberculosis resorts to yet another strategy to control phagosomal acidification, interfering with host suppressor of cytokine signaling (SOCS) protein functions. More precisely, we show that infection of macrophages with M. tuberculosis leads to granulocyte-macrophage colony-stimulating factor (GM-CSF) secretion, inducing STAT5-mediated expression of cytokine-inducible SH2-containing protein (CISH), which selectively targets the V-ATPase catalytic subunit A for ubiquitination and degradation by the proteasome. Consistently, we show that inhibition of CISH expression leads to reduced replication of M. tuberculosis in macrophages. Our findings further broaden the molecular understanding of mechanisms deployed by bacteria to survive. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  14. Mycobacterium tuberculosis Controls Phagosomal Acidification by Targeting CISH-Mediated Signaling

    Directory of Open Access Journals (Sweden)

    Christophe J. Queval

    2017-09-01

    Full Text Available Pathogens have evolved a range of mechanisms to counteract host defenses, notably to survive harsh acidic conditions in phagosomes. In the case of Mycobacterium tuberculosis, it has been shown that regulation of phagosome acidification could be achieved by interfering with the retention of the V-ATPase complexes at the vacuole. Here, we present evidence that M. tuberculosis resorts to yet another strategy to control phagosomal acidification, interfering with host suppressor of cytokine signaling (SOCS protein functions. More precisely, we show that infection of macrophages with M. tuberculosis leads to granulocyte-macrophage colony-stimulating factor (GM-CSF secretion, inducing STAT5-mediated expression of cytokine-inducible SH2-containing protein (CISH, which selectively targets the V-ATPase catalytic subunit A for ubiquitination and degradation by the proteasome. Consistently, we show that inhibition of CISH expression leads to reduced replication of M. tuberculosis in macrophages. Our findings further broaden the molecular understanding of mechanisms deployed by bacteria to survive.

  15. Regional reliability of quantitative signal targeting with alternating radiofrequency (STAR) labeling of arterial regions (QUASAR).

    Science.gov (United States)

    Tatewaki, Yasuko; Higano, Shuichi; Taki, Yasuyuki; Thyreau, Benjamin; Murata, Takaki; Mugikura, Shunji; Ito, Daisuke; Takase, Kei; Takahashi, Shoki

    2014-01-01

    Quantitative signal targeting with alternating radiofrequency labeling of arterial regions (QUASAR) is a recent spin labeling technique that could improve the reliability of brain perfusion measurements. Although it is considered reliable for measuring gray matter as a whole, it has never been evaluated regionally. Here we assessed this regional reliability. Using a 3-Tesla Philips Achieva whole-body system, we scanned four times 10 healthy volunteers, in two sessions 2 weeks apart, to obtain QUASAR images. We computed perfusion images and ran a voxel-based analysis within all brain structures. We also calculated mean regional cerebral blood flow (rCBF) within regions of interest configured for each arterial territory distribution. The mean CBF over whole gray matter was 37.74 with intraclass correlation coefficient (ICC) of .70. In white matter, it was 13.94 with an ICC of .30. Voxel-wise ICC and coefficient-of-variation maps showed relatively lower reliability in watershed areas and white matter especially in deeper white matter. The absolute mean rCBF values were consistent with the ones reported from PET, as was the relatively low variability in different feeding arteries. Thus, QUASAR reliability for regional perfusion is high within gray matter, but uncertain within white matter. © 2014 The Authors. Journal of Neuroimaging published by the American Society of Neuroimaging.

  16. The flavonoid fisetin as an anticancer agent targeting the growth signaling pathways.

    Science.gov (United States)

    Rengarajan, Thamaraiselvan; Yaacob, Nik Soriani

    2016-10-15

    Epidemiological studies show that consumption of diets rich in fruits and vegetables is associated with lower risks of cancer. This evidence has kindled interest into research on bioactive food components and has till date resulted in the identification of many compounds with cancer preventive and therapeutic potential. Among such compounds is fisetin (3,7,3,4-tetrahydroxyflavone), a flavonol that is commonly found in many fruits and vegetables such as apples, persimmons, grapes, kiwis, strawberries, onions and cucumbers. Fisetin has been shown to inhibit or retard the growth of various cancer cells in culture and implanted tumors in vivo. Fisetin targets many components of intracellular signaling pathways including regulators of cell survival and apoptosis, tumor angiogenic and metastatic switches by modulating a distinct set of upstream kinases, transcription factors and their regulators. Current evidence supports the idea that fisetin is a promising agent for cancer treatment. This review summarizes reported anticancer effects of fisetin, and re-emphasizes its potential therapeutic role in the treatment of cancer. Copyright © 2016 Elsevier B.V. All rights reserved.

  17. Nuclear localization signal targeting to macronucleus and micronucleus in binucleated ciliate Tetrahymena thermophila.

    Science.gov (United States)

    Iwamoto, Masaaki; Mori, Chie; Osakada, Hiroko; Koujin, Takako; Hiraoka, Yasushi; Haraguchi, Tokuko

    2018-06-08

    Ciliated protozoa possess two morphologically and functionally distinct nuclei: a macronucleus (MAC) and a micronucleus (MIC). The MAC is transcriptionally active and functions in all cellular events. The MIC is transcriptionally inactive during cell growth, but functions in meiotic events to produce progeny nuclei. Thus, these two nuclei must be distinguished by the nuclear proteins required for their distinct functions during cellular events such as cell proliferation and meiosis. To understand the mechanism of the nuclear transport specific to either MAC or MIC, we identified specific nuclear localization signals (NLSs) in two MAC- and MIC-specific nuclear proteins, macronuclear histone H1 and micronuclear linker histone-like protein (Mlh1), respectively. By expressing GFP-fused fragments of these proteins in Tetrahymena thermophila cells, two distinct regions in macronuclear histone H1 protein were assigned as independent MAC-specific NLSs and two distinct regions in Mlh1 protein were assigned as independent MIC-specific NLSs. These NLSs contain several essential lysine residues responsible for the MAC- and MIC-specific nuclear transport, but neither contains any consensus sequence with known monopartite or bipartite NLSs in other model organisms. Our findings contribute to understanding how specific nuclear targeting is achieved to perform distinct nuclear functions in binucleated ciliates. © 2018 The Authors. Genes to Cells published by Molecular Biology Society of Japan and John Wiley & Sons Australia, Ltd.

  18. Design of a control system for HIRFL-CSRe internal target facility in Lanzhou

    International Nuclear Information System (INIS)

    Wang Yanyu; Liu Wufeng; Shao Caojie; Lin Feiyu; Zhang Jianchuan; Xiao Wenjun

    2010-01-01

    It is described in this paper the design of the control system for HIRFL-CSRe internal target facility, in which there are many different kinds of units need to be monitored and controlled. The control system is composed of several subsystems which are designed to control the gas-jet temperature, chamber vacuum, valves and molecular pumps. A human-computer interaction interface is also realized to do the data acquisition, data processing and display. The whole system has been working stably and safely, it fully meets the requirements of physical experiments in the internal target facility. In January of 2010, the first physics experiment of the radioactive electron capture was finished successfully with the aids of this control system. (authors)

  19. Mitogen-activated protein kinase signaling pathways promote low-density lipoprotein receptor-related protein 1-mediated internalization of beta-amyloid protein in primary cortical neurons.

    Science.gov (United States)

    Yang, Wei-Na; Ma, Kai-Ge; Qian, Yi-Hua; Zhang, Jian-Shui; Feng, Gai-Feng; Shi, Li-Li; Zhang, Zhi-Chao; Liu, Zhao-Hui

    2015-07-01

    Mounting evidence suggests that the pathological hallmarks of Alzheimer's disease (AD) are caused by the intraneuronal accumulation of beta-amyloid protein (Aβ). Reuptake of extracellular Aβ is believed to contribute significantly to the intraneuronal Aβ pool in the early stages of AD. Published reports have claimed that the low-density lipoprotein receptor-related protein 1 (LRP1) mediates Aβ1-42 uptake and lysosomal trafficking in GT1-7 neuronal cells and mouse embryonic fibroblast non-neuronal cells. However, there is no direct evidence supporting the role of LRP1 in Aβ internalization in primary neurons. Our recent study indicated that p38 MAPK and ERK1/2 signaling pathways are involved in regulating α7 nicotinic acetylcholine receptor (α7nAChR)-mediated Aβ1-42 uptake in SH-SY5Y cells. This study was designed to explore the regulation of MAPK signaling pathways on LRP1-mediated Aβ internalization in neurons. We found that extracellular Aβ1-42 oligomers could be internalized into endosomes/lysosomes and mitochondria in cortical neurons. Aβ1-42 and LRP1 were also found co-localized in neurons during Aβ1-42 internalization, and they could form Aβ1-42-LRP1 complex. Knockdown of LRP1 expression significantly decreased neuronal Aβ1-42 internalization. Finally, we identified that p38 MAPK and ERK1/2 signaling pathways regulated the internalization of Aβ1-42 via LRP1. Therefore, these results demonstrated that LRP1, p38 MAPK and ERK1/2 mediated the internalization of Aβ1-42 in neurons and provided evidence that blockade of LRP1 or inhibitions of MAPK signaling pathways might be a potential approach to lowering brain Aβ levels and served a potential therapeutic target for AD. Copyright © 2015 Elsevier Ltd. All rights reserved.

  20. Mitogen activated protein kinase signaling in the kidney: Target for intervention?

    NARCIS (Netherlands)

    de Borst, M.H.; Wassef, L.; Kelly, D.J.; van Goor, H.; Navis, Ger Jan

    2006-01-01

    Mitogen activated protein kinases (MAPKs) are intracellular signal transduction molecules, which connect cell-surface receptor signals to intracellular processes. MAPKs regulate a range of cellular activities including cell proliferation, gene expression, apoptosis, cell differentiation and cytokine

  1. Adaptive Traffic Signal Control: Deep Reinforcement Learning Algorithm with Experience Replay and Target Network

    OpenAIRE

    Gao, Juntao; Shen, Yulong; Liu, Jia; Ito, Minoru; Shiratori, Norio

    2017-01-01

    Adaptive traffic signal control, which adjusts traffic signal timing according to real-time traffic, has been shown to be an effective method to reduce traffic congestion. Available works on adaptive traffic signal control make responsive traffic signal control decisions based on human-crafted features (e.g. vehicle queue length). However, human-crafted features are abstractions of raw traffic data (e.g., position and speed of vehicles), which ignore some useful traffic information and lead t...

  2. Discovering Small Molecule Inhibitors Targeted to Ligand-Stimulated RAGE-DIAPH1 Signaling Transduction

    Science.gov (United States)

    Pan, Jinhong

    The receptor of advanced glycation end product (RAGE) is a multiligand receptor of the immunoglobulin superfamily of cell surface molecules, which plays an important role in immune responses. Full-length RAGE includes three extracellular immunoglobulin domains, a transmembrane domain and an intracellular domain. It is a pattern recognition receptor that can bind diverse ligands. NMR spectroscopy and x-ray crystallization studies of the extracellular domains of RAGE indicate that RAGE ligands bind by distinct charge- and hydrophobicity-dependent mechanisms. It is found that calgranulin binding to the C1C2 domain or AGEs binding to the V domain activates extracellular signaling, which triggers interactions of the RAGE cytoplasmic tail (ctRAGE) with intracellular effector, such as diaphanous 1 (DIAPH1), to initiate signal transduction cascades. ctRAGE is essential for RAGE-ligand-mediated signal transduction and consequent modulation of gene expression and cellular properties. RAGE is over-expressed in diseased tissues of most RAGE-associated pathogenic conditions, such as complications of Alzheimer's diseases, diabetes, vascular diseases, inflammation, cancers and neurodegeneration. They are the major diseases affecting a large population worldwide. RAGE can function as a biomarker or drug target for these diseases. The cytoplasmic tail of RAGE can be used as a drug target to inhibit RAGE-induced intracellular signaling by small molecule inhibitors to treat RAGE-associated diseases. We developed a high throughput screening assay with which we probed a small molecule library of 58,000 compounds to find that 777 small molecules displayed 50% inhibition and 97 compounds demonstrated dose-dependent inhibition of the binding of ctRAGE-DIAPH1. Eventually, there were 13 compounds which displayed dose-dependent inhibition of ctRAGE binding to DIAPH1 and direct binding to ctRAGE analyzed by 15N HSQC-NMR and native tryptophan fluorescence titration experiments; thus, they were

  3. Applicability of International and DOE Target Values to ALD Destructive Measurement Applications

    International Nuclear Information System (INIS)

    Holland, M.K.

    2002-01-01

    International Target values and target value applicability are a function of the nuclear material processing campaign or application for which the accountability measurement method is being applied. Safeguarding significant quantities of nuclear-grade materials requires that accountability measurements be as accurate, precise, and representative as practically possible. In general, the ITV provides a benchmark for determining generic acceptability of the performance of the various accountability measurement methods, since it represents a performance level that is accepted as highly reliable. There are cases where it is acceptable to select alternative accountability methods not specifically referenced by the ITV, or to use the recognized measurement method, even though the uncertainties are greater than the target values

  4. The 13th International Workshop on Targetry and Target Chemistry Proceedings

    DEFF Research Database (Denmark)

    Haroun, Samar; Givskov, Alex David; Jensen, Mikael

    in situ target chemistry and the engineering required to optimize production yields. In the workshop, experience, ideas and information are freely and openly shared; learning and collaborations are fostered, with active participation by all attendees. This participation includes both formal and informal......This report contains the complete proceedings of the 13th International Workshop on Targetry and Target Chemistry. The Workshop was held at Risø National Laboratory for Sustainable Energy on July 26-28 2010. The workshop deals with the development of methods and systems for efficient production...... of the WTTC is to advance the science associated with radioisotope production targetry. The Workshops are designed to bring experienced targetry scientists together with newcomers to the field, both from industry and academia, to discuss issues of targetry and target chemistry and approaches to exploring...

  5. Treating juvenile idiopathic arthritis to target: recommendations of an international task force.

    Science.gov (United States)

    Ravelli, Angelo; Consolaro, Alessandro; Horneff, Gerd; Laxer, Ronald M; Lovell, Daniel J; Wulffraat, Nico M; Akikusa, Jonathan D; Al-Mayouf, Sulaiman M; Antón, Jordi; Avcin, Tadej; Berard, Roberta A; Beresford, Michael W; Burgos-Vargas, Ruben; Cimaz, Rolando; De Benedetti, Fabrizio; Demirkaya, Erkan; Foell, Dirk; Itoh, Yasuhiko; Lahdenne, Pekka; Morgan, Esi M; Quartier, Pierre; Ruperto, Nicolino; Russo, Ricardo; Saad-Magalhães, Claudia; Sawhney, Sujata; Scott, Christiaan; Shenoi, Susan; Swart, Joost F; Uziel, Yosef; Vastert, Sebastiaan J; Smolen, Josef S

    2018-06-01

    Recent therapeutic advances in juvenile idiopathic arthritis (JIA) have made remission an achievable goal for most patients. Reaching this target leads to improved outcomes. The objective was to develop recommendations for treating JIA to target. A Steering Committee formulated a set of recommendations based on evidence derived from a systematic literature review. These were subsequently discussed, amended and voted on by an international Task Force of 30 paediatric rheumatologists in a consensus-based, Delphi-like procedure. Although the literature review did not reveal trials that compared a treat-to-target approach with another or no strategy, it provided indirect evidence regarding an optimised approach to therapy that facilitated development of recommendations. The group agreed on six overarching principles and eight recommendations. The main treatment target, which should be based on a shared decision with parents/patients, was defined as remission, with the alternative target of low disease activity. The frequency and timeline of follow-up evaluations to ensure achievement and maintenance of the target depend on JIA category and level of disease activity. Additional recommendations emphasise the importance of ensuring adequate growth and development and avoiding long-term systemic glucocorticoid administration to maintain the target. All items were agreed on by more than 80% of the members of the Task Force. A research agenda was formulated. The Task Force developed recommendations for treating JIA to target, being aware that the evidence is not strong and needs to be expanded by future research. These recommendations can inform various stakeholders about strategies to reach optimal outcomes for JIA. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

  6. International Spine Radiosurgery Consortium Consensus Guidelines for Target Volume Definition in Spinal Stereotactic Radiosurgery

    International Nuclear Information System (INIS)

    Cox, Brett W.; Spratt, Daniel E.; Lovelock, Michael; Bilsky, Mark H.; Lis, Eric; Ryu, Samuel; Sheehan, Jason; Gerszten, Peter C.; Chang, Eric; Gibbs, Iris; Soltys, Scott; Sahgal, Arjun; Deasy, Joe; Flickinger, John; Quader, Mubina; Mindea, Stefan

    2012-01-01

    Purpose: Spinal stereotactic radiosurgery (SRS) is increasingly used to manage spinal metastases. However, target volume definition varies considerably and no consensus target volume guidelines exist. This study proposes consensus target volume definitions using common scenarios in metastatic spine radiosurgery. Methods and Materials: Seven radiation oncologists and 3 neurological surgeons with spinal radiosurgery expertise independently contoured target and critical normal structures for 10 cases representing common scenarios in metastatic spine radiosurgery. Each set of volumes was imported into the Computational Environment for Radiotherapy Research. Quantitative analysis was performed using an expectation maximization algorithm for Simultaneous Truth and Performance Level Estimation (STAPLE) with kappa statistics calculating agreement between physicians. Optimized confidence level consensus contours were identified using histogram agreement analysis and characterized to create target volume definition guidelines. Results: Mean STAPLE agreement sensitivity and specificity was 0.76 (range, 0.67-0.84) and 0.97 (range, 0.94-0.99), respectively, for gross tumor volume (GTV) and 0.79 (range, 0.66-0.91) and 0.96 (range, 0.92-0.98), respectively, for clinical target volume (CTV). Mean kappa agreement was 0.65 (range, 0.54-0.79) for GTV and 0.64 (range, 0.54-0.82) for CTV (P<.01 for GTV and CTV in all cases). STAPLE histogram agreement analysis identified optimal consensus contours (80% confidence limit). Consensus recommendations include that the CTV should include abnormal marrow signal suspicious for microscopic invasion and an adjacent normal bony expansion to account for subclinical tumor spread in the marrow space. No epidural CTV expansion is recommended without epidural disease, and circumferential CTVs encircling the cord should be used only when the vertebral body, bilateral pedicles/lamina, and spinous process are all involved or there is extensive metastatic

  7. Genomic Targets and Features of BarA-UvrY (-SirA Signal Transduction Systems.

    Directory of Open Access Journals (Sweden)

    Tesfalem R Zere

    Full Text Available The two-component signal transduction system BarA-UvrY of Escherichia coli and its orthologs globally regulate metabolism, motility, biofilm formation, stress resistance, virulence of pathogens and quorum sensing by activating the transcription of genes for regulatory sRNAs, e.g. CsrB and CsrC in E. coli. These sRNAs act by sequestering the RNA binding protein CsrA (RsmA away from lower affinity mRNA targets. In this study, we used ChIP-exo to identify, at single nucleotide resolution, genomic sites for UvrY (SirA binding in E. coli and Salmonella enterica. The csrB and csrC genes were the strongest targets of crosslinking, which required UvrY phosphorylation by the BarA sensor kinase. Crosslinking occurred at two sites, an inverted repeat sequence far upstream of the promoter and a site near the -35 sequence. DNAse I footprinting revealed specific binding of UvrY in vitro only to the upstream site, indicative of additional binding requirements and/or indirect binding to the downstream site. Additional genes, including cspA, encoding the cold-shock RNA-binding protein CspA, showed weaker crosslinking and modest or negligible regulation by UvrY. We conclude that the global effects of UvrY/SirA on gene expression are primarily mediated by activating csrB and csrC transcription. We also used in vivo crosslinking and other experimental approaches to reveal new features of csrB/csrC regulation by the DeaD and SrmB RNA helicases, IHF, ppGpp and DksA. Finally, the phylogenetic distribution of BarA-UvrY was analyzed and found to be uniquely characteristic of γ-Proteobacteria and strongly anti-correlated with fliW, which encodes a protein that binds to CsrA and antagonizes its activity in Bacillus subtilis. We propose that BarA-UvrY and orthologous TCS transcribe sRNA antagonists of CsrA throughout the γ-Proteobacteria, but rarely or never perform this function in other species.

  8. Challenges Handling Magnetospheric and Ionospheric Signals in Internal Geomagnetic Field Modelling

    DEFF Research Database (Denmark)

    Finlay, Chris; Lesur, V.; Thébault, E.

    2017-01-01

    systems in the ionosphere and magnetosphere. In order to fully exploit magnetic data to probe the physical properties and dynamics of the Earth’s interior, field models with suitable treatments of external sources, and their associated induced signals, are essential. Here we review the methods presently......-by-track analysis to characterize magnetospheric field fluctuations, differences in internal field models that result from alternative treatments of the quiet-time ionospheric field, and challenges associated with rapidly changing, but spatially correlated, magnetic signatures of polar cap current systems. Possible...

  9. Signal processing, sensor fusion, and target recognition; Proceedings of the Meeting, Orlando, FL, Apr. 20-22, 1992

    Science.gov (United States)

    Libby, Vibeke; Kadar, Ivan

    Consideration is given to a multiordered mapping technique for target prioritization, a neural network approach to multiple-target-tracking problems, a multisensor fusion algorithm for multitarget multibackground classification, deconvolutiom of multiple images of the same object, neural networks and genetic algorithms for combinatorial optimization of sensor data fusion, classification of atmospheric acoustic signals from fixed-wing aircraft, and an optics approach to sensor fusion for target recognition. Also treated are a zoom lens for automatic target recognition, a hybrid model for the analysis of radar sensors, an innovative test bed for developing and assessing air-to-air noncooperative target identification algorithms, SAR imagery scene segmentation using fractal processing, sonar feature-based bandwidth compression, laboratory experiments for a new sonar system, computational algorithms for discrete transform using fixed-size filter matrices, and pattern recognition for power systems.

  10. The evolving roles of canonical WNT signaling in stem cells and tumorigenesis: Implications in targeted cancer therapies

    Science.gov (United States)

    Yang, Ke; Wang, Xin; Zhang, Hongmei; Wang, Zhongliang; Nan, Guoxin; Li, Yasha; Zhang, Fugui; Mohammed, Maryam K.; Haydon, Rex C.; Luu, Hue H.; Bi, Yang; He, Tong-Chuan

    2015-01-01

    The canonical WNT/β-catenin signaling pathway governs a myriad of biological processes underlying development and maintenance of adult tissue homeostasis, including regulation of stem cell self-renewal, cell proliferation, differentiation, and apoptosis. WNTs are secreted lipid-modified glycoproteins that act as short-range ligands to activate receptor-mediated signaling pathways. The hallmark of the canonical pathway is the activation of β-catenin mediated transcriptional activity. Canonical WNTs control the β-catenin dynamics as the cytoplasmic level of β-catenin is tightly regulated via phosphorylation by the ‘destruction complex’, consisting of glycogen synthase kinase 3β (GSK3β), casein kinase 1α (CK1α), the scaffold protein AXIN, and the tumor suppressor adenomatous polyposis coli (APC). Aberrant regulation of this signaling cascade is associated with varieties of human diseases, especially cancers. Over the past decade, significant progress has been made in understanding the mechanisms of canonical WNT signaling. In this review, we focus on the current understanding of WNT signaling at the extracellular, cytoplasmic membrane, and intracellular/nuclear levels, including the emerging knowledge of crosstalk with other pathways. Recent progresses in developing novel WNT pathway-targeted therapies will also be reviewed. Thus, this review is intended to serve as a refresher of the current understanding about the physiologic and pathogenic roles of WNT/β-catenin signaling pathway, and to outline potential therapeutic opportunities by targeting the canonical WNT pathway. PMID:26618721

  11. DOA Estimation of Low Altitude Target Based on Adaptive Step Glowworm Swarm Optimization-multiple Signal Classification Algorithm

    Directory of Open Access Journals (Sweden)

    Zhou Hao

    2015-06-01

    Full Text Available The traditional MUltiple SIgnal Classification (MUSIC algorithm requires significant computational effort and can not be employed for the Direction Of Arrival (DOA estimation of targets in a low-altitude multipath environment. As such, a novel MUSIC approach is proposed on the basis of the algorithm of Adaptive Step Glowworm Swarm Optimization (ASGSO. The virtual spatial smoothing of the matrix formed by each snapshot is used to realize the decorrelation of the multipath signal and the establishment of a fullorder correlation matrix. ASGSO optimizes the function and estimates the elevation of the target. The simulation results suggest that the proposed method can overcome the low altitude multipath effect and estimate the DOA of target readily and precisely without radar effective aperture loss.

  12. Statistics of Acoustic Pulse Signals Through Nonlinear Internal Waves on the Continental Shelf of the Northeastern South China Sea

    National Research Council Canada - National Science Library

    Reeves, Justin M

    2008-01-01

    ...) was conducted from 13 - 15 April 2005 on the continental shelf in the northeast portion of the South China Sea to study the effects of nonlinear internal waves on the transmission of a 400-Hz signal...

  13. International target values 2010 for achievable measurement uncertainties in nuclear material accountancy

    International Nuclear Information System (INIS)

    Dias, Fabio C.; Almeida, Silvio G. de; Renha Junior, Geraldo

    2011-01-01

    The International Target Values (ITVs) are reasonable uncertainty estimates that can be used in judging the reliability of measurement techniques applied to industrial nuclear and fissile materials subject to accountancy and/or safeguards verification. In the absence of relevant experimental estimates, ITVs can also be used to select measurement techniques and calculate sample population during the planning phase of verification activities. It is important to note that ITVs represent estimates of the 'state-of-the-practice', which should be achievable under routine measurement conditions affecting both facility operators and safeguards inspectors, not only in the field, but also in laboratory. Tabulated values cover measurement methods used for the determination of volume or mass of the nuclear material, for its elemental and isotopic assays, and for its sampling. The 2010 edition represents the sixth revision of the International Target Values (ITVs), issued by the International Atomic Energy Agency (IAEA) as a Safeguards Technical Report (STR-368). The first version was released as 'Target Values' in 1979 by the Working Group on Techniques and Standards for Destructive Analysis (WGDA) of the European Safeguards Research and Development Association (ESARDA) and focused on destructive analytical methods. In the latest 2010 revision, international standards in estimating and expressing uncertainties have been considered while maintaining a format that allows comparison with the previous editions of the ITVs. Those standards have been usually applied in QC/QA programmes, as well as qualification of methods, techniques and instruments. Representatives of the Brazilian Nuclear Energy Commission (CNEN) and the Brazilian-Argentine Agency for Accounting and Control of Nuclear Materials (ABACC) participated in previous Consultants Group Meetings since the one convened to establish the first list of ITVs released in 1993 and in subsequent revisions, including the latest one

  14. Definition of internal target volume and domestric study for hepatocellular carcinoma using four-dimensional CT

    International Nuclear Information System (INIS)

    Xi Mian; Liu Mengzhong; Deng Xiaowu; Zhang Li; Huang Xiaoyan; Cai Ling

    2009-01-01

    Objective: To define individualized internal target volume (ITV) for hepatocellular carcinoma using four-dimensional (4D) CT, and to compare the differences in target volume definition and dose distribution among 3D, 4D and respiratory-gated plans. Methods: 4DCT scanning was obtained for 12 patients with hepatocellular. Gross tumor volume (GTV), clinical target volume (CTV) and normal tissues were contoured on all 10 respiratory phases of 4DCT images. The 3D, 4D and gated treatment plans were prepared for each patient using three different planning target volumes (PTVs): 1) PTV 3D was derived from a single CTV plus conventional margins; 2) PTV 4D was derived from ITV 4D , which encompassed all 10 CTVs plus setup margins (SMs); 3) PT Gating was derived from ITV Gating , which encompassed 3 CTVs within gating-window at end-expiration plus SMs. The PTV volume and dose distribution were compared among different plans. Results: The PTV3D was the largest in all 12 patients, but still missed partial target volume in 5 patients when comparing with PTV4D. Both the 4D plans and the gated plans spared more normal tissues than the 3D plans, especially the liver. Without increasing normal tissue dose, the 4D plans allowed for increasing the calculated dose from (50.8 ± 2.0) Gy (3D plans) to (54.7 ± 3.3) Gy, and the gated plans could further increase the dose to (58.0 ± 3.9) Gy. Conclusions: The 4DCT-based plans can ensure optimal target coverage with less irradiation of normal tissues and allow dose escalation when compared with 3D plans. Respiratory gated radiotherapy can further reduce the target volumes to spare more surrounding tissues, especially for patients with large extent of respiratory mobility. (authors)

  15. A model system for targeted drug release triggered by biomolecular signals logically processed through enzyme logic networks.

    Science.gov (United States)

    Mailloux, Shay; Halámek, Jan; Katz, Evgeny

    2014-03-07

    A new Sense-and-Act system was realized by the integration of a biocomputing system, performing analytical processes, with a signal-responsive electrode. A drug-mimicking release process was triggered by biomolecular signals processed by different logic networks, including three concatenated AND logic gates or a 3-input OR logic gate. Biocatalytically produced NADH, controlled by various combinations of input signals, was used to activate the electrochemical system. A biocatalytic electrode associated with signal-processing "biocomputing" systems was electrically connected to another electrode coated with a polymer film, which was dissolved upon the formation of negative potential releasing entrapped drug-mimicking species, an enzyme-antibody conjugate, operating as a model for targeted immune-delivery and consequent "prodrug" activation. The system offers great versatility for future applications in controlled drug release and personalized medicine.

  16. Wnt and Notch signaling pathway involved in wound healing by targeting c-Myc and Hes1 separately.

    Science.gov (United States)

    Shi, Yan; Shu, Bin; Yang, Ronghua; Xu, Yingbin; Xing, Bangrong; Liu, Jian; Chen, Lei; Qi, Shaohai; Liu, Xusheng; Wang, Peng; Tang, Jinming; Xie, Julin

    2015-06-16

    Wnt and Notch signaling pathways are critically involved in relative cell fate decisions within the development of cutaneous tissues. Moreover, several studies identified the above two pathways as having a significant role during wound healing. However, their biological effects during cutaneous tissues repair are unclear. We employed a self-controlled model (Sprague-Dawley rats with full-thickness skin wounds) to observe the action and effect of Wnt/β-catenin and Notch signalings in vivo. The quality of wound repair relevant to the gain/loss-of-function Wnt/β-catenin and Notch activation was estimated by hematoxylin-and-eosin and Masson staining. Immunofluorescence analysis and Western blot analysis were used to elucidate the underlying mechanism of the regulation of Wnt and Notch signaling pathways in wound healing. Meanwhile, epidermal stem cells (ESCs) were cultured in keratinocyte serum-free medium with Jaggedl or in DAPT (N-[(3,5-difluorophenyl)acetyl]-L-alanyl-2-phenyl]glycine-1,1-dimethylethyl) to investigate whether the interruption of Notch signaling contributes to the expression of Wnt/β-catenin signaling. The results showed that in vivo the gain-of-function Wnt/β-catenin and Notch activation extended the ability to promote wound closure. We further determined that activation or inhibition of Wnt signaling and Notch signaling can affect the proliferation of ESCs, the differentiation and migration of keratinocytes, and follicle regeneration by targeting c-Myc and Hes1, which ultimately lead to enhanced or delayed wound healing. Furthermore, Western blot analysis suggested that the two pathways might interact in vivo and in vitro. These results suggest that Wnt and Notch signalings play important roles in cutaneous repair by targeting c-Myc and Hes1 separately. What's more, interaction between the above two pathways might act as a vital role in regulation of wound healing.

  17. From Target to Implementation: Perspectives for the International Governance of Forest Landscape Restoration

    Directory of Open Access Journals (Sweden)

    Till Pistorius

    2014-03-01

    Full Text Available Continuing depletion of forest resources, particularly in tropical developing countries, has turned vast areas of intact ecosystems into urbanized and agricultural lands. The degree of degradation varies, but in most cases, the ecosystem functions and the ability to provide a variety of ecosystem services are severely impaired. In addition to many other challenges, successful forest restoration of these lands requires considerable resources and funding, but the ecological, economic and social benefits have the potential to outweigh the investment. As a consequence, at the international policy level, restoration is seen as a field of land use activities that provides significant contributions to simultaneously achieving different environmental and social policy objectives. Accordingly, different policy processes at the international policy level have made ecological landscape restoration a global priority, in particular the Convention on Biological Diversity with the Aichi Target 15 agreed upon in 2010, which aims at restoring 15% of all degraded land areas by 2020. While such ambitious policy targets are important for recognizing and agreeing upon solutions for environmental problems, they are unlikely to be further substantiated or governed. The objective of this paper is thus to develop a complementary governance approach to the top-down implementation of the Aichi target. Drawing on collaborative and network governance theories, we discuss the potential of a collaborative networked governance approach and perspectives for overcoming the inherent challenges facing a rapid large-scale restoration of degraded lands.

  18. Presynaptic type III neuregulin1-ErbB signaling targets {alpha}7 nicotinic acetylcholine receptors to axons.

    Science.gov (United States)

    Hancock, Melissa L; Canetta, Sarah E; Role, Lorna W; Talmage, David A

    2008-05-05

    Type III Neuregulin1 (Nrg1) isoforms are membrane-tethered proteins capable of participating in bidirectional juxtacrine signaling. Neuronal nicotinic acetylcholine receptors (nAChRs), which can modulate the release of a rich array of neurotransmitters, are differentially targeted to presynaptic sites. We demonstrate that Type III Nrg1 back signaling regulates the surface expression of alpha7 nAChRs along axons of sensory neurons. Stimulation of Type III Nrg1 back signaling induces an increase in axonal surface alpha7 nAChRs, which results from a redistribution of preexisting intracellular pools of alpha7 rather than from increased protein synthesis. We also demonstrate that Type III Nrg1 back signaling activates a phosphatidylinositol 3-kinase signaling pathway and that activation of this pathway is required for the insertion of preexisting alpha7 nAChRs into the axonal plasma membrane. These findings, in conjunction with prior results establishing that Type III Nrg1 back signaling controls gene transcription, demonstrate that Type III Nrg1 back signaling can regulate both short-and long-term changes in neuronal function.

  19. Presynaptic type III neuregulin1-ErbB signaling targets alpha7 nicotinic acetylcholine receptors to axons.

    Science.gov (United States)

    Hancock, Melissa L; Canetta, Sarah E; Role, Lorna W; Talmage, David A

    2008-06-01

    Type III Neuregulin1 (Nrg1) isoforms are membrane-tethered proteins capable of participating in bidirectional juxtacrine signaling. Neuronal nicotinic acetylcholine receptors (nAChRs), which can modulate the release of a rich array of neurotransmitters, are differentially targeted to presynaptic sites. We demonstrate that Type III Nrg1 back signaling regulates the surface expression of alpha7 nAChRs along axons of sensory neurons. Stimulation of Type III Nrg1 back signaling induces an increase in axonal surface alpha7 nAChRs, which results from a redistribution of preexisting intracellular pools of alpha7 rather than from increased protein synthesis. We also demonstrate that Type III Nrg1 back signaling activates a phosphatidylinositol 3-kinase signaling pathway and that activation of this pathway is required for the insertion of preexisting alpha7 nAChRs into the axonal plasma membrane. These findings, in conjunction with prior results establishing that Type III Nrg1 back signaling controls gene transcription, demonstrate that Type III Nrg1 back signaling can regulate both short-and long-term changes in neuronal function.

  20. Presynaptic Type III Neuregulin1-ErbB signaling targets α7 nicotinic acetylcholine receptors to axons

    Science.gov (United States)

    Hancock, Melissa L.; Canetta, Sarah E.; Role, Lorna W.; Talmage, David A.

    2008-01-01

    Type III Neuregulin1 (Nrg1) isoforms are membrane-tethered proteins capable of participating in bidirectional juxtacrine signaling. Neuronal nicotinic acetylcholine receptors (nAChRs), which can modulate the release of a rich array of neurotransmitters, are differentially targeted to presynaptic sites. We demonstrate that Type III Nrg1 back signaling regulates the surface expression of α7 nAChRs along axons of sensory neurons. Stimulation of Type III Nrg1 back signaling induces an increase in axonal surface α7 nAChRs, which results from a redistribution of preexisting intracellular pools of α7 rather than from increased protein synthesis. We also demonstrate that Type III Nrg1 back signaling activates a phosphatidylinositol 3-kinase signaling pathway and that activation of this pathway is required for the insertion of preexisting α7 nAChRs into the axonal plasma membrane. These findings, in conjunction with prior results establishing that Type III Nrg1 back signaling controls gene transcription, demonstrate that Type III Nrg1 back signaling can regulate both short-and long-term changes in neuronal function. PMID:18458158

  1. Signal Processing of Ground Penetrating Radar Using Spectral Estimation Techniques to Estimate the Position of Buried Targets

    Directory of Open Access Journals (Sweden)

    Shanker Man Shrestha

    2003-11-01

    Full Text Available Super-resolution is very important for the signal processing of GPR (ground penetration radar to resolve closely buried targets. However, it is not easy to get high resolution as GPR signals are very weak and enveloped by the noise. The MUSIC (multiple signal classification algorithm, which is well known for its super-resolution capacity, has been implemented for signal and image processing of GPR. In addition, conventional spectral estimation technique, FFT (fast Fourier transform, has also been implemented for high-precision receiving signal level. In this paper, we propose CPM (combined processing method, which combines time domain response of MUSIC algorithm and conventional IFFT (inverse fast Fourier transform to obtain a super-resolution and high-precision signal level. In order to support the proposal, detailed simulation was performed analyzing SNR (signal-to-noise ratio. Moreover, a field experiment at a research field and a laboratory experiment at the University of Electro-Communications, Tokyo, were also performed for thorough investigation and supported the proposed method. All the simulation and experimental results are presented.

  2. Cell signaling heterogeneity is modulated by both cell-intrinsic and -extrinsic mechanisms: An integrated approach to understanding targeted therapy.

    Science.gov (United States)

    Kim, Eunjung; Kim, Jae-Young; Smith, Matthew A; Haura, Eric B; Anderson, Alexander R A

    2018-03-01

    During the last decade, our understanding of cancer cell signaling networks has significantly improved, leading to the development of various targeted therapies that have elicited profound but, unfortunately, short-lived responses. This is, in part, due to the fact that these targeted therapies ignore context and average out heterogeneity. Here, we present a mathematical framework that addresses the impact of signaling heterogeneity on targeted therapy outcomes. We employ a simplified oncogenic rat sarcoma (RAS)-driven mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase-protein kinase B (PI3K-AKT) signaling pathway in lung cancer as an experimental model system and develop a network model of the pathway. We measure how inhibition of the pathway modulates protein phosphorylation as well as cell viability under different microenvironmental conditions. Training the model on this data using Monte Carlo simulation results in a suite of in silico cells whose relative protein activities and cell viability match experimental observation. The calibrated model predicts distributional responses to kinase inhibitors and suggests drug resistance mechanisms that can be exploited in drug combination strategies. The suggested combination strategies are validated using in vitro experimental data. The validated in silico cells are further interrogated through an unsupervised clustering analysis and then integrated into a mathematical model of tumor growth in a homogeneous and resource-limited microenvironment. We assess posttreatment heterogeneity and predict vast differences across treatments with similar efficacy, further emphasizing that heterogeneity should modulate treatment strategies. The signaling model is also integrated into a hybrid cellular automata (HCA) model of tumor growth in a spatially heterogeneous microenvironment. As a proof of concept, we simulate tumor responses to targeted therapies in a spatially segregated tissue structure containing tumor

  3. Signal and data processing of small targets 1990; Proceedings of the Meeting, Orlando, FL, Apr. 16-18, 1990

    Science.gov (United States)

    Drummond, Oliver E.

    Various papers on signal and data processing of small targets are presented. Individual topics addressed include: clutter rejection using multispectral processing, new sensor for automatic guidance, Doppler domain localized generalized-likelihood-ratio detector, linear filter for resolution of point sources, analysis of order-statistic filters for robust detection, distribution functions for additive Gaussian and gamma noise, temperature discrimination of closely space objects, knowledge-based tracking algorithm, detecting and tracking low-observable targets using IR, weak target detection using the entropy concept, measurement-based neural-net multitarget tracker, object-track closed-form solution in angle space, passive-sensor data association for tracking. Also discussed are: application of MHT to dim moving targets, automatic static covariance analysis with mathematica, neural network implementation of plot/track association, application of Bayesian networks to multitarget tracking, tracking clusters and extended objects with multiple sensors, target tracking by human operator, finite impulse response estimator, multitarget tracking using an extended Kalman filter, maneuvering target tracking using a two-state model algorithm, mixture reduction algorithms for target tracking in clutter, scene interpretation approach to high-level target tracking.

  4. Hsa-miR-11181 regulates Wnt signaling pathway through targeting of APC2 transcripts in SW480 cell line.

    Science.gov (United States)

    Dokanehiifard, Sadat; Soltani, Bahram M

    2018-01-30

    Wnt signaling plays important roles in differentiation, morphogenesis and development. This signaling pathway is highly regulated at all levels and microRNAs are small noncoding RNAs regulating Wnt signaling. Here, we intended to investigate hsa-miR-11181 (a novel miRNA located in TrkC gene) effect on Wnt signaling pathway in SW480 cell line. TOP/FOP flash assay indicated up-regulation of Wnt signaling, following the overexpression of hsa-miR-11181, verified through RT-qPCR. Bioinformatics analysis predicted APC1, APC2 and Axin1 might be targeted by hsa-miR-11181. Then, RT-qPCR analysis indicated that APC2 and Axin1 have been significantly down-regulated following the hsa-miR-11181 overexpression. However dual luciferase assay analysis supported only APC2 3'-UTR is directly targeted by this miRNA. Then, treatment of SW480 cells with Wnt-inhibitory small molecules supported the effect of hsa-miR-11181 at the inhibitory complex level containing APC2 protein. Consistently, viability of SW480 cells overexpressing hsa-miR-11181 was significantly elevated, measured through MTT assay. Overall, these results suggest that hsa-miR-11181 may play a crucial role in Wnt signaling regulation and confirmed that APC2 3'-UTR is targeted by hsa-miR-11181 and propose the presence of its recognition sites in the promoter or coding regions of Axin1 gene. Copyright © 2017. Published by Elsevier B.V.

  5. Structural Features Facilitating Tumor Cell Targeting and Internalization by Bleomycin and Its Disaccharide

    Science.gov (United States)

    2016-01-01

    We have shown previously that the bleomycin (BLM) carbohydrate moiety can recapitulate the tumor cell targeting effects of the entire BLM molecule, that BLM itself is modular in nature consisting of a DNA-cleaving aglycone which is delivered selectively to the interior of tumor cells by its carbohydrate moiety, and that there are disaccharides structurally related to the BLM disaccharide which are more efficient than the natural disaccharide at tumor cell targeting/uptake. Because BLM sugars can deliver molecular cargoes selectively to tumor cells, and thus potentially form the basis for a novel antitumor strategy, it seemed important to consider additional structural features capable of affecting the efficiency of tumor cell recognition and delivery. These included the effects of sugar polyvalency and net charge (at physiological pH) on tumor cell recognition, internalization, and trafficking. Since these parameters have been shown to affect cell surface recognition, internalization, and distribution in other contexts, this study has sought to define the effects of these structural features on tumor cell recognition by bleomycin and its disaccharide. We demonstrate that both can have a significant effect on tumor cell binding/internalization, and present data which suggests that the metal ions normally bound by bleomycin following clinical administration may significantly contribute to the efficiency of tumor cell uptake, in addition to their characterized function in DNA cleavage. A BLM disaccharide-Cy5** conjugate incorporating the positively charged dipeptide d-Lys-d-Lys was found to associate with both the mitochondria and the nuclear envelope of DU145 cells, suggesting possible cellular targets for BLM disaccharide–cytotoxin conjugates. PMID:25905565

  6. Structural features facilitating tumor cell targeting and internalization by bleomycin and its disaccharide.

    Science.gov (United States)

    Yu, Zhiqiang; Paul, Rakesh; Bhattacharya, Chandrabali; Bozeman, Trevor C; Rishel, Michael J; Hecht, Sidney M

    2015-05-19

    We have shown previously that the bleomycin (BLM) carbohydrate moiety can recapitulate the tumor cell targeting effects of the entire BLM molecule, that BLM itself is modular in nature consisting of a DNA-cleaving aglycone which is delivered selectively to the interior of tumor cells by its carbohydrate moiety, and that there are disaccharides structurally related to the BLM disaccharide which are more efficient than the natural disaccharide at tumor cell targeting/uptake. Because BLM sugars can deliver molecular cargoes selectively to tumor cells, and thus potentially form the basis for a novel antitumor strategy, it seemed important to consider additional structural features capable of affecting the efficiency of tumor cell recognition and delivery. These included the effects of sugar polyvalency and net charge (at physiological pH) on tumor cell recognition, internalization, and trafficking. Since these parameters have been shown to affect cell surface recognition, internalization, and distribution in other contexts, this study has sought to define the effects of these structural features on tumor cell recognition by bleomycin and its disaccharide. We demonstrate that both can have a significant effect on tumor cell binding/internalization, and present data which suggests that the metal ions normally bound by bleomycin following clinical administration may significantly contribute to the efficiency of tumor cell uptake, in addition to their characterized function in DNA cleavage. A BLM disaccharide-Cy5** conjugate incorporating the positively charged dipeptide d-Lys-d-Lys was found to associate with both the mitochondria and the nuclear envelope of DU145 cells, suggesting possible cellular targets for BLM disaccharide-cytotoxin conjugates.

  7. A New Built-in Self Test Scheme for Phase-Locked Loops Using Internal Digital Signals

    Science.gov (United States)

    Kim, Youbean; Kim, Kicheol; Kim, Incheol; Kang, Sungho

    Testing PLLs (phase-locked loops) is becoming an important issue that affects both time-to-market and production cost of electronic systems. Though a PLL is the most common mixed-signal building block, it is very difficult to test due to internal analog blocks and signals. In this paper, we propose a new PLL BIST (built-in self test) using the distorted frequency detector that uses only internal digital signals. The proposed BIST does not need to load any analog nodes of the PLL. Therefore, it provides an efficient defect-oriented structural test scheme, reduced area overhead, and improved test quality compared with previous approaches.

  8. 135La as an auger-electron emitter for targeted internal radiotherapy

    DEFF Research Database (Denmark)

    Fonslet, Jesper; Lee, Boon Quan; Tran, Thuy A.

    2018-01-01

    Introduction: 135La has favorable nuclear and chemical properties for Auger-based targeted internal radiotherapy. Here we present detailed investigations of the production, emissions, imaging characteristics, and dosimetry related to 135La therapy. Methods and Results: 135La was produced by 16.5 Me....... The generated Auger spectrum was used to recalculate cellular S-factors. Conclusion: 135La was produced with high specific activity, reactivity, radionuclidic purity, and yield. The emission spectrum and the dosimetry are favorable for internal radionuclide therapy. ....... recovered > 98 % of the 135La with an effective molar activity of 70 ±20 GBq/µmol. To better assess cellular and organ dosimetry of this nuclide, we have recalculated the X-ray and Auger emission spectra using a Monte Carlo model accounting for effects of multiple vacancies during the Auger cascade...

  9. Design and Preliminary Testing of the International Docking Adapter's Peripheral Docking Target

    Science.gov (United States)

    Foster, Christopher W.; Blaschak, Johnathan; Eldridge, Erin A.; Brazzel, Jack P.; Spehar, Peter T.

    2015-01-01

    The International Docking Adapter's Peripheral Docking Target (PDT) was designed to allow a docking spacecraft to judge its alignment relative to the docking system. The PDT was designed to be compatible with relative sensors using visible cameras, thermal imagers, or Light Detection and Ranging (LIDAR) technologies. The conceptual design team tested prototype designs and materials to determine the contrast requirements for the features. This paper will discuss the design of the PDT, the methodology and results of the tests, and the conclusions pertaining to PDT design that were drawn from testing.

  10. Genome-wide identification of Bcl11b gene targets reveals role in brain-derived neurotrophic factor signaling.

    Directory of Open Access Journals (Sweden)

    Bin Tang

    Full Text Available B-cell leukemia/lymphoma 11B (Bcl11b is a transcription factor showing predominant expression in the striatum. To date, there are no known gene targets of Bcl11b in the nervous system. Here, we define targets for Bcl11b in striatal cells by performing chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-seq in combination with genome-wide expression profiling. Transcriptome-wide analysis revealed that 694 genes were significantly altered in striatal cells over-expressing Bcl11b, including genes showing striatal-enriched expression similar to Bcl11b. ChIP-seq analysis demonstrated that Bcl11b bound a mixture of coding and non-coding sequences that were within 10 kb of the transcription start site of an annotated gene. Integrating all ChIP-seq hits with the microarray expression data, 248 direct targets of Bcl11b were identified. Functional analysis on the integrated gene target list identified several zinc-finger encoding genes as Bcl11b targets, and further revealed a significant association of Bcl11b to brain-derived neurotrophic factor/neurotrophin signaling. Analysis of ChIP-seq binding regions revealed significant consensus DNA binding motifs for Bcl11b. These data implicate Bcl11b as a novel regulator of the BDNF signaling pathway, which is disrupted in many neurological disorders. Specific targeting of the Bcl11b-DNA interaction could represent a novel therapeutic approach to lowering BDNF signaling specifically in striatal cells.

  11. Activin signaling targeted by insulin/dFOXO regulates aging and muscle proteostasis in Drosophila.

    Directory of Open Access Journals (Sweden)

    Hua Bai

    2013-11-01

    Full Text Available Reduced insulin/IGF signaling increases lifespan in many animals. To understand how insulin/IGF mediates lifespan in Drosophila, we performed chromatin immunoprecipitation-sequencing analysis with the insulin/IGF regulated transcription factor dFOXO in long-lived insulin/IGF signaling genotypes. Dawdle, an Activin ligand, is bound and repressed by dFOXO when reduced insulin/IGF extends lifespan. Reduced Activin signaling improves performance and protein homeostasis in muscles of aged flies. Activin signaling through the Smad binding element inhibits the transcription of Autophagy-specific gene 8a (Atg8a within muscle, a factor controlling the rate of autophagy. Expression of Atg8a within muscle is sufficient to increase lifespan. These data reveal how insulin signaling can regulate aging through control of Activin signaling that in turn controls autophagy, representing a potentially conserved molecular basis for longevity assurance. While reduced Activin within muscle autonomously retards functional aging of this tissue, these effects in muscle also reduce secretion of insulin-like peptides at a distance from the brain. Reduced insulin secretion from the brain may subsequently reinforce longevity assurance through decreased systemic insulin/IGF signaling.

  12. miR-958 inhibits Toll signaling and Drosomycin expression via direct targeting of Toll and Dif in Drosophila melanogaster.

    Science.gov (United States)

    Li, Shengjie; Li, Yao; Shen, Li; Jin, Ping; Chen, Liming; Ma, Fei

    2017-02-01

    Drosophila melanogaster is widely used as a model system to study innate immunity and signaling pathways related to innate immunity, including the Toll signaling pathway. Although this pathway is well studied, the precise mechanisms of posttranscriptional regulation of key components of the Toll signaling pathway by microRNAs (miRNAs) remain obscure. In this study, we used an in silico strategy in combination with the Gal80 ts -Gal4 driver system to identify microRNA-958 (miR-958) as a candidate Toll pathway regulating miRNA in Drosophila We report that overexpression of miR-958 significantly reduces the expression of Drosomycin, a key antimicrobial peptide involved in Toll signaling and the innate immune response. We further demonstrate in vitro and in vivo that miR-958 targets the Toll and Dif genes, key components of the Toll signaling pathway, to negatively regulate Drosomycin expression. In addition, a miR-958 sponge rescued the expression of Toll and Dif, resulting in increased expression of Drosomycin. These results, not only revealed a novel function and modulation pattern of miR-958, but also provided a new insight into the underlying molecular mechanisms of Toll signaling in regulation of innate immunity. Copyright © 2017 the American Physiological Society.

  13. Protein kinase C α is a central signaling node and therapeutic target for breast cancer stem cells.

    Science.gov (United States)

    Tam, Wai Leong; Lu, Haihui; Buikhuisen, Joyce; Soh, Boon Seng; Lim, Elgene; Reinhardt, Ferenc; Wu, Zhenhua Jeremy; Krall, Jordan A; Bierie, Brian; Guo, Wenjun; Chen, Xi; Liu, Xiaole Shirley; Brown, Myles; Lim, Bing; Weinberg, Robert A

    2013-09-09

    The epithelial-mesenchymal transition program becomes activated during malignant progression and can enrich for cancer stem cells (CSCs). We report that inhibition of protein kinase C α (PKCα) specifically targets CSCs but has little effect on non-CSCs. The formation of CSCs from non-stem cells involves a shift from EGFR to PDGFR signaling and results in the PKCα-dependent activation of FRA1. We identified an AP-1 molecular switch in which c-FOS and FRA1 are preferentially utilized in non-CSCs and CSCs, respectively. PKCα and FRA1 expression is associated with the aggressive triple-negative breast cancers, and the depletion of FRA1 results in a mesenchymal-epithelial transition. Hence, identifying molecular features that shift between cell states can be exploited to target signaling components critical to CSCs. Copyright © 2013 Elsevier Inc. All rights reserved.

  14. An Active Capacitor with Self-Power and Internal Feedback Control Signals

    DEFF Research Database (Denmark)

    Wang, Haoran; Wang, Huai

    2017-01-01

    This paper proposes a concept of two-terminal active capacitor implemented by power semiconductor switches and passive elements. The active capacitor has the same level of convenience as a passive one with two power terminals only. A control strategy that does not require any external feedback...... signal is proposed and a self-power scheme for gate drivers and the controller is applied to achieve the two-terminal active capacitor. The concept, control method, self-power scheme, efficiency, and impedance characteristics of the active capacitor are presented. A case study of the proposed active...... capacitor for a capacitive DC-link application is discussed. The results reveal a significantly lower overall energy storage of passive elements and a reduced cost to fulfill a specific reliability target, compared to a passive capacitor solution. Proof-of-concept experimental results are given to verify...

  15. The N-terminus of amine oxidase of Hansenula polymorpha contains a peroxisomal targeting signal

    NARCIS (Netherlands)

    Faber, Klaas Nico; Keizer-Gunnink, Ineke; Pluim, Dick; Harder, Willem; AB, Geert; Veenhuis, Marten

    1995-01-01

    Here we describe the identification of the targeting sequence of peroxisomal amine oxidase (AMO) of H. polymorpha. Deletion analysis revealed that essential targeting information is located within the extreme N-terminal 16 amino acids. Moreover, this sequence can direct a reporter protein to the

  16. Series-nonuniform rational B-spline signal feedback: From chaos to any embedded periodic orbit or target point

    Energy Technology Data Exchange (ETDEWEB)

    Shao, Chenxi, E-mail: cxshao@ustc.edu.cn; Xue, Yong; Fang, Fang; Bai, Fangzhou [Department of Computer Science and Technology, University of Science and Technology of China, Hefei 230027 (China); Yin, Peifeng [Department of Computer Science and Engineering, Pennsylvania State University, State College, Pennsylvania 16801 (United States); Wang, Binghong [Department of Modern Physics, University of Science and Technology of China, Hefei 230026 (China)

    2015-07-15

    The self-controlling feedback control method requires an external periodic oscillator with special design, which is technically challenging. This paper proposes a chaos control method based on time series non-uniform rational B-splines (SNURBS for short) signal feedback. It first builds the chaos phase diagram or chaotic attractor with the sampled chaotic time series and any target orbit can then be explicitly chosen according to the actual demand. Second, we use the discrete timing sequence selected from the specific target orbit to build the corresponding external SNURBS chaos periodic signal, whose difference from the system current output is used as the feedback control signal. Finally, by properly adjusting the feedback weight, we can quickly lead the system to an expected status. We demonstrate both the effectiveness and efficiency of our method by applying it to two classic chaotic systems, i.e., the Van der Pol oscillator and the Lorenz chaotic system. Further, our experimental results show that compared with delayed feedback control, our method takes less time to obtain the target point or periodic orbit (from the starting point) and that its parameters can be fine-tuned more easily.

  17. Series-nonuniform rational B-spline signal feedback: From chaos to any embedded periodic orbit or target point.

    Science.gov (United States)

    Shao, Chenxi; Xue, Yong; Fang, Fang; Bai, Fangzhou; Yin, Peifeng; Wang, Binghong

    2015-07-01

    The self-controlling feedback control method requires an external periodic oscillator with special design, which is technically challenging. This paper proposes a chaos control method based on time series non-uniform rational B-splines (SNURBS for short) signal feedback. It first builds the chaos phase diagram or chaotic attractor with the sampled chaotic time series and any target orbit can then be explicitly chosen according to the actual demand. Second, we use the discrete timing sequence selected from the specific target orbit to build the corresponding external SNURBS chaos periodic signal, whose difference from the system current output is used as the feedback control signal. Finally, by properly adjusting the feedback weight, we can quickly lead the system to an expected status. We demonstrate both the effectiveness and efficiency of our method by applying it to two classic chaotic systems, i.e., the Van der Pol oscillator and the Lorenz chaotic system. Further, our experimental results show that compared with delayed feedback control, our method takes less time to obtain the target point or periodic orbit (from the starting point) and that its parameters can be fine-tuned more easily.

  18. Inhibition of TLR2 signaling by small molecule inhibitors targeting a pocket within the TLR2 TIR domain

    Science.gov (United States)

    Mistry, Pragnesh; Laird, Michelle H. W.; Schwarz, Ryan S.; Greene, Shannon; Dyson, Tristan; Snyder, Greg A.; Xiao, Tsan Sam; Chauhan, Jay; Fletcher, Steven; Toshchakov, Vladimir Y.; MacKerell, Alexander D.; Vogel, Stefanie N.

    2015-01-01

    Toll-like receptor (TLR) signaling is initiated by dimerization of intracellular Toll/IL-1 receptor resistance (TIR) domains. For all TLRs except TLR3, recruitment of the adapter, myeloid differentiation primary response gene 88 (MyD88), to TLR TIR domains results in downstream signaling culminating in proinflammatory cytokine production. Therefore, blocking TLR TIR dimerization may ameliorate TLR2-mediated hyperinflammatory states. The BB loop within the TLR TIR domain is critical for mediating certain protein–protein interactions. Examination of the human TLR2 TIR domain crystal structure revealed a pocket adjacent to the highly conserved P681 and G682 BB loop residues. Using computer-aided drug design (CADD), we sought to identify a small molecule inhibitor(s) that would fit within this pocket and potentially disrupt TLR2 signaling. In silico screening identified 149 compounds and 20 US Food and Drug Administration-approved drugs based on their predicted ability to bind in the BB loop pocket. These compounds were screened in HEK293T-TLR2 transfectants for the ability to inhibit TLR2-mediated IL-8 mRNA. C16H15NO4 (C29) was identified as a potential TLR2 inhibitor. C29, and its derivative, ortho-vanillin (o-vanillin), inhibited TLR2/1 and TLR2/6 signaling induced by synthetic and bacterial TLR2 agonists in human HEK-TLR2 and THP-1 cells, but only TLR2/1 signaling in murine macrophages. C29 failed to inhibit signaling induced by other TLR agonists and TNF-α. Mutagenesis of BB loop pocket residues revealed an indispensable role for TLR2/1, but not TLR2/6, signaling, suggesting divergent roles. Mice treated with o-vanillin exhibited reduced TLR2-induced inflammation. Our data provide proof of principle that targeting the BB loop pocket is an effective approach for identification of TLR2 signaling inhibitors. PMID:25870276

  19. International target values 2010 for achievable measurement uncertainties in nuclear material accountancy

    Energy Technology Data Exchange (ETDEWEB)

    Dias, Fabio C., E-mail: fabio@ird.gov.b [Comissao Nacional de Energia Nuclear (CNEN), Rio de Janeiro, RJ (Brazil); Almeida, Silvio G. de; Renha Junior, Geraldo, E-mail: silvio@abacc.org.b, E-mail: grenha@abacc.org.b [Agencia Brasileiro-Argentina de Contabilidade e Controle de Materiais Nucleares (ABACC), Rio de Janeiro, RJ (Brazil)

    2011-07-01

    The International Target Values (ITVs) are reasonable uncertainty estimates that can be used in judging the reliability of measurement techniques applied to industrial nuclear and fissile materials subject to accountancy and/or safeguards verification. In the absence of relevant experimental estimates, ITVs can also be used to select measurement techniques and calculate sample population during the planning phase of verification activities. It is important to note that ITVs represent estimates of the 'state-of-the-practice', which should be achievable under routine measurement conditions affecting both facility operators and safeguards inspectors, not only in the field, but also in laboratory. Tabulated values cover measurement methods used for the determination of volume or mass of the nuclear material, for its elemental and isotopic assays, and for its sampling. The 2010 edition represents the sixth revision of the International Target Values (ITVs), issued by the International Atomic Energy Agency (IAEA) as a Safeguards Technical Report (STR-368). The first version was released as 'Target Values' in 1979 by the Working Group on Techniques and Standards for Destructive Analysis (WGDA) of the European Safeguards Research and Development Association (ESARDA) and focused on destructive analytical methods. In the latest 2010 revision, international standards in estimating and expressing uncertainties have been considered while maintaining a format that allows comparison with the previous editions of the ITVs. Those standards have been usually applied in QC/QA programmes, as well as qualification of methods, techniques and instruments. Representatives of the Brazilian Nuclear Energy Commission (CNEN) and the Brazilian-Argentine Agency for Accounting and Control of Nuclear Materials (ABACC) participated in previous Consultants Group Meetings since the one convened to establish the first list of ITVs released in 1993 and in subsequent revisions

  20. Preliminary study on the adjonction of a cooling system and internal target ring to the GEPL project

    International Nuclear Information System (INIS)

    Potaux, D.

    1983-01-01

    Various heavy particle storage rings (LEAR, Indiana, Uppsala) are planned for operation with combined electron cooling system and internal ultra-thin targets. The advantage of adding a similar device to the IPN cyclotron project is discussed [fr

  1. Internal Light Source-Driven Photoelectrochemical 3D-rGO/Cellulose Device Based on Cascade DNA Amplification Strategy Integrating Target Analog Chain and DNA Mimic Enzyme.

    Science.gov (United States)

    Lan, Feifei; Liang, Linlin; Zhang, Yan; Li, Li; Ren, Na; Yan, Mei; Ge, Shenguang; Yu, Jinghua

    2017-11-01

    In this work, a chemiluminescence-driven collapsible greeting card-like photoelectrochemical lab-on-paper device (GPECD) with hollow channel was demonstrated, in which target-triggering cascade DNA amplification strategy was ingeniously introduced. The GPECD had the functions of reagents storage and signal collection, and the change of configuration could control fluidic path, reaction time and alterations in electrical connectivity. In addition, three-dimentional reduced graphene oxide affixed Au flower was in situ grown on paper cellulose fiber for achieving excellent conductivity and biocompatibility. The cascade DNA amplification strategy referred to the cyclic formation of target analog chain and its trigger action to hybridization chain reaction (HCR), leading to the formation of numerous hemin/G-quadruplex DNA mimic enzyme with the presence of hemin. Subjected to the catalysis of hemin/G-quadruplex, the strong chemiluminiscence of luminol-H 2 O 2 system was obtained, which then was used as internal light source to excite photoactive materials realizing the simplification of instrument. In this analyzing process, thrombin served as proof-of-concept, and the concentration of target was converted into the DNA signal output by the specific recognition of aptamer-protein and target analog chain recycling. The target analog chain was produced in quantity with the presence of target, which further triggered abundant HCR and introduced hemin/G-quadruplex into the system. The photocurrent signal was obtained after the nitrogen-doped carbon dots sensitized ZnO was stimulated by chemiluminescence. The proposed GPECD exhibited excellent specificity and sensitivity toward thrombin with a detection limit of 16.7 fM. This judiciously engineered GPECD paved a luciferous way for detecting other protein with trace amounts in bioanalysis and clinical biomedicine.

  2. Phosphoproteomic profiling of in vivo signaling in liver by the mammalian target of rapamycin complex 1 (mTORC1.

    Directory of Open Access Journals (Sweden)

    Gokhan Demirkan

    Full Text Available Our understanding of signal transduction networks in the physiological context of an organism remains limited, partly due to the technical challenge of identifying serine/threonine phosphorylated peptides from complex tissue samples. In the present study, we focused on signaling through the mammalian target of rapamycin (mTOR complex 1 (mTORC1, which is at the center of a nutrient- and growth factor-responsive cell signaling network. Though studied extensively, the mechanisms involved in many mTORC1 biological functions remain poorly understood.We developed a phosphoproteomic strategy to purify, enrich and identify phosphopeptides from rat liver homogenates. Using the anticancer drug rapamycin, the only known target of which is mTORC1, we characterized signaling in liver from rats in which the complex was maximally activated by refeeding following 48 hr of starvation. Using protein and peptide fractionation methods, TiO(2 affinity purification of phosphopeptides and mass spectrometry, we reproducibly identified and quantified over four thousand phosphopeptides. Along with 5 known rapamycin-sensitive phosphorylation events, we identified 62 new rapamycin-responsive candidate phosphorylation sites. Among these were PRAS40, gephyrin, and AMP kinase 2. We observed similar proportions of increased and reduced phosphorylation in response to rapamycin. Gene ontology analysis revealed over-representation of mTOR pathway components among rapamycin-sensitive phosphopeptide candidates.In addition to identifying potential new mTORC1-mediated phosphorylation events, and providing information relevant to the biology of this signaling network, our experimental and analytical approaches indicate the feasibility of large-scale phosphoproteomic profiling of tissue samples to study physiological signaling events in vivo.

  3. Targeting cFMS signaling to restore immune function and eradicate HIV reservoirs

    Science.gov (United States)

    Gerngross, Lindsey

    While combination anti-retroviral therapy (cART) has improved the length and quality of life of individuals living with HIV-1 infection, the prevalence of HIV-associated neurocognitive disorders (HAND) has increased and remains a significant clinical concern. The neuropathogenesis of HAND is not completely understood, however, latent HIV infection in the central nervous system (CNS) and chronic neuroinflammation are believed to play a prominent role. CNS-associated macrophages and resident microglia are significant contributors to CNS inflammation and constitute the chief reservoir of HIV-1 infection in the CNS. Previous studies from our lab suggest monocyte/macrophage invasion of the CNS in HIV may be driven by altered monocyte/macrophage homeostasis. We have reported expansion of a monocyte subset (CD14+CD16 +CD163+) in peripheral blood of HIV+ patients that is phenotypically similar to macrophages/microglia that accumulate in the CNS as seen in post-mortem tissue. The factors driving the expansion of this monocyte subset are unknown, however, signaling through cFMS, a type III receptor tyrosine kinase (RTK), may play a role. Macrophage-colony stimulating factor (M-CSF), a ligand of cFMS, has been shown to be elevated in the cerebral spinal fluid (CSF) of individuals with the most severe form of HAND, HIV-associated dementia (HAD). M-CSF promotes a Macrophage-2-like phenotype and increases CD16 and CD163 expression in cultured monocytes. M-CSF has also been shown to increase the susceptibility of macrophages to HIV infection and enhance virus production. These findings, in addition to the known function of M-CSF in promoting macrophage survival, supports a role for M-CSF in the development and maintenance of macrophage viral reservoirs in tissues where these cells accumulate, including the CNS. Interestingly, a second ligand for cFMS, IL-34, was recently identified and reported to share some functions with M-CSF, suggesting that both ligands may contribute to HIV

  4. Performance evaluation of radiation sensors with internal signal amplification based on the BJT effect

    International Nuclear Information System (INIS)

    Bosisio, Luciano; Batignani, Giovanni; Bettarini, Stefano; Boscardin, Maurizio; Dalla Betta, Gian-Franco; Giacomini, Gabriele; Piemonte, Claudio; Verzellesi, Giovanni; Zorzi, Nicola

    2006-01-01

    Prototypes of ionizing radiation detectors with internal signal amplification based on the bipolar transistor effect have been fabricated at ITC-irst (Trento, Italy). Results from the electrical characterization and preliminary functional tests of the devices have been previously reported. Here, we present a more detailed investigation of the performance of this type of detector, with particular attention to their noise and rate limits. Measurements of the signal waveform and of the gain versus frequency dependence are performed by illuminating the devices with, respectively, pulsed or sinusoidally modulated IR light. Pulse height spectra of X-rays from an Am241 source have been taken with very simple front-end electronics (an LF351 operational amplifier) or by directly reading with an oscilloscope the voltage drop across a load resistor connected to the emitter. An equivalent noise charge (referred to input) of 380 electrons r.m.s. has been obtained with the first setup for a small device, with an active area of 0.5x0.5mm 2 and a depleted thickness of 0.6mm. The corresponding power dissipation in the BJT was 17μW. The performance limitations of the devices are discussed

  5. Electron cooling application for luminosity preservation in an experiment with internal targets at COSY

    CERN Document Server

    Meshkov, I N; Maier, R; Prasuhn, D; Sidorin, A O; Smirnov, A V; Stein, H J; Stockhorst, H; Trubnikov, G V

    2003-01-01

    This report is an investigation of the beam parameter evolution in the experiments with internal target. In calculations of the proton and deuteron beams we concentrated on cluster, atomic beam, storage cell and pellet targets at ANKE experiment mainly. In these calculations electron and stochastic cooling, intrabeam scattering, scattering on the target and residual gas atoms are taken into account. Beam parameter evolution is investigated in the long-term time scale, up to one hour, at different beam energies in the range from 1.0 to 2.7 GeV for proton beam and from 1 to 2.11 GeV for deuteron beam. The results of numerical simulations of the proton and deuteron beam parameters at different energies obtained using new version of BETACOOL program (elaborated at the first stage of this work [1]) are presented. Optimum parameters of the electron cooling system are estimated. The COSY experiment requirements can be satisfied even when electron cooling time is rather long. That allows to apply an electron cooling ...

  6. Reduced cost design of liquid lithium target for international fusion material irradiation facility (IFMIF)

    International Nuclear Information System (INIS)

    Nakamura, Hiroo; Ida, Mizuho; Sugimoto, Masayoshi; Takeuchi, Hiroshi; Yutani, Toshiaki

    2001-01-01

    The International Fusion Materials Irradiation Facility (IFMIF) is being jointly planned to provide an accelerator-based D-Li neutron source to produce intense high energy neutrons (2 MW/m 2 ) up to 200 dpa and a sufficient irradiation volume (500 cm 3 ) for testing the candidate materials and components up to about a full lifetime of their anticipated use in ITER and DEMO. To realize such a condition, 40 MeV deuteron beam with a current of 250 mA is injected into high speed liquid lithium flow with a speed of 20 m/s. Following Conceptual Design Activity (1995-1998), a design study with focus on cost reduction without changing its original mission has been done in 1999. The following major changes to the CAD target design have been considered in the study and included in the new design: i) number of the Li target has been changed from 2 to 1, ii) spare of impurity traps of the Li loop was removed although the spare will be stored in a laboratory for quick exchange, iii) building volume was reduced via design changes in lithium loop length. This paper describes the reduced cost design of the lithium target system and recent status of Key Element Technology activities. (author)

  7. The 13th international workshop on targetry and target chemistry proceedings

    International Nuclear Information System (INIS)

    Haroun, S.; Givskov, A.; Jensen, Mikael

    2011-06-01

    This report contains the complete proceedings of the 13th International Workshop on Targetry and Target Chemistry. The Workshop was held at Risoe National Laboratory for Sustainable Energy on July 26-28 2010. The workshop deals with the development of methods and systems for efficient production of radioactive isotopes with accelerators. The WTTC series of workshops was initiated for the purpose of exchanging information about the problems and solutions associated with the production of radioisotopes for biomedical research and their applications to the diagnosis and treatment of disease. The goal of the WTTC is to advance the science associated with radioisotope production targetry. The Workshops are designed to bring experienced targetry scientists together with newcomers to the field, both from industry and academia, to discuss issues of targetry and target chemistry and approaches to exploring in situ target chemistry and the engineering required to optimize production yields. In the workshop, experience, ideas and information are freely and openly shared; learning and collaborations are fostered, with active participation by all attendees. This participation includes both formal and informal sessions. The present proceedings captures both submitted abstracts and the actual presentations showed during the very successful workshop meeting number 13 in the row, the WTTC13. (Author)

  8. The 13th international workshop on targetry and target chemistry proceedings

    Energy Technology Data Exchange (ETDEWEB)

    Haroun, S. (SFU, TRIUMF (Canada)); Givskov, A.; Jensen, Mikael (Technical Univ. of Denmark. Risoe National Laboratory for Sustainable Energy, Radiation Research Division, Roskilde (Denmark))

    2011-06-15

    This report contains the complete proceedings of the 13th International Workshop on Targetry and Target Chemistry. The Workshop was held at Risoe National Laboratory for Sustainable Energy on July 26-28 2010. The workshop deals with the development of methods and systems for efficient production of radioactive isotopes with accelerators. The WTTC series of workshops was initiated for the purpose of exchanging information about the problems and solutions associated with the production of radioisotopes for biomedical research and their applications to the diagnosis and treatment of disease. The goal of the WTTC is to advance the science associated with radioisotope production targetry. The Workshops are designed to bring experienced targetry scientists together with newcomers to the field, both from industry and academia, to discuss issues of targetry and target chemistry and approaches to exploring in situ target chemistry and the engineering required to optimize production yields. In the workshop, experience, ideas and information are freely and openly shared; learning and collaborations are fostered, with active participation by all attendees. This participation includes both formal and informal sessions. The present proceedings captures both submitted abstracts and the actual presentations showed during the very successful workshop meeting number 13 in the row, the WTTC13. (Author)

  9. Detection and localization of multiple short range targets using FMCW radar signal

    KAUST Repository

    Jardak, Seifallah

    2016-07-26

    In this paper, a 24 GHz frequency-modulated continuous wave radar is used to detect and localize both stationary and moving targets. Depending on the application, the implemented software offers different modes of operation. For example, it can simply output raw data samples for advanced offline processing or directly carry out a two dimensional fast Fourier transform to estimate the location and velocity of multiple targets. To suppress clutter and detect only moving targets, two methods based on the background reduction and the slow time processing techniques are implemented. A trade-off between the two methods is presented based on their performance and the required processing time. © 2016 IEEE.

  10. Comparison of the internalization of targeted dendrimers and dendrimer-entrapped gold nanoparticles into cancer cells.

    Science.gov (United States)

    Shi, Xiangyang; Wang, Su He; Lee, Inhan; Shen, Mingwu; Baker, James R

    2009-11-01

    Dendrimer-based nanotechnology significantly advances the area of targeted cancer imaging and therapy. Herein, we compared the difference of surface acetylated fluorescein isocyanate (FI) and folic acid (FA) modified generation 5 (G5) poly(amidoamine) dendrimers (G5.NHAc-FI-FA), and dendrimer-entrapped gold nanoparticles with similar modifications ([(Au(0))(51.2)-G5.NHAc-FI-FA]) in terms of their specific internalization to FA receptor (FAR)-overexpressing cancer cells. Confocal microscopic studies show that both G5.NHAc-FI-FA and [(Au(0))(51.2-)G5.NHAc-FI-FA] exhibit similar internalization kinetics regardless of the existence of Au nanoparticles (NPs). Molecular dynamics simulation of the two different nanostructures reveals that the surface area and the FA moiety distribution from the center of the geometry are slightly different. This slight difference may not be recognized by the FARs on the cell membrane, consequently leading to similar internalization kinetics. This study underlines the fact that metal or inorganic NPs entrapped within dendrimers interact with cells in a similar way to that of dendrimers lacking host NPs. 2009 Wiley Periodicals, Inc.

  11. Nuclear and nucleolar localization signals and their targeting function in phosphatidylinositol 4-kinase PI4K230

    International Nuclear Information System (INIS)

    Kakuk, Annamaria; Friedlaender, Elza; Vereb, Gyoergy; Lisboa, Duarte; Bagossi, Peter; Toth, Gabor; Gergely, Pal; Vereb, Gyoergy

    2008-01-01

    PI4K230, an isoform of phosphatidylinositol 4-kinase, known primarily as a cytoplasmic membrane-bound enzyme, was detected recently also in the nucleolus of several cells. Here we provide mechanistic insight on the targeting function of its putative nuclear localization signal (NLS) sequences using molecular modeling, digitonin-permeabilized HeLa cells and binding to various importins. The synthetic sequence 916 NFNHIHKRIRRVADKYLSG 934 comprising a putative monopartite NLS (NLS1), targeted covalently bound fluorescent BSA to the nucleoplasm via classical importin α/β mechanism employing importins α1 and α3 but not α5. This transport was inhibited by wheat germ agglutinin and GTPγS. The sequence 1414 SKKTNRGSQLHKYYMKRRTL 1433 , a putative bipartite NLS (NLS2) proved ineffective in nuclear targeting if conjugated to fluorescently labeled BSA. Nonetheless, NLS2 or either of its basic clusters directed to the nucleolus soybean trypsin inhibitor that can pass the nuclear pore complex passively; moreover, an expressed 58 kDa fragment of PI4K230 (AA1166-1667) comprising NLS2 was also imported into the nucleus by import factors of reticulocyte lysate or by importin α1/β or α3/β complexes and localized to the nucleolus. We conclude that the putative bipartite NLS itself is a nucleolar targeting signal, and for nuclear import PI4K230 requires a larger sequence around it or, alternatively, the monopartite NLS

  12. Detection and localization of multiple short range targets using FMCW radar signal

    KAUST Repository

    Jardak, Seifallah; Kiuru, Tero; Metso, Mikko; Pursula, Pekka; Hakli, Janne; Hirvonen, Mervi; Ahmed, Sajid; Alouini, Mohamed-Slim

    2016-01-01

    In this paper, a 24 GHz frequency-modulated continuous wave radar is used to detect and localize both stationary and moving targets. Depending on the application, the implemented software offers different modes of operation. For example, it can

  13. Ligand-Occupied Integrin Internalization Links Nutrient Signaling to Invasive Migration

    Directory of Open Access Journals (Sweden)

    Elena Rainero

    2015-01-01

    Full Text Available Integrin trafficking is key to cell migration, but little is known about the spatiotemporal organization of integrin endocytosis. Here, we show that α5β1 integrin undergoes tensin-dependent centripetal movement from the cell periphery to populate adhesions located under the nucleus. From here, ligand-engaged α5β1 integrins are internalized under control of the Arf subfamily GTPase, Arf4, and are trafficked to nearby late endosomes/lysosomes. Suppression of centripetal movement or Arf4-dependent endocytosis disrupts flow of ligand-bound integrins to late endosomes/lysosomes and their degradation within this compartment. Arf4-dependent integrin internalization is required for proper lysosome positioning and for recruitment and activation of mTOR at this cellular subcompartment. Furthermore, nutrient depletion promotes subnuclear accumulation and endocytosis of ligand-engaged α5β1 integrins via inhibition of mTORC1. This two-way regulatory interaction between mTORC1 and integrin trafficking in combination with data describing a role for tensin in invasive cell migration indicate interesting links between nutrient signaling and metastasis.

  14. A targeted glycan-related gene screen reveals heparan sulfate proteoglycan sulfation regulates WNT and BMP trans-synaptic signaling.

    Directory of Open Access Journals (Sweden)

    Neil Dani

    Full Text Available A Drosophila transgenic RNAi screen targeting the glycan genome, including all N/O/GAG-glycan biosynthesis/modification enzymes and glycan-binding lectins, was conducted to discover novel glycan functions in synaptogenesis. As proof-of-product, we characterized functionally paired heparan sulfate (HS 6-O-sulfotransferase (hs6st and sulfatase (sulf1, which bidirectionally control HS proteoglycan (HSPG sulfation. RNAi knockdown of hs6st and sulf1 causes opposite effects on functional synapse development, with decreased (hs6st and increased (sulf1 neurotransmission strength confirmed in null mutants. HSPG co-receptors for WNT and BMP intercellular signaling, Dally-like Protein and Syndecan, are differentially misregulated in the synaptomatrix of these mutants. Consistently, hs6st and sulf1 nulls differentially elevate both WNT (Wingless; Wg and BMP (Glass Bottom Boat; Gbb ligand abundance in the synaptomatrix. Anterograde Wg signaling via Wg receptor dFrizzled2 C-terminus nuclear import and retrograde Gbb signaling via synaptic MAD phosphorylation and nuclear import are differentially activated in hs6st and sulf1 mutants. Consequently, transcriptional control of presynaptic glutamate release machinery and postsynaptic glutamate receptors is bidirectionally altered in hs6st and sulf1 mutants, explaining the bidirectional change in synaptic functional strength. Genetic correction of the altered WNT/BMP signaling restores normal synaptic development in both mutant conditions, proving that altered trans-synaptic signaling causes functional differentiation defects.

  15. Tetherin Suppresses Type I Interferon Signaling by Targeting MAVS for NDP52-Mediated Selective Autophagic Degradation in Human Cells.

    Science.gov (United States)

    Jin, Shouheng; Tian, Shuo; Luo, Man; Xie, Weihong; Liu, Tao; Duan, Tianhao; Wu, Yaoxing; Cui, Jun

    2017-10-19

    Tetherin (BST2/CD317) is an interferon-inducible antiviral factor known for its ability to block the release of enveloped viruses from infected cells. Yet its role in type I interferon (IFN) signaling remains poorly defined. Here, we demonstrate that Tetherin is a negative regulator of RIG-I like receptor (RLR)-mediated type I IFN signaling by targeting MAVS. The induction of Tetherin by type I IFN accelerates MAVS degradation via ubiquitin-dependent selective autophagy in human cells. Moreover, Tetherin recruits E3 ubiquitin ligase MARCH8 to catalyze K27-linked ubiquitin chains on MAVS at lysine 7, which serves as a recognition signal for NDP52-dependent autophagic degradation. Taken together, our findings reveal a negative feedback loop of RLR signaling generated by Tetherin-MARCH8-MAVS-NDP52 axis and provide insights into a better understanding of the crosstalk between selective autophagy and optimal deactivation of type I IFN signaling. Copyright © 2017 Elsevier Inc. All rights reserved.

  16. Analysis of Maneuvering Targets with Complex Motions by Two-Dimensional Product Modified Lv's Distribution for Quadratic Frequency Modulation Signals.

    Science.gov (United States)

    Jing, Fulong; Jiao, Shuhong; Hou, Changbo; Si, Weijian; Wang, Yu

    2017-06-21

    For targets with complex motion, such as ships fluctuating with oceanic waves and high maneuvering airplanes, azimuth echo signals can be modeled as multicomponent quadratic frequency modulation (QFM) signals after migration compensation and phase adjustment. For the QFM signal model, the chirp rate (CR) and the quadratic chirp rate (QCR) are two important physical quantities, which need to be estimated. For multicomponent QFM signals, the cross terms create a challenge for detection, which needs to be addressed. In this paper, by employing a novel multi-scale parametric symmetric self-correlation function (PSSF) and modified scaled Fourier transform (mSFT), an effective parameter estimation algorithm is proposed-referred to as the Two-Dimensional product modified Lv's distribution (2D-PMLVD)-for QFM signals. The 2D-PMLVD is simple and can be easily implemented by using fast Fourier transform (FFT) and complex multiplication. These measures are analyzed in the paper, including the principle, the cross term, anti-noise performance, and computational complexity. Compared to the other three representative methods, the 2D-PMLVD can achieve better anti-noise performance. The 2D-PMLVD, which is free of searching and has no identifiability problems, is more suitable for multicomponent situations. Through several simulations and analyses, the effectiveness of the proposed estimation algorithm is verified.

  17. Functions of the APC tumor suppressor protein dependent and independent of canonical WNT signaling: implications for therapeutic targeting.

    Science.gov (United States)

    Hankey, William; Frankel, Wendy L; Groden, Joanna

    2018-03-01

    The acquisition of biallelic mutations in the APC gene is a rate-limiting step in the development of most colorectal cancers and occurs in the earliest lesions. APC encodes a 312-kDa protein that localizes to multiple subcellular compartments and performs diverse functions. APC participates in a cytoplasmic complex that promotes the destruction of the transcriptional licensing factor β-catenin; APC mutations that abolish this function trigger constitutive activation of the canonical WNT signaling pathway, a characteristic found in almost all colorectal cancers. By negatively regulating canonical WNT signaling, APC counteracts proliferation, promotes differentiation, facilitates apoptosis, and suppresses invasion and tumor progression. APC further antagonizes canonical WNT signaling by interacting with and counteracting β-catenin in the nucleus. APC also suppresses tumor initiation and progression in the colorectal epithelium through functions that are independent of canonical WNT signaling. APC regulates the mitotic spindle to facilitate proper chromosome segregation, localizes to the cell periphery and cell protrusions to establish cell polarity and appropriate directional migration, and inhibits DNA replication by interacting directly with DNA. Mutations in APC are often frameshifts, insertions, or deletions that introduce premature stop codons and lead to the production of truncated APC proteins that lack its normal functions and possess tumorigenic properties. Therapeutic approaches in development for the treatment of APC-deficient tumors are focused on the inhibition of canonical WNT signaling, especially through targets downstream of APC in the pathway, or on the restoration of wild-type APC expression.

  18. Defining internal target volume (ITV) for hepatocellular carcinoma using four-dimensional CT

    International Nuclear Information System (INIS)

    X, Mian; Liu Mengzhong; Deng Xiaowu; Zhang Li; Huang Xiaoyan; Liu Hui; Li Qiaoqiao; Hu Yonghong; Cai Ling; Cui Nianji

    2007-01-01

    Background and purpose: To define individualized internal target volume (ITV) for hepatocellular carcinoma using four-dimensional computed tomography (4DCT). Materials and methods: Gross tumor volumes (GTVs) and clinical target volumes (CTVs) were contoured on all 10 respiratory phases of 4DCT scans in 10 patients with hepatocellular carcinoma. The 3D and 4D treatment plans were performed for each patient using two different planning target volumes (PTVs): (1) PTV 3D was derived from a single CTV plus conventional margins; (2) PTV 4D was derived from ITV 4D , which encompassed all 10 CTVs plus setup margins (SMs). The volumes of PTVs and dose distribution were compared between the two plans. Results: The average PTV volume of the 4D plans (328.4 ± 152.2 cm 3 ) was less than 3D plans (407.0 ± 165.6 cm 3 ). The 4D plans spared more surrounding normal tissues than 3D plans, especially normal liver. Compared with 3D plans, the mean dose to normal liver (MDTNL) decreased from 22.7 to 20.3 Gy. Without increasing the normal tissue complication probability (NTCP), the 4D plans allowed for increasing the calculated dose from 50.4 ± 1.3 to 54.2 ± 2.6 Gy, an average increase of 7.5% (range 4.0-16.0%). Conclusions: The conventional 3D plans can result in geometric miss and include excess normal tissues. The 4DCT-based plans can reduce the target volumes to spare more normal tissues and allow dose escalation compared with 3D plans

  19. c-MPL provides tumor-targeted T-cell receptor-transgenic T cells with costimulation and cytokine signals.

    Science.gov (United States)

    Nishimura, Christopher D; Brenner, Daniel A; Mukherjee, Malini; Hirsch, Rachel A; Ott, Leah; Wu, Meng-Fen; Liu, Hao; Dakhova, Olga; Orange, Jordan S; Brenner, Malcolm K; Lin, Charles Y; Arber, Caroline

    2017-12-21

    Adoptively transferred T-cell receptor (TCR)-engineered T cells depend on host-derived costimulation and cytokine signals for their full and sustained activation. However, in patients with cancer, both signals are frequently impaired. Hence, we developed a novel strategy that combines both essential signals in 1 transgene by expressing the nonlymphoid hematopoietic growth factor receptor c-MPL (myeloproliferative leukemia), the receptor for thrombopoietin (TPO), in T cells. c-MPL signaling activates pathways shared with conventional costimulatory and cytokine receptor signaling. Thus, we hypothesized that host-derived TPO, present in the tumor microenvironment, or pharmacological c-MPL agonists approved by the US Food and Drug Administration could deliver both signals to c-MPL-engineered TCR-transgenic T cells. We found that c-MPL + polyclonal T cells expand and proliferate in response to TPO, and persist longer after adoptive transfer in immunodeficient human TPO-transgenic mice. In TCR-transgenic T cells, c-MPL activation enhances antitumor function, T-cell expansion, and cytokine production and preserves a central memory phenotype. c-MPL signaling also enables sequential tumor cell killing, enhances the formation of effective immune synapses, and improves antileukemic activity in vivo in a leukemia xenograft model. We identify the type 1 interferon pathway as a molecular mechanism by which c-MPL mediates immune stimulation in T cells. In conclusion, we present a novel immunotherapeutic strategy using c-MPL-enhanced transgenic T cells responding to either endogenously produced TPO (a microenvironment factor in hematologic malignancies) or c-MPL-targeted pharmacological agents. © 2017 by The American Society of Hematology.

  20. An N-Terminal ER Export Signal Facilitates the Plasma Membrane Targeting of HCN1 Channels in Photoreceptors.

    Science.gov (United States)

    Pan, Yuan; Laird, Joseph G; Yamaguchi, David M; Baker, Sheila A

    2015-06-01

    Hyperpolarization-activated cyclic nucleotide-gated 1 (HCN1) channels are widely expressed in the retina. In photoreceptors, the hyperpolarization-activated current (Ih) carried by HCN1 is important for shaping the light response. It has been shown in multiple systems that trafficking HCN1 channels to specific compartments is key to their function. The localization of HCN1 in photoreceptors is concentrated in the plasma membrane of the inner segment (IS). The mechanisms controlling this localization are not understood. We previously identified a di-arginine endoplasmic reticulum (ER) retention motif that negatively regulates the surface targeting of HCN1. In this study, we sought to identify a forward trafficking signal that could counter the function of the ER retention signal. We studied trafficking of HCN1 and several mutants by imaging their subcellular localization in transgenic X. laevis photoreceptors. Velocity sedimentation was used to assay the assembly state of HCN1 channels. We found the HCN1 N-terminus can redirect a membrane reporter from outer segments (OS) to the plasma membrane of the IS. The sequence necessary for this behavior was mapped to a 20 amino acid region containing a leucine-based ER export motif. The ER export signal is necessary for forward trafficking but not channel oligomerization. Moreover, this ER export signal alone counteracted the di-arginine ER retention signal. We identified an ER export signal in HCN1 that functions with the ER retention signal to maintain equilibrium of HCN1 between the endomembrane system and the plasma membrane.

  1. The Rac1 hypervariable region in targeting and signaling: a tail of many stories

    NARCIS (Netherlands)

    Lam, B. Daniel; Hordijk, Peter L.

    2013-01-01

    Cellular signaling by small GTPases is critically dependent on proper spatio-temporal orchestration of activation and output. In addition to their core G (guanine nucleotide binding)-domain, small GTPases comprise a hypervariable region (HVR) and a lipid anchor that are generally accepted to control

  2. Locating proteins in the cell using TargetP, SignalP and related tools

    DEFF Research Database (Denmark)

    Emanuelsson, O.; Brunak, Søren; von Heijne, G.

    2007-01-01

    of methods to predict subcellular localization based on these sorting signals and other sequence properties. We then outline how to use a number of internet-accessible tools to arrive at a reliable subcellular localization prediction for eukaryotic and prokaryotic proteins. In particular, we provide detailed...

  3. Sphingosine-1-Phosphate (S1P) and S1P Signaling Pathway: Therapeutic Targets in Autoimmunity and Inflammation.

    Science.gov (United States)

    Tsai, Hsing-Chuan; Han, May H

    2016-07-01

    Sphingosine-1-phosphate (S1P) and S1P receptors (S1PR) are ubiquitously expressed. S1P-S1PR signaling has been well characterized in immune trafficking and activation in innate and adaptive immune systems. However, the full extent of its involvement in the pathogenesis of autoimmune diseases is not well understood. FTY720 (fingolimod), a non-selective S1PR modulator, significantly decreased annualized relapse rates in relapsing-remitting multiple sclerosis (MS). FTY720, which primarily targets S1P receptor 1 as a functional antagonist, arrests lymphocyte egress from secondary lymphoid tissues and reduces neuroinflammation in the central nervous system (CNS). Recent studies suggest that FTY720 also decreases astrogliosis and promotes oligodendrocyte differentiation within the CNS and may have therapeutic benefit to prevent brain atrophy. Since S1P signaling is involved in multiple immune functions, therapies targeting S1P axis may be applicable to treat autoimmune diseases other than MS. Currently, over a dozen selective S1PR and S1P pathway modulators with potentially superior therapeutic efficacy and better side-effect profiles are in the pipeline of drug development. Furthermore, newly characterized molecules such as apolipoprotein M (ApoM) (S1P chaperon) and SPNS2 (S1P transporter) are also potential targets for treatment of autoimmune diseases. Finally, the application of therapies targeting S1P and S1P signaling pathways may be expanded to treat several other immune-mediated disorders (such as post-infectious diseases, post-stroke and post-stroke dementia) and inflammatory conditions beyond their application in primary autoimmune diseases.

  4. Targeting the phosphatidylinositol 3-kinase/Akt/mechanistic target of rapamycin signaling pathway in B-lineage acute lymphoblastic leukemia: An update.

    Science.gov (United States)

    Simioni, Carolina; Martelli, Alberto M; Zauli, Giorgio; Vitale, Marco; McCubrey, James A; Capitani, Silvano; Neri, Luca M

    2018-04-18

    Despite considerable progress in treatment protocols, B-lineage acute lymphoblastic leukemia (B-ALL) displays a poor prognosis in about 15-20% of pediatric cases and about 60% of adult patients. In addition, life-long irreversible late effects from chemo- and radiation therapy, including secondary malignancies, are a growing problem for leukemia survivors. Targeted therapy holds promising perspectives for cancer treatment as it may be more effective and have fewer side effects than conventional therapies. The phosphatidylinositol 3-phosphate kinase (PI3K)/Akt/mechanistic target of rapamycin (mTOR) signaling pathway is a key regulatory cascade which controls proliferation, survival and drug-resistance of cancer cells, and it is frequently upregulated in the different subtypes of B-ALL, where it plays important roles in the pathophysiology, maintenance and progression of the disease. Moreover, activation of this signaling cascade portends a poorer prognosis in both pediatric and adult B-ALL patients. Promising preclinical data on PI3K/Akt/mTOR inhibitors have documented their anticancer activity in B-ALL and some of these novel drugs have entered clinical trials as they could lead to a longer event-free survival and reduce therapy-associated toxicity for patients with B-ALL. This review highlights the current status of PI3K/Akt/mTOR inhibitors in B-ALL, with an emphasis on emerging evidence of the superior efficacy of synergistic combinations involving the use of traditional chemotherapeutics or other novel, targeted agents. © 2018 Wiley Periodicals, Inc.

  5. Targeting Epidermal Growth Factor Receptor-Related Signaling Pathways in Pancreatic Cancer.

    Science.gov (United States)

    Philip, Philip A; Lutz, Manfred P

    2015-10-01

    Pancreatic cancer is aggressive, chemoresistant, and characterized by complex and poorly understood molecular biology. The epidermal growth factor receptor (EGFR) pathway is frequently activated in pancreatic cancer; therefore, it is a rational target for new treatments. However, the EGFR tyrosine kinase inhibitor erlotinib is currently the only targeted therapy to demonstrate a very modest survival benefit when added to gemcitabine in the treatment of patients with advanced pancreatic cancer. There is no molecular biomarker to predict the outcome of erlotinib treatment, although rash may be predictive of improved survival; EGFR expression does not predict the biologic activity of anti-EGFR drugs in pancreatic cancer, and no EGFR mutations are identified as enabling the selection of patients likely to benefit from treatment. Here, we review clinical studies of EGFR-targeted therapies in combination with conventional cytotoxic regimens or multitargeted strategies in advanced pancreatic cancer, as well as research directed at molecules downstream of EGFR as alternatives or adjuncts to receptor targeting. Limitations of preclinical models, patient selection, and trial design, as well as the complex mechanisms underlying resistance to EGFR-targeted agents, are discussed. Future clinical trials must incorporate translational research end points to aid patient selection and circumvent resistance to EGFR inhibitors.

  6. Modeling internal deformation of salt structures targeted for radioactive waste disposal

    International Nuclear Information System (INIS)

    Chemia, Zurab

    2008-01-01

    This thesis uses results of systematic numerical models to argue that externally inactive salt structures, which are potential targets for radioactive waste disposal, might be internally active due to the presence of dense layers or blocks within a salt layer. The three papers that support this thesis use the Gorleben salt diapir (NW Germany), which was targeted as a future final repository for high-grade radioactive waste, as a general guideline. The first two papers present systematic studies of the parameters that control the development of a salt diapir and how it entrains a dense anhydrite layer. Results from these numerical models show that the entrainment of a dense anhydrite layer within a salt diapir depends on four parameters: sedimentation rate, viscosity of salt, perturbation width and the stratigraphic location of the dense layer. The combined effect of these four parameters, which has a direct impact on the rate of salt supply (volume/area of the salt that is supplied to the diapir with time), shape a diapir and the mode of entrainment. Salt diapirs down-built with sedimentary units of high viscosity can potentially grow with an embedded anhydrite layer and deplete their source layer (salt supply ceases). However, when salt supply decreases dramatically or ceases entirely, the entrained anhydrite layer/segments start to sink within the diapir. In inactive diapirs, sinking of the entrained anhydrite layer is inevitable and strongly depends on the rheology of the salt, which is in direct contact with the anhydrite layer. During the post-depositional stage, if the effective viscosity of salt falls below the threshold value of around 10 18 -10 19 Pa s, the mobility of anhydrite blocks might influence any repository within the diapir. However, the internal deformation of the salt diapir by the descending blocks decreases with increase in effective viscosity of salt. The results presented in this thesis suggest that it is highly likely that salt structures

  7. Efforts to save 244Pu in Mark 18A targets for use in international safeguards measurements

    International Nuclear Information System (INIS)

    Goldberg, Steven A.; Cappis, John; Clarke, Stephanie; Whitesel, Robert

    2001-01-01

    Full text: The Office of Arms Control and Nonproliferation and the Office of Security and Emergency Operations are working collaboratively to evaluate the disposition of a large quantity of the 244 Pu isotope contained in 65 Mark ISA targets at the Savannah River Site (SRS). 244 Pu is used as a standard reference material for plutonium analytical measurements required for both domestic and international safeguards. 244 Pu is particularly valuable for high accuracy measurements of plutonium in small samples containing trace quantities of plutonium (environmental analysis) and for measurements of material through-put in bulk processing facilities handling large volumes of plutonium and plutonium-bearing materials. In October 2000, an assessment team was tasked by the U.S. Department of Energy (DOE) Under Secretary to evaluate pathways and costs for the chemical separation and isotopic enrichment of the 244 Pu identified in the targets. Even though the target materials have recently been designated as a National Resource, they are scheduled for waste disposal unless funds can be identified and assigned to the project. Background information on the Mark ISA targets and a review of the assessment process are presented below to inform other organizations and governments of current efforts to examine potential disposition options and to solicit international cooperation for the extraction of the 244 Pu. Background - The United States possesses the bulk of the world's supply of the rare isotope 244 Pu. This isotope was produced by extremely long neutron irradiation of 242 Pu in a high-flux reactor during experiments used primarily to create isotopes of medical interest. In its separated enriched form, 244 Pu is regarded as the most accurate and desirable spike for safeguards, forensics, and environmental analysis of plutonium, allowing the simultaneous measurement of a sample for isotopic abundances and elemental concentration. Such measurements are a critical component of

  8. Multimodal Nanomedicine Strategies for Targeting Cancer Cells as well as Cancer Stem Cell Signalling Mechanisms.

    Science.gov (United States)

    Kanwar, Jagat R; Samarasinghe, Rasika M; Kamalapuram, Sishir K; Kanwar, Rupinder K

    2017-01-01

    Increasing evidence suggests that stem cells, a small population of cells with unique selfrenewable and tumour regenerative capacity, are aiding tumour re-growth and multidrug resistance. Conventional therapies are highly ineffective at eliminating these cells leading to relapse of disease and formation of chemoresistance tumours. Cancer and stem cells targeted therapies that utilizes nanotherapeutics to delivery anti-cancer drugs to specific sites are continuously investigated. This review focuses on recent research using nanomedicine and targeting entities to eliminate cancer cells and cancer stem cells. Current nanotherapeutics in clinical trials along with more recent publications on targeted therapies are addressed. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  9. Size and targeting to PECAM vs ICAM control endothelial delivery, internalization and protective effect of multimolecular SOD conjugates.

    Science.gov (United States)

    Shuvaev, Vladimir V; Muro, Silvia; Arguiri, Evguenia; Khoshnejad, Makan; Tliba, Samira; Christofidou-Solomidou, Melpo; Muzykantov, Vladimir R

    2016-07-28

    Controlled endothelial delivery of SOD may alleviate abnormal local surplus of superoxide involved in ischemia-reperfusion, inflammation and other disease conditions. Targeting SOD to endothelial surface vs. intracellular compartments is desirable to prevent pathological effects of external vs. endogenous superoxide, respectively. Thus, SOD conjugated with antibodies to cell adhesion molecule PECAM (Ab/SOD) inhibits pro-inflammatory signaling mediated by endogenous superoxide produced in the endothelial endosomes in response to cytokines. Here we defined control of surface vs. endosomal delivery and effect of Ab/SOD, focusing on conjugate size and targeting to PECAM vs. ICAM. Ab/SOD enlargement from about 100 to 300nm enhanced amount of cell-bound SOD and protection against extracellular superoxide. In contrast, enlargement inhibited endocytosis of Ab/SOD and diminished mitigation of inflammatory signaling of endothelial superoxide. In addition to size, shape is important: endocytosis of antibody-coated spheres was more effective than that of polymorphous antibody conjugates. Further, targeting to ICAM provides higher endocytic efficacy than targeting to PECAM. ICAM-targeted Ab/SOD more effectively mitigated inflammatory signaling by intracellular superoxide in vitro and in animal models, although total uptake was inferior to that of PECAM-targeted Ab/SOD. Therefore, both geometry and targeting features of Ab/SOD conjugates control delivery to cell surface vs. endosomes for optimal protection against extracellular vs. endosomal oxidative stress, respectively. Copyright © 2016 Elsevier B.V. All rights reserved.

  10. Use of microparticles as internal targets for nuclear physics with storage rings

    Energy Technology Data Exchange (ETDEWEB)

    Berdoz, A; Heinz, A; Meyer, H O; Pancella, P; Rinckel, T; Ross, A; Sperisen, F; Young, D

    1989-04-01

    We report on the development of ultrathin (10/sup 14/ to 10/sup 16/ at/cm/sup 2/) internal targets for storage rings using microparticles. A ''dust beam'' is created by a gas-particle mixture flowing through a capillary into vacuum. In a laminar flow, the viscous drag accelerates the particles in the direction of the gas flow, while the Bernoulli force concentrates them near the axis of the tube. At the exist of the tube the gas diffuses, but the particles, due to their inertia, continue with small divergence. This property will allow us to differentially pump the carrier gas along the dust beam axis before the microparticles enter the high vacuum of the storage ring. (orig.).

  11. Use of microparticles as internal targets for nuclear physics with storage rings

    International Nuclear Information System (INIS)

    Berdoz, A.; Heinz, A.; Meyer, H.O.; Pancella, P.; Rinckel, T.; Ross, A.; Sperisen, F.; Young, D.

    1989-01-01

    We report on the development of ultrathin (10 14 to 10 16 at/cm 2 ) internal targets for storage rings using microparticles. A ''dust beam'' is created by a gas-particle mixture flowing through a capillary into vacuum. In a laminar flow, the viscous drag accelerates the particles in the direction of the gas flow, while the Bernoulli force concentrates them near the axis of the tube. At the exist of the tube the gas diffuses, but the particles, due to their inertia, continue with small divergence. This property will allow us to differentially pump the carrier gas along the dust beam axis before the microparticles enter the high vacuum of the storage ring. (orig.)

  12. Delineation of Internal Mammary Nodal Target Volumes in Breast Cancer Radiation Therapy

    Energy Technology Data Exchange (ETDEWEB)

    Jethwa, Krishan R.; Kahila, Mohamed M. [Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota (United States); Hunt, Katie N. [Department of Radiology, Mayo Clinic, Rochester, Minnesota (United States); Brown, Lindsay C.; Corbin, Kimberly S.; Park, Sean S.; Yan, Elizabeth S. [Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota (United States); Boughey, Judy C. [Department of Surgery, Mayo Clinic, Rochester, Minnesota (United States); Mutter, Robert W., E-mail: mutter.robert@mayo.edu [Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota (United States)

    2017-03-15

    Purpose: The optimal clinical target volume for internal mammary (IM) node irradiation is uncertain in an era of increasingly conformal volume-based treatment planning for breast cancer. We mapped the location of gross internal mammary lymph node (IMN) metastases to identify areas at highest risk of harboring occult disease. Methods and Materials: Patients with axial imaging of IMN disease were identified from a breast cancer registry. The IMN location was transferred onto the corresponding anatomic position on representative axial computed tomography images of a patient in the treatment position and compared with consensus group guidelines of IMN target delineation. Results: The IMN location in 67 patients with 130 IMN metastases was mapped. The location was in the first 3 intercostal spaces in 102 of 130 nodal metastases (78%), whereas 18 of 130 IMNs (14%) were located caudal to the third intercostal space and 10 of 130 IMNs (8%) were located cranial to the first intercostal space. Of the 102 nodal metastases within the first 3 intercostal spaces, 54 (53%) were located within the Radiation Therapy Oncology Group consensus volume. Relative to the IM vessels, 19 nodal metastases (19%) were located medially with a mean distance of 2.2 mm (SD, 2.9 mm) whereas 29 (28%) were located laterally with a mean distance of 3.6 mm (SD, 2.5 mm). Ninety percent of lymph nodes within the first 3 intercostal spaces would have been encompassed within a 4-mm medial and lateral expansion on the IM vessels. Conclusions: In women with indications for elective IMN irradiation, a 4-mm medial and lateral expansion on the IM vessels may be appropriate. In women with known IMN involvement, cranial extension to the confluence of the IM vein with the brachiocephalic vein with or without caudal extension to the fourth or fifth interspace may be considered provided that normal tissue constraints are met.

  13. The control system of the polarized internal target of ANKE at COSY

    Energy Technology Data Exchange (ETDEWEB)

    Kleines, H. [Zentralinstitut fuer Elektronik, Forschungszentrum Juelich, 52425 Juelich (Germany); Sarkadi, J. [Zentralinstitut fuer Elektronik, Forschungszentrum Juelich, 52425 Juelich (Germany); Zwoll, K. [Zentralinstitut fuer Elektronik, Forschungszentrum Juelich, 52425 Juelich (Germany); Engels, R. [Institut fuer Kernphysik, Forschungszentrum Juelich, 52425 Juelich (Germany); Grigoryev, K. [Institut fuer Kernphysik, Forschungszentrum Juelich, 52425 Juelich (Germany); Mikirtychyants, M. [Institut fuer Kernphysik, Forschungszentrum Juelich, 52425 Juelich (Germany); Nekipelov, M. [Institut fuer Kernphysik, Forschungszentrum Juelich, 52425 Juelich (Germany); Rathmann, F. [Institut fuer Kernphysik, Forschungszentrum Juelich, 52425 Juelich (Germany); Seyfarth, H. [Institut fuer Kernphysik, Forschungszentrum Juelich, 52425 Juelich (Germany)]. E-mail: h.seyfarth@fz-juelich.de; Kravtsov, P. [St. Petersburg Nuclear Physics Institute, 188350 Gatchina (Russian Federation); Vasilyev, A. [St. Petersburg Nuclear Physics Institute, 188350 Gatchina (Russian Federation)

    2006-05-10

    The polarized internal target for the ANKE experiment at the Cooler Synchrotron COSY of the Forschungszentrum Juelich utilizes a polarized atomic beam source to feed a storage cell with polarized hydrogen or deuterium atoms. The nuclear polarization is measured with a Lamb-shift polarimeter. For common control of the two systems, industrial equipment was selected providing reliable, long-term support and remote control of the target as well as measurement and optimization of its operating parameters. The interlock system has been implemented on the basis of SIEMENS SIMATIC S7-300 family of programmable logic controllers. In order to unify the interfacing to the control computer, all front-end equipment is connected via the PROFIBUS DP fieldbus. The process control software was implemented using the Windows-based WinCC toolkit from SIEMENS. The variety of components, to be controlled, and the logical structure of the control and interlock system are described. Finally, a number of applications derived from the present development to other, new installations are briefly mentioned.

  14. The control system of the polarized internal target of ANKE at COSY

    Science.gov (United States)

    Kleines, H.; Sarkadi, J.; Zwoll, K.; Engels, R.; Grigoryev, K.; Mikirtychyants, M.; Nekipelov, M.; Rathmann, F.; Seyfarth, H.; Kravtsov, P.; Vasilyev, A.

    2006-05-01

    The polarized internal target for the ANKE experiment at the Cooler Synchrotron COSY of the Forschungszentrum Jülich utilizes a polarized atomic beam source to feed a storage cell with polarized hydrogen or deuterium atoms. The nuclear polarization is measured with a Lamb-shift polarimeter. For common control of the two systems, industrial equipment was selected providing reliable, long-term support and remote control of the target as well as measurement and optimization of its operating parameters. The interlock system has been implemented on the basis of SIEMENS SIMATIC S7-300 family of programmable logic controllers. In order to unify the interfacing to the control computer, all front-end equipment is connected via the PROFIBUS DP fieldbus. The process control software was implemented using the Windows-based WinCC toolkit from SIEMENS. The variety of components, to be controlled, and the logical structure of the control and interlock system are described. Finally, a number of applications derived from the present development to other, new installations are briefly mentioned.

  15. International Target Values 2010 for Measurement Uncertainties in Safeguarding Nuclear Materials

    Energy Technology Data Exchange (ETDEWEB)

    Zhao, M.; Penkin, M.; Norman, C.; Balsley, S. [IAEA, Vienna (Australia); others, and

    2012-12-15

    This issue of the International Target Values (ITVs) represents the sixth revision, following the first release of such tables issued in 1979 by the ESARDA/WGDA. The ITVs are uncertainties to be considered in judging the reliability of analytical techniques applied to industrial nuclear and fissile material, which are subject to safeguards verification. The tabulated values represent estimates of the 'state of the practice' which should be achievable under routine measurement conditions. The most recent standard conventions in representing uncertainty have been considered, while maintaining a format that allows comparison with the previous releases of the ITVs. The present report explains why target values are needed, how the concept evolved and how they relate to the operator's and inspector's measurement systems. The ITVs-2010 are intended to be used by plant operators and safeguards organizations, as a reference of the quality of measurements achievable in nuclear material accountancy, and for planning purposes. The report suggests that the use of ITVs can be beneficial for statistical inferences regarding the significance of operator-inspector differences whenever valid performance values are not available.

  16. Logical network of genotoxic stress-induced NF-kappaB signal transduction predicts putative target structures for therapeutic intervention strategies

    Directory of Open Access Journals (Sweden)

    Rainer Poltz

    2009-12-01

    Full Text Available Rainer Poltz1, Raimo Franke1,#, Katrin Schweitzer1, Steffen Klamt2, Ernst-Dieter Gilles2, Michael Naumann11Institute of Experimental Internal Medicine, Otto von Guericke University, Magdeburg, Germany; 2Max Planck Institute for Dynamics of Complex Technical Systems, Magdeburg, Germany; #Present address: Department of Chemical Biology, Helmholtz Centre for Infection Research, Braunschweig, GermanyAbstract: Genotoxic stress is induced by a broad range of DNA-damaging agents and could lead to a variety of human diseases including cancer. DNA damage is also therapeutically induced for cancer treatment with the aim to eliminate tumor cells. However, the effectiveness of radio- and chemotherapy is strongly hampered by tumor cell resistance. A major reason for radio- and chemotherapeutic resistances is the simultaneous activation of cell survival pathways resulting in the activation of the transcription factor nuclear factor-kappa B (NF-κB. Here, we present a Boolean network model of the NF-κB signal transduction induced by genotoxic stress in epithelial cells. For the representation and analysis of the model, we used the formalism of logical interaction hypergraphs. Model reconstruction was based on a careful meta-analysis of published data. By calculating minimal intervention sets, we identified p53-induced protein with a death domain (PIDD, receptor-interacting protein 1 (RIP1, and protein inhibitor of activated STAT y (PIASy as putative therapeutic targets to abrogate NF-κB activation resulting in apoptosis. Targeting these structures therapeutically may potentiate the effectiveness of radio- and chemotherapy. Thus, the presented model allows a better understanding of the signal transduction in tumor cells and provides candidates as new therapeutic target structures.Keywords: apoptosis, Boolean network, cancer therapy, DNA-damage response, NF-κB

  17. 135La as an Auger-electron emitter for targeted internal radiotherapy

    Science.gov (United States)

    Fonslet, J.; Lee, B. Q.; Tran, T. A.; Siragusa, M.; Jensen, M.; Kibédi, T.; E Stuchbery, A.; Severin, G. W.

    2018-01-01

    135La has favorable nuclear and chemical properties for Auger-based targeted internal radiotherapy. Here we present detailed investigations of the production, emissions, and dosimetry related to 135La therapy. 135La was produced by 16.5 MeV proton irradiation of metallic natBa on a medical cyclotron, and was isolated and purified by trap-and-release on weak cation-exchange resin. The average production rate was 407  ±  19 MBq µA-1 (saturation activity), and the radionuclidic purity was 98% at 20 h post irradiation. Chemical separation recovered  >  98 % of the 135La with an effective molar activity of 70  ±  20 GBq µmol-1. To better assess cellular and organ dosimetry of this nuclide, we have calculated the x-ray and Auger emission spectra using a Monte Carlo model accounting for effects of multiple vacancies during the Auger cascade. The generated Auger spectrum was used to calculate cellular S-factors. 135La was produced with high specific activity, reactivity, radionuclidic purity, and yield. The emission spectrum and the dosimetry are favorable for internal radionuclide therapy.

  18. Dosimetric Advantages of Midventilation Compared With Internal Target Volume for Radiation Therapy of Pancreatic Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Lens, Eelco, E-mail: e.lens@amc.uva.nl; Horst, Astrid van der; Versteijne, Eva; Tienhoven, Geertjan van; Bel, Arjan

    2015-07-01

    Purpose: The midventilation (midV) approach can be used to take respiratory-induced pancreatic tumor motion into account during radiation therapy. In this study, the dosimetric consequences for organs at risk and tumor coverage of using a midV approach compared with using an internal target volume (ITV) were investigated. Methods and Materials: For each of the 18 patients, 2 treatment plans (25 × 2.0 Gy) were created, 1 using an ITV and 1 using a midV approach. The midV dose distribution was blurred using the respiratory-induced motion from 4-dimensional computed tomography. The resulting planning target volume (PTV) coverage for this blurred dose distribution was analyzed; PTV coverage was required to be at least V{sub 95%} >98%. In addition, the change in PTV size and the changes in V{sub 10Gy}, V{sub 20Gy}, V{sub 30Gy}, V{sub 40Gy}, D{sub mean} and D{sub 2cc} for the stomach and for the duodenum were analyzed; differences were tested for significance using the Wilcoxon signed-rank test. Results: Using a midV approach resulted in sufficient target coverage. A highly significant PTV size reduction of 13.9% (P<.001) was observed. Also, all dose parameters for the stomach and duodenum, except the D{sub 2cc} of the duodenum, improved significantly (P≤.002). Conclusions: By using the midV approach to account for respiratory-induced tumor motion, a significant PTV reduction and significant dose reductions to the stomach and to the duodenum can be achieved when irradiating pancreatic tumors.

  19. Dosimetric Advantages of Midventilation Compared With Internal Target Volume for Radiation Therapy of Pancreatic Cancer

    International Nuclear Information System (INIS)

    Lens, Eelco; Horst, Astrid van der; Versteijne, Eva; Tienhoven, Geertjan van; Bel, Arjan

    2015-01-01

    Purpose: The midventilation (midV) approach can be used to take respiratory-induced pancreatic tumor motion into account during radiation therapy. In this study, the dosimetric consequences for organs at risk and tumor coverage of using a midV approach compared with using an internal target volume (ITV) were investigated. Methods and Materials: For each of the 18 patients, 2 treatment plans (25 × 2.0 Gy) were created, 1 using an ITV and 1 using a midV approach. The midV dose distribution was blurred using the respiratory-induced motion from 4-dimensional computed tomography. The resulting planning target volume (PTV) coverage for this blurred dose distribution was analyzed; PTV coverage was required to be at least V 95% >98%. In addition, the change in PTV size and the changes in V 10Gy , V 20Gy , V 30Gy , V 40Gy , D mean and D 2cc for the stomach and for the duodenum were analyzed; differences were tested for significance using the Wilcoxon signed-rank test. Results: Using a midV approach resulted in sufficient target coverage. A highly significant PTV size reduction of 13.9% (P<.001) was observed. Also, all dose parameters for the stomach and duodenum, except the D 2cc of the duodenum, improved significantly (P≤.002). Conclusions: By using the midV approach to account for respiratory-induced tumor motion, a significant PTV reduction and significant dose reductions to the stomach and to the duodenum can be achieved when irradiating pancreatic tumors

  20. Pharmacological Targeting SHP-1-STAT3 Signaling Is a Promising Therapeutic Approach for the Treatment of Colorectal Cancer

    Directory of Open Access Journals (Sweden)

    Li-Ching Fan

    2015-09-01

    Full Text Available STAT3 activation is associated with poor prognosis in human colorectal cancer (CRC. Our previous data demonstrated that regorafenib (Stivarga is a pharmacological agonist of SH2 domain-containing phosphatase 1 (SHP-1 that enhances SHP-1 activity and induces apoptosis by targeting STAT3 signals in CRC. This study aimed to find a therapeutic drug that is more effective than regorafenib for CRC treatment. Here, we showed that SC-43 was more effective than regorafenib at inducing apoptosis in vitro and suppressing tumorigenesis in vivo. SC-43 significantly increased SHP-1 activity, downregulated p-STAT3Tyr705 level, and induced apoptosis in CRC cells. An SHP-1 inhibitor or knockdown of SHP-1 by siRNA both significantly rescued the SC-43–induced apoptosis and decreased p-STAT3Tyr705 level. Conversely, SHP-1 overexpression increased the effects of SC-43 on apoptosis and p-STAT3Tyr705 level. These data suggest that SC-43–induced apoptosis mediated through the loss of p-STAT3Tyr705 was dependent on SHP-1 function. Importantly, SC-43–enhanced SHP-1 activity was because of the docking potential of SC-43, which relieved the autoinhibited N-SH2 domain of SHP-1 and inhibited p-STAT3Tyr705 signals. Importantly, we observed that a significant negative correlation existed between SHP-1 and p-STAT3Tyr705expression in CRC patients (P = .038. Patients with strong SHP-1 and weak p-STAT3Tyr705 expression had significantly higher overall survival compared with patients with weak SHP-1 and strong p-STAT3Tyr705 expression (P = .029. In conclusion, SHP-1 is suitable to be a useful prognostic marker and a pharmacological target for CRC treatment. Targeting SHP-1-STAT3 signaling by SC-43 may serve as a promising pharmacotherapy for CRC.

  1. Immunohistochemical analysis of the mechanistic target of rapamycin and hypoxia signalling pathways in basal cell carcinoma and trichoepithelioma.

    Directory of Open Access Journals (Sweden)

    Tjinta Brinkhuizen

    Full Text Available BACKGROUND: Basal cell carcinoma (BCC is the most common cancer in Caucasians. Trichoepithelioma (TE is a benign neoplasm that strongly resembles BCC. Both are hair follicle (HF tumours. HFs are hypoxic microenvironments, therefore we hypothesized that hypoxia-induced signalling pathways could be involved in BCC and TE as they are in other human malignancies. Hypoxia-inducible factor 1 (HIF1 and mechanistic/mammalian target of rapamycin (mTOR are key players in these pathways. OBJECTIVES: To determine whether HIF1/mTOR signalling is involved in BCC and TE. METHODS: We used immunohistochemical staining of formalin-fixed paraffin-embedded BCC (n = 45 and TE (n = 35 samples to assess activity of HIF1, mTORC1 and their most important target genes. The percentage positive tumour cells was assessed manually in a semi-quantitative manner and categorized (0%, 80%. RESULTS: Among 45 BCC and 35 TE examined, expression levels were respectively 81% and 57% (BNIP3, 73% and 75% (CAIX, 79% and 86% (GLUT1, 50% and 19% (HIF1α, 89% and 88% (pAKT, 55% and 61% (pS6, 15% and 25% (pMTOR, 44% and 63% (PHD2 and 44% and 49% (VEGF-A. CAIX, Glut1 and PHD2 expression levels were significantly higher in TE when only samples with at least 80% expression were included. CONCLUSIONS: HIF and mTORC1 signalling seems active in both BCC and TE. There are no appreciable differences between the two with respect to pathway activity. At this moment immunohistochemical analyses of HIF, mTORC1 and their target genes does not provide a reliable diagnostic tool for the discrimination of BCC and TE.

  2. Nonmuscle Myosin II Is Required for Internalization of the Epidermal Growth Factor Receptor and Modulation of Downstream Signaling*

    Science.gov (United States)

    Kim, Jong Hyun; Wang, Aibing; Conti, Mary Anne; Adelstein, Robert S.

    2012-01-01

    Ligand-induced internalization of the epidermal growth factor receptor (EGFR) is an important process for regulating signal transduction, cellular dynamics, and cell-cell communication. Here, we demonstrate that nonmuscle myosin II (NM II) is required for the internalization of the EGFR and to trigger the EGFR-dependent activation of ERK and AKT. The EGFR was identified as a protein that interacts with NM II by co-immunoprecipitation and mass spectrometry analysis. This interaction requires both the regulatory light chain 20 (RLC20) of NM II and the kinase domain of the EGFR. Two paralogs of NM II, NM II-A, and NM II-B can act to internalize the EGFR, depending on the cell type and paralog content of the cell line. Loss (siRNA) or inhibition (25 μm blebbistatin) of NM II attenuates the internalization of the EGFR and impairs EGFR-dependent activation of ERK and AKT. Both internalization of the EGFR and downstream signaling to ERK and AKT can be partially restored in siRNA-treated cells by introduction of wild type (WT) GFP-NM II, but cannot be restored by motor mutant NM II. Taken together, these results suggest that NM II plays a role in the internalization of the EGFR and EGFR-mediated signaling pathways. PMID:22718763

  3. Unbiased Combinatorial Genomic Approaches to Identify Alternative Therapeutic Targets within the TSC Signaling Network

    Science.gov (United States)

    2013-06-01

    metabolic changes and results in muscle dystrophy . Cell Metab 8: 411–424 72. Schieke SM, Phillips D, McCoy JP, Aponte AM, Shen RF, Balaban RS, Finkel T...alterations in melting temperature following TALEN treatment and reductions in mRNA levels, indicating that mutations are produced (see example of the...peak was detected following CRISPR treatment indicating the production of mutations (see example of the targeted yellow gene in Figure 2D

  4. Targeting activator protein 1 signaling pathway by bioactive natural agents: Possible therapeutic strategy for cancer prevention and intervention.

    Science.gov (United States)

    Tewari, Devesh; Nabavi, Seyed Fazel; Nabavi, Seyed Mohammad; Sureda, Antoni; Farooqi, Ammad Ahmad; Atanasov, Atanas G; Vacca, Rosa Anna; Sethi, Gautam; Bishayee, Anupam

    2018-02-01

    Activator protein 1 (AP-1) is a key transcription factor in the control of several cellular processes responsible for cell survival proliferation and differentiation. Dysfunctional AP-1 expression and activity are involved in several severe diseases, especially inflammatory disorders and cancer. Therefore, targeting AP-1 has recently emerged as an attractive therapeutic strategy for cancer prevention and therapy. This review summarizes our current understanding of AP-1 biology and function as well as explores and discusses several natural bioactive compounds modulating AP-1-associated signaling pathways for cancer prevention and intervention. Current limitations, challenges, and future directions of research are also critically discussed. Copyright © 2017 Elsevier Ltd. All rights reserved.

  5. Chloroquine targets pancreatic cancer stem cells via inhibition of CXCR4 and hedgehog signaling

    DEFF Research Database (Denmark)

    Balic, Anamaria; Sørensen, Morten Dræby; Trabulo, Sara Maria

    2014-01-01

    effectively eliminating established tumors and improved overall survival. The inhibitory effect of chloroquine was not related to inhibition of autophagy, but was due to inhibition of CXCL12/CXCR4 signaling, resulting in reduced phosphorylation of ERK and STAT3. Furthermore, chloroquine showed potent...... is an effective adjuvant therapy to chemotherapy, offering more efficient tumor elimination and improved cure rates. Chloroquine should be further explored in the clinical setting as its success may help to more rapidly improve the poor prognosis of patients with pancreatic cancer...

  6. The microRNA-132/212 family fine-tunes multiple targets in Angiotensin II signalling in cardiac fibroblasts

    DEFF Research Database (Denmark)

    Eskildsen, Tilde V; Schneider, Mikael; Sandberg, Maria B

    2015-01-01

    INTRODUCTION: MicroRNAs (miRNAs) are emerging as key regulators of cardiovascular development and disease; however, the cardiac miRNA target molecules are not well understood. We and others have described the Angiotensin II (AngII)-induced miR-132/212 family as novel regulators of cardiovascular...... in silico and in vitro experiments to identify miR-132/212 molecular targets in primary rat cardiac fibroblasts. RESULTS: MiR-132/212 overexpression increased fibroblast cell size and mRNA arrays detected several hundred genes that were differentially expressed, including a wide panel of receptors...... pathways that fine-tuned by miR-132/212, suggesting a role for this miRNA family as master signalling switches in cardiac fibroblasts. Our data underscore the potential for miRNA tools to manipulate a large array of molecules and thereby control biological function....

  7. Spared internal but impaired external reward prediction error signals in major depressive disorder during reinforcement learning.

    Science.gov (United States)

    Bakic, Jasmina; Pourtois, Gilles; Jepma, Marieke; Duprat, Romain; De Raedt, Rudi; Baeken, Chris

    2017-01-01

    Major depressive disorder (MDD) creates debilitating effects on a wide range of cognitive functions, including reinforcement learning (RL). In this study, we sought to assess whether reward processing as such, or alternatively the complex interplay between motivation and reward might potentially account for the abnormal reward-based learning in MDD. A total of 35 treatment resistant MDD patients and 44 age matched healthy controls (HCs) performed a standard probabilistic learning task. RL was titrated using behavioral, computational modeling and event-related brain potentials (ERPs) data. MDD patients showed comparable learning rate compared to HCs. However, they showed decreased lose-shift responses as well as blunted subjective evaluations of the reinforcers used during the task, relative to HCs. Moreover, MDD patients showed normal internal (at the level of error-related negativity, ERN) but abnormal external (at the level of feedback-related negativity, FRN) reward prediction error (RPE) signals during RL, selectively when additional efforts had to be made to establish learning. Collectively, these results lend support to the assumption that MDD does not impair reward processing per se during RL. Instead, it seems to alter the processing of the emotional value of (external) reinforcers during RL, when additional intrinsic motivational processes have to be engaged. © 2016 Wiley Periodicals, Inc.

  8. Self-focusing therapeutic gene delivery with intelligent gene vector swarms: intra-swarm signalling through receptor transgene expression in targeted cells.

    Science.gov (United States)

    Tolmachov, Oleg E

    2015-01-01

    are then attracted to and internalized into the intended target cells via the expressed cognate strongly binding extra-cellular receptor, causing escalation of gene transfer into these cells and increasing the copy number of the therapeutic gene expression modules. Such self-focusing swarms of gene vectors can be either homogeneous, with 'scout' and 'therapeutic' members of the swarm being structurally identical, or, alternatively, heterogeneous (split), with 'scout' and 'therapeutic' members of the swarm being structurally specialized. It is hoped that the proposed self-focusing cell-targeted gene vector swarms with receptor-mediated intra-swarm signalling could be particularly effective in 'top-up' gene delivery scenarios, achieving high-level and sustained expression of therapeutic transgenes that are prone to shut-down through degradation and silencing. Crucially, in contrast to low-precision 'general location' vector guidance by diffusible chemo-attractants, ear-marking non-diffusible receptors can provide high-accuracy targeting of therapeutic vector particles to the specific cell, which has undergone a 'successful cell-specific hit' by a 'scout' vector particle. Opportunities for cell targeting could be expanded, since in the proposed model of self-focusing it could be possible to probe a broad selection of intra-cellular determinants of cell-specificity and not just to rely exclusively on extra-cellular markers of cell-specificity. By employing such self-focusing gene vectors for the improvement of cell-targeted delivery of therapeutic genes, e.g., in cancer therapy or gene addition therapy of recessive genetic diseases, it could be possible to broaden a leeway for the reduction of the vector load and, consequently, to minimize undesired vector cytotoxicity, immune reactions, and the risk of inadvertent genetic modification of germline cells in genetic treatment in vivo. Copyright © 2014 Elsevier B.V. All rights reserved.

  9. HLH-29 regulates ovulation in C. elegans by targeting genes in the inositol triphosphate signaling pathway

    Directory of Open Access Journals (Sweden)

    Ana White

    2012-02-01

    The reproductive cycle in the nematode Caenorhabditis elegans depends in part on the ability of the mature oocyte to ovulate into the spermatheca, fuse with the sperm during fertilization, and then exit the spermatheca as a fertilized egg. This cycle requires the integration of signals between the germ cells and the somatic gonad and relies heavily on the precise control of inositol 1,4,5 triphosphate (IP3levels. The HLH-29 protein, one of five Hairy/Enhancer of Split (HES homologs in C. elegans, was previously shown to affect development of the somatic gonad. Here we show that HLH-29 expression in the adult spermatheca is strongly localized to the distal spermatheca valve and to the spermatheca-uterine valve, and that loss of hlh-29 activity interferes with oocyte entry into and egg exit from the spermatheca. We show that HLH-29 can regulate the transcriptional activity of the IP3 signaling pathway genes ppk-1, ipp-5, and plc-1 and provide evidence that hlh-29 acts in a genetic pathway with each of these genes. We propose that the HES-like protein HLH-29 acts in the spermatheca of larval and adult animals to effectively increase IP3 levels during the reproductive cycle.

  10. Brain signal variability is modulated as a function of internal and external demand in younger and older adults.

    Science.gov (United States)

    Grady, Cheryl L; Garrett, Douglas D

    2018-04-01

    Variability in the Blood Oxygen-Level Dependent (BOLD) signal from fMRI is often associated with better cognitive performance and younger age. It has been proposed that neural variability enables flexible responding to uncertainty in a changing environment. However, signal variability reflecting environmental uncertainty may reduce to the extent that a task depends on internally-directed attention and is supported by neural "solutions" that are schematic and relatively stable within each individual. Accordingly, we examined the hypothesis that BOLD variability will be low at rest, higher during internally-directed tasks, and higher still during externally-directed tasks, and that this effect will be reduced with aging. Modulation of BOLD variability across conditions was consistent with these hypotheses, and was associated with faster and more stable behavioral performance in both young and older adults. These data support the idea that brain signal variability may modulate in response to environmental uncertainty, which is presumed to be greater in the external environment than in the internal milieu. Reduced flexibility of signal variability with age may indicate less ability to switch between internal and external brain states. Copyright © 2017 Elsevier Inc. All rights reserved.

  11. AVSS 2007: IEEE International Conference onAdvanced Video and Signal based Surveillance, London, UK, September 2007

    DEFF Research Database (Denmark)

    Fihl, Preben

    This technical report will cover the participation in the IEEE International Conference on Advanced Video and Signal based Surveillance in September 2007. The report will give a concise description of the most relevant topics presented at the conference, focusing on the work related to the HERMES...... project and human motion and action recognition. Our contribution to the conference will also be described....

  12. Ultrasound-targeted microbubble destruction enhances delayed BMC delivery and attenuates post-infarction cardiac remodelling by inducing engraftment signals.

    Science.gov (United States)

    Chen, Yanmei; Zhang, Chuanxi; Shen, Shuxin; Guo, Shengcun; Zhong, Lintao; Li, Xinzhong; Chen, Guojun; Chen, Gangbin; He, Xiang; Huang, Chixiong; He, Nvqin; Liao, Wangjun; Liao, Yulin; Bin, Jianping

    2016-12-01

    Delayed administration of bone marrow cells (BMCs) at 2-4 weeks after successful reperfusion in patients with acute myocardial infarction (MI) does not improve cardiac function. The reduction in engraftment signals observed following this time interval might impair the effects of delayed BMC treatment. In the present study, we aimed to determine whether ultrasound-targeted microbubble destruction (UTMD) treatment could increase engraftment signals, enhance the delivery of delayed BMCs and subsequently attenuate post-infarction cardiac remodelling. A myocardial ischaemia/reperfusion (I/R) model was induced in Wistar rats via left coronary ligation for 45 min followed by reperfusion. Western blotting revealed that engraftment signals peaked at 7 days post-I/R and were dramatically lower at 14 days post-I/R. The lower engraftment signals at 14 days post-I/R could be triggered by UTMD treatment at a mechanical index of 1.0-1.9. The troponin I levels in the 1.9 mechanical index group were higher than in the other groups. Simultaneous haematoxylin and eosin staining and fluorescence revealed that the number of engrafted BMCs in the ischaemic zone was greater in the group treated with both UTMD and delayed BMC transplantation than in the control groups (PBMC transplantation improved cardiac function and decreased cardiac fibrosis at 4 weeks after treatment, as compared with control groups (both PBMC transplantation increased capillary density, myocardial cell proliferation and c-kit + cell proliferation. These findings indicated that UTMD treatment could induce engraftment signals and enhance homing of delayed BMCs to ischaemic myocardium, attenuating post-infarction cardiac remodelling by promoting neovascularization, cardiomyogenesis and expansion of cardiac c-kit + cells. © 2016 The Author(s). published by Portland Press Limited on behalf of the Biochemical Society.

  13. Crosstalk between bone niche and immune system: osteoimmunology signaling as a potential target for cancer treatment.

    Science.gov (United States)

    Criscitiello, Carmen; Viale, Giulia; Gelao, Lucia; Esposito, Angela; De Laurentiis, Michele; De Placido, Sabino; Santangelo, Michele; Goldhirsch, Aron; Curigliano, Giuseppe

    2015-02-01

    There is a well recognized link between the bone and the immune system and in recent years there has been a major effort to elucidate the multiple functions of the molecules expressed in both bone and immune cells. Several molecules that were initially identified and studied in the immune system have been shown to have essential functions also in the bone. An interdisciplinary field embracing immune and bone biology has been brought together and called "osteoimmunology". The co-regulation of the skeletal and immune systems strikingly exemplifies the extreme complexity of such an interaction. Their interdependency must be considered in designing therapeutic approaches for either of the two systems. In other words, it is necessary to think of the osteoimmune system as a complex physiological unit. Denosumab was originally introduced to specifically target bone resorption, but it is now under evaluation for its effect on the long term immune response. Similarly, our current and still growing knowledge of the intimate link between the immune system and bone will be beneficial for the safety of drugs targeting either of these integrated systems. Given the large number of molecules exerting functions on both the skeletal and immune systems, osteoimmunological understanding is becoming increasingly important. Both bone and immune systems are frequently disrupted in cancer; and they may be crucial in regulating tumor growth and progression. Some therapies - such as bisphosphonates and receptor activator of NF-κB ligand (RANKL) targeted drugs - that aim at reducing pathologic osteolysis in cancer may interact with the immune system, thus providing potential favorable effects on survival. Copyright © 2014 Elsevier Ltd. All rights reserved.

  14. International Experience with Key Program Elements of IndustrialEnergy Efficiency or Greenhouse Gas Emissions Reduction Target-SettingPrograms

    Energy Technology Data Exchange (ETDEWEB)

    Price, Lynn; Galitsky, Christina; Kramer, Klaas Jan

    2008-02-02

    Target-setting agreements, also known as voluntary ornegotiated agreements, have been used by a number of governments as amechanism for promoting energy efficiency within the industrial sector. Arecent survey of such target-setting agreement programs identified 23energy efficiency or GHG emissions reduction voluntary agreement programsin 18 countries. International best practice related to target-settingagreement programs calls for establishment of a coordinated set ofpolicies that provide strong economic incentives as well as technical andfinancial support to participating industries. The key program elementsof a target-setting program are the target-setting process,identification of energy-saving technologies and measures usingenergy-energy efficiency guidebooks and benchmarking as well as byconducting energy-efficiency audits, development of an energy-savingsaction plan, development and implementation of energy managementprotocols, development of incentives and supporting policies, monitoringprogress toward targets, and program evaluation. This report firstprovides a description of three key target-setting agreement programs andthen describes international experience with the key program elementsthat comprise such programs using information from the three keytarget-setting programs as well as from other international programsrelated to industrial energy efficiency or GHG emissionsreductions.

  15. Yeast carboxypeptidase Y vacuolar targeting signal is defined by four propeptide amino acids

    DEFF Research Database (Denmark)

    Valls, L A; Winther, Jakob R.; Stevens, T H

    1990-01-01

    The amino-terminal propeptide of carboxypeptidase Y (CPY) is necessary and sufficient for targeting this glycoprotein to the vacuole of Saccharomyces cerevisiae. A 16 amino acid stretch of the propeptide was subjected to region-directed mutagenesis using randomized oligonucleotides. Mutations...... sort and deliver only the wild-type molecule to the vacuole. These results indicate that the PRC1 missorting mutations are cis-dominant, implying that the mutant forms of proCPY are secreted as a consequence of failing to interact with the sorting apparatus, rather than a general poisoning...

  16. Targeting Ligand Dependent and Ligand Independent Androgen Receptor Signaling in Prostate Cancer

    Science.gov (United States)

    2014-10-01

    flanking residues around the LXXLL motif to our lead D2 compound. * To facilitate the synthesis of tris-benzamide analogues designed to target AR...we used only alkyl groups such as n- propyl , isopropyl, n-butyl, isobutyl, sec-butyl, n-pentyl and isopentyl groups for side chain diversity of the...by reacting 3-alkoxy-4-nitrobenzoyl chlorides 2 with methyl 3-alkoxy-4-aminobenzoates 3 (Scheme 1).21 NO2 O NHO R2 O R1 O O NH2 O R1 O Oa N H NO2 O

  17. Clathrin-dependent internalization, signaling, and metabolic processing of guanylyl cyclase/natriuretic peptide receptor-A.

    Science.gov (United States)

    Somanna, Naveen K; Mani, Indra; Tripathi, Satyabha; Pandey, Kailash N

    2018-04-01

    Cardiac hormones, atrial and brain natriuretic peptides (ANP and BNP), have pivotal roles in renal hemodynamics, neuroendocrine signaling, blood pressure regulation, and cardiovascular homeostasis. Binding of ANP and BNP to the guanylyl cyclase/natriuretic peptide receptor-A (GC-A/NPRA) induces rapid internalization and trafficking of the receptor via endolysosomal compartments, with concurrent generation of cGMP. However, the mechanisms of the endocytotic processes of NPRA are not well understood. The present study, using 125 I-ANP binding assay and confocal microscopy, examined the function of dynamin in the internalization of NPRA in stably transfected human embryonic kidney-293 (HEK-293) cells. Treatment of recombinant HEK-293 cells with ANP time-dependently accelerated the internalization of receptor from the cell surface to the cell interior. However, the internalization of ligand-receptor complexes of NPRA was drastically decreased by the specific inhibitors of clathrin- and dynamin-dependent receptor internalization, almost 85% by monodansylcadaverine, 80% by chlorpromazine, and 90% by mutant dynamin, which are specific blockers of endocytic vesicle formation. Visualizing the internalization of NPRA and enhanced GFP-tagged NPRA in HEK-293 cells by confocal microscopy demonstrated the formation of endocytic vesicles after 5 min of ANP treatment; this effect was blocked by the inhibitors of clathrin and by mutant dynamin construct. Our results suggest that NPRA undergoes internalization via clathrin-mediated endocytosis as part of its normal itinerary, including trafficking, signaling, and metabolic degradation.

  18. Optogenetic control of mitochondrial metabolism and Ca2+ signaling by mitochondria-targeted opsins.

    Science.gov (United States)

    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.

  19. Targeting Adenosine Signaling in Parkinson's Disease: From Pharmacological to Non-pharmacological Approaches

    Directory of Open Access Journals (Sweden)

    Luiza R. Nazario

    2017-11-01

    Full Text Available Parkinson's disease (PD is one of the most prevalent neurodegenerative disease displaying negative impacts on both the health and social ability of patients and considerable economical costs. The classical anti-parkinsonian drugs based in dopaminergic replacement are the standard treatment, but several motor side effects emerge during long-term use. This mini-review presents the rationale to several efforts from pre-clinical and clinical studies using adenosine receptor antagonists as a non-dopaminergic therapy. As several studies have indicated that the monotherapy with adenosine receptor antagonists reaches limited efficacy, the usage as a co-adjuvant appeared to be a promising strategy. The formulation of multi-targeted drugs, using adenosine receptor antagonists and other neurotransmitter systems than the dopaminergic one as targets, have been receiving attention since Parkinson's disease presents a complex biological impact. While pharmacological approaches to cure or ameliorate the conditions of PD are the leading strategy in this area, emerging positive aspects have arisen from non-pharmacological approaches and adenosine function inhibition appears to improve both strategies.

  20. Targeting the PI3K signaling pathway in KRAS mutant colon cancer

    International Nuclear Information System (INIS)

    Hong, Suntaek; Kim, SoYoung; Kim, Hye Youn; Kang, Myunghee; Jang, Ho Hee; Lee, Won-Suk

    2015-01-01

    Metastatic colorectal cancer (CRC) patients with v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations are resistant to monoclonal antibody that targets the epidermal growth factor receptor such as cetuximab. BKM120 targets phosphatidylinositide-3-kinase (PIK3CA), but it is unknown whether BKM120 can reverse cetuximab resistance in KRAS mutant CRC. Human CRC cell lines with KRAS mutations (DLD-1, HCT116, and LoVo) were used to test the effect of cetuximab, BKM120, and cetuximab plus BKM120 on cell proliferation in vitro and in vivo. BKM120 reduced cell proliferation in a concentration-dependent manner in the LoVo (PI3KCA wild type) as well as the HCT116 and DLD1 cells (that carry a PI3KCA mutation). BKM120 only inhibited ERK phosphorylation in LoVo cells (PIK3CA wild type), but not in DLD1 or HCT116 cells at a concentration of 1 μmol/L. Treatment with cetuximab and BKM120 significantly reduced the growth of xenograft tumors originating from KRAS mutant cells compared with cetuximab alone (P = 0.034). BKM120 may overcome cetuximab resistance in colon cancer cells with KRAS mutation

  1. Targeting multiple pro-apoptotic signaling pathways with curcumin in prostate cancer cells

    Science.gov (United States)

    Rivera, Mariela; Ramos, Yanilda; Rodríguez-Valentín, Madeline; López-Acevedo, Sheila; Cubano, Luis A.; Zou, Jin; Zhang, Qiang; Wang, Guangdi

    2017-01-01

    Curcumin, an extract from the turmeric rhizome (Curcuma longa), is known to exhibit anti-inflammatory, antioxidant, chemopreventive and antitumoral activities against aggressive and recurrent cancers. Accumulative data indicate that curcumin may induce cancer cell death. However, the detailed mechanism underlying its pro-apoptotic and anti-cancer effects remains to be elucidated. In the present study, we examined the signaling pathways triggered by curcumin, specifically, the exact molecular mechanisms of curcumin-induced apoptosis in highly metastatic human prostate cancer cells. The effect of curcumin was evaluated using for the first time in prostate cancer, a gel-free shotgun quantitative proteomic analysis coupled with Tandem Mass Tag isobaric labeling-based-signaling networks. Results were confirmed at the gene expression level by qRT-PCR and at the protein expression level by western blot and flow cytometry. Our findings revealed that curcumin induced an Endoplasmic Reticulum stress-mediated apoptosis in PC3. The mechanisms by which curcumin promoted cell death in these cells were associated with cell cycle arrest, increased reactive oxygen species, autophagy and the Unfolded Protein Response. Furthermore, the upregulation of ER stress was measured using key indicators of ER stress: Glucose-Regulated Protein 78, Inositol-Requiring Enzyme 1 alpha, Protein Disulfide isomerase and Calreticulin. Chronic ER stress induction was concomitant with the upregulation of pro-apoptotic markers (caspases 3,9,12) and Poly (ADP-ribose) polymerase. The downregulated proteins include anti-apoptotic and anti-tumor markers, supporting their curcumin-induced pro-apoptotic role in prostate cancer cells. Taken together, these data suggest that curcumin may serve as a promising anticancer agent by inducing a chronic ER stress mediated cell death and activation of cell cycle arrest, UPR, autophagy and oxidative stress responses. PMID:28628644

  2. Targeting multiple pro-apoptotic signaling pathways with curcumin in prostate cancer cells.

    Directory of Open Access Journals (Sweden)

    Mariela Rivera

    Full Text Available Curcumin, an extract from the turmeric rhizome (Curcuma longa, is known to exhibit anti-inflammatory, antioxidant, chemopreventive and antitumoral activities against aggressive and recurrent cancers. Accumulative data indicate that curcumin may induce cancer cell death. However, the detailed mechanism underlying its pro-apoptotic and anti-cancer effects remains to be elucidated. In the present study, we examined the signaling pathways triggered by curcumin, specifically, the exact molecular mechanisms of curcumin-induced apoptosis in highly metastatic human prostate cancer cells. The effect of curcumin was evaluated using for the first time in prostate cancer, a gel-free shotgun quantitative proteomic analysis coupled with Tandem Mass Tag isobaric labeling-based-signaling networks. Results were confirmed at the gene expression level by qRT-PCR and at the protein expression level by western blot and flow cytometry. Our findings revealed that curcumin induced an Endoplasmic Reticulum stress-mediated apoptosis in PC3. The mechanisms by which curcumin promoted cell death in these cells were associated with cell cycle arrest, increased reactive oxygen species, autophagy and the Unfolded Protein Response. Furthermore, the upregulation of ER stress was measured using key indicators of ER stress: Glucose-Regulated Protein 78, Inositol-Requiring Enzyme 1 alpha, Protein Disulfide isomerase and Calreticulin. Chronic ER stress induction was concomitant with the upregulation of pro-apoptotic markers (caspases 3,9,12 and Poly (ADP-ribose polymerase. The downregulated proteins include anti-apoptotic and anti-tumor markers, supporting their curcumin-induced pro-apoptotic role in prostate cancer cells. Taken together, these data suggest that curcumin may serve as a promising anticancer agent by inducing a chronic ER stress mediated cell death and activation of cell cycle arrest, UPR, autophagy and oxidative stress responses.

  3. Targeting TGF-β Signaling by Antisense Oligonucleotide-mediated Knockdown of TGF-β Type I Receptor

    Directory of Open Access Journals (Sweden)

    Dwi U Kemaladewi

    2014-01-01

    Full Text Available Duchenne muscular dystrophy (DMD is caused by lack of functional dystrophin and results in progressive myofiber damage and degeneration. In addition, impaired muscle regeneration and fibrosis contribute to the progressive pathology of DMD. Importantly, transforming growth factor-β (TGF-β is implicated in DMD pathology and is known to stimulate fibrosis and inhibit muscle regeneration. In this study, we present a new strategy to target TGF-β signaling cascades by specifically inhibiting the expression of TGF-β type I receptor TGFBR1 (ALK5. Antisense oligonucleotides (AONs were designed to specifically induce exon skipping of mouse ALK5 transcripts. AON-induced exon skipping of ALK5 resulted in specific downregulation of full-length receptor transcripts in vitro in different cell types, repression of TGF-β activity, and enhanced C2C12 myoblast differentiation. To determine the effect of these AONs in dystrophic muscles, we performed intramuscular injections of ALK5 AONs in mdx mice, which resulted in a decrease in expression of fibrosis-related genes and upregulation of Myog expression compared to control AON-injected muscles. In summary, our study presents a novel method to target TGF-β signaling cascades with potential beneficial effects for DMD.

  4. The Peroxisomal Targeting Signal 1 in sterol carrier protein 2 is autonomous and essential for receptor recognition

    Directory of Open Access Journals (Sweden)

    Bond Charles S

    2011-03-01

    Full Text Available Abstract Background The majority of peroxisomal matrix proteins destined for translocation into the peroxisomal lumen are recognised via a C-terminal Peroxisomal Target Signal type 1 by the cycling receptor Pex5p. The only structure to date of Pex5p in complex with a cargo protein is that of the C-terminal cargo-binding domain of the receptor with sterol carrier protein 2, a small, model peroxisomal protein. In this study, we have tested the contribution of a second, ancillary receptor-cargo binding site, which was found in addition to the characterised Peroxisomal Target Signal type 1. Results To investigate the function of this secondary interface we have mutated two key residues from the ancillary binding site and analyzed the level of binding first by a yeast-two-hybrid assay, followed by quantitative measurement of the binding affinity and kinetics of purified protein components and finally, by in vivo measurements, to determine translocation capability. While a moderate but significant reduction of the interaction was found in binding assays, we were not able to measure any significant defects in vivo. Conclusions Our data therefore suggest that at least in the case of sterol carrier protein 2 the contribution of the second binding site is not essential for peroxisomal import. At this stage, however, we cannot rule out that other cargo proteins may require this ancillary binding site.

  5. Peroxisome Proliferator-Activated Receptor-γ Ligands: Potential Pharmacological Agents for Targeting the Angiogenesis Signaling Cascade in Cancer

    Directory of Open Access Journals (Sweden)

    Costas Giaginis

    2008-01-01

    Full Text Available Peroxisome proliferator-activated receptor-γ (PPAR-γ has currently been considered as molecular target for the treatment of human metabolic disorders. Experimental data from in vitro cultures, animal models, and clinical trials have shown that PPAR-γ ligand activation regulates differentiation and induces cell growth arrest and apoptosis in a variety of cancer types. Tumor angiogenesis constitutes a multifaceted process implicated in complex downstream signaling pathways that triggers tumor growth, invasion, and metastasis. In this aspect, accumulating in vitro and in vivo studies have provided extensive evidence that PPAR-γ ligands can function as modulators of the angiogenic signaling cascade. In the current review, the crucial role of PPAR-γ ligands and the underlying mechanisms participating in tumor angiogenesis are summarized. Targeting PPAR-γ may prove to be a potential therapeutic strategy in combined treatments with conventional chemotherapy; however, special attention should be taken as there is also substantial evidence to support that PPAR-γ ligands can enhance angiogenic phenotype in tumoral cells.

  6. THE HYDROGENOSOMAL ENZYME HYDROGENASE FROM THE ANAEROBIC FUNGUS NEOCALLIMASTIX SP L2 IS RECOGNIZED BY ANTIBODIES, DIRECTED AGAINST THE C-TERMINAL MICROBODY PROTEIN TARGETING SIGNAL SKL

    NARCIS (Netherlands)

    MARVINSIKKEMA, FD; KRAAK, MN; VEENHUIS, M; GOTTSCHAL, JC; PRINS, RA

    The question was addressed whether antibodies directed against the general microbody C-terminal protein targeting signal SKL recognized hydrogenosomal proteins from Neocallimastix sp. L2. Immunofluorescence, immunocytochemistry and Western blotting experiments using these antibodies indicated the

  7. KSHV Entry and Trafficking in Target Cells—Hijacking of Cell Signal Pathways, Actin and Membrane Dynamics

    Directory of Open Access Journals (Sweden)

    Binod Kumar

    2016-11-01

    Full Text Available Kaposi’s sarcoma associated herpesvirus (KSHV is etiologically associated with human endothelial cell hyperplastic Kaposi’s sarcoma and B-cell primary effusion lymphoma. KSHV infection of adherent endothelial and fibroblast cells are used as in vitro models for infection and KSHV enters these cells by host membrane bleb and actin mediated macropinocytosis or clathrin endocytosis pathways, respectively. Infection in endothelial and fibroblast cells is initiated by the interactions between multiple viral envelope glycoproteins and cell surface associated heparan sulfate (HS, integrins (α3β1, αVβ3 and αVβ5, and EphA2 receptor tyrosine kinase (EphA2R. This review summarizes the accumulated studies demonstrating that KSHV manipulates the host signal pathways to enter and traffic in the cytoplasm of the target cells, to deliver the viral genome into the nucleus, and initiate viral gene expression. KSHV interactions with the cell surface receptors is the key platform for the manipulations of host signal pathways which results in the simultaneous induction of FAK, Src, PI3-K, Rho-GTPase, ROS, Dia-2, PKC ζ, c-Cbl, CIB1, Crk, p130Cas and GEF-C3G signal and adaptor molecules that play critical roles in the modulation of membrane and actin dynamics, and in the various steps of the early stages of infection such as entry and trafficking towards the nucleus. The Endosomal Sorting Complexes Required for Transport (ESCRT proteins are also recruited to assist in viral entry and trafficking. In addition, KSHV interactions with the cell surface receptors also induces the host transcription factors NF-κB, ERK1/2, and Nrf2 early during infection to initiate and modulate viral and host gene expression. Nuclear delivery of the viral dsDNA genome is immediately followed by the host innate responses such as the DNA damage response (DDR, inflammasome and interferon responses. Overall, these studies form the initial framework for further studies of

  8. Targeting p53 via JNK pathway: a novel role of RITA for apoptotic signaling in multiple myeloma.

    Science.gov (United States)

    Saha, Manujendra N; Jiang, Hua; Yang, Yijun; Zhu, Xiaoyun; Wang, Xiaoming; Schimmer, Aaron D; Qiu, Lugui; Chang, Hong

    2012-01-01

    The low frequency of p53 alterations e.g., mutations/deletions (∼10%) in multiple myeloma (MM) makes this tumor type an ideal candidate for p53-targeted therapies. RITA is a small molecule which can induce apoptosis in tumor cells by activating the p53 pathway. We previously showed that RITA strongly activates p53 while selectively inhibiting growth of MM cells without inducing genotoxicity, indicating its potential as a drug lead for p53-targeted therapy in MM. However, the molecular mechanisms underlying the pro-apoptotic effect of RITA are largely undefined. Gene expression analysis by microarray identified a significant number of differentially expressed genes associated with stress response including c-Jun N-terminal kinase (JNK) signaling pathway. By Western blot analysis we further confirmed that RITA induced activation of p53 in conjunction with up-regulation of phosphorylated ASK-1, MKK-4 and c-Jun. These results suggest that RITA induced the activation of JNK signaling. Chromatin immunoprecipitation (ChIP) analysis showed that activated c-Jun binds to the activator protein-1 (AP-1) binding site of the p53 promoter region. Disruption of the JNK signal pathway by small interfering RNA (siRNA) against JNK or JNK specific inhibitor, SP-600125 inhibited the activation of p53 and attenuated apoptosis induced by RITA in myeloma cells carrying wild type p53. On the other hand, p53 transcriptional inhibitor, PFT-α or p53 siRNA not only inhibited the activation of p53 transcriptional targets but also blocked the activation of c-Jun suggesting the presence of a positive feedback loop between p53 and JNK. In addition, RITA in combination with dexamethasone, known as a JNK activator, displays synergistic cytotoxic responses in MM cell lines and patient samples. Our study unveils a previously undescribed mechanism of RITA-induced p53-mediated apoptosis through JNK signaling pathway and provides the rationale for combination of p53 activating drugs with JNK

  9. Targeting p53 via JNK pathway: a novel role of RITA for apoptotic signaling in multiple myeloma.

    Directory of Open Access Journals (Sweden)

    Manujendra N Saha

    Full Text Available The low frequency of p53 alterations e.g., mutations/deletions (∼10% in multiple myeloma (MM makes this tumor type an ideal candidate for p53-targeted therapies. RITA is a small molecule which can induce apoptosis in tumor cells by activating the p53 pathway. We previously showed that RITA strongly activates p53 while selectively inhibiting growth of MM cells without inducing genotoxicity, indicating its potential as a drug lead for p53-targeted therapy in MM. However, the molecular mechanisms underlying the pro-apoptotic effect of RITA are largely undefined. Gene expression analysis by microarray identified a significant number of differentially expressed genes associated with stress response including c-Jun N-terminal kinase (JNK signaling pathway. By Western blot analysis we further confirmed that RITA induced activation of p53 in conjunction with up-regulation of phosphorylated ASK-1, MKK-4 and c-Jun. These results suggest that RITA induced the activation of JNK signaling. Chromatin immunoprecipitation (ChIP analysis showed that activated c-Jun binds to the activator protein-1 (AP-1 binding site of the p53 promoter region. Disruption of the JNK signal pathway by small interfering RNA (siRNA against JNK or JNK specific inhibitor, SP-600125 inhibited the activation of p53 and attenuated apoptosis induced by RITA in myeloma cells carrying wild type p53. On the other hand, p53 transcriptional inhibitor, PFT-α or p53 siRNA not only inhibited the activation of p53 transcriptional targets but also blocked the activation of c-Jun suggesting the presence of a positive feedback loop between p53 and JNK. In addition, RITA in combination with dexamethasone, known as a JNK activator, displays synergistic cytotoxic responses in MM cell lines and patient samples. Our study unveils a previously undescribed mechanism of RITA-induced p53-mediated apoptosis through JNK signaling pathway and provides the rationale for combination of p53 activating drugs with

  10. MicroRNA-1297 inhibits prostate cancer cell proliferation and invasion by targeting the AEG-1/Wnt signaling pathway

    International Nuclear Information System (INIS)

    Liang, Xuan; Li, Hecheng; Fu, Delai; Chong, Tie; Wang, Ziming; Li, Zhaolun

    2016-01-01

    MicroRNAs (miRNAs) have been known to be implicated in tumorigenic programs. miR-1297 has been reported to be dysregulated and involved in cancer progression in many types of human cancers. However, the expression level and the role of miR-1297 in prostate cancer remain unclear. Herein, we aimed to investigate the potential role and molecular mechanism of miR-1297 in prostate cancer progression. We found that miR-1297 was significantly downregulated in human prostate cancer specimens as well as in several prostate cancer cell lines. In addition, functional experiments demonstrated that overexpression of miR-1297 remarkably inhibited prostate cancer cell proliferation and invasion whereas miR-1297 suppression significantly promoted prostate cancer cell proliferation and invasion. Bioinformatics analysis showed that the Astrocyte elevated gene-1 (AEG-1), a well-known oncogene, is a predicted target of miR-1297. Dual-luciferase reporter assay showed that miR-1297 was able to directly target the 3’-untranslated region of AEG-1. In addition, RT-qPCR and Western blot analysis showed that miR-1297 regulated the mRNA and protein expression levels of AEG-1. We also showed that miR-1297 was able to regulate the Wnt signaling pathway. Moreover, rescue assays indicated that AEG-1 contributed to miR-1297-endowed effects on cell proliferation and invasion as well as Wnt signaling pathway. Taken together, these findings suggest that miR-1297 inhibits prostate cancer proliferation and invasion by targeting AEG-1, thereby providing novel insight into understanding the pathogenesis of prostate cancer. Thus, miR-1297 may be a novel potential therapeutic candidate to treat prostate cancer. - Highlights: • miR-1297 is decreased in prostate cancer. • miR-1297 inhibits prostate cancer cell proliferation and invasion. • miR-1297 targets and inhibits AEG-1. • miR-1297 regulates AEG-1/Wnt signaling pathway.

  11. Co-stimulatory signaling determines tumor antigen sensitivity and persistence of CAR T cells targeting PSCA+ metastatic prostate cancer.

    Science.gov (United States)

    Priceman, Saul J; Gerdts, Ethan A; Tilakawardane, Dileshni; Kennewick, Kelly T; Murad, John P; Park, Anthony K; Jeang, Brook; Yamaguchi, Yukiko; Yang, Xin; Urak, Ryan; Weng, Lihong; Chang, Wen-Chung; Wright, Sarah; Pal, Sumanta; Reiter, Robert E; Wu, Anna M; Brown, Christine E; Forman, Stephen J

    2018-01-01

    Advancing chimeric antigen receptor (CAR)-engineered adoptive T cells for the treatment of solid cancers is a major focus in the field of immunotherapy, given impressive recent clinical responses in hematological malignancies. Prostate cancer may be amenable to T cell-based immunotherapy since several tumor antigens, including prostate stem-cell antigen (PSCA), are widely over-expressed in metastatic disease. While antigen selectivity of CARs for solid cancers is crucial, it is problematic due to the absence of truly restricted tumor antigen expression and potential safety concerns with "on-target off-tumor" activity. Here, we show that the intracellular co-stimulatory signaling domain can determine a CAR's sensitivity for tumor antigen expression. A 4-1BB intracellular co-stimulatory signaling domain in PSCA-CARs confers improved selectivity for higher tumor antigen density, reduced T cell exhaustion phenotype, and equivalent tumor killing ability compared to PSCA-CARs containing the CD28 co-stimulatory signaling domain. PSCA-CARs exhibit robust in vivo anti-tumor activity in patient-derived bone-metastatic prostate cancer xenograft models, and 4-1BB-containing CARs show superior T cell persistence and control of disease compared with CD28-containing CARs. Our study demonstrates the importance of co-stimulation in defining an optimal CAR T cell, and also highlights the significance of clinically relevant models in developing solid cancer CAR T cell therapies.

  12. Co-stimulatory signaling determines tumor antigen sensitivity and persistence of CAR T cells targeting PSCA+ metastatic prostate cancer

    Science.gov (United States)

    Priceman, Saul J.; Gerdts, Ethan A.; Tilakawardane, Dileshni; Kennewick, Kelly T.; Murad, John P.; Park, Anthony K.; Jeang, Brook; Yamaguchi, Yukiko; Urak, Ryan; Weng, Lihong; Chang, Wen-Chung; Wright, Sarah; Pal, Sumanta; Reiter, Robert E.; Brown, Christine E.; Forman, Stephen J.

    2018-01-01

    ABSTRACT Advancing chimeric antigen receptor (CAR)-engineered adoptive T cells for the treatment of solid cancers is a major focus in the field of immunotherapy, given impressive recent clinical responses in hematological malignancies. Prostate cancer may be amenable to T cell-based immunotherapy since several tumor antigens, including prostate stem-cell antigen (PSCA), are widely over-expressed in metastatic disease. While antigen selectivity of CARs for solid cancers is crucial, it is problematic due to the absence of truly restricted tumor antigen expression and potential safety concerns with “on-target off-tumor” activity. Here, we show that the intracellular co-stimulatory signaling domain can determine a CAR's sensitivity for tumor antigen expression. A 4-1BB intracellular co-stimulatory signaling domain in PSCA-CARs confers improved selectivity for higher tumor antigen density, reduced T cell exhaustion phenotype, and equivalent tumor killing ability compared to PSCA-CARs containing the CD28 co-stimulatory signaling domain. PSCA-CARs exhibit robust in vivo anti-tumor activity in patient-derived bone-metastatic prostate cancer xenograft models, and 4-1BB-containing CARs show superior T cell persistence and control of disease compared with CD28-containing CARs. Our study demonstrates the importance of co-stimulation in defining an optimal CAR T cell, and also highlights the significance of clinically relevant models in developing solid cancer CAR T cell therapies. PMID:29308300

  13. The crosstalk between Target of Rapamycin (TOR) and Jasmonic Acid (JA) signaling existing in Arabidopsis and cotton.

    Science.gov (United States)

    Song, Yun; Zhao, Ge; Zhang, Xueyan; Li, Linxuan; Xiong, Fangjie; Zhuo, Fengping; Zhang, Chaojun; Yang, Zuoren; Datla, Raju; Ren, Maozhi; Li, Fuguang

    2017-04-04

    Target of rapamycin (TOR) acts as an important regulator of cell growth, development and stress responses in most examined diploid eukaryotes. However, little is known about TOR in tetraploid species such as cotton. Here, we show that TORC1-S6K-RPS6, the major signaling components, are conserved and further expanded in cotton genome. Though the cotton seedlings are insensitive to rapamycin, AZD8055, the second-generation inhibitor of TOR, can significantly suppress the growth in cotton. Global transcriptome analysis revealed that genes associated with jasmonic acid (JA) biosynthesis and transduction were significantly altered in AZD8055 treated cotton seedlings, suggesting the potential crosstalk between TOR and JA signaling. Pharmacological and genetic approaches have been employed to get further insights into the molecular mechanism of the crosstalk between TOR and JA. Combination of AZD8055 with methyl jasmonate can synergistically inhibit cotton growth, and additionally JA levels were significantly increased when cotton seedlings were subjected to AZD8055. JA biosynthetic and signaling mutants including jar1, coi1-2 and myc2-2 displayed TOR inhibitor-resistant phenotypes, whereas COI1 overexpression transgenic lines and jaz10 exhibited sensitivity to AZD8055. Consistently, cotton JAZ can partially rescue TOR-suppressed phenotypes in Arabidopsis. These evidences revealed that the crosstalk between TOR and JA pathway operates in cotton and Arabidopsis.

  14. R-2HG Exhibits Anti-tumor Activity by Targeting FTO/m6A/MYC/CEBPA Signaling.

    Science.gov (United States)

    Su, Rui; Dong, Lei; Li, Chenying; Nachtergaele, Sigrid; Wunderlich, Mark; Qing, Ying; Deng, Xiaolan; Wang, Yungui; Weng, Xiaocheng; Hu, Chao; Yu, Mengxia; Skibbe, Jennifer; Dai, Qing; Zou, Dongling; Wu, Tong; Yu, Kangkang; Weng, Hengyou; Huang, Huilin; Ferchen, Kyle; Qin, Xi; Zhang, Bin; Qi, Jun; Sasaki, Atsuo T; Plas, David R; Bradner, James E; Wei, Minjie; Marcucci, Guido; Jiang, Xi; Mulloy, James C; Jin, Jie; He, Chuan; Chen, Jianjun

    2018-01-11

    R-2-hydroxyglutarate (R-2HG), produced at high levels by mutant isocitrate dehydrogenase 1/2 (IDH1/2) enzymes, was reported as an oncometabolite. We show here that R-2HG also exerts a broad anti-leukemic activity in vitro and in vivo by inhibiting leukemia cell proliferation/viability and by promoting cell-cycle arrest and apoptosis. Mechanistically, R-2HG inhibits fat mass and obesity-associated protein (FTO) activity, thereby increasing global N 6 -methyladenosine (m 6 A) RNA modification in R-2HG-sensitive leukemia cells, which in turn decreases the stability of MYC/CEBPA transcripts, leading to the suppression of relevant pathways. Ectopically expressed mutant IDH1 and S-2HG recapitulate the effects of R-2HG. High levels of FTO sensitize leukemic cells to R-2HG, whereas hyperactivation of MYC signaling confers resistance that can be reversed by the inhibition of MYC signaling. R-2HG also displays anti-tumor activity in glioma. Collectively, while R-2HG accumulated in IDH1/2 mutant cancers contributes to cancer initiation, our work demonstrates anti-tumor effects of 2HG in inhibiting proliferation/survival of FTO-high cancer cells via targeting FTO/m 6 A/MYC/CEBPA signaling. Copyright © 2017 Elsevier Inc. All rights reserved.

  15. Activation of mammalian target of rapamycin signaling promotes cell cycle progression and protects cells from apoptosis in mantle cell lymphoma.

    Science.gov (United States)

    Peponi, Evangelia; Drakos, Elias; Reyes, Guadalupe; Leventaki, Vasiliki; Rassidakis, George Z; Medeiros, L Jeffrey

    2006-12-01

    Mantle cell lymphoma (MCL) is characterized by the t(11;14) and cyclin D1 overexpression. However, additional molecular events are most likely required for oncogenesis, possibly through cell cycle and apoptosis deregulation. We hypothesized that mammalian target of rapamycin (mTOR) is activated in MCL and contributes to tumor proliferation and survival. In MCL cell lines, pharmacological inhibition of the phosphoinositide 3-kinase/AKT pathway was associated with decreased phosphorylation (activation) of mTOR and its downstream targets phosphorylated (p)-4E-BP1, p-p70S6 kinase, and p-ribosomal protein S6, resulting in apoptosis and cell cycle arrest. These changes were associated with down-regulation of cyclin D1 and the anti-apoptotic proteins cFLIP, BCL-XL, and MCL-1. Furthermore, silencing of mTOR expression using mTOR-specific short interfering RNA decreased phosphorylation of mTOR signaling proteins and induced cell cycle arrest and apoptosis. Silencing of eukaryotic initiation factor (eIF4E), a downstream effector of mTOR, recapitulated these results. We also assessed mTOR signaling in MCL tumors using immunohistochemical methods and a tissue microarray: 10 of 30 (33%) expressed Ser473p-AKT, 13 of 21 (62%) Ser2448p-mTOR, 22 of 22 (100%) p-p70S6K, and 5 of 20 (25%) p-ribosomal protein S6. Total eIF4E binding protein 1 and eukaryotic initiation factor 4E were expressed in 13 of 14 (93%) and 16 of 29 (55%) MCL tumors, respectively. These findings suggest that the mTOR signaling pathway is activated and may contribute to cell cycle progression and tumor cell survival in MCL.

  16. Sonic hedgehog signaling inhibition provides opportunities for targeted therapy by sulforaphane in regulating pancreatic cancer stem cell self-renewal.

    Directory of Open Access Journals (Sweden)

    Mariana Rodova

    Full Text Available Dysregulation of the sonic hedgehog (Shh signaling pathway has been associated with cancer stem cells (CSC and implicated in the initiation of pancreatic cancer. Pancreatic CSCs are rare tumor cells characterized by their ability to self-renew, and are responsible for tumor recurrence accompanied by resistance to current therapies. The lethality of these incurable, aggressive and invasive pancreatic tumors remains a daunting clinical challenge. Thus, the objective of this study was to investigate the role of Shh pathway in pancreatic cancer and to examine the molecular mechanisms by which sulforaphane (SFN, an active compound in cruciferous vegetables, inhibits self-renewal capacity of human pancreatic CSCs. Interestingly, we demonstrate here that Shh pathway is highly activated in pancreatic CSCs and plays important role in maintaining stemness by regulating the expression of stemness genes. Given the requirement for Hedgehog in pancreatic cancer, we investigated whether hedgehog blockade by SFN could target the stem cell population in pancreatic cancer. In an in vitro model, human pancreatic CSCs derived spheres were significantly inhibited on treatment with SFN, suggesting the clonogenic depletion of the CSCs. Interestingly, SFN inhibited the components of Shh pathway and Gli transcriptional activity. Interference of Shh-Gli signaling significantly blocked SFN-induced inhibitory effects demonstrating the requirement of an active pathway for the growth of pancreatic CSCs. SFN also inhibited downstream targets of Gli transcription by suppressing the expression of pluripotency maintaining factors (Nanog and Oct-4 as well as PDGFRα and Cyclin D1. Furthermore, SFN induced apoptosis by inhibition of BCL-2 and activation of caspases. Our data reveal the essential role of Shh-Gli signaling in controlling the characteristics of pancreatic CSCs. We propose that pancreatic cancer preventative effects of SFN may result from inhibition of the Shh pathway

  17. Synergistic effects of targeted PI3K signaling inhibition and chemotherapy in liposarcoma.

    Directory of Open Access Journals (Sweden)

    Shang Guo

    Full Text Available While liposarcoma is the second most common soft tissue malignant tumor, the molecular pathogenesis in this malignancy is poorly understood. Our goal was therefore to expand the understanding of molecular mechanisms that drive liposarcoma and identify therapeutically-susceptible genetic alterations. We studied a cohort of high-grade liposarcomas and benign lipomas across multiple disease sites, as well as two liposarcoma cell lines, using multiplexed mutational analysis. Nucleic acids extracted from diagnostic patient tissue were simultaneously interrogated for 150 common mutations across 15 essential cancer genes using a clinically-validated platform for cancer genotyping. Western blot analysis was implemented to detect activation of downstream pathways. Liposarcoma cell lines were used to determine the effects of PI3K targeted drug treatment with or without chemotherapy. We identified mutations in the PIK3CA gene in 4 of 18 human liposarcoma patients (22%. No PIK3CA mutations were identified in benign lipomas. Western blot analysis confirmed downstream activation of AKT in both PIK3CA mutant and non-mutant liposarcoma samples. PI-103, a dual PI3K/mTOR inhibitor, effectively inhibited the activation of the PI3K/AKT in liposarcoma cell lines and induced apoptosis. Importantly, combination with PI-103 treatment strongly synergized the growth-inhibitory effects of the chemotherapy drugs doxorubicin and cisplatin in liposarcoma cells. Taken together, these findings suggest that activation of the PI3K/AKT pathway is an important cancer mechanism in liposarcoma. Targeting the PI3K/AKT/pathway with small molecule inhibitors in combination with chemotherapy could be exploited as a novel strategy in the treatment of liposarcoma.

  18. Internal model of gravity for hand interception: parametric adaptation to zero-gravity visual targets on Earth.

    Science.gov (United States)

    Zago, Myrka; Lacquaniti, Francesco

    2005-08-01

    Internal model is a neural mechanism that mimics the dynamics of an object for sensory motor or cognitive functions. Recent research focuses on the issue of whether multiple internal models are learned and switched to cope with a variety of conditions, or single general models are adapted by tuning the parameters. Here we addressed this issue by investigating how the manual interception of a moving target changes with changes of the visual environment. In our paradigm, a virtual target moves vertically downward on a screen with different laws of motion. Subjects are asked to punch a hidden ball that arrives in synchrony with the visual target. By using several different protocols, we systematically found that subjects do not develop a new internal model appropriate for constant speed targets, but they use the default gravity model and reduce the central processing time. The results imply that adaptation to zero-gravity targets involves a compression of temporal processing through the cortical and subcortical regions interconnected with the vestibular cortex, which has previously been shown to be the site of storage of the internal model of gravity.

  19. An experiment to study CP violation in the B system using an internal target at the HERA proton ring

    International Nuclear Information System (INIS)

    Hofmann, W.

    1993-01-01

    Using the HERA proton beam striking an internal wire target, sufficient numbers of B mesons are produced to allow the search for CP violation in B decays with a sensitivity Δsin(2β)∼0.05, provided that the detector can accept and separate multiple interactions per bunch crossing. This report summarizes our present views concerning the layout of the target, of the spectrometer, and of the trigger system, which selects events containing J/ψ candidates. (orig.)

  20. Targeting Fibroblast Growth Factor 23 Signaling with Antibodies and Inhibitors, Is There a Rationale?

    Directory of Open Access Journals (Sweden)

    Seiji Fukumoto

    2018-02-01

    Full Text Available Fibroblast growth factor 23 (FGF23 is a phosphotropic hormone mainly produced by bone. FGF23 reduces serum phosphate by suppressing intestinal phosphate absorption through reducing 1,25-dihydroxyvitamin D and proximal tubular phosphate reabsorption. Excessive actions of FG23 result in several kinds of hypophosphatemic rickets/osteomalacia including X-linked hypophosphatemic rickets (XLH and tumor-induced osteomalacia. While neutral phosphate and active vitamin D are standard therapies for child patients with XLH, these medications have several limitations both in their effects and adverse events. Several approaches that inhibit FGF23 actions including anti-FGF23 antibodies and inhibitors of FGF signaling have been shown to improve phenotypes of model mice for FG23-related hypophosphatemic diseases. In addition, clinical trials indicated that a humanized anti-FGF23 antibody increased serum phosphate and improved quality of life in patients with XLH. Furthermore, circulatory FGF23 is high in patients with chronic kidney disease (CKD. Many epidemiological studies indicated the association between high FGF23 levels and various adverse events especially in patients with CKD. However, it is not known whether the inhibition of FGF23 activities in patients with CKD is beneficial for these patients. In this review, recent findings concerning the modulation of FGF23 activities are discussed.

  1. Therapeutic Potential of Thymoquinone in Glioblastoma Treatment: Targeting Major Gliomagenesis Signaling Pathways

    Directory of Open Access Journals (Sweden)

    Fabliha Ahmed Chowdhury

    2018-01-01

    Full Text Available Glioblastoma multiforme (GBM is one of the most devastating brain tumors with median survival of one year and presents unique challenges to therapy because of its aggressive behavior. Current treatment strategy involves surgery, radiotherapy, immunotherapy, and adjuvant chemotherapy even though optimal management requires a multidisciplinary approach and knowledge of potential complications from both the disease and its treatment. Thymoquinone (TQ, the main bioactive component of Nigella sativa L., has exhibited anticancer effects in numerous preclinical studies. Due to its multitargeting nature, TQ interferes in a wide range of tumorigenic processes and counteract carcinogenesis, malignant growth, invasion, migration, and angiogenesis. TQ can specifically sensitize tumor cells towards conventional cancer treatments and minimize therapy-associated toxic effects in normal cells. Its potential to enter brain via nasal pathway due to volatile nature of TQ adds another advantage in overcoming blood-brain barrier. In this review, we summarized the potential role of TQ in different signaling pathways in GBM that have undergone treatment with standard therapeutic modalities or with TQ. Altogether, we suggest further comprehensive evaluation of TQ in preclinical and clinical level to delineate its implied utility as novel therapeutics to combat the challenges for the treatment of GBM.

  2. Reverting doxorubicin resistance in colon cancer by targeting a key signaling protein, steroid receptor coactivator.

    Science.gov (United States)

    Xiong, Sang; Xiao, Gong-Wei

    2018-04-01

    Although there have been notable improvements in treatments against cancer, further research is required. In colon cancer, nearly all patients eventually experience drug resistance and stop responding to the approved drugs, making treatment difficult. Steroid receptor coactivator (SRC) is an oncogenic nuclear receptor coactivator that serves an important role in drug resistance. The present study generated a doxorubicin-resistant colon cancer cell line, in which the upregulation/activation of SRC was responsible for drug resistance, which in turn activated AKT. Overexpression of receptor tyrosine kinase-like epidermal growth factor receptor and insulin-like growth factor 1 receptor also induced SRC expression. It was observed that doxorubicin resistance in colon cancer also induced epithelial to mesenchymal transition, a decrease in expression of epithelial marker E-cadherin and an increase in the expression of mesenchymal markers, including N-cadherin and vimentin. Additionally, the present study indicated that SRC acts as a common signaling node, and inhibiting SRC in combination with doxorubicin treatment in doxorubicin-resistant cells aids in reversing the resistance. Thus, the present study suggests that activation of SRC is responsible for doxorubicin resistance in colon cancer. However, further research is required to understand the complete mechanism of how drug resistance occurs and how it may be tackled to treat patients.

  3. Kaempferol inhibits cell proliferation and glycolysis in esophagus squamous cell carcinoma via targeting EGFR signaling pathway.

    Science.gov (United States)

    Yao, Shihua; Wang, Xiaowei; Li, Chunguang; Zhao, Tiejun; Jin, Hai; Fang, Wentao

    2016-08-01

    Antitumor activity of kaempferol has been studied in various tumor types, but its potency in esophagus squamous cell carcinoma is rarely known. Here, we reported the activity of kaempferol against esophagus squamous cell carcinoma as well as its antitumor mechanisms. Results of cell proliferation and colony formation assay showed that kaempferol substantially inhibited tumor cell proliferation and clone formation in vitro. Flow cytometric analysis demonstrated that tumor cells were induced G0/G1 phase arrest after kaempferol treatment, and the expression of protein involved in cell cycle regulation was dramatically changed. Except the potency on cell proliferation, we also discovered that kaempferol had a significant inhibitory effect against tumor glycolysis. With the downregulation of hexokinase-2, glucose uptake and lactate production in tumor cells were dramatically declined. Mechanism studies revealed kaempferol had a direct effect on epidermal growth factor receptor (EGFR) activity, and along with the inhibition of EGFR, its downstream signaling pathways were also markedly suppressed. Further investigations found that exogenous overexpression of EGFR in tumor cells substantially attenuated glycolysis suppression induced by kaempferol, which implied that EGFR also played an important role in kaempferol-mediated glycolysis inhibition. Finally, the antitumor activity of kaempferol was validated in xenograft model and kaempferol prominently restrained tumor growth in vivo. Meanwhile, dramatic decrease of EGFR activity and hexokinase-2 expression were observed in kaempferol-treated tumor tissue, which confirmed these findings in vitro. Briefly, these studies suggested that kaempferol, or its analogues, may serve as effective candidates for esophagus squamous cell carcinoma management.

  4. Pathophysiology of cardiac hypertrophy and heart failure: signaling pathways and novel therapeutic targets.

    Science.gov (United States)

    Tham, Yow Keat; Bernardo, Bianca C; Ooi, Jenny Y Y; Weeks, Kate L; McMullen, Julie R

    2015-09-01

    The onset of heart failure is typically preceded by cardiac hypertrophy, a response of the heart to increased workload, a cardiac insult such as a heart attack or genetic mutation. Cardiac hypertrophy is usually characterized by an increase in cardiomyocyte size and thickening of ventricular walls. Initially, such growth is an adaptive response to maintain cardiac function; however, in settings of sustained stress and as time progresses, these changes become maladaptive and the heart ultimately fails. In this review, we discuss the key features of pathological cardiac hypertrophy and the numerous mediators that have been found to be involved in the pathogenesis of cardiac hypertrophy affecting gene transcription, calcium handling, protein synthesis, metabolism, autophagy, oxidative stress and inflammation. We also discuss new mediators including signaling proteins, microRNAs, long noncoding RNAs and new findings related to the role of calcineurin and calcium-/calmodulin-dependent protein kinases. We also highlight mediators and processes which contribute to the transition from adaptive cardiac remodeling to maladaptive remodeling and heart failure. Treatment strategies for heart failure commonly include diuretics, angiotensin converting enzyme inhibitors, angiotensin II receptor blockers and β-blockers; however, mortality rates remain high. Here, we discuss new therapeutic approaches (e.g., RNA-based therapies, dietary supplementation, small molecules) either entering clinical trials or in preclinical development. Finally, we address the challenges that remain in translating these discoveries to new and approved therapies for heart failure.

  5. Proceedings of the Fifth International Workshop on Targetry and Target Chemistry

    International Nuclear Information System (INIS)

    Dahl, J.R.; Ferrieri, R.; Finn, R.; Schlyer, D.J.

    1994-01-01

    The goal of the International Workshop on Targetry and Target Chemistry series has always been to provide an open forum for discussion of medical radionuclide production, primarily with particle accelerators. The format is intended to encourage the participants to set the direction of the ensuing discussion, allowing the participants to focus on areas of greatest immediate interest. The preceding workshops have set this tone and this workshop was designed to continue in this spirit. The topics of each session were selected by the local organizing committee after discussion with many of the attendees of the previous workshops. The formality of the workshops has gradually increased from the first rather small, very informal gathering in Heidelburg to the larger contingent present in Villigen, but the open discussion of topics of preoccupation has been maintained. Each Workshop has had areas of particular fascination. In the Fifth workshop the major focus was on the development of new accelerators and on the production of ammonia. Selected papers are indexed separately for inclusion in the Energy Science and Technology Database

  6. Proceedings of the Fifth International Workshop on Targetry and Target Chemistry

    Energy Technology Data Exchange (ETDEWEB)

    Dahl, J.R.; Ferrieri, R.; Finn, R.; Schlyer, D.J. [eds.

    1994-12-31

    The goal of the International Workshop on Targetry and Target Chemistry series has always been to provide an open forum for discussion of medical radionuclide production, primarily with particle accelerators. The format is intended to encourage the participants to set the direction of the ensuing discussion, allowing the participants to focus on areas of greatest immediate interest. The preceding workshops have set this tone and this workshop was designed to continue in this spirit. The topics of each session were selected by the local organizing committee after discussion with many of the attendees of the previous workshops. The formality of the workshops has gradually increased from the first rather small, very informal gathering in Heidelburg to the larger contingent present in Villigen, but the open discussion of topics of preoccupation has been maintained. Each Workshop has had areas of particular fascination. In the Fifth workshop the major focus was on the development of new accelerators and on the production of ammonia. Selected papers are indexed separately for inclusion in the Energy Science and Technology Database.

  7. Targeting International Food Aid Programmes: The Case of Productive Safety Net Programme in Tigray, Ethiopia

    Directory of Open Access Journals (Sweden)

    Hossein Azadi

    2017-09-01

    Full Text Available Ethiopia has experienced more than five major droughts in the past three decades, leading to high dependency on international food aids. Nevertheless, studies indicate that asset depletion has not been prevented; neither did food insecurity diminish. Since 2004/5, the Productive Safety Net Programme (PSNP has been implemented to improve food security in Tigray, Northern Ethiopia. Critics point out that the implementation of food aid programmes can have negative impacts as well as positive outcomes for local communities. Accordingly, this survey study aimed to analyse the distribution and allocation of food aids in the Productive Safety Net Programme (PSNP in Tigray. Results of 479 interviews revealed that targeting different households in the PSNP has been considerably linked to socio-demographic attributes among which age and size of family were decisive factors to receive food aids. Furthermore, older households with smaller family size received more direct support. Inequality between genders was another major finding of this study. When combined with the marital status, there was also a big difference in the percentage of married or unmarried women receiving food aids. These findings could provide fundamental information for policy intervention to correct food security programmes at household level and reduce hunger. Given that, socio-demographic factors can help to identify particular and usually different requirements, vulnerabilities and coping strategies of the members of the food aid programme, so that they can be much more addressed when an emergency happens.

  8. A polarized hydrogen/deuterium atomic beam source for internal target experiments

    International Nuclear Information System (INIS)

    Szczerba, D.; Buuren, L.D. van; Brand, J.F.J. van den; Bulten, H.J.; Ferro-Luzzi, M.; Klous, S.; Kolster, H.; Lang, J.; Mul, F.; Poolman, H.R.; Simani, M.C.

    2000-01-01

    A high-brightness hydrogen/deuterium atomic beam source is presented. The apparatus, previously used in electron scattering experiments with tensor-polarized deuterium (Ferro-Luzzi et al., Phys. Rev. Lett. 77 (1996) 2630; van den Brand et al., Phys. Rev. Lett. 78 (1997) 1235; Zhou et al., Phys. Rev. Lett. 82 (1998) 687; Bouwhuis et al., Phys. Rev. Lett. 82 (1999) 3755), was configured as a source for internal target experiments to measure single- and double-polarization observables, with either polarized hydrogen or vector/tensor polarized deuterium. The atomic beam intensity was enhanced by a factor of ∼2.5 by optimizing the Stern-Gerlach focusing system using high tip-field (∼1.5 T) rare-earth permanent magnets, and by increasing the pumping speed in the beam-formation chamber. Fluxes of (5.9±0.2)x10 16 1 H/s were measured in a diameter 12 mmx122 mm compression tube with its entrance at a distance of 27 cm from the last focusing element. The total output flux amounted to (7.6±0.2)x10 16 1 H/s

  9. Target of rapamycin complex 2 signals to downstream effector yeast protein kinase 2 (Ypk2) through adheres-voraciously-to-target-of-rapamycin-2 protein 1 (Avo1) in Saccharomyces cerevisiae.

    Science.gov (United States)

    Liao, Hsien-Ching; Chen, Mei-Yu

    2012-02-24

    The conserved Ser/Thr kinase target of rapamycin (TOR) serves as a central regulator in controlling cell growth-related functions. There exist two distinct TOR complexes, TORC1 and TORC2, each coupling to specific downstream effectors and signaling pathways. In Saccharomyces cerevisiae, TORC2 is involved in regulating actin organization and maintaining cell wall integrity. Ypk2 (yeast protein kinase 2), a member of the cAMP-dependent, cGMP-dependent, and PKC (AGC) kinase family, is a TORC2 substrate known to participate in actin and cell wall regulation. Employing avo3(ts) mutants with defects in TORC2 functions that are suppressible by active Ypk2, we investigated the molecular interactions involved in mediating TORC2 signaling to Ypk2. GST pulldown assays in yeast lysates demonstrated physical interactions between Ypk2 and components of TORC2. In vitro binding assays revealed that Avo1 directly binds to Ypk2. In avo3(ts) mutants, the TORC2-Ypk2 interaction was reduced and could be restored by AVO1 overexpression, highlighting the important role of Avo1 in coupling TORC2 to Ypk2. The interaction was mapped to an internal region (amino acids 600-840) of Avo1 and a C-terminal region of Ypk2. Ypk2(334-677), a truncated form of Ypk2 containing the Avo1-interacting region, was able to interfere with Avo1-Ypk2 interaction in vitro. Overexpressing Ypk2(334-677) in yeast cells resulted in a perturbation of TORC2 functions, causing defective cell wall integrity, aberrant actin organization, and diminished TORC2-dependent Ypk2 phosphorylation evidenced by the loss of an electrophoretic mobility shift. Together, our data support the conclusion that the direct Avo1-Ypk2 interaction is crucial for TORC2 signaling to the downstream Ypk2 pathway.

  10. A Recombinant Secondary Antibody Mimic as a Target-specific Signal Amplifier and an Antibody Immobilizer in Immunoassays.

    Science.gov (United States)

    Min, Junseon; Song, Eun Kyung; Kim, Hansol; Kim, Kyoung Taek; Park, Tae Joo; Kang, Sebyung

    2016-04-11

    We construct a novel recombinant secondary antibody mimic, GST-ABD, which can bind to the Fc regions of target-bound primary antibodies and acquire multiple HRPs simultaneously. We produce it in tenth of mg quantities with a bacterial overexpression system and simple purification procedures, significantly reducing the manufacturing cost and time without the use of animals. GST-ABD is effectively conjugated with 3 HRPs per molecule on an average and selectively bind to the Fc region of primary antibodies derived from three different species (mouse, rabbit, and rat). HRP-conjugated GST-ABD (HRP-GST-ABD) is successfully used as an alternative to secondary antibodies to amplify target-specific signals in both ELISA and immunohistochemistry regardless of the target molecules and origin of primary antibodies used. GST-ABD also successfully serves as an anchoring adaptor on the surface of GSH-coated plates for immobilizing antigen-capturing antibodies in an orientation-controlled manner for sandwich-type indirect ELISA through simple molecular recognition without any complicated chemical modification.

  11. Oligomerization of Paramagnetic Substrates Result in Signal Amplification and Can be Used for MR Imaging of Molecular Targets

    Directory of Open Access Journals (Sweden)

    Alexei Bogdanov

    2002-01-01

    Full Text Available Magnetic resonance imaging (MRI has evolved into a sophisticated, noninvasive imaging modality capable of high-resolution anatomical and functional characterization of transgenic animals. To expand the capabilities MRI, we have developed a novel MR signal amplification (MRamp strategy based on enzyme-mediated polymerization of paramagnetic substrates into oligomers of higher magnetic relaxivity. The substrates consist of chelated gadolinium covalently bound to phenols, which then serve as electron donors during enzymatic hydrogen peroxide reduction by peroxidase. The converted monomers undergo rapid condensation into paramagnetic oligomers leading to a threefold increase in atomic relaxivity (R1/Gd. The observed relaxivity changes are largely due to an increase in the rotational correlation time τr of the lanthanide. Three applications of the developed system are demonstrated: (1 imaging of nanomolar amounts of an oxidoreductase (peroxidase; (2 detection of a model ligand using an enzyme-linked immunoadsorbent assay format; and (3 imaging of E-selectin on the surface of endothelial cells probed for with an anti-E-selectin – peroxidase conjugate. The development of “enzyme sensing” probes is expected to have utility for a number of applications including in vivo detection of specific molecular targets. One particular advantage of the MRamp technique is that the same paramagnetic substrate can be potentially used to identify different molecular targets by attaching enzymes to various antibodies or other target-seeking molecules.

  12. Optimization of the internal target system of the C V-28 cyclotron at IPEN-CNEN/SP

    International Nuclear Information System (INIS)

    Araujo, Sumair Gouveia de

    1996-01-01

    The C V-28 cyclotron at IPEN-CNEN/S P is used mainly for radioisotope production to be utilized in nuclear medicine for diagnostic purposes. Among these radioisotopes we can cite 67 Ga and 111 In, which are obtained by irradiation of Zn and Cd solid targets. Up to now, the irradiations were performed in the external beam line, which has limitations in beam current due to the extraction system, that can at best extract between 50 and 70% of the produced beam. This is a critical point for an efficient radioisotope production. A possible solution to achieve high beam currents is a system that allows the irradiation of these solid targets with the internal beam. In this case, the total produced beam can be used. For this, the objective of this work was to modify and improve the internal target system of the C V-28 Cyclotron, which had three critical points in the original project, that made the system useless. First, the transport of the target to the irradiation position was modified: the pneumatic tube was changed to a motor drive service. Secondly, the target cooling system was improved. Third and the most critical, the modification on the locking system of the target holder that could bring the cyclotron tank to atmosphere. These modifications implied on a change in all logical sequence of the target control. With these modifications the system became more versatile and showed more reproducibility and reliability than the original internal target system. The loss of mass in natural Zn targets irradiated with currents up to 80 μA was negligible. The production yield of 67 Ga obtained, at EOB, was 21.2 MBq/μAh (0.57 mCi/μAh), that is in good agreement with those obtained in the irradiation with external beams. (author)

  13. Adrenergic Signaling: A Targetable Checkpoint Limiting Development of the Antitumor Immune Response

    Science.gov (United States)

    Qiao, Guanxi; Chen, Minhui; Bucsek, Mark J.; Repasky, Elizabeth A.; Hylander, Bonnie L.

    2018-01-01

    An immune response must be tightly controlled so that it will be commensurate with the level of response needed to protect the organism without damaging normal tissue. The roles of cytokines and chemokines in orchestrating these processes are well known, but although stress has long been thought to also affect immune responses, the underlying mechanisms were not as well understood. Recently, the role of nerves and, specifically, the sympathetic nervous system, in regulating immune responses is being revealed. Generally, an acute stress response is beneficial but chronic stress is detrimental because it suppresses the activities of effector immune cells while increasing the activities of immunosuppressive cells. In this review, we first discuss the underlying biology of adrenergic signaling in cells of both the innate and adaptive immune system. We then focus on the effects of chronic adrenergic stress in promoting tumor growth, giving examples of effects on tumor cells and immune cells, explaining the methods commonly used to induce stress in preclinical mouse models. We highlight how this relates to our observations that mandated housing conditions impose baseline chronic stress on mouse models, which is sufficient to cause chronic immunosuppression. This problem is not commonly recognized, but it has been shown to impact conclusions of several studies of mouse physiology and mouse models of disease. Moreover, the fact that preclinical mouse models are chronically immunosuppressed has critical ramifications for analysis of any experiments with an immune component. Our group has found that reducing adrenergic stress by housing mice at thermoneutrality or treating mice housed at cooler temperatures with β-blockers reverses immunosuppression and significantly improves responses to checkpoint inhibitor immunotherapy. These observations are clinically relevant because there are numerous retrospective epidemiological studies concluding that cancer patients who were

  14. A concerted kinase interplay identifies PPARgamma as a molecular target of ghrelin signaling in macrophages.

    Directory of Open Access Journals (Sweden)

    Annie Demers

    2009-11-01

    Full Text Available The peroxisome proliferator-activator receptor PPARgamma plays an essential role in vascular biology, modulating macrophage function and atherosclerosis progression. Recently, we have described the beneficial effect of combined activation of the ghrelin/GHS-R1a receptor and the scavenger receptor CD36 to induce macrophage cholesterol release through transcriptional activation of PPARgamma. Although the interplay between CD36 and PPARgamma in atherogenesis is well recognized, the contribution of the ghrelin receptor to regulate PPARgamma remains unknown. Here, we demonstrate that ghrelin triggers PPARgamma activation through a concerted signaling cascade involving Erk1/2 and Akt kinases, resulting in enhanced expression of downstream effectors LXRalpha and ABC sterol transporters in human macrophages. These effects were associated with enhanced PPARgamma phosphorylation independently of the inhibitory conserved serine-84. Src tyrosine kinase Fyn was identified as being recruited to GHS-R1a in response to ghrelin, but failure of activated Fyn to enhance PPARgamma Ser-84 specific phosphorylation relied on the concomitant recruitment of docking protein Dok-1, which prevented optimal activation of the Erk1/2 pathway. Also, substitution of Ser-84 preserved the ghrelin-induced PPARgamma activity and responsiveness to Src inhibition, supporting a mechanism independent of Ser-84 in PPARgamma response to ghrelin. Consistent with this, we found that ghrelin promoted the PI3-K/Akt pathway in a Galphaq-dependent manner, resulting in Akt recruitment to PPARgamma, enhanced PPARgamma phosphorylation and activation independently of Ser-84, and increased expression of LXRalpha and ABCA1/G1. Collectively, these results illustrate a complex interplay involving Fyn/Dok-1/Erk and Galphaq/PI3-K/Akt pathways to transduce in a concerted manner responsiveness of PPARgamma to ghrelin in macrophages.

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

    Science.gov (United States)

    Akino, Yuichi; Oh, Ryoong-Jin; Masai, Norihisa; Shiomi, Hiroya; Inoue, Toshihiko

    2014-11-01

    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. 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 acquired 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 Potential). The concordance between ITV Potential and ITV estimated with 4DCT (ITV 4DCT) was evaluated using the Dice's similarity coefficient (DSC). The distance between blood vessel positions

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

    Energy Technology Data Exchange (ETDEWEB)

    Akino, Yuichi, E-mail: akino@radonc.med.osaka-u.ac.jp [Department of Radiation Oncology, Osaka University Graduate School of Medicine, Suita, Osaka 5650871, Japan and Miyakojima IGRT Clinic, Miyakojima-ku, Osaka 5340021 (Japan); Oh, Ryoong-Jin; Masai, Norihisa; Shiomi, Hiroya; Inoue, Toshihiko [Miyakojima IGRT Clinic, Miyakojima-ku, Osaka 5340021 (Japan)

    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 acquired 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

  17. An Epstein-Barr Virus MicroRNA Blocks Interleukin-1 (IL-1) Signaling by Targeting IL-1 Receptor 1.

    Science.gov (United States)

    Skinner, Camille M; Ivanov, Nikita S; Barr, Sarah A; Chen, Yan; Skalsky, Rebecca L

    2017-11-01

    Epstein-Barr virus (EBV) encodes >44 viral microRNAs (miRNAs) that are differentially expressed throughout infection, can be detected in Epstein-Barr virus (EBV)-positive tumors, and manipulate several biological processes, including cell proliferation, apoptosis, and immune responses. Here, we show that EBV BHRF1-2 miRNAs block NF-κB activation following treatment with proinflammatory cytokines, specifically interleukin-1β (IL-1β). Analysis of EBV PAR-CLIP miRNA targetome data sets combined with pathway analysis revealed multiple BHRF1-2 miRNA targets involved in interleukin signaling pathways. By further analyzing changes in cellular gene expression patterns, we identified the IL-1 receptor 1 (IL1R1) as a direct target of miR-BHRF1-2-5p. Targeting the IL1R1 3' untranslated region (UTR) by EBV miR-BHRF1-2-5p was confirmed using 3'-UTR luciferase reporter assays and Western blot assays. Manipulation of EBV BHRF1-2 miRNA activity in latently infected B cells altered steady-state cytokine levels and disrupted IL-1β responsiveness. These studies demonstrate functionally relevant BHRF1-2 miRNA interactions during EBV infection, which is an important step in understanding their roles in pathogenesis. IMPORTANCE IL-1 signaling plays an important role in inflammation and early activation of host innate immune responses following virus infection. Here, we demonstrate that a viral miRNA downregulates the IL-1 receptor 1 during EBV infection, which consequently alters the responsiveness of cells to IL-1 stimuli and changes the cytokine expression levels within infected cell populations. We postulate that this viral miRNA activity not only disrupts IL-1 autocrine and paracrine signaling loops that can alert effector cells to sites of infection but also provides a survival advantage by dampening excessive inflammation that may be detrimental to the infected cell. Copyright © 2017 American Society for Microbiology.

  18. SU-F-J-137: Intrafractional Change of the Relationship Between Internal Fiducials and External Breathing Signal in Pancreatic Cancer Stereotactic Body Radiation Therapy

    Energy Technology Data Exchange (ETDEWEB)

    Pettersson, N; Murphy, J; Simpson, D; Cervino, L [University of California, San Diego, La Jolla, CA (United States)

    2016-06-15

    Purpose: The use of respiratory gating for management of breathing motion during stereotactic body radiation therapy (SBRT) relies on a consistent relationship between the breathing signal and the actual position of the internal target. This relationship was investigated in patients treated for pancreatic cancer. Methods: Four patients with pancreatic cancer undergoing SBRT that had implanted fiducials in the tumor were included in this study. Treatment plans were generated based on the exhale phases (30–70%) from the pre-treatment 4DCT. The margin between the internal target volume (ITV) and the planning target volume was three mm. After patient setup using cone-beam CT, simultaneous fluoroscopic imaging and breathing motion monitoring were used during at least three breathing cycles to verify the fiducial position and to optimize the gating window. After treatment, fluoroscopic images were acquired for verification purposes and exported for retrospective analyses. Fiducial positions were determined using a template-matching algorithm. For each dataset, we established a linear relationship between the fiducial position and the anterior-posterior (AP) breathing signal. The relationships before and after treatment were compared and the dose distribution impact evaluated. Results: Seven pre- and post-treatment fluoroscopic pairs were available for fiducial position analyses in the superior-inferior (SI) and left-right (LR) directions, and five in the AP direction. Time between image acquisitions was typically six to eight minutes. An average absolute change of 1.2±0.7 mm (range: 0.1–1.7) of the SI fiducial position relative to the external signal was found. Corresponding numbers for the LR and AP fiducial positions were 0.9±1.0 mm (range: 0.2–3.0) and 0.5±0.4 mm (range: 0.2–1.2), respectively. The dose distribution impact was small in both the ITV and organs-at-risk. Conclusion: The relationship change between fiducial position and external breathing

  19. SU-F-J-137: Intrafractional Change of the Relationship Between Internal Fiducials and External Breathing Signal in Pancreatic Cancer Stereotactic Body Radiation Therapy

    International Nuclear Information System (INIS)

    Pettersson, N; Murphy, J; Simpson, D; Cervino, L

    2016-01-01

    Purpose: The use of respiratory gating for management of breathing motion during stereotactic body radiation therapy (SBRT) relies on a consistent relationship between the breathing signal and the actual position of the internal target. This relationship was investigated in patients treated for pancreatic cancer. Methods: Four patients with pancreatic cancer undergoing SBRT that had implanted fiducials in the tumor were included in this study. Treatment plans were generated based on the exhale phases (30–70%) from the pre-treatment 4DCT. The margin between the internal target volume (ITV) and the planning target volume was three mm. After patient setup using cone-beam CT, simultaneous fluoroscopic imaging and breathing motion monitoring were used during at least three breathing cycles to verify the fiducial position and to optimize the gating window. After treatment, fluoroscopic images were acquired for verification purposes and exported for retrospective analyses. Fiducial positions were determined using a template-matching algorithm. For each dataset, we established a linear relationship between the fiducial position and the anterior-posterior (AP) breathing signal. The relationships before and after treatment were compared and the dose distribution impact evaluated. Results: Seven pre- and post-treatment fluoroscopic pairs were available for fiducial position analyses in the superior-inferior (SI) and left-right (LR) directions, and five in the AP direction. Time between image acquisitions was typically six to eight minutes. An average absolute change of 1.2±0.7 mm (range: 0.1–1.7) of the SI fiducial position relative to the external signal was found. Corresponding numbers for the LR and AP fiducial positions were 0.9±1.0 mm (range: 0.2–3.0) and 0.5±0.4 mm (range: 0.2–1.2), respectively. The dose distribution impact was small in both the ITV and organs-at-risk. Conclusion: The relationship change between fiducial position and external breathing

  20. Estrogen enhanced cell-cell signalling in breast cancer cells exposed to targeted irradiation

    International Nuclear Information System (INIS)

    Shao, Chunlin; Folkard, Melvyn; Held, Kathryn D; Prise, Kevin M

    2008-01-01

    Radiation-induced bystander responses, where cells respond to their neighbours being irradiated are being extensively studied. Although evidence shows that bystander responses can be induced in many types of cells, it is not known whether there is a radiation-induced bystander effect in breast cancer cells, where the radiosensitivity may be dependent on the role of the cellular estrogen receptor (ER). This study investigated radiation-induced bystander responses in estrogen receptor-positive MCF-7 and estrogen receptor-negative MDA-MB-231 breast cancer cells. The influence of estrogen and anti-estrogen treatments on the bystander response was determined by individually irradiating a fraction of cells within the population with a precise number of helium-3 using a charged particle microbeam. Damage was scored as chromosomal damage measured as micronucleus formation. A bystander response measured as increased yield of micronucleated cells was triggered in both MCF-7 and MDA-MB-231 cells. The contribution of the bystander response to total cell damage in MCF-7 cells was higher than that in MDA-MB-231 cells although the radiosensitivity of MDA-MB-231 was higher than MCF-7. Treatment of cells with 17β-estradiol (E2) increased the radiosensitivity and the bystander response in MCF-7 cells, and the effect was diminished by anti-estrogen tamoxifen (TAM). E2 also increased the level of intracellular reactive oxygen species (ROS) in MCF-7 cells in the absence of radiation. In contrast, E2 and TAM had no influence on the bystander response and ROS levels in MDA-MB-231 cells. Moreover, the treatment of MCF-7 cells with antioxidants eliminated both the E2-induced ROS increase and E2-enhanced bystander response triggered by the microbeam irradiation, which indicates that ROS are involved in the E2-enhanced bystander micronuclei formation after microbeam irradiation. The observation of bystander responses in breast tumour cells may offer new potential targets for radiation

  1. Arabidopsis chromatin-associated HMGA and HMGB use different nuclear targeting signals and display highly dynamic localization within the nucleus

    DEFF Research Database (Denmark)

    Launholt, Dorte; Merkle, Thomas; Houben, Andreas

    2006-01-01

    In plants, the chromatin-associated high mobility group (HMG) proteins occur in twosubfamilies termedHMGAandHMGB.The HMGAproteins are characterized by the presence of four AT-hookDNAbinding motifs, and theHMGBproteins contain anHMG boxDNAbinding domain. As architectural factors, theHMGproteins ap......In plants, the chromatin-associated high mobility group (HMG) proteins occur in twosubfamilies termedHMGAandHMGB.The HMGAproteins are characterized by the presence of four AT-hookDNAbinding motifs, and theHMGBproteins contain anHMG boxDNAbinding domain. As architectural factors, the...... of interphase nuclei, whereas none of the proteins associate with condensed mitotic chromosomes. HMGA is targeted to the nucleus by a monopartite nuclear localization signal, while efficient nuclear accumulation of HMGB1/5 requires large portions of the basic N-terminal part of the proteins. The acidic C...

  2. An Experimental Infarct Targeting the Internal Capsule: Histopathological and Ultrastructural Changes

    Directory of Open Access Journals (Sweden)

    Chang-Woo Han

    2017-05-01

    Full Text Available Background Stroke involving the cerebral white matter (WM has increased in prevalence, but most experimental studies have focused on ischemic injury of the gray matter. This study was performed to investigate the WM in a unique rat model of photothrombotic infarct targeting the posterior limb of internal capsule (PLIC, focusing on the identification of the most vulnerable structure in WM by ischemic injury, subsequent glial reaction to the injury, and the fundamental histopathologic feature causing different neurologic outcomes. Methods Light microscopy with immunohistochemical stains and electron microscopic examinations of the lesion were performed between 3 hours and 21 days post-ischemic injury. Results Initial pathological change develops in myelinated axon, concomitantly with reactive change of astrocytes. The first pathology to present is nodular loosening to separate the myelin sheath with axonal wrinkling. Subsequent pathologies include rupture of the myelin sheath with extrusion of axonal organelles, progressive necrosis, oligodendrocyte degeneration and death, and reactive gliosis. Increase of glial fibrillary acidic protein (GFAP immunoreactivity is an early event in the ischemic lesion. WM pathologies result in motor dysfunction. Motor function recovery after the infarct was correlated to the extent of PLIC injury proper rather than the infarct volume. Conclusions Pathologic changes indicate that the cerebral WM, independent of cortical neurons, is highly vulnerable to the effects of focal ischemia, among which myelin sheath is first damaged. Early increase of GFAP immunoreactivity indicates that astrocyte response initially begins with myelinated axonal injury, and supports the biologic role related to WM injury or plasticity. The reaction of astrocytes in the experimental model might be important for the study of pathogenesis and treatment of the WM stroke.

  3. HES1, a target of Notch signaling, is elevated in canine osteosarcoma, but reduced in the most aggressive tumors.

    Science.gov (United States)

    Dailey, Deanna D; Anfinsen, Kristin P; Pfaff, Liza E; Ehrhart, E J; Charles, J Brad; Bønsdorff, Tina B; Thamm, Douglas H; Powers, Barbara E; Jonasdottir, Thora J; Duval, Dawn L

    2013-07-01

    Hairy and enhancer of split 1 (HES1), a basic helix-loop-helix transcriptional repressor, is a downstream target of Notch signaling. Notch signaling and HES1 expression have been linked to growth and survival in a variety of human cancer types and have been associated with increased metastasis and invasiveness in human osteosarcoma cell lines. Osteosarcoma (OSA) is an aggressive cancer demonstrating both high metastatic rate and chemotherapeutic resistance. The current study examined expression of Notch signaling mediators in primary canine OSA tumors and canine and human osteosarcoma cell lines to assess their role in OSA development and progression. Reverse transcriptase - quantitative PCR (RT-qPCR) was utilized to quantify HES1, HEY1, NOTCH1 and NOTCH2 gene expression in matched tumor and normal metaphyseal bone samples taken from dogs treated for appendicular OSA at the Colorado State University Veterinary Teaching Hospital. Gene expression was also assessed in tumors from dogs with a disease free interval (DFI) of  300 days following treatment with surgical amputation followed by standard chemotherapy. Immunohistochemistry was performed to confirm expression of HES1. Data from RT-qPCR and immunohistochemical (IHC) experiments were analyzed using REST2009 software and survival analysis based on IHC expression employed the Kaplan-Meier method and log rank analysis. Unbiased clustered images were generated from gene array analysis data for Notch/HES1 associated genes. Gene array analysis of Notch/HES1 associated genes suggested alterations in the Notch signaling pathway may contribute to the development of canine OSA. HES1 mRNA expression was elevated in tumor samples relative to normal bone, but decreased in tumor samples from dogs with a DFI 300 days. NOTCH2 and HEY1 mRNA expression was also elevated in tumors relative to normal bone, but was not differentially expressed between the DFI tumor groups. Survival analysis confirmed an association between

  4. Chimeric peptides as modulators of CK2-dependent signaling: Mechanism of action and off-target effects.

    Science.gov (United States)

    Zanin, Sofia; Sandre, Michele; Cozza, Giorgio; Ottaviani, Daniele; Marin, Oriano; Pinna, Lorenzo A; Ruzzene, Maria

    2015-10-01

    Protein kinase CK2 is a tetrameric enzyme composed of two catalytic (α/α') and two regulatory (β) subunits. It has a global prosurvival function, especially in cancer, and represents an attractive therapeutic target. Most CK2 inhibitors available so far are ATP-competitive compounds; however, the possibility to block only the phosphorylation of few substrates has been recently explored, and a compound composed of a Tat cell-penetrating peptide and an active cyclic peptide, selected for its ability to bind to the CK2 substrate E7 protein of human papilloma virus, has been developed [Perea et al., Cancer Res. 2004; 64:7127-7129]. By using a similar chimeric peptide (CK2 modulatory chimeric peptide, CK2-MCP), we performed a study to dissect its molecular mechanism of action and the signaling pathways that it affects in cells. We found that it directly interacts with CK2 itself, counteracting the regulatory and stabilizing functions of the β subunit. Cell treatment with CK2-MCP induces a rapid decrease of the amount of CK2 subunits, as well as of other signaling proteins. Concomitant cell death is observed, more pronounced in tumor cells and not accompanied by apoptotic events. CK2 relocalizes to lysosomes, whose proteases are activated, while the proteasome machinery is inhibited. Several sequence variants of the chimeric peptide have been also synthesized, and their effects compared to those of the parental peptide. Intriguingly, the Tat moiety is essential not only for cell penetration but also for the in vitro efficacy of the peptide. We conclude that this class of chimeric peptides, in addition to altering some properties of CK2 holoenzyme, affects several other cellular targets, causing profound perturbations of cell biology. This article is part of a Special Issue entitled: Inhibitors of Protein Kinases. Copyright © 2015 Elsevier B.V. All rights reserved.

  5. Signaling Network Assessment of Mutations and Copy Number Variations Predict Breast Cancer Subtype-Specific Drug Targets

    Directory of Open Access Journals (Sweden)

    Naif Zaman

    2013-10-01

    Full Text Available Individual cancer cells carry a bewildering number of distinct genomic alterations (e.g., copy number variations and mutations, making it a challenge to uncover genomic-driven mechanisms governing tumorigenesis. Here, we performed exome sequencing on several breast cancer cell lines that represent two subtypes, luminal and basal. We integrated these sequencing data and functional RNAi screening data (for the identification of genes that are essential for cell proliferation and survival onto a human signaling network. Two subtype-specific networks that potentially represent core-signaling mechanisms underlying tumorigenesis were identified. Within both networks, we found that genes were differentially affected in different cell lines; i.e., in some cell lines a gene was identified through RNAi screening, whereas in others it was genomically altered. Interestingly, we found that highly connected network genes could be used to correctly classify breast tumors into subtypes on the basis of genomic alterations. Further, the networks effectively predicted subtype-specific drug targets, which were experimentally validated.

  6. Targeting PERK signaling with the small molecule GSK2606414 prevents neurodegeneration in a model of Parkinson's disease.

    Science.gov (United States)

    Mercado, Gabriela; Castillo, Valentina; Soto, Paulina; López, Nélida; Axten, Jeffrey M; Sardi, Sergio P; Hoozemans, Jeroen J M; Hetz, Claudio

    2018-04-01

    Parkinson's disease (PD) is the second most common neurodegenerative disorder, leading to the progressive decline of motor control due to the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc). Accumulating evidence suggest that altered proteostasis is a salient feature of PD, highlighting perturbations to the endoplasmic reticulum (ER), the main compartment involved in protein folding and secretion. PERK is a central ER stress sensor that enforces adaptive programs to recover homeostasis through a block of protein translation and the induction of the transcription factor ATF4. In addition, chronic PERK signaling results in apoptosis induction and neuronal dysfunction due to the repression in the translation of synaptic proteins. Here we confirmed the activation of PERK signaling in postmortem brain tissue derived from PD patients and three different rodent models of the disease. Pharmacological targeting of PERK by the oral administration of GSK2606414 demonstrated efficient inhibition of the pathway in the SNpc after experimental ER stress stimulation. GSK2606414 protected nigral-dopaminergic neurons against a PD-inducing neurotoxin, improving motor performance. The neuroprotective effects of PERK inhibition were accompanied by an increase in dopamine levels and the expression of synaptic proteins. However, GSK2606414 treated animals developed secondary effects possibly related to pancreatic toxicity. This study suggests that strategies to attenuate ER stress levels may be effective to reduce neurodegeneration in PD. Copyright © 2018 Elsevier Inc. All rights reserved.

  7. miRNA targeted signaling pathway in the early stage of denervated fast and slow muscle atrophy

    Directory of Open Access Journals (Sweden)

    Gang Li

    2016-01-01

    Full Text Available Denervation often results in skeletal muscle atrophy. Different mechanisms seem to be involved in the determination between denervated slow and fast skeletal muscle atrophy. At the epigenetic level, miRNAs are thought to be highly involved in the pathophysiological progress of denervated muscles. We used miRNA microarrays to determine miRNA expression profiles from a typical slow muscle (soleus muscle and a typical fast muscle (tibialis anterior muscle at an early denervation stage in a rat model. Results showed that miR-206, miR-195, miR-23a, and miR-30e might be key factors in the transformation process from slow to fast muscle in denervated slow muscles. Additionally, certain miRNA molecules (miR-214, miR-221, miR-222, miR-152, miR-320, and Let-7e could be key regulatory factors in the denervated atrophy process involved in fast muscle. Analysis of signaling pathway networks revealed the miRNA molecules that were responsible for regulating certain signaling pathways, which were the final targets (e.g., p38 MAPK pathway; Pax3/Pax7 regulates Utrophin and follistatin by HDAC4; IGF1/PI3K/Akt/mTOR pathway regulates atrogin-1 and MuRF1 expression via FoxO phosphorylation. Our results provide a better understanding of the mechanisms of denervated skeletal muscle pathophysiology.

  8. Magnetic resonance imaging signal intensity of temporomandibular joint disk and posterior attachment in patients with internal derangement

    International Nuclear Information System (INIS)

    Jeong, Yeon Hwa; Cho, Bong Hae

    2001-01-01

    To analyze the possible association between magnetic resonance imaging signal intensity of temporomandibular joint disk and posterior attachment, and the type and extent of disk displacement, disk donfiguration, effusion and clinical signs in patients with internal derangement. Magnetic resonance images of the 132 temporomandibular joints of 66 patients with temporomandibular joint displacement were analyzed. The clinical findings were obtained by retrospective review of the patients' records. The type and extent of disk displacement, disk configuration and effusion were evaluated on the proton density MR images. The signal intensity from the anterior band, posterior band and posterior attachment were measured on MR images. The associations between the type and extent of disk displacement, disk configuration, effusion and clinical signs and the MR signal intensity of disk and posterior attachment were statistically analyzed by student's t-test. Of 132 joints, 87 (65.9%) showed anterior disk displacement with reduction (ADR) and 45 (34.1%) showed anterior disk displacement without reduction (ADnR). This signals from posterior attachments were lower in joints with ADnR than those of ADR (p<0.05). The results showed statistically significant (p<0.05) association between the type and extent of disk displacement and disk configuration, and decreased signal intensity of posterior attachment. There were no statistical associations between pain, noise and limited mouth opening, and signal intensity of disk and posterior attachment. The average signal from posterior attachment was lower in joints with ADnR than that of ADR. The type and extent of disk displacement and disk configuration appeared to be correlated with the signal intensity from posterior attachment

  9. miR-150 suppresses the proliferation and tumorigenicity of leukemia stem cells by targeting the Nanog signaling pathway

    Directory of Open Access Journals (Sweden)

    Dan-dan Xu

    2016-11-01

    Full Text Available Proliferation, a key feature of cancer cells, accounts for the majority of cancer-related diseases resulting in mortality. MicroRNAs (miRNAs plays important post-transcriptional modulation roles by acting on multiple signaling pathways, but the underlying mechanism in proliferation and tumorigenicity is unclear. Here, we identified the role of miR-150 in proliferation and tumorigenicity in leukemia stem cells (LSCs (CD34+CD38- cells. miR-150 expression was significantly down-regulated in LSCs from leukemia cell lines and clinical samples. Functional assays demonstrated that increased miR-150 expression inhibited proliferation and clonal and clonogenic growth, enhanced chemosensitivity, and attenuated tumorigenic activity of LSCs in vitro. Transplantation animal studies revealed that miR-150 overexpression progressively abrogates tumour growth. Immunohistochemistry assays demonstrated that miR-150 overexpression enhanced caspase-3 level and reduced Ki-67 level. Moreover, luciferase reporter assays indicated Nanog is a direct and functional target of miR-150. Nanog silencing using small interfering RNA recapitulated anti-proliferation and tumorigenicity inhibition effects. Furthermore, miR-150 directly down-regulated the expression of other cancer stem cell factors including Notch2 and CTNNB1. These results provide insights into the specific biological behaviour of miR-150 in regulating LSC proliferation and tumorigenicity. Targeting this miR-150/Nanog axis would be a helpful therapeutic strategy to treat acute myeloid leukemia.

  10. ONC201 Targets AR and AR-V7 Signaling, Reduces PSA, and Synergizes with Everolimus in Prostate Cancer.

    Science.gov (United States)

    Lev, Avital; Lulla, Amriti R; Ross, Brian C; Ralff, Marie D; Makhov, Petr B; Dicker, David T; El-Deiry, Wafik S

    2018-05-01

    Androgen receptor (AR) signaling plays a key role in prostate cancer progression, and androgen deprivation therapy (ADT) is a mainstay clinical treatment regimen for patients with advanced disease. Unfortunately, most prostate cancers eventually become androgen-independent and resistant to ADT with patients progressing to metastatic castration-resistant prostate cancer (mCRPC). Constitutively activated AR variants (AR-V) have emerged as mediators of resistance to AR-targeted therapy and the progression of mCRPC, and they represent an important therapeutic target. Out of at least 15 AR-Vs described thus far, AR-V7 is the most abundant, and its expression correlates with ADT resistance. ONC201/TIC10 is the founding member of the imipridone class of small molecules and has shown anticancer activity in a broad range of tumor types. ONC201 is currently being tested in phase I/II clinical trials for advanced solid tumors, including mCRPC, and hematologic malignancies. There has been promising activity observed in patients in early clinical testing. This study demonstrates preclinical single-agent efficacy of ONC201 using in vitro and in vivo models of prostate cancer. ONC201 has potent antiproliferative and proapoptotic effects in both castration-resistant and -sensitive prostate cancer cells. Furthermore, the data demonstrate that ONC201 downregulates the expression of key drivers of prostate cancer such as AR-V7 and downstream target genes including the clinically used biomarker PSA (KLK3). Finally, the data also provide a preclinical rationale for combination of ONC201 with approved therapeutics for prostate cancer such as enzalutamide, everolimus (mTOR inhibitor), or docetaxel. Implications: The preclinical efficacy of ONC201 as a single agent or in combination, in hormone-sensitive or castration-resistant prostate cancer, suggests the potential for immediate clinical translation. Mol Cancer Res; 16(5); 754-66. ©2018 AACR . ©2018 American Association for Cancer

  11. Silibinin inhibits fibronectin induced motility, invasiveness and survival in human prostate carcinoma PC3 cells via targeting integrin signaling

    Energy Technology Data Exchange (ETDEWEB)

    Deep, Gagan [Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Denver, Aurora, CO (United States); University of Colorado Cancer Center, University of Colorado Denver, Aurora, CO (United States); Kumar, Rahul; Jain, Anil K. [Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Denver, Aurora, CO (United States); Agarwal, Chapla [Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Denver, Aurora, CO (United States); University of Colorado Cancer Center, University of Colorado Denver, Aurora, CO (United States); Agarwal, Rajesh, E-mail: Rajesh.agarwal@ucdenver.edu [Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Denver, Aurora, CO (United States); University of Colorado Cancer Center, University of Colorado Denver, Aurora, CO (United States)

    2014-10-15

    Highlights: • Silibinin inhibits fibronectin-induce motile morphology in PC3 cells. • Silibinin inhibits fibronectin-induced migration and invasion in PC3 cells. • Silibinin targets fibronectin-induced integrins and downstream signaling molecule. - Abstract: Prostate cancer (PCA) is the 2nd leading cause of cancer-related deaths among men in the United States. Preventing or inhibiting metastasis-related events through non-toxic agents could be a useful approach for lowering high mortality among PCA patients. We have earlier reported that natural flavonoid silibinin possesses strong anti-metastatic efficacy against PCA however, mechanism/s of its action still remains largely unknown. One of the major events during metastasis is the replacement of cell–cell interaction with integrins-based cell–matrix interaction that controls motility, invasiveness and survival of cancer cells. Accordingly, here we examined silibinin effect on advanced human PCA PC3 cells’ interaction with extracellular matrix component fibronectin. Silibinin (50–200 μM) treatment significantly decreased the fibronectin (5 μg/ml)-induced motile morphology via targeting actin cytoskeleton organization in PC3 cells. Silibinin also decreased the fibronectin-induced cell proliferation and motility but significantly increased cell death in PC3 cells. Silibinin also inhibited the PC3 cells invasiveness in Transwell invasion assays with fibronectin or cancer associated fibroblasts (CAFs) serving as chemoattractant. Importantly, PC3-luc cells cultured on fibronectin showed rapid dissemination and localized in lungs following tail vein injection in athymic male nude mice; however, in silibinin-treated PC3-luc cells, dissemination and lung localization was largely compromised. Molecular analyses revealed that silibinin treatment modulated the fibronectin-induced expression of integrins (α5, αV, β1 and β3), actin-remodeling (FAK, Src, GTPases, ARP2 and cortactin), apoptosis (cPARP and

  12. Silibinin inhibits fibronectin induced motility, invasiveness and survival in human prostate carcinoma PC3 cells via targeting integrin signaling

    International Nuclear Information System (INIS)

    Deep, Gagan; Kumar, Rahul; Jain, Anil K.; Agarwal, Chapla; Agarwal, Rajesh

    2014-01-01

    Highlights: • Silibinin inhibits fibronectin-induce motile morphology in PC3 cells. • Silibinin inhibits fibronectin-induced migration and invasion in PC3 cells. • Silibinin targets fibronectin-induced integrins and downstream signaling molecule. - Abstract: Prostate cancer (PCA) is the 2nd leading cause of cancer-related deaths among men in the United States. Preventing or inhibiting metastasis-related events through non-toxic agents could be a useful approach for lowering high mortality among PCA patients. We have earlier reported that natural flavonoid silibinin possesses strong anti-metastatic efficacy against PCA however, mechanism/s of its action still remains largely unknown. One of the major events during metastasis is the replacement of cell–cell interaction with integrins-based cell–matrix interaction that controls motility, invasiveness and survival of cancer cells. Accordingly, here we examined silibinin effect on advanced human PCA PC3 cells’ interaction with extracellular matrix component fibronectin. Silibinin (50–200 μM) treatment significantly decreased the fibronectin (5 μg/ml)-induced motile morphology via targeting actin cytoskeleton organization in PC3 cells. Silibinin also decreased the fibronectin-induced cell proliferation and motility but significantly increased cell death in PC3 cells. Silibinin also inhibited the PC3 cells invasiveness in Transwell invasion assays with fibronectin or cancer associated fibroblasts (CAFs) serving as chemoattractant. Importantly, PC3-luc cells cultured on fibronectin showed rapid dissemination and localized in lungs following tail vein injection in athymic male nude mice; however, in silibinin-treated PC3-luc cells, dissemination and lung localization was largely compromised. Molecular analyses revealed that silibinin treatment modulated the fibronectin-induced expression of integrins (α5, αV, β1 and β3), actin-remodeling (FAK, Src, GTPases, ARP2 and cortactin), apoptosis (cPARP and

  13. International target values 2000 for measurement uncertainties in safeguarding nuclear materials

    International Nuclear Information System (INIS)

    Aigner, H.; Binner, R.; Kuhn, E.

    2001-01-01

    The IAEA has prepared a revised and updated version of International Target Values (ITVs) for uncertainty components in measurements of nuclear material. The ITVs represent uncertainties to be considered in judging the reliability of analytical techniques applied to industrial nuclear and fissile material subject to safeguards verification. The tabulated values represent estimates of the 'state of the practice' which ought to be achievable under routine conditions by adequately equipped, experienced laboratories. The ITVs 2000 are intended to be used by plant operators and safeguards organizations as a reference of the quality of measurements achievable in nuclear material accountancy, and for planning purposes. The IAEA prepared a draft of a technical report presenting the proposed ITVs 2000, and in April 2000 the chairmen or officers of the panels or organizations listed below were invited to co- author the report and to submit the draft to a discussion by their panels and organizations. Euratom Safeguards Inspectorate, ESAKDA Working Group on Destructive Analysis, ESARDA Working Group on Non Destructive Analysis, Institute of Nuclear Material Management, Japanese Expert Group on ITV-2000, ISO Working Group on Analyses in Spent Fuel Reprocessing, ISO Working Group on Analyses in Uranium Fuel Fabrication, ISO Working Group on Analyses in MOX Fuel Fabrication, Agencia Brasileno-Argentina de Contabilidad y Control de Materiales Nucleares (ABACC). Comments from the above groups were received and incorporated into the final version of the document, completed in April 2001. The ITVs 2000 represent target standard uncertainties, expressing the precision achievable under stipulated conditions. These conditions typically fall in one of the two following categories: 'repeatability conditions' normally encountered during the measurements done within one inspection period; or 'reproducibility conditions' involving additional sources of measurement variability such as

  14. MO-F-CAMPUS-J-03: Sorting 2D Dynamic MR Images Using Internal Respiratory Signal for 4D MRI

    International Nuclear Information System (INIS)

    Wen, Z; Hui, C; Beddar, S; Stemkens, B; Tijssen, R; Berg, C van den

    2015-01-01

    Purpose: To develop a novel algorithm to extract internal respiratory signal (IRS) for sorting dynamic magnetic resonance (MR) images in order to achieve four-dimensional (4D) MR imaging. Methods: Dynamic MR images were obtained with the balanced steady state free precession by acquiring each two-dimensional sagittal slice repeatedly for more than one breathing cycle. To generate a robust IRS, we used 5 different representative internal respiratory surrogates in both the image space (body area) and the Fourier space (the first two low-frequency phase components in the anterior-posterior direction, and the first two low-frequency phase components in the superior-inferior direction). A clustering algorithm was then used to search for a group of similar individual internal signals, which was then used to formulate the final IRS. A phantom study and a volunteer study were performed to demonstrate the effectiveness of this algorithm. The IRS was compared to the signal from the respiratory bellows. Results: The IRS computed by our algorithm matched well with the bellows signal in both the phantom and the volunteer studies. On average, the normalized cross correlation between the IRS and the bellows signal was 0.97 in the phantom study and 0.87 in the volunteer study, respectively. The average difference between the end inspiration times in the IRS and bellows signal was 0.18 s in the phantom study and 0.14 s in the volunteer study, respectively. 4D images sorted based on the IRS showed minimal mismatched artifacts, and the motion of the anatomy was coherent with the respiratory phases. Conclusion: A novel algorithm was developed to generate IRS from dynamic MR images to achieve 4D MR imaging. The performance of the IRS was comparable to that of the bellows signal. It can be easily implemented into the clinic and potentially could replace the use of external respiratory surrogates. This research was partially funded by the the Center for Radiation Oncology Research from

  15. Rapamycin targeting mTOR and hedgehog signaling pathways blocks human rhabdomyosarcoma growth in xenograft murine model

    Energy Technology Data Exchange (ETDEWEB)

    Kaylani, Samer Z. [Division of Hematology and Oncology, Department of Pediatrics, University of Alabama at Birmingham, 1600 7th Avenue South, ACC 414, Birmingham, AL 35233 (United States); Xu, Jianmin; Srivastava, Ritesh K. [Department of Dermatology and Skin Diseases Research Center, University of Alabama at Birmingham, 1530 3rd Avenue South, VH 509, Birmingham, AL 35294-0019 (United States); Kopelovich, Levy [Division of Cancer Prevention, National Cancer Institute, Bethesda (United States); Pressey, Joseph G. [Division of Hematology and Oncology, Department of Pediatrics, University of Alabama at Birmingham, 1600 7th Avenue South, ACC 414, Birmingham, AL 35233 (United States); Athar, Mohammad, E-mail: mathar@uab.edu [Department of Dermatology and Skin Diseases Research Center, University of Alabama at Birmingham, 1530 3rd Avenue South, VH 509, Birmingham, AL 35294-0019 (United States)

    2013-06-14

    Graphical abstract: Intervention of poorly differentiated RMS by rapamycin: In poorly differentiated RMS, rapamycin blocks mTOR and Hh signaling pathways concomitantly. This leads to dampening in cell cycle regulation and induction of apoptosis. This study provides a rationale for the therapeutic intervention of poorly differentiated RMS by treating patients with rapamycin alone or in combination with other chemotherapeutic agents. -- Highlights: •Rapamycin abrogates RMS tumor growth by modulating proliferation and apoptosis. •Co-targeting mTOR/Hh pathways underlie the molecular basis of effectiveness. •Reduction in mTOR/Hh pathways diminish EMT leading to reduced invasiveness. -- Abstract: Rhabdomyosarcomas (RMS) represent the most common childhood soft-tissue sarcoma. Over the past few decades outcomes for low and intermediate risk RMS patients have slowly improved while patients with metastatic or relapsed RMS still face a grim prognosis. New chemotherapeutic agents or combinations of chemotherapies have largely failed to improve the outcome. Based on the identification of novel molecular targets, potential therapeutic approaches in RMS may offer a decreased reliance on conventional chemotherapy. Thus, identification of effective therapeutic agents that specifically target relevant pathways may be particularly beneficial for patients with metastatic and refractory RMS. The PI3K/AKT/mTOR pathway has been found to be a potentially attractive target in RMS therapy. In this study, we provide evidence that rapamycin (sirolimus) abrogates growth of RMS development in a RMS xenograft mouse model. As compared to a vehicle-treated control group, more than 95% inhibition in tumor growth was observed in mice receiving parenteral administration of rapamycin. The residual tumors in rapamycin-treated group showed significant reduction in the expression of biomarkers indicative of proliferation and tumor invasiveness. These tumors also showed enhanced apoptosis

  16. An experiment to study CP violation in the B system using an internal target at the HERA proton ring

    International Nuclear Information System (INIS)

    Hofmann, W.

    1993-03-01

    A group of physicists centered around the ARGUS collaboration got interested in hadron accelerators as a prolific source of B hadrons. The group is presently studying the option of a major-B-physics experiment to be performed at the HERA proton storage ring in fixed target mode using an internal target. Basic goal of the experiment is the detection of CP violation in the 'gold plated' B 0 → J/Ψ K s decay mode, using a dedicated detector triggered on lepton pairs from J/Ψ decay. (orig./HSI)

  17. Adhesion of axolemmal fragments to Schwann cells: a signal- and target-specific process closely linked to axolemmal induction of Schwann cell mitosis

    International Nuclear Information System (INIS)

    Sobue, G.; Pleasure, D.

    1985-01-01

    Radioiodinated rat CNS axolemmal fragments adhered to cultured rat Schwann cells by a time-, temperature-, and concentration-dependent process independent of extracellular ionized calcium. Adhesion showed target and signal specificity; axolemmal fragments adhered to endoneurial or dermal fibroblasts to a much lesser extent than to Schwann cells, and plasma membrane fragments from skeletal muscle, erythrocytes, or PNS myelin adhered to Schwann cells to a lesser extent than did axolemmal fragments. Brief trypsinization removed 94 to 97% of bound radioactivity from Schwann cells previously incubated with 125 I-axolemmal fragments for up to 24 hr, indicating that adhesion was largely a surface phenomenon rather than the result of rapid internalization of axolemmal fragments by the Schwann cells. When adhesion was compared to the axolemmal mitogenic response of Schwann cells, the concentration of axolemmal fragments yielding half-maximal adhesion was the same as the concentration producing half-maximal stimulation of Schwann cell mitosis. Trypsin digestion, homogenization, or heating of axolemmal fragments before application to cultured Schwann cells diminished adhesion and axolemmal fragment-induced stimulation of Schwann cell mitosis in a parallel fashion. Whereas adhesion of axolemmal fragments to the surfaces of the cultured Schwann cells reached completion within 4 hr in this assay system, induction of Schwann cell mitosis by the fragments required contact with Schwann cells for a minimum of 6 to 8 hr and reached a maximum when the axolemmal fragments had adhered to the Schwann cells for 24 hr or more

  18. Molecular mechanisms and signaling pathways of angiotensin II-induced muscle wasting: potential therapeutic targets for cardiac cachexia

    Science.gov (United States)

    Yoshida, Tadashi; Tabony, A. Michael; Galvez, Sarah; Mitch, William E.; Higashi, Yusuke; Sukhanov, Sergiy; Delafontaine, Patrice

    2013-01-01

    Cachexia is a serious complication of many chronic diseases, such as congestive heart failure (CHF) and chronic kidney disease (CKD). Many factors are involved in the development of cachexia, and there is increasing evidence that angiotensin II (Ang II), the main effector molecule of the renin-angiotensin system (RAS), plays an important role in this process. Patients with advanced CHF or CKD often have increased Ang II levels and cachexia, and angiotensin-converting enzyme (ACE) inhibitor treatment improves weight loss. In rodent models, an increase in systemic Ang II leads to weight loss through increased protein breakdown, reduced protein synthesis in skeletal muscle and decreased appetite. Ang II activates the ubiquitin-proteasome system via generation of reactive oxygen species and via inhibition of the insulin-like growth factor-1 signaling pathway. Furthermore, Ang II inhibits 5′ AMP-activated protein kinase (AMPK) activity and disrupts normal energy balance. Ang II also increases cytokines and circulating hormones such as tumor necrosis factor-α, interleukin-6, serum amyloid-A, glucocorticoids and myostatin, which regulate muscle protein synthesis and degradation. Ang II acts on hypothalamic neurons to regulate orexigenic/anorexigenic neuropeptides, such as neuropeptide-Y, orexin and corticotropin-releasing hormone, leading to reduced appetite. Also, Ang II may regulate skeletal muscle regenerative processes. Several clinical studies have indicated that blockade of Ang II signaling via ACE inhibitors or Ang II type 1 receptor blockers prevents weight loss and improves muscle strength. Thus the RAS is a promising target for the treatment of muscle atrophy in patients with CHF and CKD. PMID:23769949

  19. Pituitary adenylate cyclase activating polypeptide (PACAP signalling exerts chondrogenesis promoting and protecting effects: implication of calcineurin as a downstream target.

    Directory of Open Access Journals (Sweden)

    Tamás Juhász

    Full Text Available Pituitary adenylate cyclase activating polypeptide (PACAP is an important neurotrophic factor influencing differentiation of neuronal elements and exerting protecting role during traumatic injuries or inflammatory processes of the central nervous system. Although increasing evidence is available on its presence and protecting function in various peripheral tissues, little is known about the role of PACAP in formation of skeletal components. To this end, we aimed to map elements of PACAP signalling in developing cartilage under physiological conditions and during oxidative stress. mRNAs of PACAP and its receptors (PAC1,VPAC1, VPAC2 were detectable during differentiation of chicken limb bud-derived chondrogenic cells in micromass cell cultures. Expression of PAC1 protein showed a peak on days of final commitment of chondrogenic cells. Administration of either the PAC1 receptor agonist PACAP 1-38, or PACAP 6-38 that is generally used as a PAC1 antagonist, augmented cartilage formation, stimulated cell proliferation and enhanced PAC1 and Sox9 protein expression. Both variants of PACAP elevated the protein expression and activity of the Ca-calmodulin dependent Ser/Thr protein phosphatase calcineurin. Application of PACAPs failed to rescue cartilage formation when the activity of calcineurin was pharmacologically inhibited with cyclosporine A. Moreover, exogenous PACAPs prevented diminishing of cartilage formation and decrease of calcineurin activity during oxidative stress. As an unexpected phenomenon, PACAP 6-38 elicited similar effects to those of PACAP 1-38, although to a different extent. On the basis of the above results, we propose calcineurin as a downstream target of PACAP signalling in differentiating chondrocytes either in normal or pathophysiological conditions. Our observations imply the therapeutical perspective that PACAP can be applied as a natural agent that may have protecting effect during joint inflammation and/or may promote

  20. How weak are the signals? International price indices and multinational enterprises

    OpenAIRE

    Lorraine Eden; Peter Rodriguez

    2004-01-01

    International price indices (IPIs) provide the most timely and comprehensive market information available to international business. How do multinational enterprises (MNEs) affect the validity of IPIs? We review the earlier debate over methods for calculating IPIs, which concluded that unit values were inferior to specification prices, although most governments produce only unit value indexes. We explore three ways in which MNEs can affect the validity of IPIs: determining the ‘representative...

  1. MicroRNA-24 promotes 3T3-L1 adipocyte differentiation by directly targeting the MAPK7 signaling

    Energy Technology Data Exchange (ETDEWEB)

    Jin, Min, E-mail: min_jin@zju.edu.cn [Division of Reproductive Medicine & Infertility, The Second Affiliated Hospital, School of Medicine, Zhejiang University, 88#, Jiefang Rd., Hangzhou, Zhejiang, 310009 (China); Wu, Yutao; Wang, Jing [School of Medicine, Zhejiang University, 288# Yuhangtang Rd, Hangzhou, Zhejiang, 310003 (China); Chen, Jian; Huang, Yiting; Rao, Jinpeng; Feng, Chun [Division of Reproductive Medicine & Infertility, The Second Affiliated Hospital, School of Medicine, Zhejiang University, 88#, Jiefang Rd., Hangzhou, Zhejiang, 310009 (China)

    2016-05-20

    Over the past years, MicroRNAs (miRNAs) act as a vital role in harmony with gene regulation and maintaining cellular homeostasis. It is well testified that miRNAshave been involved in numerous physiological and pathological processes, including embryogenesis, cell fate decision, and cellular differentiation. Adipogenesis is an organized process of cellular differentiation by which pre-adipocytes differentiate towards mature adipocytes, and it is tightly modulated by a series of transcription factors such as peroxisome proliferator-activated receptor γ (PPAR-γ) and sterol regulatory-element binding proteins 1 (SREBP1). However, the molecular mechanisms underlying the connection between miRNAs and adipogenesis-related transcription factors remain obscure. In this study, we unveiled that miR- 24 was remarkably upregulated during 3T3-L1 adipogenesis. Overexpression of miR-24 significantly promoted 3T3-L1 adipogenesis, as evidenced by its ability to increase the expression of PPAR-γ and SREBP1, lipid droplet formation and triglyceride (TG) accumulation. Furthermore, we found that neither ectopic expression of miR-24nor miR-24 inhibitor affect cell proliferation and cell cycle progression. Finally, we demonstrated that miR-24 plays the modulational role by directly repressing MAPK7, a key number in the MAPK signaling pathway. These data indicate that miR-24 is a novel positive regulator of adipocyte differentiation by targeting MAPK7, which provides new insights into the molecular mechanism of miRNA-mediated cellular differentiation. -- Highlights: •We firstly found miR-24 was upregulated in 3T3-L1 pre-adipocytes differentiation. •miR-24 promoted 3T3-L1 pre-adipocytes differentiation while silencing the expression of miR-24 had an opposite function. •miR-24 regulated 3T3-L1 differentiation by directly targeting MAPK7 signaling pathway. •miR-24did not affect 3T3-L1 pre-adipocytes cellular proliferation.

  2. Internal models of target motion: expected dynamics overrides measured kinematics in timing manual interceptions.

    Science.gov (United States)

    Zago, Myrka; Bosco, Gianfranco; Maffei, Vincenzo; Iosa, Marco; Ivanenko, Yuri P; Lacquaniti, Francesco

    2004-04-01

    Prevailing views on how we time the interception of a moving object assume that the visual inputs are informationally sufficient to estimate the time-to-contact from the object's kinematics. Here we present evidence in favor of a different view: the brain makes the best estimate about target motion based on measured kinematics and an a priori guess about the causes of motion. According to this theory, a predictive model is used to extrapolate time-to-contact from expected dynamics (kinetics). We projected a virtual target moving vertically downward on a wide screen with different randomized laws of motion. In the first series of experiments, subjects were asked to intercept this target by punching a real ball that fell hidden behind the screen and arrived in synchrony with the visual target. Subjects systematically timed their motor responses consistent with the assumption of gravity effects on an object's mass, even when the visual target did not accelerate. With training, the gravity model was not switched off but adapted to nonaccelerating targets by shifting the time of motor activation. In the second series of experiments, there was no real ball falling behind the screen. Instead the subjects were required to intercept the visual target by clicking a mousebutton. In this case, subjects timed their responses consistent with the assumption of uniform motion in the absence of forces, even when the target actually accelerated. Overall, the results are in accord with the theory that motor responses evoked by visual kinematics are modulated by a prior of the target dynamics. The prior appears surprisingly resistant to modifications based on performance errors.

  3. Prospects for a deuterium internal target, tensor polarized by optical pumping: spin exchange

    International Nuclear Information System (INIS)

    Green, M.C.

    1984-01-01

    The prospects for a tensor polarized deuterium target (approx. 10 15 atoms/cm 2 ) appropriate for nuclear physics studies in medium and high energy particle storage rings are discussed. Using the technique of electron spin exchange with an optically pumped sodium (or potassium) vapor, we hope to polarize deuterium at a rate approx. 10 17 atoms/sec. Predictions for the deuterium polarization for a particular target cell design will be presented leading to the identification of the required optical pumping power and cell wall depolarization probability to attain optimum performance. The technical obstacles to be surmounted in such a target design will also be discussed

  4. Cellular Internalization of Fibroblast Growth Factor-12 Exerts Radioprotective Effects on Intestinal Radiation Damage Independently of FGFR Signaling

    Energy Technology Data Exchange (ETDEWEB)

    Nakayama, Fumiaki, E-mail: f_naka@nirs.go.jp [Advanced Radiation Biology Research Program, Research Center for Charged Particle Therapy, Chiba (Japan); Umeda, Sachiko [Advanced Radiation Biology Research Program, Research Center for Charged Particle Therapy, Chiba (Japan); Yasuda, Takeshi [Radiation Emergency Medicine Research Program, Research Center for Radiation Emergency Medicine, National Institute of Radiological Sciences, Chiba (Japan); Fujita, Mayumi [Advanced Radiation Biology Research Program, Research Center for Charged Particle Therapy, Chiba (Japan); Asada, Masahiro [Signaling Molecules Research Group, Biomedical Research Institute, National Institute of Advanced Industrial Science and Technology, Tsukuba (Japan); Meineke, Viktor [Bundeswehr Institute of Radiobiology affiliated to the University of Ulm, Munich (Germany); Imamura, Toru [Signaling Molecules Research Group, Biomedical Research Institute, National Institute of Advanced Industrial Science and Technology, Tsukuba (Japan); Imai, Takashi [Advanced Radiation Biology Research Program, Research Center for Charged Particle Therapy, Chiba (Japan)

    2014-02-01

    Purpose: Several fibroblast growth factors (FGFs) were shown to inhibit radiation-induced tissue damage through FGF receptor (FGFR) signaling; however, this signaling was also found to be involved in the pathogenesis of several malignant tumors. In contrast, FGF12 cannot activate any FGFRs. Instead, FGF12 can be internalized readily into cells using 2 cell-penetrating peptide domains (CPP-M, CPP-C). Therefore, this study focused on clarifying the role of FGF12 internalization in protection against radiation-induced intestinal injury. Methods and Materials: Each FGF or peptide was administered intraperitoneally to BALB/c mice in the absence of heparin 24 hours before or after total body irradiation with γ rays at 9 to 12 Gy. Several radioprotective effects were examined in the jejunum. Results: Administration of FGF12 after radiation exposure was as effective as pretreatment in significantly promoting intestinal regeneration, proliferation of crypt cells, and epithelial differentiation. Two domains, comprising amino acid residues 80 to 109 and 140 to 169 of FGF12B, were identified as being responsible for the radioprotective activity, so that deletion of both domains from FGF12B resulted in a reduction in activity. Interestingly, these regions included the CPP-M and CPP-C domains, respectively; however, CPP-C by itself did not show an antiapoptotic effect. In addition, FGF1, prototypic FGF, possesses a domain corresponding to CPP-M, whereas it lacks CPP-C, so the fusion of FGF1 with CPP-C (FGF1/CPP-C) enhanced cellular internalization and increased radioprotective activity. However, FGF1/CPP-C reduced in vitro mitogenic activity through FGFRs compared with FGF1, implying that FGFR signaling might not be essential for promoting the radioprotective effect of FGF1/CPP-C. In addition, internalized FGF12 suppressed the activation of p38α after irradiation, resulting in reduced radiation-induced apoptosis. Conclusions: These findings indicate that FGF12 can protect the

  5. New radiological examination for tumor in the internal auditory canal by combination of air CT cisternography and target imaging

    Energy Technology Data Exchange (ETDEWEB)

    Yagishita, A.; Shiga, I.; Kanzaki, H. (Keio Univ., Tokyo (Japan). School of Medicine)

    1982-07-01

    A 56-year-old man was admitted to the hospital because of progressive right hearing disturbance and tinnitus. An x-ray film of the skull demonstrated dilatation of the right internal auditory canal. Intravcnously enhanced CT didn't reveal any tumor in the right cerebellopontine angle. An intracanalicular tumor was demonstrated by air CT cisternography with target imaging, and confirmed by surgery. This method is useful for the radiological evaluation of the intracanalicular tumors.

  6. A new radiological examination for tumor in the internal auditory canal by combination of air CT cisternography and target imaging

    International Nuclear Information System (INIS)

    Yagishita, Akira; Shiga, Itsuo; Kanzaki, Hitoshi

    1982-01-01

    A 56-year-old man was admitted to the hospital because of progressive right hearing disturbance and tinnitus. An x-ray film of the skull demonstrated dilatation of the right internal auditory canal. Intravcnously enhanced CT didn't reveal any tumor in the right cerebellopontine angle. An intracanalicular tumor was demonstrated by air CT cisternography with target imaging, and confirmed by surgery. This method is useful for the radiological evaluation of the intracanalicular tumors. (author)

  7. New radiological examination for tumor in the internal auditory canal by combination of air CT cisternography and target imaging

    Energy Technology Data Exchange (ETDEWEB)

    Yagishita, A; Shiga, I; Kanzaki, H [Keio Univ., Tokyo (Japan). School of Medicine

    1982-07-01

    A 56-year-old man was admitted to the hospital because of progressive right hearing disturbance and tinnitus. An x-ray film of the skull demonstrated dilatation of the right internal auditory canal. Intravcnously enhanced CT didn't reveal any tumor in the right cerebellopontine angle. An intracanalicular tumor was demonstrated by air CT cisternography with target imaging, and confirmed by surgery. This method is useful for the radiological evaluation of the intracanalicular tumors.

  8. The Ste20 kinase misshapen regulates both photoreceptor axon targeting and dorsal closure, acting downstream of distinct signals.

    Science.gov (United States)

    Su, Y C; Maurel-Zaffran, C; Treisman, J E; Skolnik, E Y

    2000-07-01

    We have previously shown that the Ste20 kinase encoded by misshapen (msn) functions upstream of the c-Jun N-terminal kinase (JNK) mitogen-activated protein kinase module in Drosophila. msn is required to activate the Drosophila JNK, Basket (Bsk), to promote dorsal closure of the embryo. A mammalian homolog of Msn, Nck interacting kinase, interacts with the SH3 domains of the SH2-SH3 adapter protein Nck. We now show that Msn likewise interacts with Dreadlocks (Dock), the Drosophila homolog of Nck. dock is required for the correct targeting of photoreceptor axons. We have performed a structure-function analysis of Msn in vivo in Drosophila in order to elucidate the mechanism whereby Msn regulates JNK and to determine whether msn, like dock, is required for the correct targeting of photoreceptor axons. We show that Msn requires both a functional kinase and a C-terminal regulatory domain to activate JNK in vivo in Drosophila. A mutation in a PXXP motif on Msn that prevents it from binding to the SH3 domains of Dock does not affect its ability to rescue the dorsal closure defect in msn embryos, suggesting that Dock is not an upstream regulator of msn in dorsal closure. Larvae with only this mutated form of Msn show a marked disruption in photoreceptor axon targeting, implicating an SH3 domain protein in this process; however, an activated form of Msn is not sufficient to rescue the dock mutant phenotype. Mosaic analysis reveals that msn expression is required in photoreceptors in order for their axons to project correctly. The data presented here genetically link msn to two distinct biological events, dorsal closure and photoreceptor axon pathfinding, and thus provide the first evidence that Ste20 kinases of the germinal center kinase family play a role in axonal pathfinding. The ability of Msn to interact with distinct classes of adapter molecules in dorsal closure and photoreceptor axon pathfinding may provide the flexibility that allows it to link to distinct

  9. Comparative gene expression analysis of Dtg, a novel target gene of Dpp signaling pathway in the early Drosophila melanogaster embryo.

    Science.gov (United States)

    Hodar, Christian; Zuñiga, Alejandro; Pulgar, Rodrigo; Travisany, Dante; Chacon, Carlos; Pino, Michael; Maass, Alejandro; Cambiazo, Verónica

    2014-02-10

    In the early Drosophila melanogaster embryo, Dpp, a secreted molecule that belongs to the TGF-β superfamily of growth factors, activates a set of downstream genes to subdivide the dorsal region into amnioserosa and dorsal epidermis. Here, we examined the expression pattern and transcriptional regulation of Dtg, a new target gene of Dpp signaling pathway that is required for proper amnioserosa differentiation. We showed that the expression of Dtg was controlled by Dpp and characterized a 524-bp enhancer that mediated expression in the dorsal midline, as well as, in the differentiated amnioserosa in transgenic reporter embryos. This enhancer contained a highly conserved region of 48-bp in which bioinformatic predictions and in vitro assays identified three Mad binding motifs. Mutational analysis revealed that these three motifs were necessary for proper expression of a reporter gene in transgenic embryos, suggesting that short and highly conserved genomic sequences may be indicative of functional regulatory regions in D. melanogaster genes. Dtg orthologs were not detected in basal lineages of Dipterans, which unlike D. melanogaster develop two extra-embryonic membranes, amnion and serosa, nevertheless Dtg orthologs were identified in the transcriptome of Musca domestica, in which dorsal ectoderm patterning leads to the formation of a single extra-embryonic membrane. These results suggest that Dtg was recruited as a new component of the network that controls dorsal ectoderm patterning in the lineage leading to higher Cyclorrhaphan flies, such as D. melanogaster and M. domestica. Copyright © 2013 Elsevier B.V. All rights reserved.

  10. A cryptic targeting signal creates a mitochondrial FEN1 isoform with tailed R-Loop binding properties.

    Directory of Open Access Journals (Sweden)

    Lawrence Kazak

    Full Text Available A growing number of DNA transacting proteins is found in the nucleus and in mitochondria, including the DNA repair and replication protein Flap endonuclease 1, FEN1. Here we show a truncated FEN1 isoform is generated by alternative translation initiation, exposing a mitochondrial targeting signal. The shortened form of FEN1, which we term FENMIT, localizes to mitochondria, based on import into isolated organelles, immunocytochemistry and subcellular fractionation. In vitro FENMIT binds to flap structures containing a 5' RNA flap, and prefers such substrates to single-stranded RNA. FENMIT can also bind to R-loops, and to a lesser extent to D-loops. Exposing human cells to ethidium bromide results in the generation of RNA/DNA hybrids near the origin of mitochondrial DNA replication. FENMIT is recruited to the DNA under these conditions, and is released by RNase treatment. Moreover, high levels of recombinant FENMIT expression inhibit mtDNA replication, following ethidium bromide treatment. These findings suggest FENMIT interacts with RNA/DNA hybrids in mitochondrial DNA, such as those found at the origin of replication.

  11. Rationale for Possible Targeting of Histone Deacetylase Signaling in Cancer Diseases with a Special Reference to Pancreatic Cancer

    Directory of Open Access Journals (Sweden)

    Mehdi Ouaïssi

    2011-01-01

    Full Text Available There is ongoing interest to identify signaling pathways and genes that play a key role in carcinogenesis and the development of resistance to antitumoral drugs. Given that histone deacetylases (HDACs interact with various partners through complex molecular mechanims leading to the control of gene expression, they have captured the attention of a large number of researchers. As a family of transcriptional corepressors, they have emerged as important regulators of cell differentiation, cell cycle progression, and apoptosis. Several HDAC inhibitors (HDACis have been shown to efficiently protect against the growth of tumor cells in vitro as well as in vivo. The pancreatic cancer which represents one of the most aggressive cancer still suffers from inefficient therapy. Recent data, although using in vitro tumor cell cultures and in vivo chimeric mouse model, have shown that some of the HDACi do express antipancreatic tumor activity. This provides hope that some of the HDACi could be potential efficient anti-pancreatic cancer drugs. The purpose of this review is to analyze some of the current data of HDACi as possible targets of drug development and to provide some insight into the current problems with pancreatic cancer and points of interest for further study of HDACi as potential molecules for pancreatic cancer adjuvant therapy.

  12. Chronic stress enhances progression of periodontitis via α1-adrenergic signaling: a potential target for periodontal disease therapy.

    Science.gov (United States)

    Lu, Huaixiu; Xu, Minguang; Wang, Feng; Liu, Shisen; Gu, Jing; Lin, Songshan

    2014-10-17

    This study assessed the roles of chronic stress (CS) in the stimulation of the sympathetic nervous system and explored the underlying mechanisms of periodontitis. Using an animal model of periodontitis and CS, the expression of tyrosine hydroxylase (TH) and the protein levels of the α1-adrenergic receptor (α1-AR) and β2-adrenergic receptor (β2-AR) were assessed. Furthermore, human periodontal ligament fibroblasts (HPDLFs) were stimulated with lipopolysaccharide (LPS) to mimic the process of inflammation. The proliferation of the HPDLFs and the expression of α1-AR and β2-AR were assessed. The inflammatory-related cytokines interleukin (IL)-1β, IL-6 and IL-8 were detected after pretreatment with the α1/β2-AR blockers phentolamine/propranolol, both in vitro and in vivo. Results show that periodontitis under CS conditions enhanced the expression of TH, α1-AR and β2-AR. Phentolamine significantly reduced the inflammatory cytokine levels. Furthermore, we observed a marked decrease in HPDLF proliferation and the increased expression of α1-ARfollowing LPS pretreatment. Pretreatment with phentolamine dramatically ameliorated LPS-inhibited cell proliferation. In addition, the blocking of α1-ARsignaling also hindered the upregulation of the inflammatory-related cytokines IL-1β, IL-6 and IL-8. These results suggest that CS can significantly enhance the pathological progression of periodontitis by an α1-adrenergic signaling-mediated inflammatory response. We have identified a potential therapeutic target for the treatment of periodontal disease, particularly in those patients suffering from concurrent CS.

  13. Optimization of Signal Timing of Intersections by Internal Metering of Queue Time Ratio of Vehicles in Network Scale

    Directory of Open Access Journals (Sweden)

    Mina Ghanbarikarekani

    2016-06-01

    Full Text Available Optimization of signal timing in urban network is usually done by minimizing the delay times or queue lengths. Sincethe effect of each intersection on the whole network is not considered in the mentioned methods, traffic congestion may occur in network links. Therefore, this paper has aimed to provide a timing optimization algorithm for traffic signals using internal timing policy based on balancing queue time ratio of vehicles in network links. In the proposed algorithm, the difference between the real queue time ratio and the optimum one for each link of intersection was minimized. To evaluate the efficiency of the proposed algorithm on traffic performance, the proposed algorithm was applied in a hypothetical network. By comparing the simulating software outputs, before and after implementing the algorithm, it was concluded that the queue time ratio algorithm has improved the traffic parameters by increasing the flow as well as reducing the delay time and density of the network.

  14. Quantitative analysis of phosphoinositide 3-kinase (PI3K) signaling using live-cell total internal reflection fluorescence (TIRF) microscopy.

    Science.gov (United States)

    Johnson, Heath E; Haugh, Jason M

    2013-12-02

    This unit focuses on the use of total internal reflection fluorescence (TIRF) microscopy and image analysis methods to study the dynamics of signal transduction mediated by class I phosphoinositide 3-kinases (PI3Ks) in mammalian cells. The first four protocols cover live-cell imaging experiments, image acquisition parameters, and basic image processing and segmentation. These methods are generally applicable to live-cell TIRF experiments. The remaining protocols outline more advanced image analysis methods, which were developed in our laboratory for the purpose of characterizing the spatiotemporal dynamics of PI3K signaling. These methods may be extended to analyze other cellular processes monitored using fluorescent biosensors. Copyright © 2013 John Wiley & Sons, Inc.

  15. Targeting Interventions: Moderators of the Effects of Expressive Writing and Assertiveness Training on the Adjustment of International University Students

    Science.gov (United States)

    Hijazi, Alaa M.; Tavakoli, Shedeh; Slavin-Spenny, Olga M.; Lumley, Mark A.

    2011-01-01

    Acculturative stress is a common experience for international students and is associated with psychological and physical problems. In a previous study, the authors reported that two stress reduction interventions—expressive writing (EW) and assertiveness training (AT)—had limited overall benefits among international students at an American University. The current analyses of data from that study investigated whether individual differences moderated the effects of EW and AT. Results indicate that greater acculturative stress at baseline predicted greater improvement from both interventions, compared with control. Women benefited more from AT than EW, except that EW improved women’s physical symptoms. Men benefited more from EW than AT. Students with limited emotional awareness and expression tended to benefit from both interventions, relative to control. Finally, nation of origin cultural differences generally did not predict outcomes. It is concluded that the benefits of EW and AT and can be enhanced by targeting these interventions to specific subgroups of international students. PMID:21660220

  16. Development of a personalized dosimetric tool for radiation protection in case of internal contamination and targeted radiotherapy in nuclear medicine

    International Nuclear Information System (INIS)

    Chiavassa, S.

    2005-12-01

    Current internal dosimetric estimations are based on the M.I.R.D. formalism and used standard mathematical models. These standard models are often far from a given patient morphology and do not allow to perform patient-specific dosimetry. The aim of this study was to develop a personalized dosimetric tool, which takes into account real patient morphology, composition and densities. This tool, called O.E.D.I.P.E., a French acronym of Tool for the Evaluation of Personalized Internal Dose, is a user-friendly graphical interface. O.E.D.I.P.E. allows to create voxel-based patient-specific geometries and associates them with the M.C.N.P.X. Monte Carlo code. Radionuclide distribution and absorbed dose calculation can be performed at the organ and voxel scale. O.E.D.I.P.E. can be used in nuclear medicine for targeted radiotherapy and in radiation protection in case of internal contamination. (author)

  17. Chloroplasts as source and target of cellular redox regulation: a discussion on chloroplast redox signals in the context of plant physiology.

    Science.gov (United States)

    Baier, Margarete; Dietz, Karl-Josef

    2005-06-01

    During the evolution of plants, chloroplasts have lost the exclusive genetic control over redox regulation and antioxidant gene expression. Together with many other genes, all genes encoding antioxidant enzymes and enzymes involved in the biosynthesis of low molecular weight antioxidants were transferred to the nucleus. On the other hand, photosynthesis bears a high risk for photo-oxidative damage. Concomitantly, an intricate network for mutual regulation by anthero- and retrograde signals has emerged to co-ordinate the activities of the different genetic and metabolic compartments. A major focus of recent research in chloroplast regulation addressed the mechanisms of redox sensing and signal transmission, the identification of regulatory targets, and the understanding of adaptation mechanisms. In addition to redox signals communicated through signalling cascades also used in pathogen and wounding responses, specific chloroplast signals control nuclear gene expression. Signalling pathways are triggered by the redox state of the plastoquinone pool, the thioredoxin system, and the acceptor availability at photosystem I, in addition to control by oxolipins, tetrapyrroles, carbohydrates, and abscisic acid. The signalling function is discussed in the context of regulatory circuitries that control the expression of antioxidant enzymes and redox modulators, demonstrating the principal role of chloroplasts as the source and target of redox regulation.

  18. SGIP1 alters internalization and modulates signaling of activated cannabinoid receptor 1 in a biased manner

    Czech Academy of Sciences Publication Activity Database

    Hájková, Alena; Techlovská, Šárka; Dvořáková, Michaela; Chambers, Jayne Nicole; Kumpošt, Jiří; Hubálková, Pavla; Prezeau, L.; Blahoš, Jaroslav

    2016-01-01

    Roč. 107, léto (2016), s. 201-214 ISSN 0028-3908 R&D Projects: GA ČR GAP303/12/2408 Institutional support: RVO:68378050 Keywords : Seven transmembrane receptors * G-protein coupled receptors * Cannabinoid receptor 1 * Protein-protein interactions * Bias signaling * Receptor endocytosis Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 5.012, year: 2016

  19. Internalizing Null Extraterrestrial "Signals": An Astrobiological App for a Technological Society

    OpenAIRE

    Chaisson, Eric J.

    2014-01-01

    One of the beneficial outcomes of searching for life in the Universe is that it grants greater awareness of our own problems here on Earth. Lack of contact with alien beings to date might actually comprise a null "signal" pointing humankind toward a viable future. Astrobiology has surprising practical applications to human society; within the larger cosmological context of cosmic evolution, astrobiology clarifies the energetic essence of complex systems throughout the Universe, including tech...

  20. Quantification and Minimization of Uncertainties of Internal Target Volume for Stereotactic Body Radiation Therapy of Lung Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Ge Hong [Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina (United States); Department of Radiation Oncology, Henan Cancer Hospital, the Affiliated Cancer Hospital of Zhengzhou University, Henan (China); Cai Jing; Kelsey, Chris R. [Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina (United States); Yin Fangfang, E-mail: fangfang.yin@duke.edu [Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina (United States)

    2013-02-01

    Purpose: To quantify uncertainties in delineating an internal target volume (ITV) and to understand how these uncertainties may be individually minimized for stereotactic body radiation therapy (SBRT) of early stage non-small cell lung cancer (NSCLC). Methods and Materials: Twenty patients with NSCLC who were undergoing SBRT were imaged with free-breathing 3-dimensional computed tomography (3DCT) and 10-phase 4-dimensional CT (4DCT) for delineating gross tumor volume (GTV){sub 3D} and ITV{sub 10Phase} (ITV3). The maximum intensity projection (MIP) CT was also calculated from 10-phase 4DCT for contouring ITV{sub MIP} (ITV1). Then, ITV{sub COMB} (ITV2), ITV{sub 10Phase+GTV3D} (ITV4), and ITV{sub 10Phase+ITVCOMB} (ITV5) were generated by combining ITV{sub MIP} and GTV{sub 3D}, ITV{sub 10phase} and GTV{sub 3D}, and ITV{sub 10phase} and ITV{sub COMB}, respectively. All 6 volumes (GTV{sub 3D} and ITV1 to ITV5) were delineated in the same lung window by the same radiation oncologist. The percentage of volume difference (PVD) between any 2 different volumes was determined and was correlated to effective tumor diameter (ETD), tumor motion ranges, R{sub 3D}, and the amplitude variability of the recorded breathing signal (v) to assess their volume variations. Results: The mean (range) tumor motion (R{sub SI}, R{sub AP}, R{sub ML}, and R{sub 3D}) and breathing variability (v) were 7.6 mm (2-18 mm), 4.0 mm (2-8 mm), 3.3 mm (0-7.5 mm), 9.9 mm (4.1-18.7 mm), and 0.17 (0.07-0.37), respectively. The trend of volume variation was GTV{sub 3D} target volumes showed statistical significance (P{<=}.001), except for ITV2 and ITV3 (P=.594). The PVDs for all volume pairs correlated negatively with ETD (r{<=}-0.658, P{<=}.006) and positively with

  1. Light-controlled endosomal escape of the novel CD133-targeting immunotoxin AC133-saporin by photochemical internalization - A minimally invasive cancer stem cell-targeting strategy.

    Science.gov (United States)

    Bostad, Monica; Olsen, Cathrine Elisabeth; Peng, Qian; Berg, Kristian; Høgset, Anders; Selbo, Pål Kristian

    2015-05-28

    The cancer stem cell (CSC) marker CD133 is an attractive target to improve antitumor therapy. We have used photochemical internalization (PCI) for the endosomal escape of the novel CD133-targeting immunotoxin AC133-saporin (PCIAC133-saporin). PCI employs an endocytic vesicle-localizing photosensitizer, which generates reactive oxygen species upon light-activation causing a rupture of the vesicle membranes and endosomal escape of entrapped drugs. Here we show that AC133-saporin co-localizes with the PCI-photosensitizer TPCS2a, which upon light exposure induces cytosolic release of AC133-saporin. PCI of picomolar levels of AC133-saporin in colorectal adenocarcinoma WiDr cells blocked cell proliferation and induced 100% inhibition of cell viability and colony forming ability at the highest light doses, whereas no cytotoxicity was obtained in the absence of light. Efficient PCI-based CD133-targeting was in addition demonstrated in the stem-cell-like, triple negative breast cancer cell line MDA-MB-231 and in the aggressive malignant melanoma cell line FEMX-1, whereas no enhanced targeting was obtained in the CD133-negative breast cancer cell line MCF-7. PCIAC133-saporin induced mainly necrosis and a minimal apoptotic response based on assessing cleavage of caspase-3 and PARP, and the TUNEL assay. PCIAC133-saporin resulted in S phase arrest and reduced LC3-II conversion compared to control treatments. Notably, co-treatment with Bafilomycin A1 and PCIAC133-saporin blocked LC3-II conversion, indicating a termination of the autophagic flux in WiDr cells. For the first time, we demonstrate laser-controlled targeting of CD133 in vivo. After only one systemic injection of AC133-saporin and TPCS2a, a strong anti-tumor response was observed after PCIAC133-saporin. The present PCI-based endosomal escape technology represents a minimally invasive strategy for spatio-temporal, light-controlled targeting of CD133+ cells in localized primary tumors or metastasis. Copyright © 2015

  2. Genome-wide Analysis of RARβ Transcriptional Targets in Mouse Striatum Links Retinoic Acid Signaling with Huntington's Disease and Other Neurodegenerative Disorders.

    Science.gov (United States)

    Niewiadomska-Cimicka, Anna; Krzyżosiak, Agnieszka; Ye, Tao; Podleśny-Drabiniok, Anna; Dembélé, Doulaye; Dollé, Pascal; Krężel, Wojciech

    2017-07-01

    Retinoic acid (RA) signaling through retinoic acid receptors (RARs), known for its multiple developmental functions, emerged more recently as an important regulator of adult brain physiology. How RAR-mediated regulation is achieved is poorly known, partly due to the paucity of information on critical target genes in the brain. Also, it is not clear how reduced RA signaling may contribute to pathophysiology of diverse neuropsychiatric disorders. We report the first genome-wide analysis of RAR transcriptional targets in the brain. Using chromatin immunoprecipitation followed by high-throughput sequencing and transcriptomic analysis of RARβ-null mutant mice, we identified genomic targets of RARβ in the striatum. Characterization of RARβ transcriptional targets in the mouse striatum points to mechanisms through which RAR may control brain functions and display neuroprotective activity. Namely, our data indicate with statistical significance (FDR 0.1) a strong contribution of RARβ in controlling neurotransmission, energy metabolism, and transcription, with a particular involvement of G-protein coupled receptor (p = 5.0e -5 ), cAMP (p = 4.5e -4 ), and calcium signaling (p = 3.4e -3 ). Many identified RARβ target genes related to these pathways have been implicated in Alzheimer's, Parkinson's, and Huntington's disease (HD), raising the possibility that compromised RA signaling in the striatum may be a mechanistic link explaining the similar affective and cognitive symptoms in these diseases. The RARβ transcriptional targets were particularly enriched for transcripts affected in HD. Using the R6/2 transgenic mouse model of HD, we show that partial sequestration of RARβ in huntingtin protein aggregates may account for reduced RA signaling reported in HD.

  3. Rac1/β-Catenin Signalling Pathway Contributes to Trophoblast Cell Invasion by Targeting Snail and MMP9

    Directory of Open Access Journals (Sweden)

    Minghua Fan

    2016-03-01

    Full Text Available Background/Aims: Preeclampsia is an idiopathic and serious complication during gestation in which placental trophoblast cells differentiate into several functional subtypes, including highly invasive extravillous trophoblasts (EVTs. Although the cause and pathogenesis of preeclampsia have remained unclear, numerous studies have suggested that the inadequacy of EVT invasion leads to imperfect uterine spiral artery remodelling, which plays a crucial role in the development of preeclampsia. Rac1, or Ras-related C3 botulinum toxin substrate 1, was found to be a key regulator of the migration, invasion uand apoptosis of various tumour cells. Because EVTs share similar invasive and migratory biological behaviours with malignant cells, this study aimed to determine whether the Rac1 signalling pathway affects trophoblast invasion and is thus involved in the pathogenesis of preeclampsia. Methods: We measured the activity of Rac1 and its downstream targets, β-catenin, Snail and MMP9 in placental tissues from patients experiencing a normal pregnancy and those with preeclampsia. Furthermore, we treated HTR-8/SVneo cells with a shRNA Rac1 vector and the β-catenin inhibitor IWP-2 and explored Rac1 signalling pathway activation as well as the effects of Snail and β-catenin on trophoblast invasion. Results: In placental samples from patients experiencing a normal pregnancy and those with preeclampsia, active Rac1 levels and MMP9 protein and mRNA levels were significantly decreased in term pregnancy samples compared to early pregnancy samples. Lower levels were found in preeclampsia samples than in normal term pregnancy samples, and these levels significantly declined in severe preeclampsia samples compared with mild preeclampsia samples. Further analyses demonstrated that both Rac1 shRNA and the β-catenin inhibitor significantly suppressed MMP9 and Snail activation in trophoblasts, thus impairing trophoblast invasion. Notably, silencing Rac1 down

  4. Neuronal targeting, internalization, and biological activity of a recombinant atoxic derivative of botulinum neurotoxin A

    Science.gov (United States)

    Botulinum neurotoxins (BoNT) have the unique capacity to cross epithelial barriers, target neuromuscular junctions, and translocate active metalloprotease component to the cytosol of motor neurons. We have taken advantage of the molecular carriers responsible for this trafficking to create a family ...

  5. The methylotrophic yeast Hansenula polymorpha contains an inducible import pathway for peroxisomal matrix proteins with an N-terminal targeting signal (PTS2 proteins)

    NARCIS (Netherlands)

    Faber, Klaas Nico; Haima, Pieter; Gietl, Christine; Harder, Willem; Ab, Geert; Veenhuis, Marten

    1994-01-01

    Two main types of peroxisomal targeting signals have been identified that reside either at the extreme C terminus (PTS1) or the N terminus (PTS2) of the protein. In the methylotrophic yeast Hansenula polymorpha the majority of peroxisomal matrix proteins are of the PTS1 type. Thus far, for H.

  6. Cost effects of international trade in meeting EU renewable electricity targets

    International Nuclear Information System (INIS)

    Voogt, M.H.; Uyterlinde, M.A.

    2006-01-01

    The European market for renewable electricity received a major stimulus from the adoption of the Directive on the Promotion of Renewable Electricity. The Directive specifies the indicative targets for electricity supply from renewable energy sources (RES-E) to be reached in European Union (EU) Member States in the year 2010. It also requires Member States to certify the origin of their renewable electricity production. This article presents a first EU-wide quantitative evaluation of the effects of meeting the targets, using an EU-wide system for tradable green certificates (TGC). We calculate the equilibrium price of green certificates and identify which countries are likely to export or import certificates. Cost advantages of participating in such an EU-wide trading scheme are determined for each of the Member States. Moreover, we identify which choice of technologies results in meeting targets at least costs. Results are obtained from a model that quantifies the effects of achieving the RES-E targets in the EU with and without trade. The article provides a brief insight in this model as well as the methodology that was used to specify cost potential curves for renewable electricity in each of the 15 EU Member States. Model calculations show that within the EU-wide TGC system, the total production costs of the last option needed to satisfy the overall EU RES-E target equals 9.2 eurocent/kWh. Assuming that the production price of electricity on the European power market would equal 3 eurocent/kWh in the year 2010, the indicative green certificate price equals 6.2 eurocent/kWh. We conclude that implementation of an EU-wide TGC system is a cost-efficient way of stimulating renewable electricity supply

  7. Targeting apoptosis signalling kinase-1 (ASK-1 does not prevent the development of neuropathy in streptozotocin-induced diabetic mice.

    Directory of Open Access Journals (Sweden)

    Victoria L Newton

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

  8. Contribution of the residue at position 4 within classical nuclear localization signals to modulating interaction with importins and nuclear targeting.

    Science.gov (United States)

    Smith, Kate M; Di Antonio, Veronica; Bellucci, Luca; Thomas, David R; Caporuscio, Fabiana; Ciccarese, Francesco; Ghassabian, Hanieh; Wagstaff, Kylie M; Forwood, Jade K; Jans, David A; Palù, Giorgio; Alvisi, Gualtiero

    2018-08-01

    Nuclear import involves the recognition by importin (IMP) superfamily members of nuclear localization signals (NLSs) within protein cargoes destined for the nucleus, the best understood being recognition of classical NLSs (cNLSs) by the IMPα/β1 heterodimer. Although the cNLS consensus [K-(K/R)-X-(K/R) for positions P2-P5] is generally accepted, recent studies indicated that the contribution made by different residues at the P4 position can vary. Here, we apply a combination of microscopy, molecular dynamics, crystallography, in vitro binding, and bioinformatics approaches to show that the nature of residues at P4 indeed modulates cNLS function in the context of a prototypical Simian Virus 40 large tumor antigen-derived cNLS (KKRK, P2-5). Indeed, all hydrophobic substitutions in place of R impaired binding to IMPα and nuclear targeting, with the largest effect exerted by a G residue at P4. Substitution of R with neutral hydrophobic residues caused the loss of electrostatic and van der Waals interactions between the P4 residue side chains and IMPα. Detailed bioinformatics analysis confirmed the importance of the P4 residue for cNLS function across the human proteome, with specific residues such as G being associated with low activity. Furthermore, we validate our findings for two additional cNLSs from human cytomegalovirus (HCMV) DNA polymerase catalytic subunit UL54 and processivity factor UL44, where a G residue at P4 results in a 2-3-fold decrease in NLS activity. Our results thus showed that the P4 residue makes a hitherto poorly appreciated contribution to nuclear import efficiency, which is essential to determining the precise nuclear levels of cargoes. Copyright © 2018 Elsevier B.V. All rights reserved.

  9. 3D-segmentation of the 18F-choline PET signal for target volume definition in radiation therapy of the prostate.

    Science.gov (United States)

    Ciernik, I Frank; Brown, Derek W; Schmid, Daniel; Hany, Thomas; Egli, Peter; Davis, J Bernard

    2007-02-01

    Volumetric assessment of PET signals becomes increasingly relevant for radiotherapy (RT) planning. Here, we investigate the utility of 18F-choline PET signals to serve as a structure for semi-automatic segmentation for forward treatment planning of prostate cancer. 18F-choline PET and CT scans of ten patients with histologically proven prostate cancer without extracapsular growth were acquired using a combined PET/CT scanner. Target volumes were manually delineated on CT images using standard software. Volumes were also obtained from 18F-choline PET images using an asymmetrical segmentation algorithm. PTVs were derived from CT 18F-choline PET based clinical target volumes (CTVs) by automatic expansion and comparative planning was performed. As a read-out for dose given to non-target structures, dose to the rectal wall was assessed. Planning target volumes (PTVs) derived from CT and 18F-choline PET yielded comparable results. Optimal matching of CT and 18F-choline PET derived volumes in the lateral and cranial-caudal directions was obtained using a background-subtracted signal thresholds of 23.0+/-2.6%. In antero-posterior direction, where adaptation compensating for rectal signal overflow was required, optimal matching was achieved with a threshold of 49.5+/-4.6%. 3D-conformal planning with CT or 18F-choline PET resulted in comparable doses to the rectal wall. Choline PET signals of the prostate provide adequate spatial information amendable to standardized asymmetrical region growing algorithms for PET-based target volume definition for external beam RT.

  10. Towards understanding the lifespan extension by reduced insulin signaling: bioinformatics analysis of DAF-16/FOXO direct targets in Caenorhabditis elegans.

    Science.gov (United States)

    Li, Yan-Hui; Zhang, Gai-Gai

    2016-04-12

    DAF-16, the C. elegans FOXO transcription factor, is an important determinant in aging and longevity. In this work, we manually curated FOXODB http://lyh.pkmu.cn/foxodb/, a database of FOXO direct targets. It now covers 208 genes. Bioinformatics analysis on 109 DAF-16 direct targets in C. elegans found interesting results. (i) DAF-16 and transcription factor PQM-1 co-regulate some targets. (ii) Seventeen targets directly regulate lifespan. (iii) Four targets are involved in lifespan extension induced by dietary restriction. And (iv) DAF-16 direct targets might play global roles in lifespan regulation.

  11. A new inhibitor of the β-arrestin/AP2 endocytic complex reveals interplay between GPCR internalization and signalling

    Science.gov (United States)

    Beautrait, Alexandre; Paradis, Justine S.; Zimmerman, Brandon; Giubilaro, Jenna; Nikolajev, Ljiljana; Armando, Sylvain; Kobayashi, Hiroyuki; Yamani, Lama; Namkung, Yoon; Heydenreich, Franziska M.; Khoury, Etienne; Audet, Martin; Roux, Philippe P.; Veprintsev, Dmitry B.; Laporte, Stéphane A.; Bouvier, Michel

    2017-04-01

    In addition to G protein-coupled receptor (GPCR) desensitization and endocytosis, β-arrestin recruitment to ligand-stimulated GPCRs promotes non-canonical signalling cascades. Distinguishing the respective contributions of β-arrestin recruitment to the receptor and β-arrestin-promoted endocytosis in propagating receptor signalling has been limited by the lack of selective analytical tools. Here, using a combination of virtual screening and cell-based assays, we have identified a small molecule that selectively inhibits the interaction between β-arrestin and the β2-adaptin subunit of the clathrin adaptor protein AP2 without interfering with the formation of receptor/β-arrestin complexes. This selective β-arrestin/β2-adaptin inhibitor (Barbadin) blocks agonist-promoted endocytosis of the prototypical β2-adrenergic (β2AR), V2-vasopressin (V2R) and angiotensin-II type-1 (AT1R) receptors, but does not affect β-arrestin-independent (transferrin) or AP2-independent (endothelin-A) receptor internalization. Interestingly, Barbadin fully blocks V2R-stimulated ERK1/2 activation and blunts cAMP accumulation promoted by both V2R and β2AR, supporting the concept of β-arrestin/AP2-dependent signalling for both G protein-dependent and -independent pathways.

  12. Development of a thin, internal superconducting polarisation magnet for the polarised target

    Energy Technology Data Exchange (ETDEWEB)

    Bornstein, Marcel; Dutz, Hartmut; Goertz, Stefan; Reeve, Scott; Runkel, Stefan [Physikalisches Institut, Bonn Univ. (Germany)

    2016-07-01

    In order to improve the figure of merit of double-polarisation experiments at CB-ELSA in Bonn, the Polarised Target is working on a new dilution refrigerator. For maximum polarisation of nucleons low temperatures and a high homogeneous magnetic field within the target area is needed. A thin, superconducting magnet is in development, which will create a continuous longitudinal magnetic field of 2.5 T and which will be used within the new refrigerator. The solenoidal geometry of this magnet uses two additional correction coils, placed at a well defined calculated position, for reaching the homogeneity criteria of 10{sup -4} needed for the dynamic nuclear process. Practically, the superconducting wires as well as the correction coils have to be placed with maximum precision: Small fluctuations of the distance between the current loops can diminish the requested homogeneity. A second build prototype passes first tests and looks promising to fulfil the particular requirements.

  13. Development of an thin, internal superconducting polarisation magnet for the polarised target

    Energy Technology Data Exchange (ETDEWEB)

    Altfelde, Timo; Bornstein, Marcel; Dutz, Hartmut; Goertz, Stefan; Miebach, Roland; Reeve, Scott; Runkel, Stefan; Sommer, Marco; Streit, Benjamin [Physikalisches Institut, Bonn (Germany)

    2015-07-01

    In order to improve the figure of merit of double-polarisation experiments at CB-ELSA in Bonn, the Polarised Target is working on a new dilution refrigerator. For maximum polarisation of nucleons low temperatures and a high homogeneous magnetic field within the target area is needed. A thin, superconducting magnet is in development, which will create a continuous longitudinal magnetic field of 2.5 T and which will be used within the new refrigerator. The solenoidal geometry of this magnet uses two additional correction coils, placed at a well defined calculated position, for reaching the homogeneity criteria of 10{sup -4} needed for the dynamic nuclear polarisation process. Practically, the superconducting wires as well as the correction coils have to be placed with maximum precision: Small fluctuations of the distance between the current loops can diminish the requested homogeneity.

  14. Lujan Center Mark-IV Target Neutronics Design Internal Review Report

    Energy Technology Data Exchange (ETDEWEB)

    Lisowski, Paul W. [Los Alamos National Lab. (LANL), Los Alamos, NM (United States); Gallmeier, Franz [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Guber, Klaus [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)

    2018-02-26

    The 1L Target Moderator Reflector System (TMRS) at the Lujan Center will need to be replaced before the CY 2020 operating cycle. A Physics Division design team investigated options for improving the overall target performance for nuclear science research with minimal reduction in performance for materials science. This review concluded that devoting an optimized arrangement of the Lujan TMRS upper tier to nuclear science and using the lower tier for materials science can achieve those goals. This would open the opportunity for enhanced nuclear science research in an important neutron energy range for NNSA. There will be no other facility in the US that will compete in the keV energy range provided flight paths and instrumentation are developed to take advantage of the neutron flux and resolution.

  15. Generation of X-rays by electrons recycling through thin internal targets of cyclic accelerators

    Science.gov (United States)

    Kaplin, V.; Kuznetsov, S.; Uglov, S.

    2018-05-01

    The use of thin (recycling effect) of electrons through them. The multiplicity of electron passes (M) is determined by the electron energy, accelerator parameters, the thickness, structure and material of a target and leads to an increase in the effective target thickness and the efficiency of radiation generation. The increase of M leads to the increase in the emittance of electron beams which can change the characteristics of radiation processes. The experimental results obtained using the Tomsk synchrotron and betatron showed the possibility of increasing the yield and brightness of coherent X-rays generated by the electrons passing (recycling) through thin crystals and periodic multilayers placed into the chambers of accelerators, when the recycling effect did not influence on the spectral and angular characteristics of generated X-rays.

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

    Energy Technology Data Exchange (ETDEWEB)

    Li, Zhi [Department of Human Anatomy and Histoembryology, College of Basic Medical Sciences, Jilin University (China); Li, Youjun, E-mail: liyoujunn@126.com [Department of Human Anatomy and Histoembryology, College of Basic Medical Sciences, Jilin University (China); Wang, Nan; Yang, Lifeng; Zhao, Wei; Zeng, Xiandong [Central Hospital Affiliated to Shenyang Medical College (China)

    2016-03-18

    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 protein 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.

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

    International Nuclear Information System (INIS)

    Li, Zhi; Li, Youjun; Wang, Nan; Yang, Lifeng; Zhao, Wei; Zeng, Xiandong

    2016-01-01

    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 protein 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.

  18. Direct Signal-to-Noise Quality Comparison between an Electronic and Conventional Stethoscope aboard the International Space Station

    Science.gov (United States)

    Marshburn, Thomas; Cole, Richard; Ebert, Doug; Bauer, Pete

    2014-01-01

    Introduction: Evaluation of heart, lung, and bowel sounds is routinely performed with the use of a stethoscope to help detect a broad range of medical conditions. Stethoscope acquired information is even more valuable in a resource limited environments such as the International Space Station (ISS) where additional testing is not available. The high ambient noise level aboard the ISS poses a specific challenge to auscultation by stethoscope. An electronic stethoscope's ambient noise-reduction, greater sound amplification, recording capabilities, and sound visualization software may be an advantage to a conventional stethoscope in this environment. Methods: A single operator rated signal-to-noise quality from a conventional stethoscope (Littman 2218BE) and an electronic stethoscope (Litmann 3200). Borborygmi, pulmonic, and cardiac sound quality was ranked with both stethoscopes. Signal-to-noise rankings were preformed on a 1 to 10 subjective scale with 1 being inaudible, 6 the expected quality in an emergency department, 8 the expected quality in a clinic, and 10 the clearest possible quality. Testing took place in the Japanese Pressurized Module (JPM), Unity (Node 2), Destiny (US Lab), Tranquility (Node 3), and the Cupola of the International Space Station. All examinations were conducted at a single point in time. Results: The electronic stethoscope's performance ranked higher than the conventional stethoscope for each body sound in all modules tested. The electronic stethoscope's sound quality was rated between 7 and 10 in all modules tested. In comparison, the traditional stethoscope's sound quality was rated between 4 and 7. The signal to noise ratio of borborygmi showed the biggest difference between stethoscopes. In the modules tested, the auscultation of borborygmi was rated between 5 and 7 by the conventional stethoscope and consistently 10 by the electronic stethoscope. Discussion: This stethoscope comparison was limited to a single operator. However, we

  19. Measuring elimination of podoconiosis, endemicity classifications, case definition and targets: an international Delphi exercise.

    Science.gov (United States)

    Deribe, Kebede; Wanji, Samuel; Shafi, Oumer; Muheki Tukahebwa, Edridah; Umulisa, Irenee; Davey, Gail

    2015-09-01

    Podoconiosis is one of the major causes of lymphoedema in the tropics. Nonetheless, currently there are no endemicity classifications or elimination targets to monitor the effects of interventions. This study aimed at establishing case definitions and indicators that can be used to assess endemicity, elimination and clinical outcomes of podoconiosis. This paper describes the result of a Delphi technique used among 28 experts. A questionnaire outlining possible case definitions, endemicity classifications, elimination targets and clinical outcomes was developed. The questionnaire was distributed to experts working on podoconiosis and other neglected tropical diseases in two rounds. The experts rated the importance of case definitions, endemic classifications, elimination targets and the clinical outcome measures. Median and mode were used to describe the central tendency of expert responses. The coefficient of variation was used to describe the dispersals of expert responses. Consensus on definitions and indicators for assessing endemicity, elimination and clinical outcomes of podoconiosis directed at policy makers and health workers was achieved following the two rounds of Delphi approach among the experts. Based on the two Delphi rounds we discuss potential indicators and endemicity classification of this disabling disease, and the ongoing challenges to its elimination in countries with the highest prevalence. Consensus will help to increase effectiveness of podoconiosis elimination efforts and ensure comparability of outcome data. © The Author 2015. Published by Oxford University Press on behalf of Royal Society of Tropical Medicine and Hygiene.

  20. Scaling up towards international targets for AIDS, tuberculosis, and malaria: contribution of global fund-supported programs in 2011-2015.

    Directory of Open Access Journals (Sweden)

    Itamar Katz

    Full Text Available OBJECTIVE: The paper projects the contribution to 2011-2015 international targets of three major pandemics by programs in 140 countries funded by the Global Fund to Fight AIDS, Tuberculosis and Malaria, the largest external financier of tuberculosis and malaria programs and a major external funder of HIV programs in low and middle income countries. DESIGN: Estimates, using past trends, for the period 2011-2015 of the number of persons receiving antiretroviral (ARV treatment, tuberculosis case detection using the internationally approved DOTS strategy, and insecticide-treated nets (ITNs to be delivered by programs in low and middle income countries supported by the Global Fund compared to international targets established by UNAIDS, Stop TB Partnership, Roll Back Malaria Partnership and the World Health Organisation. RESULTS: Global Fund-supported programs are projected to provide ARV treatment to 5.5-5.8 million people, providing 30%-31% of the 2015 international target. Investments in tuberculosis and malaria control will enable reaching in 2015 60%-63% of the international target for tuberculosis case detection and 30%-35% of the ITN distribution target in sub-Saharan Africa. CONCLUSION: Global Fund investments will substantially contribute to the achievement by 2015 of international targets for HIV, TB and malaria. However, additional large scale international and domestic financing is needed if these targets are to be reached by 2015.

  1. Selecting and assessing a target firm for an international merger or acquisition

    OpenAIRE

    Veselinova, Elena; Gogova Samonikov, Marija; Matlievska, Margarita; Sajnoski, Krste

    2011-01-01

    International mergers and acquisitions (M & A) as a way of restructuring the companies represent an important part of the world of corporate finance. Every day the Wall Street investment bankers arrange M & A transactions in which individual companies are merging together to form larger and stronger companies than they are. Not surprisingly, such activities often appear on the news. These contracts totaled hundreds of millions, even billions of dollars. They determine the future of the compan...

  2. Does internal climate variability overwhelm climate change signals in streamflow? The upper Po and Rhone basin case studies

    International Nuclear Information System (INIS)

    Fatichi, S.; Rimkus, S.; Burlando, P.; Bordoy, R.

    2014-01-01

    Projections of climate change effects in streamflow are increasingly required to plan water management strategies. These projections are however largely uncertain due to the spread among climate model realizations, internal climate variability, and difficulties in transferring climate model results at the spatial and temporal scales required by catchment hydrology. A combination of a stochastic downscaling methodology and distributed hydrological modeling was used in the ACQWA project to provide projections of future streamflow (up to year 2050) for the upper Po and Rhone basins, respectively located in northern Italy and south-western Switzerland. Results suggest that internal (stochastic) climate variability is a fundamental source of uncertainty, typically comparable or larger than the projected climate change signal. Therefore, climate change effects in streamflow mean, frequency, and seasonality can be masked by natural climatic fluctuations in large parts of the analyzed regions. An exception to the overwhelming role of stochastic variability is represented by high elevation catchments fed by glaciers where streamflow is expected to be considerably reduced due to glacier retreat, with consequences appreciable in the main downstream rivers in August and September. Simulations also identify regions (west upper Rhone and Toce, Ticino river basins) where a strong precipitation increase in the February to April period projects streamflow beyond the range of natural climate variability during the melting season. This study emphasizes the importance of including internal climate variability in climate change analyses, especially when compared to the limited uncertainty that would be accounted for by few deterministic projections. The presented results could be useful in guiding more specific impact studies, although design or management decisions should be better based on reliability and vulnerability criteria as suggested by recent literature. - Highlights:

  3. Does internal climate variability overwhelm climate change signals in streamflow? The upper Po and Rhone basin case studies

    Energy Technology Data Exchange (ETDEWEB)

    Fatichi, S., E-mail: simone.fatichi@ifu.baug.ethz.ch; Rimkus, S.; Burlando, P.; Bordoy, R.

    2014-09-15

    Projections of climate change effects in streamflow are increasingly required to plan water management strategies. These projections are however largely uncertain due to the spread among climate model realizations, internal climate variability, and difficulties in transferring climate model results at the spatial and temporal scales required by catchment hydrology. A combination of a stochastic downscaling methodology and distributed hydrological modeling was used in the ACQWA project to provide projections of future streamflow (up to year 2050) for the upper Po and Rhone basins, respectively located in northern Italy and south-western Switzerland. Results suggest that internal (stochastic) climate variability is a fundamental source of uncertainty, typically comparable or larger than the projected climate change signal. Therefore, climate change effects in streamflow mean, frequency, and seasonality can be masked by natural climatic fluctuations in large parts of the analyzed regions. An exception to the overwhelming role of stochastic variability is represented by high elevation catchments fed by glaciers where streamflow is expected to be considerably reduced due to glacier retreat, with consequences appreciable in the main downstream rivers in August and September. Simulations also identify regions (west upper Rhone and Toce, Ticino river basins) where a strong precipitation increase in the February to April period projects streamflow beyond the range of natural climate variability during the melting season. This study emphasizes the importance of including internal climate variability in climate change analyses, especially when compared to the limited uncertainty that would be accounted for by few deterministic projections. The presented results could be useful in guiding more specific impact studies, although design or management decisions should be better based on reliability and vulnerability criteria as suggested by recent literature. - Highlights:

  4. Nature of extracellular signal that triggers RhoA/ROCK activation for the basal internal anal sphincter tone in humans

    Science.gov (United States)

    Singh, Jagmohan; Kumar, Sumit; Phillips, Benjamin

    2015-01-01

    The extracellular signal that triggers activation of rho-associated kinase (RhoA/ROCK), the major molecular determinant of basal internal anal sphincter (IAS) smooth muscle tone, is not known. Using human IAS tissues, we identified the presence of the biosynthetic machineries for angiotensin II (ANG II), thromboxane A2 (TXA2), and prostaglandin F2α (PGF2α). These end products of the renin-angiotensin system (RAS) (ANG II) and arachidonic acid (TXA2 and PGF2α) pathways and their effects in human IAS vs. rectal smooth muscle (RSM) were studied. A multipronged approach utilizing immunocytochemistry, Western blot analyses, and force measurements was implemented. Additionally, in a systematic analysis of the effects of respective inhibitors along different steps of biosynthesis and those of antagonists, their end products were evaluated either individually or in combination. To further describe the molecular mechanism for the IAS tone via these pathways, we monitored RhoA/ROCK activation and its signal transduction cascade. Data showed characteristically higher expression of biosynthetic machineries of RAS and AA pathways in the IAS compared with the RSM. Additionally, specific inhibition of the arachidonic acid (AA) pathway caused ∼80% decrease in the IAS tone, whereas that of RAS lead to ∼20% decrease. Signal transduction studies revealed that the end products of both AA and RAS pathways cause increase in the IAS tone via activation of RhoA/ROCK. Both AA and RAS (via the release of their end products TXA2, PGF2α, and ANG II, respectively), provide extracellular signals which activate RhoA/ROCK for the maintenance of the basal tone in human IAS. PMID:25882611

  5. Constitutively internalized dopamine transporter is targeted to late endosomes and lysosomal degradation in heterologous cell lines and dopaminergic neurons

    DEFF Research Database (Denmark)

    Eriksen, Jacob; Madsen, Kenneth; Vægter, Christian Bjerggaard

    and amphetamine, a substrate of the DAT. In antibody feeding experiments we observed that Tac-DAT was constitutively internalized faster than Tac alone and using an ELISA based assay we could quantify time-dependent intracellular accumulation of the transporter. Incubation with inhibitors of lysosomal degradation...... (leupeptin, chloroquine, or ammonium chloride) increased the amount of transporter accumulated intracellularly over time, suggesting that constitutively endocytosed transporter was targeted to lysosomal degradation. This was further supported by expression of Tac-DAT in the immortalized dopaminergic cell...... dopaminergic neurons and visualized the DAT directly in the neurons using the fluorescent cocaine analog JHC 1-064. These data showed pronounced colocalization upon constitutive internalization with Lysotracker, a late endosomal/lysosomal marker; however only little co-lolization was observed with Alexa488...

  6. Canonical and non-canonical WNT signaling in cancer stem cells and their niches: Cellular heterogeneity, omics reprogramming, targeted therapy and tumor plasticity (Review)

    Science.gov (United States)

    Katoh, Masaru

    2017-01-01

    Cancer stem cells (CSCs), which have the potential for self-renewal, differentiation and de-differentiation, undergo epigenetic, epithelial-mesenchymal, immunological and metabolic reprogramming to adapt to the tumor microenvironment and survive host defense or therapeutic insults. Intra-tumor heterogeneity and cancer-cell plasticity give rise to therapeutic resistance and recurrence through clonal replacement and reactivation of dormant CSCs, respectively. WNT signaling cascades cross-talk with the FGF, Notch, Hedgehog and TGFβ/BMP signaling cascades and regulate expression of functional CSC markers, such as CD44, CD133 (PROM1), EPCAM and LGR5 (GPR49). Aberrant canonical and non-canonical WNT signaling in human malignancies, including breast, colorectal, gastric, lung, ovary, pancreatic, prostate and uterine cancers, leukemia and melanoma, are involved in CSC survival, bulk-tumor expansion and invasion/metastasis. WNT signaling-targeted therapeutics, such as anti-FZD1/2/5/7/8 monoclonal antibody (mAb) (vantictumab), anti-LGR5 antibody-drug conjugate (ADC) (mAb-mc-vc-PAB-MMAE), anti-PTK7 ADC (PF-06647020), anti-ROR1 mAb (cirmtuzumab), anti-RSPO3 mAb (rosmantuzumab), small-molecule porcupine inhibitors (ETC-159, WNT-C59 and WNT974), tankyrase inhibitors (AZ1366, G007-LK, NVP-TNKS656 and XAV939) and β-catenin inhibitors (BC2059, CWP232228, ICG-001 and PRI-724), are in clinical trials or preclinical studies for the treatment of patients with WNT-driven cancers. WNT signaling-targeted therapeutics are applicable for combination therapy with BCR-ABL, EGFR, FLT3, KIT or RET inhibitors to treat a subset of tyrosine kinase-driven cancers because WNT and tyrosine kinase signaling cascades converge to β-catenin for the maintenance and expansion of CSCs. WNT signaling-targeted therapeutics might also be applicable for combination therapy with immune checkpoint blockers, such as atezolizumab, avelumab, durvalumab, ipilimumab, nivolumab and pembrolizumab, to treat cancers

  7. Simulations of Collisional Disruption at the Catastrophic Impact Energy Threshold: Effect of the Target's Internal Structure and Diameter

    Science.gov (United States)

    Michel, P.; Benz, W.; Richardson, D. C.

    2005-08-01

    Recent simulations of asteroid break-ups, including both the fragmentation of the parent body and the gravitational interactions of the fragments, have allowed to reproduced successfully the main properties of asteroid families formed in different regimes of impact energy. Here, using the same kind of simulations, we concentrate on a single regime of impact energy, the so-called catastrophic threshold usually designated by Qcrit, which results in the escape of half of the target's mass. Considering a wide range of diameter values and two kinds of internal structures of the parent body, monolithic and pre-shattered, we analyse their potential influences on the value of Qcrit and on the collisional outcome limited here to the fragment size and ejection speed distributions, which are the main outcome properties used by collisional models to study the evolutions of the different populations of small bodies. For all the considered diameters and the two internal structures of the parent body, we confirm that the process of gravitational reaccumulation is at the origin of the largest remnant's mass. We then find that, for a given diameter of the parent body, the impact energy corresponding to the catastrophic disruption threshold is highly dependent on the internal structure of the parent body. In particular, a pre-shattered parent body containing only damaged zones but no macroscopic voids is easier to disrupt than a monolithic parent body. Other kinds of internal properties that can also characterize small bodies in real populations will be investigated in a future work.

  8. Treating rheumatoid arthritis to target: 2014 update of the recommendations of an international task force

    Science.gov (United States)

    Smolen, Josef S; Breedveld, Ferdinand C; Burmester, Gerd R; Bykerk, Vivian; Dougados, Maxime; Emery, Paul; Kvien, Tore K; Navarro-Compán, M Victoria; Oliver, Susan; Schoels, Monika; Scholte-Voshaar, Marieke; Stamm, Tanja; Stoffer, Michaela; Takeuchi, Tsutomu; Aletaha, Daniel; Andreu, Jose Louis; Aringer, Martin; Bergman, Martin; Betteridge, Neil; Bijlsma, Hans; Burkhardt, Harald; Combe, Bernard; Durez, Patrick; Fonseca, Joao Eurico; Gibofsky, Alan; Gomez-Reino, Juan J; Graninger, Winfried; Hannonen, Pekka; Haraoui, Boulos; Kouloumas, Marios; Landewe, Robert; Martin-Mola, Emilio; Nash, Peter; Ostergaard, Mikkel; Östör, Andrew; Richards, Pam; Sokka-Isler, Tuulikki; Thorne, Carter; Tzioufas, Athanasios G; van Vollenhoven, Ronald; de Wit, Martinus

    2016-01-01

    Background Reaching the therapeutic target of remission or low-disease activity has improved outcomes in patients with rheumatoid arthritis (RA) significantly. The treat-to-target recommendations, formulated in 2010, have provided a basis for implementation of a strategic approach towards this therapeutic goal in routine clinical practice, but these recommendations need to be re-evaluated for appropriateness and practicability in the light of new insights. Objective To update the 2010 treat-to-target recommendations based on systematic literature reviews (SLR) and expert opinion. Methods A task force of rheumatologists, patients and a nurse specialist assessed the SLR results and evaluated the individual items of the 2010 recommendations accordingly, reformulating many of the items. These were subsequently discussed, amended and voted upon by >40 experts, including 5 patients, from various regions of the world. Levels of evidence, strengths of recommendations and levels of agreement were derived. Results The update resulted in 4 overarching principles and 10 recommendations. The previous recommendations were partly adapted and their order changed as deemed appropriate in terms of importance in the view of the experts. The SLR had now provided also data for the effectiveness of targeting low-disease activity or remission in established rather than only early disease. The role of comorbidities, including their potential to preclude treatment intensification, was highlighted more strongly than before. The treatment aim was again defined as remission with low-disease activity being an alternative goal especially in patients with long-standing disease. Regular follow-up (every 1–3 months during active disease) with according therapeutic adaptations to reach the desired state was recommended. Follow-up examinations ought to employ composite measures of disease activity that include joint counts. Additional items provide further details for particular aspects of the

  9. PEGASYS---A proposed internal target facility for the PEP storage ring

    International Nuclear Information System (INIS)

    Van Biber, K.

    1988-07-01

    A proposal for an integral gas-jet target and forward spectrometer for the PEP storage ring is described. The beam structure, allowable, luminosity (L = 10 33 cm/sup /minus/2/s/sup /minus/1/ for H 2 , D 2 ) and energy (E/sub e/ ≤ 15 GeV) make the ring ideal for multiparticle coincidence studies in the scaling regime, and where perturbative QCD may be an apt description of some exclusive and semi-inclusive reactions. 14 refs., 7 figs

  10. History of the bubble chamber and related active- and internal-target nuclear tracking detectors

    International Nuclear Information System (INIS)

    Becchetti, F.D.

    2015-01-01

    Donald Glaser, 1960 Nobel laureate in Physics, recently passed away (2013), as have many of his colleagues who were involved with the early development of bubble chambers at the University of Michigan. In this paper I will review those early years and the subsequent wide-spread application of active-target (AT) bubble chambers that dominated high-energy physics (HEP) research for over thirty years. Some of the related, but more modern nuclear tracking detectors being used in HEP, neutrino astrophysics and dark-matter searches also will be discussed

  11. Basic evaluation of signal transmission in a real-time internal radiation dose measurement system

    International Nuclear Information System (INIS)

    Shinohe, K.; Takura, T.; Sato, F.; Matsuki, H.; Yamada, S.; Sato, T.

    2009-01-01

    In radiation therapy, excessive exposure to radiation occurs because the dose actually delivered to the tumor is not known. As a result, a patient suffers from side effects. To solve this problem, a system is needed in which the delivered dose is measured inside the body and the dose data are transmitted from inside to outside of the body during radiation therapy. If such a system is realized, it will be possible to treat cancer safely and effectively. The proposed real-time internal radiation dose measurement system consists of an implantable dosimeter, a wireless communication system, and a wireless feeding system. In this study, a wireless communication system that uses magnetic fields was investigated. As a result, a communication distance of 200 mm was obtained. It was confirmed that radiation dose data could be transmitted outside the body when the communication distance is the required 200 mm. (author)

  12. Physiological regulation through learnt control of appetites by contingencies among signals from external and internal environments.

    Science.gov (United States)

    Booth, David A

    2008-11-01

    As reviewed by [Cooper, S. J. (2008). From Claude Bernard to Walter Cannon: emergence of the concept of homeostasis. Appetite 51, 419-27.] Claude Bernard's idea of stabilisation of bodily states, as realised in Walter B. Cannon's conception of homeostasis, took mathematical form during the 1940s in the principle that externally originating disturbance of a physiological parameter can feed an informative signal around the brain to trigger counteractive processes--a corrective mechanism known as negative feedback, in practice reliant on feedforward. Three decades later, enough was known of the physiology and psychology of eating and drinking for calculations to show how experimentally demonstrated mechanisms of feedforward that had been learnt from negative feedback combine to regulate exchanges of water and energy between the body and the surroundings. Subsequent systemic physiology, molecular neuroscience and experimental psychology, however, have been traduced by a misconception that learnt controls of intake are 'non-homeostatic', the myth of biological 'set points' and an historic failure to address evidence for the ingestion-adapting information-processing mechanisms on which an operationally integrative theory of eating and drinking relies.

  13. Safety aspects of tritium in ICF reactors with internally-breeding targets

    International Nuclear Information System (INIS)

    Ragheb, M.; Miley, G.H.; University of Illinois, Urbana, IL)

    1985-01-01

    The LOTRIT inertial confinement reactor concept employs a deuterium burning target with a DT spark trigger core. This eliminates the need for tritium breeding in a blanket, and leads to a minimization of the tritium inventory and of the possibility of metal fire hazards if lead is used instead of lithium for first wall protection. The active fuel inventory in the fuel cycle and blanket per MJ of energy produced is only 5 percent of the DT case. The most significant reduction in the total tritium inventory is in the target manufacture and storage areas, and is about 1.8% of the DT case per unit of fusion energy produced. If the goal is to reduce the risk from tritium releases from fusion reactors to below that of fission reactors, it is estimated that the tritium releases must be maintained at 0.13-5.0 Ci/day. Attaining these values will be costly, technologically difficult and will constrain the design options in DTbased systems, but may be within the realm of systems using the LOTRIT concept

  14. Internal dosimetry through GATE simulations of preclinical radiotherapy using a melanin-targeting ligand

    International Nuclear Information System (INIS)

    Perrot, Y; Donnarieix, D; Maigne, L; Degoul, F; Auzeloux, P; Bonnet, M; Cachin, F; Chezal, J M; Labarre, P; Moins, N; Papon, J; Rbah-Vidal, L; Vidal, A; Miot-Noirault, E

    2014-01-01

    The GATE Monte Carlo simulation platform based on the Geant4 toolkit is under constant improvement for dosimetric calculations. In this study, we explore its use for the dosimetry of the preclinical targeted radiotherapy of melanoma using a new specific melanin-targeting radiotracer labeled with iodine 131. Calculated absorbed fractions and S values for spheres and murine models (digital and CT-scan-based mouse phantoms) are compared between GATE and EGSnrc Monte Carlo codes considering monoenergetic electrons and the detailed energy spectrum of iodine 131. The behavior of Geant4 standard and low energy models is also tested. Following the different authors’ guidelines concerning the parameterization of electron physics models, this study demonstrates an agreement of 1.2% and 1.5% with EGSnrc, respectively, for the calculation of S values for small spheres and mouse phantoms. S values calculated with GATE are then used to compute the dose distribution in organs of interest using the activity distribution in mouse phantoms. This study gives the dosimetric data required for the translation of the new treatment to the clinic. (paper)

  15. Treating rheumatoid arthritis to target: Revision of the 2014 International Expert Group Recommendations

    Directory of Open Access Journals (Sweden)

    N. T. Vatutin

    2016-01-01

    Full Text Available The paper presents a new edition (2014 of basic approaches to therapy of rheumatoid arthritis (RA based on the principle of «Treat to target », which has been elaborated by the experts of the European League Against Rheumatism (EULAR and the American College of Rheumatology (ACR. The revised recommendations consider the results of numerous randomized controlled and cohort studies, as well as the data of an extensive systematic review of the literature. The new 2014 version contains 4 basic principles and 10 recommendations for the management of patients with RA. When making the updated recommendations, the experts took into account particularly issues, such as criteria for defining a remission, the need to minimize comorbidities in patients with RA and to individualize its therapy, as well as their working ability. The basic principles in the management of patients with RA, by using a treat-to-target strategy, are discussed in detail and the rewording of the main points of the 2010 recommendations and their new edition are substantiated.

  16. Team knowledge assessment of nursing on international targets patient safety in an intensive care unit

    Directory of Open Access Journals (Sweden)

    Maria Nathália da Silva Souza

    2017-08-01

    Full Text Available Background e Objectives: The quality of hospital care provided to the patient and the safety of their stay at the site triggered discussions around the world after the analysis of epidemiological studies conducted in the USA that concluded the high rate of adverse events in the hospital setting Caused by professional error, with that the theme gained strength and motivated discussions about the care models applied to the patients. Therefore the research was aimed at evaluating the knowledge of the Nursing Team of the Intensive Care Unit sector of a public hospital in Recife-PE on the International Patient Safety Goals. Methods: A cross-sectional study with descriptive quantitative approach was carried out from June to August 2016. Data collection was performed through a semi-structured questionnaire that addressed the social and professional aspects of the respondents. The studied variables: gender, age, professional category and training time. The data were analyzed in epiinfo software version 3.2.2. Results: The sample consisted of 50 professionals, 18% of whom were Nurses and 82% were Nursing technicians. Most respondents scored more than 50% of questions about international patient safety goals and had more than one employment relationship. Conclusion: It was verified that the lack of training, work overload and more of an employment relationship can contribute to a precarious professional assistance. KEYWORDS: Patient Safety. Nursing. Safety Management. Intensive Care Units

  17. A technique of using gated-CT images to determine internal target volume (ITV) for fractionated stereotactic lung radiotherapy

    International Nuclear Information System (INIS)

    Jin Jianyue; Ajlouni, Munther; Chen Qing; Yin, Fang-Fang; Movsas, Benjamin

    2006-01-01

    Background and purpose: To develop and evaluate a technique and procedure of using gated-CT images in combination with PET image to determine the internal target volume (ITV), which could reduce the planning target volume (PTV) with adequate target coverage. Patients and methods: A skin marker-based gating system connected to a regular single slice CT scanner was used for this study. A motion phantom with adjustable motion amplitude was used to evaluate the CT gating system. Specifically, objects of various sizes/shapes, considered as virtual tumors, were placed on the phantom to evaluate the number of phases of gated images required to determine the ITV while taking into account tumor size, shape and motion. A procedure of using gated-CT and PET images to define ITV for patients was developed and was tested in patients enrolled in an IRB approved protocol. Results: The CT gating system was capable of removing motion artifacts for target motion as large as 3-cm when it was gated at optimal phases. A phantom study showed that two gated-CT scans at the end of expiration and the end of inspiration would be sufficient to determine the ITV for tumor motion less than 1-cm, and another mid-phase scan would be required for tumors with 2-cm motion, especially for small tumors. For patients, the ITV encompassing visible tumors in all sets of gated-CT and regular spiral CT images seemed to be consistent with the target volume determined from PET images. PTV expanded from the ITV with a setup uncertainty margin had less volume than PTVs from spiral CT images with a 10-mm generalized margin or an individualized margin determined at fluoroscopy. Conclusions: A technique of determining the ITV using gated-CT images was developed and was clinically implemented successfully for fractionated stereotactic lung radiotherapy

  18. Pulmonary tumors induced in the rat by the internal α irradiation; target cells and sensitive cells

    International Nuclear Information System (INIS)

    Fritsch, P.; Masse, R.; Nolibe, D.; Metivier, H.; Morin, M.; Lafuma, J.

    1977-01-01

    Over, 500 rat pulmonary tumors induced by inhalation of various radionuclides have been examined by means of the usual histological methods and ultrastructurally for part of them. Tumor grafts were obtained and several lines have been preserved for several years. The malignity of some varieties: circumscribed epidermoid carcinoma, fibrosarcoma derived from stromareaction, bronchiolo alveolar carcinoma was thus established. It was not possible to establish any relation between the turnover per day and the incidence of pulmonary tumors whatever the correction factor applied taking account of the distribution of the delivered dose. The possibility of showing unapparent lesions of the target cells by grafts of immunodepressed animals suggested that local regulating mechanisms are of particular significance [fr

  19. Third-line Targeted Therapy in Metastatic Renal Cell Carcinoma: Results from the International Metastatic Renal Cell Carcinoma Database Consortium.

    Science.gov (United States)

    Wells, J Connor; Stukalin, Igor; Norton, Craig; Srinivas, Sandy; Lee, Jae Lyun; Donskov, Frede; Bjarnason, Georg A; Yamamoto, Haru; Beuselinck, Benoit; Rini, Brian I; Knox, Jennifer J; Agarwal, Neeraj; Ernst, D Scott; Pal, Sumanta K; Wood, Lori A; Bamias, Aristotelis; Alva, Ajjai S; Kanesvaran, Ravindran; Choueiri, Toni K; Heng, Daniel Y C

    2017-02-01

    The use of third-line targeted therapy (TTT) in metastatic renal cell carcinoma (mRCC) is not well characterized and varies due to the lack of robust data to guide treatment decisions. This study examined the use of third-line therapy in a large international population. To evaluate the use and efficacy of targeted therapy in a third-line setting. Twenty-five international cancer centers provided consecutive data on 4824 mRCC patients who were treated with an approved targeted therapy. One thousand and twelve patients (21%) received TTT and were included in the analysis. Patients were analyzed for overall survival (OS) and progression-free survival using Kaplan-Meier curves, and were evaluated for overall response. Cox regression analyses were used to determine the statistical association between OS and the six factors included in the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) prognostic model. Subgroup analysis was performed on patients stratified by their IMDC prognostic risk status. Everolimus was the most prevalent third-line therapy (27.5%), but sunitinib, sorafenib, pazopanib, temsirolimus, and axitinib were all utilized in over ≥9% of patients. Patients receiving any TTT had an OS of 12.4 mo, a progression-free survival of 3.9 mo, and 61.1% of patients experienced an overall response of stable disease or better. Patients not receiving TTT had an OS of 2.1 mo. Patients with favorable- (7.2%) or intermediate-risk (65.3%) disease had the highest OS with TTT, 29.9 mo and 15.5 mo, respectively, while poor-risk (27.5%) patients survived 5.5 mo. Results are limited by the retrospective nature of the study. TTT remains highly heterogeneous. The IMDC prognostic criteria can be used to stratify third-line patients. TTT use in favorable- and intermediate-risk patients was associated with the greatest OS. Patients with favorable- and intermediate-prognostic criteria disease treated with third-line targeted therapy have an associated

  20. Intra-arterial high signals on arterial spin labeling perfusion images predict the occluded internal carotid artery segment

    International Nuclear Information System (INIS)

    Sogabe, Shu; Satomi, Junichiro; Tada, Yoshiteru; Kanematsu, Yasuhisa; Kuwayama, Kazuyuki; Yagi, Kenji; Yoshioka, Shotaro; Mizobuchi, Yoshifumi; Mure, Hideo; Yamaguchi, Izumi; Kitazato, Keiko T.; Nagahiro, Shinji; Abe, Takashi; Harada, Masafumi; Yamamoto, Nobuaki; Kaji, Ryuji

    2017-01-01

    Arterial spin labeling (ASL) involves perfusion imaging using the inverted magnetization of arterial water. If the arterial arrival times are longer than the post-labeling delay, labeled spins are visible on ASL images as bright, high intra-arterial signals (IASs); such signals were found within occluded vessels of patients with acute ischemic stroke. The identification of the occluded segment in the internal carotid artery (ICA) is crucial for endovascular treatment. We tested our hypothesis that high IASs on ASL images can predict the occluded segment. Our study included 13 patients with acute ICA occlusion who had undergone angiographic and ASL studies within 48 h of onset. We retrospectively identified the high IAS on ASL images and angiograms and recorded the occluded segment and the number of high IAS-positive slices on ASL images. The ICA segments were classified as cervical (C1), petrous (C2), cavernous (C3), and supraclinoid (C4). Of seven patients with intracranial ICA occlusion, five demonstrated high IASs at C1-C2, suggesting that high IASs could identify stagnant flow proximal to the occluded segment. Among six patients with extracranial ICA occlusion, five presented with high IASs at C3-C4, suggesting that signals could identify the collateral flow via the ophthalmic artery. None had high IASs at C1-C2. The mean number of high IAS-positive slices was significantly higher in patients with intra- than extracranial ICA occlusion. High IASs on ASL images can identify slow stagnant and collateral flow through the ophthalmic artery in patients with acute ICA occlusion and help to predict the occlusion site. (orig.)

  1. Intra-arterial high signals on arterial spin labeling perfusion images predict the occluded internal carotid artery segment

    Energy Technology Data Exchange (ETDEWEB)

    Sogabe, Shu; Satomi, Junichiro; Tada, Yoshiteru; Kanematsu, Yasuhisa; Kuwayama, Kazuyuki; Yagi, Kenji; Yoshioka, Shotaro; Mizobuchi, Yoshifumi; Mure, Hideo; Yamaguchi, Izumi; Kitazato, Keiko T.; Nagahiro, Shinji [Tokushima University Graduate School, Department of Neurosurgery, Tokushima (Japan); Abe, Takashi; Harada, Masafumi [Tokushima University Graduate School, Department of Radiology, Tokushima (Japan); Yamamoto, Nobuaki; Kaji, Ryuji [Tokushima University Graduate School, Department of Clinical Neurosciences, Institute of Biomedical Biosciences, Tokushima (Japan)

    2017-06-15

    Arterial spin labeling (ASL) involves perfusion imaging using the inverted magnetization of arterial water. If the arterial arrival times are longer than the post-labeling delay, labeled spins are visible on ASL images as bright, high intra-arterial signals (IASs); such signals were found within occluded vessels of patients with acute ischemic stroke. The identification of the occluded segment in the internal carotid artery (ICA) is crucial for endovascular treatment. We tested our hypothesis that high IASs on ASL images can predict the occluded segment. Our study included 13 patients with acute ICA occlusion who had undergone angiographic and ASL studies within 48 h of onset. We retrospectively identified the high IAS on ASL images and angiograms and recorded the occluded segment and the number of high IAS-positive slices on ASL images. The ICA segments were classified as cervical (C1), petrous (C2), cavernous (C3), and supraclinoid (C4). Of seven patients with intracranial ICA occlusion, five demonstrated high IASs at C1-C2, suggesting that high IASs could identify stagnant flow proximal to the occluded segment. Among six patients with extracranial ICA occlusion, five presented with high IASs at C3-C4, suggesting that signals could identify the collateral flow via the ophthalmic artery. None had high IASs at C1-C2. The mean number of high IAS-positive slices was significantly higher in patients with intra- than extracranial ICA occlusion. High IASs on ASL images can identify slow stagnant and collateral flow through the ophthalmic artery in patients with acute ICA occlusion and help to predict the occlusion site. (orig.)

  2. Missense mutations in IHH impair Indian Hedgehog signaling in C3H10T1/2 cells: Implications for brachydactyly type A1, and new targets for Hedgehog signaling.

    Science.gov (United States)

    Guo, Shengzhen; Zhou, Jian; Gao, Bo; Hu, Jianxin; Wang, Hongsheng; Meng, Junwei; Zhao, Xinzhi; Ma, Gang; Lin, Chuwen; Xiao, Yue; Tang, Wei; Zhu, Xuming; Cheah, Kathryn S E; Feng, Guoying; Chan, Danny; He, Lin

    2010-01-01

    Heterozygous missense mutations in IHH result in Brachydactyly type A1 (BDA1; OMIM 112500), a condition characterized by the shortening of digits due to hypoplasia/aplasia of the middle phalanx. Indian Hedgehog signaling regulates the proliferation and differentiation of chondrocytes and is essential for endochondral bone formation. Analyses of activated IHH signaling in C3H10T1/2 cells showed that three BDA1-associated mutations (p.E95K, p.D100E and p.E131K) severely impaired the induction of targets such as Ptch1 and Gli1. However, this was not a complete loss of function, suggesting that these mutations may affect the interaction with the receptor PTCH1 or its partners, with an impact on the induction potency. From comparative microarray expression analyses and quantitative real-time PCR, we identified three additional targets, Sostdc1, Penk1 and Igfbp5, which were also severely affected. Penk1 and Igfbp5 were confirmed to be regulated by GLI1, while the induction of Sostdc1 by IHH is independent of GLI1. SOSTDC1 is a BMP antagonist, and altered BMP signaling is known to affect digit formation. The role of Penk1 and Igfbp5 in skeletogenesis is not known. However, we have shown that both Penk1 and Igfbp5 are expressed in the interzone region of the developing joint of mouse digits, providing another link for a role for IHH signaling in the formation of the distal digits.

  3. Development of Detector Systems for Internal and Fixed Target Heavy Ion Physics Experiments

    International Nuclear Information System (INIS)

    Golubev, Pavel

    2003-04-01

    This thesis deals with intermediate energy heavy ion reactions with the particular aim to study the nuclear matter equation of state which defines the relation between statistical parameters of a fermionic system. The development of equipment for two experiments, CA47 at The Svedberg Laboratory in Uppsala, Sweden and R16 at Kernfysisch Versneller Inst. (KVI), Groningen, The Netherlands, are described. CA47 contains the CHICSi detector, a modular, ultra-high vacuum (UHV) compatible, multi-detector system, covering a solid angle of 3pi sr around the collision point. Together with two auxiliary detector systems CHICSi is placed at the cluster-jet target chamber of the CELSIUS storage ring. This thesis gives a technical overview of the detector and the development carried out in order to achieve the desired detection performance. Some laboratory and in-beam tests are described and the analysis of the first experimental results is discussed. The nuclear intensity interferometry experiment (R16) was performed in a dedicated beam-line of the AGOR superconducting cyclotron. Small-angle two-particle correlations were measured for the E/A = 61 MeV 36 Ar + 27 Al, 112 Sn, 124 Sn reactions, together with singles spectra. The experimental energy distributions of neutrons and light charged particles for the 36 Ar + 27 Al reaction have been analyzed with a Maxwellian multi-source prescription. These results, together with correlation function data, are used to extract information on the size of the emitting sources and their time evolution

  4. Diagnostics of plasma produced by femtosecond laser pulse impact upon a target with an internal nanostructure

    International Nuclear Information System (INIS)

    Skobelev, I. Yu.; Faenov, A. Ya.; Gasilov, S. V.; Pikuz, T. A.; Pikuz, S. A.; Magunov, A. I.; Boldarev, A. S.; Gasilov, V. A.

    2010-01-01

    X-ray diagnostics of the interaction of femtosecond laser pulses with intensities of 10 16 -10 18 W/cm 2 with CO 2 clusters and frozen nanosize water particles is carried out. The stage of cluster expansion and the formation of a plasma channel, which governs the parameters of the formed X-ray radiation source and accelerated ion flows, is studied. The measurements are based on recording spatially resolved X-ray spectra of H- and He-like oxygen ions. Utilization of Rydberg transitions for spectra diagnostics makes it possible to determine plasma parameters on a time scale of t ∼ 10 ps after the beginning of a femtosecond pulse. The role of the rear edge of the laser pulse in sustaining the plasma temperature at a level of ∼100 eV in the stage of a nonadiabatic cluster expansion is shown. The analysis of the profiles and relative intensities of spectral lines allows one to determine the temperature and density of plasma electrons and distinguish the populations of 'thermal' ions and ions that are accelerated up to energies of a few tens of kiloelectronvolts. It is shown that the use of solid clusters made of frozen nanoscale water droplets as targets leads to a substantial increase in the number of fast He-like ions. In this case, however, the efficiency of acceleration of H-like ions does not increase, because the time of their ionization in plasma exceeds the time of cluster expansion.

  5. Al-Qaida threats and strategies : the religious justification for targeting the international energy economy

    Energy Technology Data Exchange (ETDEWEB)

    Williams, J.F.

    2008-03-15

    Methods of analyzing threats generated by terrorists against the energy industry were discussed. Threat was defined as the product of an adversary's capability, intent, and authority to engage a target using a specific attack mode. The paper argued that robust models for threat must demonstrate a cultural awareness of the adversary in question. The study used an al-Qaida attack to develop and critique the religious justification offered by Salafi-Jihadi religious scholars for attacking the energy industry. The importance of the fatawa's religious authority was evaluated, and cultural drivers for al-Qaida were explored in relation to the threat model. An assessment of past terrorist acts against energy industry infrastructure was conducted. Various relevant fatawa issued by religious scholars were discussed. Socio-political and religious attributes of the al-Qaida movement were outlined using the Combating Terrorism Center's militant ideology atlas. The threat equation was expanded to include authority and cultural influences. The threat model was developed by assigning information to bins of capability, intent, and authority in order to assess and evaluate data. The Kalman filter technique was used to determine threat drivers. 98 refs., 20 figs.

  6. Targeting G-Protein Signaling for the Therapeutics of Prostate Tumor Bone Metastases and the Associated Chronic Bone Pain

    Science.gov (United States)

    2015-09-01

    Cancer Bone Metastasis, heterotrimeric G protein  subunits, G protein-coupled receptors, signal transduction 16. SECURITY CLASSIFICATION OF: 17...TRPV1 expression/function in cultured mouse DRG sensory neurons. Accomplishments: we initially attempted to manipulate Gsignaling in isolated DRG ...increase in AKT activation. Since AKT activation will activate TRPV1 channel in DRG neurons, we cannot further assess the effect of G1 and Gt

  7. A HIF-regulated VHL-PTP1B-Src signaling axis identifies a therapeutic target in Renal Cell Carcinoma

    OpenAIRE

    Suwaki, Natsuko; Vanhecke, Elsa; Atkins, Katelyn M.; Graf, Manuela; Swabey, Katherine; Huang, Paul; Schraml, Peter; Moch, Holger; Cassidy, Amy; Brewer, Daniel; Al-Lazikani, Bissan; Workman, Paul; De-Bono, Johann; Kaye, Stan B.; Larkin, James

    2011-01-01

    Metastatic renal cell carcinoma (RCC) is a molecularly heterogeneous disease that is intrinsically resistant to chemotherapy and radiotherapy. While VEGF and mTOR targeted therapies have shown clinical activity, their effects are variable and short-lived, underscoring the need for improved treatment strategies for RCC. Here, we used quantitative phosphoproteomics and immunohistochemical profiling of 346 RCC specimens to determine that Src kinase signaling is elevated in RCC cells that retain ...

  8. Agrin-LRP4-MuSK signaling as a therapeutic target for myasthenia gravis and other neuromuscular disorders.

    Science.gov (United States)

    Ohno, Kinji; Ohkawara, Bisei; Ito, Mikako

    2017-10-01

    Signal transduction at the neuromuscular junction (NMJ) is compromised in a diverse array of diseases including myasthenia gravis, Lambert-Eaton myasthenic syndrome, Isaacs' syndrome, congenital myasthenic syndromes, Fukuyama-type congenital muscular dystrophy, amyotrophic lateral sclerosis, and sarcopenia. Except for sarcopenia, all are orphan diseases. In addition, the NMJ signal transduction is impaired by tetanus, botulinum, curare, α-bungarotoxin, conotoxins, organophosphate, sarin, VX, and soman to name a few. Areas covered: This review covers the agrin-LRP4-MuSK signaling pathway, which drives clustering of acetylcholine receptors (AChRs) and ensures efficient signal transduction at the NMJ. We also address diseases caused by autoantibodies against the NMJ molecules and by germline mutations in genes encoding the NMJ molecules. Expert opinion: Representative small compounds to treat the defective NMJ signal transduction are cholinesterase inhibitors, which exert their effects by increasing the amount of acetylcholine at the synaptic space. Another possible therapeutic strategy to enhance the NMJ signal transduction is to increase the number of AChRs, but no currently available drug has this functionality.

  9. Non-targeted glycosidic profiling of international wines using neutral loss-high resolution mass spectrometry.

    Science.gov (United States)

    Barnaba, C; Dellacassa, E; Nicolini, G; Nardin, T; Serra, M; Larcher, R

    2018-07-06

    Many metabolites naturally occur as glycosides, since sugar moieties can be crucial for their biological activity and increase their water solubility. In the plant kingdom they may occur as glycosides or sugar esters, depending on precursor chemical structure, and in wine they have traditionally attracted attention due to their organoleptic properties, such as astringency and bitterness, and because they affect the colour and aroma of wines. A new approach directed at detailed description of glycosides in a large selection of monovarietal wines (8 samples each of Pinot Blanc, Muller Thurgau, Riesling, Traminer, Merlot, Pinot Noir and Cabernet Sauvignon) was developed by combining high performance liquid chromatography with high resolution tandem mass spectrometry. Analytical separation was performed on an Accucore™ Polar Premium LC column, while mass analysis was performed in negative ion mode with an non-targeted screening approach, using a Full MS/AIF/NL dd-MS 2 experiment at a resolving power of 140,000 FWHM. Over 280 glycoside-like compounds were detected, of which 133 (including low-molecular weight phenols, flavonoids and monoterpenols) were tentatively identified in the form of pentose (6), deoxyhexose (17), hexose (73), hexose-pentose (16), hexose-deoxyhexose (7), dihexose (5) and hexose ester (9) derivatives. It was not possible to univocally define the corresponding chemical structure for the remaining 149 glycosides. Non-parametric statistical analysis showed it was possible to well characterise the glycosylated profile of all red and Traminer wines, while the identified glycosides were almost entirely lacking in Pinot Blanc, Riesling and Muller Thurgau wines. Also Tukey's Honestly Significant Difference test (p wines from each other according to their glycosylated profile. Copyright © 2018 Elsevier B.V. All rights reserved.

  10. Development of Detector Systems for Internal and Fixed Target Heavy Ion Physics Experiments

    Energy Technology Data Exchange (ETDEWEB)

    Golubev, Pavel

    2003-04-01

    This thesis deals with intermediate energy heavy ion reactions with the particular aim to study the nuclear matter equation of state which defines the relation between statistical parameters of a fermionic system. The development of equipment for two experiments, CA47 at The Svedberg Laboratory in Uppsala, Sweden and R16 at Kernfysisch Versneller Inst. (KVI), Groningen, The Netherlands, are described. CA47 contains the CHICSi detector, a modular, ultra-high vacuum (UHV) compatible, multi-detector system, covering a solid angle of 3pi sr around the collision point. Together with two auxiliary detector systems CHICSi is placed at the cluster-jet target chamber of the CELSIUS storage ring. This thesis gives a technical overview of the detector and the development carried out in order to achieve the desired detection performance. Some laboratory and in-beam tests are described and the analysis of the first experimental results is discussed. The nuclear intensity interferometry experiment (R16) was performed in a dedicated beam-line of the AGOR superconducting cyclotron. Small-angle two-particle correlations were measured for the E/A = 61 MeV {sup 36}Ar + {sup 27}Al, {sup 112}Sn, {sup 124}Sn reactions, together with singles spectra. The experimental energy distributions of neutrons and light charged particles for the {sup 36}Ar + {sup 27}Al reaction have been analyzed with a Maxwellian multi-source prescription. These results, together with correlation function data, are used to extract information on the size of the emitting sources and their time evolution.

  11. International comparison of the factors influencing reimbursement of targeted anti-cancer drugs.

    Science.gov (United States)

    Lim, Carol Sunghye; Lee, Yun-Gyoo; Koh, Youngil; Heo, Dae Seog

    2014-11-29

    Reimbursement policies for anti-cancer drugs vary among countries even though they rely on the same clinical evidence. We compared the pattern of publicly funded drug programs and analyzed major factors influencing the differences. We investigated reimbursement policies for 19 indications with targeted anti-cancer drugs that are used variably across ten countries. The available incremental cost-effectiveness ratio (ICER) data were retrieved for each indication. Based on the comparison between actual reimbursement decisions and the ICERs, we formulated a reimbursement adequacy index (RAI): calculating the proportion of cost-effective decisions, either reimbursement of cost-effective indications or non-reimbursement of cost-ineffective indications, out of the total number of indications for each country. The relationship between RAI and other indices were analyzed, including governmental dependency on health technology assessment, as well as other parameters for health expenditure. All the data used in this study were gathered from sources publicly available online. Japan and France were the most likely to reimburse indications (16/19), whereas Sweden and the United Kingdom were the least likely to reimburse them (5/19 and 6/19, respectively). Indications with high cost-effectiveness values were more likely to be reimbursed (ρ = -0.68, P = 0.001). The three countries with high RAI scores each had a healthcare system that was financed by general taxation. Although reimbursement policies for anti-cancer drugs vary among countries, we found a strong correlation of reimbursements for those indications with lower ICERs. Countries with healthcare systems financed by general taxation demonstrated greater cost-effectiveness as evidenced by reimbursement decisions of anti-cancer drugs.

  12. Toxicity assessment of molecularly targeted drugs incorporated into multiagent chemotherapy regimens for pediatric Acute Lymphocytic Leukemia (ALL): Review from an International Consensus Conference

    NARCIS (Netherlands)

    T.M. Horton (Terzah); R. Sposto (Richard); P. Brown (Patrick); C.P. Reynolds (Patrick); S.P. Hunger (Stephen); N.J. Winick (Naomi); E.A. Raetz (Elizabeth); W.L. Carroll (William); R.J. Arceci (Robert); M.J. Borowitz (Michael); P.S. Gaynon (Paul); L. Gore (Lia); S. Jeha (Sima); B.J. Maurer (Barry); S.E. Siegel (Stuart); A. Biondi (Andrea); P. Kearns (Pamela); A. Narendran (Aru); L.B. Silverman (Lewis); M.A. Smith (Malcolm); C.M. Zwaan (Christian Michel); J.A. Whitlock (James)

    2010-01-01

    textabstractOne of the challenges of incorporating molecularly targeted drugs into multi-agent chemotherapy (backbone) regimens is defining dose-limiting toxicities (DLTs) of the targeted agent against the background of toxicities of the backbone regimen. An international panel of 22 pediatric acute

  13. Does internal climate variability overwhelm climate change signals in streamflow? The upper Po and Rhone basin case studies.

    Science.gov (United States)

    Fatichi, S; Rimkus, S; Burlando, P; Bordoy, R

    2014-09-15

    Projections of climate change effects in streamflow are increasingly required to plan water management strategies. These projections are however largely uncertain due to the spread among climate model realizations, internal climate variability, and difficulties in transferring climate model results at the spatial and temporal scales required by catchment hydrology. A combination of a stochastic downscaling methodology and distributed hydrological modeling was used in the ACQWA project to provide projections of future streamflow (up to year 2050) for the upper Po and Rhone basins, respectively located in northern Italy and south-western Switzerland. Results suggest that internal (stochastic) climate variability is a fundamental source of uncertainty, typically comparable or larger than the projected climate change signal. Therefore, climate change effects in streamflow mean, frequency, and seasonality can be masked by natural climatic fluctuations in large parts of the analyzed regions. An exception to the overwhelming role of stochastic variability is represented by high elevation catchments fed by glaciers where streamflow is expected to be considerably reduced due to glacier retreat, with consequences appreciable in the main downstream rivers in August and September. Simulations also identify regions (west upper Rhone and Toce, Ticino river basins) where a strong precipitation increase in the February to April period projects streamflow beyond the range of natural climate variability during the melting season. This study emphasizes the importance of including internal climate variability in climate change analyses, especially when compared to the limited uncertainty that would be accounted for by few deterministic projections. The presented results could be useful in guiding more specific impact studies, although design or management decisions should be better based on reliability and vulnerability criteria as suggested by recent literature. Copyright © 2013

  14. Evasion of anti-growth signaling: a key step in tumorigenesis and potential target for treatment and prophylaxis by natural compounds

    Science.gov (United States)

    Amin, A.R.M. Ruhul; Karpowicz, Phillip A.; Carey, Thomas E.; Arbiser, Jack; Nahta, Rita; Chen, Zhuo G.; Dong, Jin-Tang; Kucuk, Omer; Khan, Gazala N.; Huang, Gloria S.; Mi, Shijun; Lee, Ho-Young; Reichrath, Joerg; Honoki, Kanya; Georgakilas, Alexandros G.; Amedei, Amedeo; Amin, Amr; Helferich, Bill; Boosani, Chandra S.; Ciriolo, Maria Rosa; Chen, Sophie; Mohammed, Sulma I.; Azmi, Asfar S.; Keith, W Nicol; Bhakta, Dipita; Halicka, Dorota; Niccolai, Elena; Fujii, Hiromasa; Aquilano, Katia; Ashraf, S. Salman; Nowsheen, Somaira; Yang, Xujuan; Bilsland, Alan; Shin, Dong M.

    2015-01-01

    The evasion of anti-growth signaling is an important characteristic of cancer cells. In order to continue to proliferate, cancer cells must somehow uncouple themselves from the many signals that exist to slow down cell growth. Here, we define the anti-growth signaling process, and review several important pathways involved in growth signaling: p53, phosphatase and tensin homolog (PTEN), retinoblastoma protein (Rb), Hippo, growth differentiation factor 15 (GDF15), AT-rich interactive domain 1A (ARID1A), Notch, insulin-like growth factor (IGF), and Krüppel-like factor 5 (KLF5) pathways. Aberrations in these processes in cancer cells involve mutations and thus the suppression of genes that prevent growth, as well as mutation and activation of genes involved in driving cell growth. Using these pathways as examples, we prioritize molecular targets that might be leveraged to promote anti-growth signaling in cancer cells. Interestingly, naturally-occurring phytochemicals found in human diets (either singly or as mixtures) may promote anti-growth signaling, and do so without the potentially adverse effects associated with synthetic chemicals. We review examples of naturally-occurring phytochemicals that may be applied to prevent cancer by antagonizing growth signaling, and propose one phytochemical for each pathway. These are: epigallocatechin-3-gallate (EGCG) for the Rb pathway, luteolin for p53, curcumin for PTEN, porphyrins for Hippo, genistein for GDF15, resveratrol for ARID1A, withaferin A for Notch and diguelin for the IGF1-receptor pathway. The coordination of anti-growth signaling and natural compound studies will provide insight into the future application of these compounds in the clinical setting. PMID:25749195

  15. Direct Targeting of β-Catenin by a Small Molecule Stimulates Proteasomal Degradation and Suppresses Oncogenic Wnt/β-Catenin Signaling

    Directory of Open Access Journals (Sweden)

    So-Young Hwang

    2016-06-01

    Full Text Available The Wnt/β-catenin signaling pathway plays a major role in tissue homeostasis, and its dysregulation can lead to various human diseases. Aberrant activation of β-catenin is oncogenic and is a critical driver in the development and progression of human cancers. Despite the significant potential of targeting the oncogenic β-catenin pathway for cancer therapy, the development of specific inhibitors remains insufficient. Using a T cell factor (TCF-dependent luciferase-reporter system, we screened for small-molecule compounds that act against Wnt/β-catenin signaling and identified MSAB (methyl 3-{[(4-methylphenylsulfonyl]amino}benzoate as a selective inhibitor of Wnt/β-catenin signaling. MSAB shows potent anti-tumor effects selectively on Wnt-dependent cancer cells in vitro and in mouse cancer models. MSAB binds to β-catenin, promoting its degradation, and specifically downregulates Wnt/β-catenin target genes. Our findings might represent an effective therapeutic strategy for cancers addicted to the Wnt/β-catenin signaling pathway.

  16. Brassinosteriod Insensitive 2 (BIN2) acts as a downstream effector of the Target of Rapamycin (TOR) signaling pathway to regulate photoautotrophic growth in Arabidopsis.

    Science.gov (United States)

    Xiong, Fangjie; Zhang, Rui; Meng, Zhigang; Deng, Kexuan; Que, Yumei; Zhuo, Fengping; Feng, Li; Guo, Sundui; Datla, Raju; Ren, Maozhi

    2017-01-01

    The components of the target of rapamycin (TOR) signaling pathway have been well characterized in heterotrophic organisms from yeast to humans. However, because of rapamycin insensitivity, embryonic lethality in tor null mutants and a lack of reliable ways of detecting TOR protein kinase in higher plants, the key players upstream and downstream of TOR remain largely unknown in plants. Using engineered rapamycin-sensitive Binding Protein 12-2 (BP12-2) plants, the present study showed that combined treatment with rapamycin and active-site TOR inhibitors (asTORis) results in synergistic inhibition of TOR activity and plant growth in Arabidopsis. Based on this system, we revealed that TOR signaling plays a crucial role in modulating the transition from heterotrophic to photoautotrophic growth in Arabidopsis. Ribosomal protein S6 kinase 2 (S6K2) was identified as a direct downstream target of TOR, and the growth of TOR-suppressed plants could be rescued by up-regulating S6K2. Systems, genetic, and biochemical analyses revealed that Brassinosteriod Insensitive 2 (BIN2) acts as a novel downstream effector of S6K2, and the phosphorylation of BIN2 depends on TOR-S6K2 signaling in Arabidopsis. By combining pharmacological with genetic and biochemical approaches, we determined that the TOR-S6K2-BIN2 signaling pathway plays important roles in regulating the photoautotrophic growth of Arabidopsis. © 2016 The Authors. New Phytologist © 2016 New Phytologist Trust.

  17. Do All Lives Have the Same Value? Support for International Military Interventions as a Function of Political System and Public Opinion of Target States

    NARCIS (Netherlands)

    Falomir-Pichastor, J.M.; Pereira, A.; Staerklé, C.; Butera, F.

    2012-01-01

    This research examined the support for international military interventions as a function of the political system and the public opinion of the target country. In two experiments, we informed participants about a possible military intervention by the international community towards a sovereign

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

    Science.gov (United States)

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

    2014-01-01

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

  19. Should internal mammary lymph nodes in breast cancer be a target for the radiation oncologist?

    International Nuclear Information System (INIS)

    Freedman, Gary M.; Fowble, Barbara L.; Nicolaou, Nicos; Sigurdson, Elin R.; Torosian, Michael H.; Boraas, Marcia C.; Hoffman, John P.

    2000-01-01

    Purpose: The elective treatment of internal mammary lymph nodes (IMNs) in breast cancer is controversial. Previous randomized trials have not shown a benefit to the extended radical mastectomy or elective IMN irradiation overall, but a survival benefit has been suggested by some for subgroups of patients with medial tumors and positive axillary lymph nodes. The advent of effective systemic chemotherapy and potential for serious cardiac morbidity have also been factors leading to the decreased use of IMN irradiation during the past decade. The recent publishing of positive trials testing postmastectomy radiation that had included regional IMN irradiation has renewed interest in their elective treatment. The purpose of this study is to critically review historical and new data regarding IMNs in breast cancer. Methods and Materials: The historical incidence of occult IMN positivity in operable breast cancer is reviewed, and the new information provided by sentinel lymph node studies also discussed. The results of published randomized prospective trials testing the value of elective IMN dissection and/or radiation are analyzed. The data regarding patterns of failure following elective IMN treatment is studied to determine its impact on local-regional control, distant metastases, and survival. A conclusion is drawn regarding the merits of elective IMN treatment based on this review of the literature. Results: Although controversial, the existing data from prospective, randomized trials of IMN treatment do not seem to support their elective dissection or irradiation. While it has not been shown to contribute to a survival benefit, the IMN irradiation increases the risk of cardiac toxicity that has effaced the value of radiation of the chest wall in reducing breast cancer deaths in previous randomized studies and meta-analyses. Sentinel lymph node mapping provides an opportunity to further evaluate the IMN chain in early stage breast cancer. Biopsy of 'hot' nodes may be

  20. Ovatodiolide Targets β-Catenin Signaling in Suppressing Tumorigenesis and Overcoming Drug Resistance in Renal Cell Carcinoma

    Directory of Open Access Journals (Sweden)

    Jar-Yi Ho

    2013-01-01

    Full Text Available Dysregulated β-catenin signaling is intricately involved in renal cell carcinoma (RCC carcinogenesis and progression. Determining potential β-catenin signaling inhibitors would be helpful in ameliorating drug resistance in advanced or metastatic RCC. Screening for β-catenin signaling inhibitors involved in silico inquiry of the PubChem Bioactivity database followed by TCF/LEF reporter assay. The biological effects of ovatodiolide were evaluated in 4 RCC cell lines in vitro and 2 RCC cell lines in a mouse xenograft model. The synergistic effects of ovatodiolide and sorafenib or sunitinib were examined in 2 TKI-resistant RCC cell lines. Ovatodiolide, a pure compound of Anisomeles indica, inhibited β-catenin signaling and reduced RCC cell viability, survival, migration/invasion, and in vitro cell or in vivo mouse tumorigenicity. Cytotoxicity was significantly reduced in a normal kidney epithelial cell line with the treatment. Ovatodiolide reduced phosphorylated β-catenin (S552 that inhibited β-catenin nuclear translocation. Moreover, ovatodiolide decreased β-catenin stability and impaired the association of β-catenin and transcription factor 4. Ovatodiolide combined with sorafenib or sunitinib overcame drug resistance in TKI-resistant RCC cells. Ovatodiolide may be a potent β-catenin signaling inhibitor, with synergistic effects with sorafenib or sunitinib, and therefore, a useful candidate for improving RCC therapy.

  1. Cost management in the internal value chain of integrated application of activity-based costing, Kaizen concept and target costing

    Directory of Open Access Journals (Sweden)

    Pešić-Tomić Vesna

    2014-01-01

    Full Text Available The objective of this paper is an effort to view the possibilities of integrated use of target costing, activity based costing and Kaizen concept in the internal value chain as the central link of the entire chain. The idea is to stimulate the company management to think about the costs, position they take in the structure of price cost and their influence on forming the sales price since it is very important to produce right product for the consumer, of desired quality and functionality but along with as low production costs as possible. It is therefore needed to construct the right design of a product and provide its production at the shortest possible time along with as low costs as possible which will impact the efficiency of the entire value chain.

  2. Spherical cauliflower-like carbon dust formed by interaction between deuterium plasma and graphite target and its internal structure

    Energy Technology Data Exchange (ETDEWEB)

    Ohno, N. [Department of Energy Engineering and Science, Graduate School of Engineering, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8603 (Japan)], E-mail: ohno@ees.nagoya-u.ac.jp; Yoshimi, M. [Department of Energy Engineering and Science, Graduate School of Engineering, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8603 (Japan); Tokitani, M. [National Institute for Fusion Science, Oroshi 322-6, Toki 509-5292 (Japan); Takamura, S. [Department of Electronics, Aichi Institute of Technology, Yakusa-cho, Toyota 470-0392 (Japan); Tokunaga, K.; Yoshida, N. [Research Institute for Applied Mechanics, Kyushu University, Kasuga, Fukuoka 816-8580 (Japan)

    2009-06-15

    Simulated experiments to produce carbon dust particles with cauliflower structure have been performed in a liner plasma device, NAGDIS-II by exposing high density deuterium plasma to a graphite sample (IG-430U). Formation of carbon dust depends on the surface temperature and the incident ion energy. At a surface temperature 600-700 K, a lot of isolated spherical dust particles are observed on the graphite target. The internal structure of an isolated dust particle was observed with Focused Ion Beam (FIB) system and Transmission Electron Microscope (TEM) in detail. FIB analysis clearly shows there exist honey-combed cell structure with thin carbon walls in the dust particle and the dust particle grows from the graphite surface. TEM image also shows that the dust particle is made of amorphous carbon with crystallized grains with diameters of 10-50 nm.

  3. Green tea polyphenol, (−)-epigallocatechin-3-gallate, induces toxicity in human skin cancer cells by targeting β-catenin signaling

    Energy Technology Data Exchange (ETDEWEB)

    Singh, Tripti [Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL 35294 (United States); Katiyar, Santosh K., E-mail: skatiyar@uab.edu [Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL 35294 (United States); Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35294 (United States); Birmingham Veterans Affairs Medical Center, Birmingham, AL 35233 (United States)

    2013-12-01

    The green tea polyphenol, (−)-epigallocatechin-3-gallate (EGCG), has been shown to have anti-carcinogenic effects in several skin tumor models, and efforts are continued to investigate the molecular targets responsible for its cytotoxic effects to cancer cells. Our recent observation that β-catenin is upregulated in skin tumors suggested the possibility that the anti-skin carcinogenic effects of EGCG are mediated, at least in part, through its effects on β-catenin signaling. We have found that treatment of the A431 and SCC13 human skin cancer cell lines with EGCG resulted in reduced cell viability and increased cell death and that these cytotoxic effects were associated with inactivation of β-catenin signaling. Evidence of EGCG-induced inactivation of β-catenin included: (i) reduced accumulation of nuclear β-catenin; (ii) enhanced levels of casein kinase1α, reduced phosphorylation of glycogen synthase kinase-3β, and increased phosphorylation of β-catenin on critical serine{sup 45,33/37} residues; and (iii) reduced levels of matrix metalloproteinase (MMP)-2 and MMP-9, which are down-stream targets of β-catenin. Treatment of cells with prostaglandin E2 (PGE{sub 2}) enhanced the accumulation of β-catenin and enhanced β-catenin signaling. Treatment with either EGCG or an EP2 antagonist (AH6809) reduced the PGE{sub 2}-enhanced levels of cAMP, an upstream regulator of β-catenin. Inactivation of β-catenin by EGCG resulted in suppression of cell survival signaling proteins. siRNA knockdown of β-catenin in A431 and SCC13 cells reduced cell viability. Collectively, these data suggest that induction of cytotoxicity in skin cancer cells by EGCG is mediated by targeting of β-catenin signaling and that the β-catenin signaling is upregulated by inflammatory mediators. - Highlights: • EGCG inhibits cancer cell viability through inactivation of β-catenin signaling. • Inactivation of β-catenin involves the downregulation of inflammatory mediators. • EGCG

  4. 10-Hydroxy-2-decenoic Acid, the Major Lipid Component of Royal Jelly, Extends the Lifespan of Caenorhabditis elegans through Dietary Restriction and Target of Rapamycin Signaling

    Directory of Open Access Journals (Sweden)

    Yoko Honda

    2015-01-01

    Full Text Available Royal jelly (RJ produced by honeybees has been reported to possess diverse health-beneficial properties and has been implicated to have a function in longevity across diverse species as well as honeybees. 10-Hydroxy-2-decenoic acid (10-HDA, the major lipid component of RJ produced by honeybees, was previously shown to increase the lifespan of Caenorhabditis elegans. The objective of this study is to elucidate signaling pathways that are involved in the lifespan extension by 10-HDA. 10-HDA further extended the lifespan of the daf-2 mutants, which exhibit long lifespan through reducing insulin-like signaling (ILS, indicating that 10-HDA extended lifespan independently of ILS. On the other hand, 10-HDA did not extend the lifespan of the eat-2 mutants, which show long lifespan through dietary restriction caused by a food-intake defect. This finding indicates that 10-HDA extends lifespan through dietary restriction signaling. We further found that 10-HDA did not extend the lifespan of the long-lived mutants in daf-15, which encodes Raptor, a target of rapamycin (TOR components, indicating that 10-HDA shared some longevity control mechanisms with TOR signaling. Additionally, 10-HDA was found to confer tolerance against thermal and oxidative stress. 10-HDA increases longevity not through ILS but through dietary restriction and TOR signaling in C. elegans.

  5. Analysis of Maneuvering Targets with Complex Motions by Two-Dimensional Product Modified Lv’s Distribution for Quadratic Frequency Modulation Signals

    Directory of Open Access Journals (Sweden)

    Fulong Jing

    2017-06-01

    Full Text Available For targets with complex motion, such as ships fluctuating with oceanic waves and high maneuvering airplanes, azimuth echo signals can be modeled as multicomponent quadratic frequency modulation (QFM signals after migration compensation and phase adjustment. For the QFM signal model, the chirp rate (CR and the quadratic chirp rate (QCR are two important physical quantities, which need to be estimated. For multicomponent QFM signals, the cross terms create a challenge for detection, which needs to be addressed. In this paper, by employing a novel multi-scale parametric symmetric self-correlation function (PSSF and modified scaled Fourier transform (mSFT, an effective parameter estimation algorithm is proposed—referred to as the Two-Dimensional product modified Lv’s distribution (2D-PMLVD—for QFM signals. The 2D-PMLVD is simple and can be easily implemented by using fast Fourier transform (FFT and complex multiplication. These measures are analyzed in the paper, including the principle, the cross term, anti-noise performance, and computational complexity. Compared to the other three representative methods, the 2D-PMLVD can achieve better anti-noise performance. The 2D-PMLVD, which is free of searching and has no identifiability problems, is more suitable for multicomponent situations. Through several simulations and analyses, the effectiveness of the proposed estimation algorithm is verified.

  6. 10-Hydroxy-2-decenoic Acid, the Major Lipid Component of Royal Jelly, Extends the Lifespan of Caenorhabditis elegans through Dietary Restriction and Target of Rapamycin Signaling.

    Science.gov (United States)

    Honda, Yoko; Araki, Yoko; Hata, Taketoshi; Ichihara, Kenji; Ito, Masafumi; Tanaka, Masashi; Honda, Shuji

    2015-01-01

    Royal jelly (RJ) produced by honeybees has been reported to possess diverse health-beneficial properties and has been implicated to have a function in longevity across diverse species as well as honeybees. 10-Hydroxy-2-decenoic acid (10-HDA), the major lipid component of RJ produced by honeybees, was previously shown to increase the lifespan of Caenorhabditis elegans. The objective of this study is to elucidate signaling pathways that are involved in the lifespan extension by 10-HDA. 10-HDA further extended the lifespan of the daf-2 mutants, which exhibit long lifespan through reducing insulin-like signaling (ILS), indicating that 10-HDA extended lifespan independently of ILS. On the other hand, 10-HDA did not extend the lifespan of the eat-2 mutants, which show long lifespan through dietary restriction caused by a food-intake defect. This finding indicates that 10-HDA extends lifespan through dietary restriction signaling. We further found that 10-HDA did not extend the lifespan of the long-lived mutants in daf-15, which encodes Raptor, a target of rapamycin (TOR) components, indicating that 10-HDA shared some longevity control mechanisms with TOR signaling. Additionally, 10-HDA was found to confer tolerance against thermal and oxidative stress. 10-HDA increases longevity not through ILS but through dietary restriction and TOR signaling in C. elegans.

  7. Targeting the PDGF-B/PDGFR-β Interface with Destruxin A5 to Selectively Block PDGF-BB/PDGFR-ββ Signaling and Attenuate Liver Fibrosis

    Directory of Open Access Journals (Sweden)

    Xingqi Wang

    2016-05-01

    Full Text Available PDGF-BB/PDGFR-ββ signaling plays very crucial roles in the process of many diseases such as liver fibrosis. However, drug candidates with selective a