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Sample records for naturally occurring her2

  1. In vivo tracking of genetically engineered, anti-HER2/neu directed natural killer cells to HER2/neu positive mammary tumors with magnetic resonance imaging

    International Nuclear Information System (INIS)

    Daldrup-Link, Heike E.; Meier, Reinhardt; Metz, Stephan; Settles, Marcus; Rummeny, Ernst J.; Rudelius, Martina; Piontek, Guido; Schlegel, Juergen; Piert, Morand; Uherek, Christoph; Wels, Winfried

    2005-01-01

    The purpose of this study is to optimize labeling of the human natural killer (NK) cell line NK-92 with iron-oxide-based contrast agents and to monitor the in vivo distribution of genetically engineered NK-92 cells, which are directed against HER2/neu receptors, to HER2/neu positive mammary tumors with magnetic resonance (MR) imaging. Parental NK-92 cells and genetically modified HER2/neu specific NK-92-scFv(FRP5)-zeta cells, expressing a chimeric antigen receptor specific to the tumor-associated ErbB2 (HER2/neu) antigen, were labeled with ferumoxides and ferucarbotran using simple incubation, lipofection and electroporation techniques. Labeling efficiency was evaluated by MR imaging, Prussian blue stains and spectrometry. Subsequently, ferucarbotran-labeled NK-92-scFv(FRP5)-zeta (n=3) or parental NK-92 cells were intravenously injected into the tail vein of six mice with HER2/neu-positive NIH 3T3 mammary tumors, implanted in the mammary fat pad. The accumulation of the cells in the tumors was monitored by MR imaging before and 12 and 24 h after cell injection (p.i.). MR data were correlated with histopathology. Both the parental NK-92 and the genetically modified NK-92-scFv(FRP5)-zeta cells could be labeled with ferucarbotran and ferumoxides by lipofection and electroporation, but not by simple incubation. The intracellular cytoplasmatic iron-oxide uptake was significantly higher after labeling with ferucarbotran than ferumoxides (P 6 NK-92-scFv(FRP5)-zeta cells into tumor-bearing mice, MR showed a progressive signal decline in HER2/neu-positive mammary tumors at 12 and 24 h (p.i.). Conversely, injection of 5 x 10 6 parental NK-92 control cells, not directed against HER2/neu receptors, did not cause significant signal intensity changes of the tumors. Histopathology confirmed an accumulation of the former, but not the latter cells in tumor tissue. The human natural killer cell line NK-92 can be efficiently labeled with clinically applicable iron-oxide contrast

  2. In vivo tracking of genetically engineered, anti-HER2/neu directed natural killer cells to HER2/neu positive mammary tumors with magnetic resonance imaging

    Energy Technology Data Exchange (ETDEWEB)

    Daldrup-Link, Heike E. [UCSF Medical Center, Department of Radiology, San Francisco, CA (United States); Meier, Reinhardt; Metz, Stephan; Settles, Marcus; Rummeny, Ernst J. [Technical University Munich, Department of Radiology, Munich (Germany); Rudelius, Martina; Piontek, Guido; Schlegel, Juergen [Technical University Munich, Institute of Pathology, Division of Neuropathology, Munich (Germany); Piert, Morand [Technical University Munich, Department of Nuclear Medicine, Munich (Germany); Uherek, Christoph; Wels, Winfried [University of Frankfurt, Georg Speyer House, Frankfurt (Germany)

    2005-01-01

    The purpose of this study is to optimize labeling of the human natural killer (NK) cell line NK-92 with iron-oxide-based contrast agents and to monitor the in vivo distribution of genetically engineered NK-92 cells, which are directed against HER2/neu receptors, to HER2/neu positive mammary tumors with magnetic resonance (MR) imaging. Parental NK-92 cells and genetically modified HER2/neu specific NK-92-scFv(FRP5)-zeta cells, expressing a chimeric antigen receptor specific to the tumor-associated ErbB2 (HER2/neu) antigen, were labeled with ferumoxides and ferucarbotran using simple incubation, lipofection and electroporation techniques. Labeling efficiency was evaluated by MR imaging, Prussian blue stains and spectrometry. Subsequently, ferucarbotran-labeled NK-92-scFv(FRP5)-zeta (n=3) or parental NK-92 cells were intravenously injected into the tail vein of six mice with HER2/neu-positive NIH 3T3 mammary tumors, implanted in the mammary fat pad. The accumulation of the cells in the tumors was monitored by MR imaging before and 12 and 24 h after cell injection (p.i.). MR data were correlated with histopathology. Both the parental NK-92 and the genetically modified NK-92-scFv(FRP5)-zeta cells could be labeled with ferucarbotran and ferumoxides by lipofection and electroporation, but not by simple incubation. The intracellular cytoplasmatic iron-oxide uptake was significantly higher after labeling with ferucarbotran than ferumoxides (P<0.05). After intravenous injection of 5 x 10{sup 6} NK-92-scFv(FRP5)-zeta cells into tumor-bearing mice, MR showed a progressive signal decline in HER2/neu-positive mammary tumors at 12 and 24 h (p.i.). Conversely, injection of 5 x 10{sup 6} parental NK-92 control cells, not directed against HER2/neu receptors, did not cause significant signal intensity changes of the tumors. Histopathology confirmed an accumulation of the former, but not the latter cells in tumor tissue. The human natural killer cell line NK-92 can be efficiently

  3. Interplay between Natural Killer Cells and Anti-HER2 Antibodies: Perspectives for Breast Cancer Immunotherapy

    Directory of Open Access Journals (Sweden)

    Aura Muntasell

    2017-11-01

    Full Text Available Overexpression of the human epidermal growth factor receptor 2 (HER2 defines a subgroup of breast tumors with aggressive behavior. The addition of HER2-targeted antibodies (i.e., trastuzumab, pertuzumab to chemotherapy significantly improves relapse-free and overall survival in patients with early-stage and advanced disease. Nonetheless, considerable proportions of patients develop resistance to treatment, highlighting the need for additional and co-adjuvant therapeutic strategies. HER2-specific antibodies can trigger natural killer (NK cell-mediated antibody-dependent cellular cytotoxicity and indirectly enhance the development of tumor-specific T cell immunity; both mechanisms contributing to their antitumor efficacy in preclinical models. Antibody-dependent NK cell activation results in the release of cytotoxic granules as well as the secretion of pro-inflammatory cytokines (i.e., IFNγ and TNFα and chemokines. Hence, NK cell tumor suppressive functions include direct cytolytic killing of tumor cells as well as the regulation of subsequent antitumor adaptive immunity. Albeit tumors with gene expression signatures associated to the presence of cytotoxic lymphocyte infiltrates benefit from trastuzumab-based treatment, NK cell-related biomarkers of response/resistance to HER2-specific therapeutic antibodies in breast cancer patients remain elusive. Several variables, including (i the configuration of the patient NK cell repertoire; (ii tumor molecular features (i.e., estrogen receptor expression; (iii concomitant therapeutic regimens (i.e., chemotherapeutic agents, tyrosine kinase inhibitors; and (iv evasion mechanisms developed by progressive breast tumors, have been shown to quantitatively and qualitatively influence antibody-triggered NK cell responses. In this review, we discuss possible interventions for restoring/enhancing the therapeutic activity of HER2 therapeutic antibodies by harnessing NK cell antitumor potential through

  4. Asymptomatic Changes in Cardiac Function Can Occur in DCIS Patients Following Treatment with HER-2/neu Pulsed Dendritic Cell Vaccines

    Science.gov (United States)

    Bahl, Susan; Roses, Robert; Sharma, Anupama; Koldovsky, Ursula; Xu, Shuwen; Weinstein, Susan; Nisenbaum, Harvey; Fox, Kevin; Pasha, Theresa; Zhang, Paul; Araujo, Louis; Carver, Joseph; Czerniecki, Brian J

    2009-01-01

    Background Targeting HER-2/neu with Trastuzumab has been associated with development of cardiac toxicity. Methods Twenty-seven patients with ductal carcinoma in situ (DCIS) of the breast completed an IRB approved clinical trial of a HER-2/neu targeted dendritic cell based vaccine. Four weekly vaccinations were administered prior to surgical resection. All subjects underwent pre- and post-vaccine cardiac monitoring by MUGA/ECHO scanning allowing for a comparison of cardiac function. Results In 3 of 27 vaccinated patients (11%) transient asymptomatic decrements in ejection fraction of greater than 15% were noted after vaccination. Notably, evidence of circulating anti-HER-2/neu antibody was found prior to vaccination in all three patients, but cardiac toxicity was not noted until induction of cellular mediated immune responses. Conclusions This is the first description of HER-2/neu targeted vaccination associated with an incidence of cardiac changes, and the induction of cellular immune responses combined with antibody may contribute to changes in cardiac function. PMID:19800453

  5. Tracking of [{sup 18}F]FDG-labeled natural killer cells to HER2/neu-positive tumors

    Energy Technology Data Exchange (ETDEWEB)

    Meier, Reinhard [Department of Radiology, University of California San Francisco (United States)], E-mail: reinhardt.meier@gmail.com; Piert, Morand [Department of Radiology, Division of Nuclear Medicine, University of Michigan (United States); Piontek, Guido; Rudelius, Martina [Institute of Pathology, Klinikum rechts der Isar, Technische Universitaet Muenchen (Germany); Oostendorp, Robert A. [3rd Department of Internal Medicine, Klinikum rechts der Isar, Technische Universitaet Muenchen (Germany); Senekowitsch-Schmidtke, Reingard [Department of Nuclear Medicine, Klinikum rechts der Isar, Technische Universitaet Muenchen (Germany); Henning, Tobias D. [Department of Radiology, University of California San Francisco (United States); Wels, Winfried S.; Uherek, Christoph [Chemotherapeutisches Forschungsinstitut, Georg-Speyer-Haus, Frankfurt am Main (Germany); Rummeny, Ernst J. [Department of Radiology, Klinikum rechts der Isar, Technische Universitaet Muenchen (Germany); Daldrup-Link, Heike E. [Department of Radiology, University of California San Francisco (United States)

    2008-07-15

    Introduction: The objective of this study was to label the human natural killer (NK) cell line NK-92 with [{sup 18}F]fluoro-deoxy-glucose (FDG) for subsequent in vivo tracking to HER2/neu-positive tumors. Methods: NK-92 cells were genetically modified to NK-92-scFv(FRP5)-zeta cells, which express a chimeric antigen receptor that is specific to the tumor-associated ErbB2 (HER2/neu) antigen. NK-92 and NK-92-scFv(FRP5)-zeta cells were labeled with [{sup 18}F]FDG by simple incubation at different settings. Labeling efficiency was evaluated by a gamma counter. Subsequently, [{sup 18}F]FDG-labeled parental NK-92 or NK-92-scFv(FRP5)-zeta cells were intravenously injected into mice with implanted HER2/neu-positive NIH/3T3 tumors. Radioactivity in tumors was quantified by digital autoradiography and correlated with histopathology. Results: The NK-92 and NK-92-scFv(FRP5)-zeta cells could be efficiently labeled with [{sup 18}F]FDG by simple incubation. Optimal labeling efficiencies (80%) were achieved using an incubation period of 60 min and additional insulin (10 IU/ml). After injection of 5x10{sup 6} [{sup 18}F]FDG-labeled NK-92-scFv(FRP5)-zeta cells into tumor-bearing mice, digital autoradiography showed an increased uptake of radioactivity in HER2/neu-positive tumors at 60 min postinjection. Conversely, injection of 5x10{sup 6} NK-92 cells not directed against HER2/neu receptors did not result in increased uptake of radioactivity in the tumors. Histopathology confirmed an accumulation of the NK-92-scFv(FRP5)-zeta cells, but not the parental NK cells, in tumor tissues. Conclusion: The human NK cell line NK-92 can be directed against HER2/neu antigens by genetic modification. The genetically modified NK cells can be efficiently labeled with [{sup 18}F]FDG, and the accumulation of these labeled NK cells in HER2/neu-positive tumors can be monitored with autoradiography.

  6. Tracking of [18F]FDG-labeled natural killer cells to HER2/neu-positive tumors

    International Nuclear Information System (INIS)

    Meier, Reinhard; Piert, Morand; Piontek, Guido; Rudelius, Martina; Oostendorp, Robert A.; Senekowitsch-Schmidtke, Reingard; Henning, Tobias D.; Wels, Winfried S.; Uherek, Christoph; Rummeny, Ernst J.; Daldrup-Link, Heike E.

    2008-01-01

    Introduction: The objective of this study was to label the human natural killer (NK) cell line NK-92 with [ 18 F]fluoro-deoxy-glucose (FDG) for subsequent in vivo tracking to HER2/neu-positive tumors. Methods: NK-92 cells were genetically modified to NK-92-scFv(FRP5)-zeta cells, which express a chimeric antigen receptor that is specific to the tumor-associated ErbB2 (HER2/neu) antigen. NK-92 and NK-92-scFv(FRP5)-zeta cells were labeled with [ 18 F]FDG by simple incubation at different settings. Labeling efficiency was evaluated by a gamma counter. Subsequently, [ 18 F]FDG-labeled parental NK-92 or NK-92-scFv(FRP5)-zeta cells were intravenously injected into mice with implanted HER2/neu-positive NIH/3T3 tumors. Radioactivity in tumors was quantified by digital autoradiography and correlated with histopathology. Results: The NK-92 and NK-92-scFv(FRP5)-zeta cells could be efficiently labeled with [ 18 F]FDG by simple incubation. Optimal labeling efficiencies (80%) were achieved using an incubation period of 60 min and additional insulin (10 IU/ml). After injection of 5x10 6 [ 18 F]FDG-labeled NK-92-scFv(FRP5)-zeta cells into tumor-bearing mice, digital autoradiography showed an increased uptake of radioactivity in HER2/neu-positive tumors at 60 min postinjection. Conversely, injection of 5x10 6 NK-92 cells not directed against HER2/neu receptors did not result in increased uptake of radioactivity in the tumors. Histopathology confirmed an accumulation of the NK-92-scFv(FRP5)-zeta cells, but not the parental NK cells, in tumor tissues. Conclusion: The human NK cell line NK-92 can be directed against HER2/neu antigens by genetic modification. The genetically modified NK cells can be efficiently labeled with [ 18 F]FDG, and the accumulation of these labeled NK cells in HER2/neu-positive tumors can be monitored with autoradiography

  7. Naturally Occurring Radioactive Materials (NORM)

    International Nuclear Information System (INIS)

    Gray, P.

    1997-01-01

    This paper discusses the broad problems presented by Naturally Occuring Radioactive Materials (NORM). Technologically Enhanced naturally occuring radioactive material includes any radionuclides whose physical, chemical, radiological properties or radionuclide concentration have been altered from their natural state. With regard to NORM in particular, radioactive contamination is radioactive material in an undesired location. This is a concern in a range of industries: petroleum; uranium mining; phosphorus and phosphates; fertilizers; fossil fuels; forestry products; water treatment; metal mining and processing; geothermal energy. The author discusses in more detail the problem in the petroleum industry, including the isotopes of concern, the hazards they present, the contamination which they cause, ways to dispose of contaminated materials, and regulatory issues. He points out there are three key programs to reduce legal exposure and problems due to these contaminants: waste minimization; NORM assesment (surveys); NORM compliance (training)

  8. Naturally Occurring Radioactive Materials (NORM)

    Energy Technology Data Exchange (ETDEWEB)

    Gray, P. [ed.

    1997-02-01

    This paper discusses the broad problems presented by Naturally Occuring Radioactive Materials (NORM). Technologically Enhanced naturally occuring radioactive material includes any radionuclides whose physical, chemical, radiological properties or radionuclide concentration have been altered from their natural state. With regard to NORM in particular, radioactive contamination is radioactive material in an undesired location. This is a concern in a range of industries: petroleum; uranium mining; phosphorus and phosphates; fertilizers; fossil fuels; forestry products; water treatment; metal mining and processing; geothermal energy. The author discusses in more detail the problem in the petroleum industry, including the isotopes of concern, the hazards they present, the contamination which they cause, ways to dispose of contaminated materials, and regulatory issues. He points out there are three key programs to reduce legal exposure and problems due to these contaminants: waste minimization; NORM assesment (surveys); NORM compliance (training).

  9. Naturally occurring radionuclides in food

    International Nuclear Information System (INIS)

    Djujic, I.

    1995-01-01

    The naturally occurring radionuclides are the major source of radiation exposure to humans. The principal way of natural radiation exposure is the inhalation of 222 Rn decay products (about 85% of the total). The remainder is equally divided between internally deposited radionuclides, cosmic and terrestrial sources. In the present study, the content of 40 K, 210 Pb, 226 Ra, 230 Th, 232 Th and 238 U in representative food samples (milk, pork, beef, potatoes, wheat and corn flour) and samples of different food items that do not represent entire national production but provide interesting additional data for approximative calculation of naturally occurring radionuclide intake is presented. Daily weight of food eaten, participation of food groups, as well as daily intake by food of mentioned naturally occurring radionuclides in the Serbian diet was obtained on the base of house hold budget surveys. The result obtained for daily intake estimates in mBq for Serbian population are 78.1 ( 40 K), 38.2( 210 Pb), 52.3( 226 Ra), 2.0( 230 Th) and 12.5( 238 U). (author)

  10. Naturally-occurring alpha activity

    Energy Technology Data Exchange (ETDEWEB)

    Mayneord, W V

    1960-12-01

    In view of the difficulties of assessing the significance of man-made radioactivity it is important to study for comparison the background of natural radioactivity against which the human race has evolved and lives. It is also important to define the present levels of activity so that it will be possible to detect and study as quickly as possible any changes which may occur owing to the release into the environment of new radioactive materials. Moreover, by the study of the behaviour of natural radioactivity light may be shed upon that of the artificially produced isotopes and a number of analogies traced between the two groups. These concepts have led to studies of naturally-occurring radioactive materials alongside a programme of research into fission products in food, water and air, as well as studies of the metabolism of both sets of materials in the human body. Since the last report there has been a useful increase in our knowledge of natural radioactivity in the biosphere, and its levels relative to the new man-made activities. These studies have necessitated technical developments, particularly in the methods of measuring and identifying alpha-ray emitters, to which group many of the more important natural radioactive materials belong.

  11. Naturally occurring methyl salicylate glycosides.

    Science.gov (United States)

    Mao, Ping; Liu, Zizhen; Xie, Meng; Jiang, Rui; Liu, Weirui; Wang, Xiaohong; Meng, Shen; She, Gaimei

    2014-01-01

    As an important part of non steroids anti-inflammation drug (NSAIDs), salicylate has developed from natural substance salicylic acid to natrium salicylicum, to aspirin. Now, methyl salicylate glycoside, a new derivative of salicylic acid, is modified with a -COOH group integrated one methyl radical into formic ether, and a -OH linked with a monosaccharide, a disaccharide or a trisaccharide unit by glycosidic linkage. It has the similar pharmacological activities, anti-inflammatory, analgesic, antipyretic and antithrombotic as the previous salicylates' without resulting in serious side effects, particularly the gastrointestinal toxicity. Owing to the superiority of those significant bioactivities, methyl salicylate glycosides have became a hot research area in NSAIDs for several years. This paper compiles all 9 naturally occurring methyl salicylate glycosides, their distribution of the resource and pharmacological mechanism, which could contribute to the new drug discovery.

  12. Naturally occurring ω-Hydroxyacids.

    Science.gov (United States)

    Wertz, P W

    2018-02-01

    ω-Hydroxyacids are fatty acids bearing a hydroxyl group on the terminal carbon. They are found in mammals and higher plants and are often involved in providing a permeability barrier, the primary purpose of which is to reduce water loss. Some ω-hydroxyacid derivatives may be involved in waterproofing and signalling. The purpose of this review was to survey the known natural sources of ω-hydroxyacids. ω-Hydroxyacids are produced by two different P450-dependent mechanisms. The longer (30-34 carbons) ω-hydroxyacids are produced by chain extension from palmitic acid until the chain extends across the membrane in which the extension is taking place, and then the terminal carbon is hydroxylated. Shorter fatty acids can be hydroxylated directly to produce C16 and C18 ω-hydroxyacids found in plants and 20-eicosatetraenoic acid (20-HETE) by a different P450. The C16 and C18 ω-hydroxyacids are components of polymers in plants. The long-chain ω-hydroxyacids are found in epidermal sphingolipids, in giant-ring lactones from the sebum of members of the equidae, as a component of meibum and in carnauba wax and wool wax. © 2017 Society of Cosmetic Scientists and the Société Française de Cosmétologie.

  13. Drill machine guidance using natural occurring radiation

    International Nuclear Information System (INIS)

    Dahl, H.D.; Schroeder, R.L.; Williams, B.J.

    1980-01-01

    A drilling machine guidance system is described which uses only the naturally occuring radiation within the seam or stratum of interest. The apparatus can be used for guiding horizontal drilling machines through coal seams and the like. (U.K.)

  14. Natural occurring radioactive substances. Vol. 1

    Energy Technology Data Exchange (ETDEWEB)

    Emara, A E [National Center for radiation Research and Technology Atomic Energy Authority, Cairo (Egypt)

    1996-03-01

    Naturally occurring radioactive substances produced by cosmic rays of those of terrestrial origin are surveyed. The different radioactive decay series are discussed. Special emphasis is given to the element radium as regards its properties and distribution in different environmental samples. The properties of naturally occurring k-40 and its distribution in different natural media are also outlined. Induced radionuclides which are formed as a result of the interaction of cosmic rays with the constituents of the atmosphere are mentioned. In this respect the intensity of natural background radiation and the dose at different locations and levels is surveyed. Some regions of exceptionally high radioactivity which result in high exposure rates are mentioned. Monazite deposits and water springs are mentioned in some detail. The Oklo phenomenon as a natural reactor is also discussed. 8 tabs.

  15. Natural occurring radioactive substances. Vol. 1

    International Nuclear Information System (INIS)

    Emara, A.E.

    1996-01-01

    Naturally occurring radioactive substances produced by cosmic rays of those of terrestrial origin are surveyed. The different radioactive decay series are discussed. Special emphasis is given to the element radium as regards its properties and distribution in different environmental samples. The properties of naturally occurring k-40 and its distribution in different natural media are also outlined. Induced radionuclides which are formed as a result of the interaction of cosmic rays with the constituents of the atmosphere are mentioned. In this respect the intensity of natural background radiation and the dose at different locations and levels is surveyed. Some regions of exceptionally high radioactivity which result in high exposure rates are mentioned. Monazite deposits and water springs are mentioned in some detail. The Oklo phenomenon as a natural reactor is also discussed. 8 tabs

  16. Determination of natural occurring radionuclides concentrations

    International Nuclear Information System (INIS)

    Stajic, J.; Markovic, V.; Krstic, D.; Nikezic, D.

    2011-01-01

    Tobacco smoke contains certain concentrations of naturally occurring radionuclides from radioactive chains of uranium and thorium - 214 Pb, 214 Bi, 228 Ac, 208 Tl, 226 Ra, 232 Th and 40 K. Inhaling of tobacco smoke leads to internal exposure of man. In order to estimate absorbed dose of irradiation it is necessary to determine concentrations of radionuclides present in the tobacco leaves. In this paper specific activities of naturally occurring radionuclides were measured in tobacco samples from cigarettes which are used in Serbia. [sr

  17. Formal synthesis of naturally occurring norephedrine

    Indian Academy of Sciences (India)

    A concise and simple synthesis of 1-hydroxy-phenethylamine derivatives has been achieved following classical organic transformations using commercially available chiral pools. The said derivatives were explored for the synthesis of naturally occurring bio-active small molecules. Formal synthesis of norephedrine, virolin ...

  18. Percieved functions of naturally occurring autobiographical memories

    DEFF Research Database (Denmark)

    Treebak, L. S.; Henriksen, J. R.; Lundhus, S.

    2005-01-01

    The main empirical reference on functions of autobiographical memories is still Hyman & Faries (1992) who used the cue-word-method and retrospective judgements. We used diaries to sample naturally occurring autobiographical memories and participants? perceived use of these. Results partly replicate...

  19. A naturally occurring trap for antiprotons

    International Nuclear Information System (INIS)

    Eades, J.; Morita, N.; Ito, T.M.

    1993-05-01

    The phenomenon of delayed annihilation of antiprotons in helium is the first instance of a naturally occurring trap for antimatter in ordinary matter. Recent studies of this effect at CERN are summarized, and plans are described for laser excitation experiments to test its interpretation in terms of metastable exotic helium atom formation. (author)

  20. Leachability of naturally occurring radioactive materials

    International Nuclear Information System (INIS)

    Desideri, D.; Feduzi, L.; Meli, M.A.; Roselli, C.

    2006-01-01

    Naturally occurring radioactive materials (NORM) are present in the environment and can be concentrated by technical activities, particularly those involving natural resources. These NORM deposits are highly stable and very insoluble under environmental conditions at the earth's surface. However, reducing or oxidant conditions or pH changes may enable a fraction of naturally occurring radionuclides to eventually be released to the environment. Leachability of 210 Pb and 210 Po was determined in three samples coming from a refractories production plant (dust, sludge, finished product), in one dust sample from a steelwork and in one ash sample coming from an electric power station. A sequential extraction method consisting of five operationally-defined fractions was used. The average leaching potential observed in the samples from the refractory industry is very low (mean values: 5.8% for 210 Pb and 1.7% for 210 Po). The 210 Pb and 210 Po leachability increases for the ash sample coming from an electric power plant using carbon (17.8% for 210 Pb and 10.0% for 210 Po); for the dust sample coming from a steelwork, the percent soluble fraction is 41.1% for 210 Pb and 8.5% for 210 Po. For all samples the results obtained show that 210 Pb is slightly more soluble than 210 Po. (author)

  1. Introduction to naturally occurring radioactive material

    Energy Technology Data Exchange (ETDEWEB)

    Egidi, P.

    1997-08-01

    Naturally occurring radioactive material (NORM) is everywhere; we are exposed to it every day. It is found in our bodies, the food we eat, the places where we live and work, and in products we use. We are also bathed in a sea of natural radiation coming from the sun and deep space. Living systems have adapted to these levels of radiation and radioactivity. But some industrial practices involving natural resources concentrate these radionuclides to a degree that they may pose risk to humans and the environment if they are not controlled. Other activities, such as flying at high altitudes, expose us to elevated levels of NORM. This session will concentrate on diffuse sources of technologically-enhanced (TE) NORM, which are generally large-volume, low-activity waste streams produced by industries such as mineral mining, ore benefication, production of phosphate Fertilizers, water treatment and purification, and oil and gas production. The majority of radionuclides in TENORM are found in the uranium and thorium decay chains. Radium and its subsequent decay products (radon) are the principal radionuclides used in characterizing the redistribution of TENORM in the environment by human activity. We will briefly review other radionuclides occurring in nature (potassium and rubidium) that contribute primarily to background doses. TENORM is found in many waste streams; for example, scrap metal, sludges, slags, fluids, and is being discovered in industries traditionally not thought of as affected by radionuclide contamination. Not only the forms and volumes, but the levels of radioactivity in TENORM vary. Current discussions about the validity of the linear no dose threshold theory are central to the TENORM issue. TENORM is not regulated by the Atomic Energy Act or other Federal regulations. Control and regulation of TENORM is not consistent from industry to industry nor from state to state. Proposed regulations are moving from concentration-based standards to dose

  2. HER-2 amplification in tubular carcinoma of the breast.

    Science.gov (United States)

    Oakley, Gerard J; Tubbs, Raymond R; Crowe, Joseph; Sebek, Bruce; Budd, G Thomas; Patrick, Rebecca J; Procop, Gary W

    2006-07-01

    The prognostic and therapeutic implications of HER-2 gene amplification and estrogen and progesterone receptor status in breast cancer are well described. To address the relative paucity of information concerning HER-2 amplification for tubular carcinomas, we assessed the frequency of gene amplification in 55 tubular carcinomas of the breast from 54 patients, 5 of which had axillary node metastases. The HER-2 gene copy number was assessed by fluorescence in situ hybridization for the majority of tumors analyzed, whereas estrogen and progesterone receptor status was achieved by immunohistochemical analysis. HER-2 gene amplification was not observed in any of the tumors examined, and most were estrogen receptor-positive. This HER-2 gene amplification frequency was significantly lower than the frequency of gene amplification previously reported for all invasive ductal carcinoma of no special type (P < .01). HER-2 gene amplification likely occurs infrequently, or not at all, in tubular carcinomas of the breast, whereas most express estrogen receptors.

  3. Bioassay of naturally occurring allelochemicals for phytotoxicity.

    Science.gov (United States)

    Leather, G R; Einhellig, F A

    1988-10-01

    The bioassay has been one of the most widely used tests to demonstrate allelopathic activity. Often, claims that a particular plant species inhibits the growth of another are based entirely on the seed germination response to solvent extracts of the suspected allelopathic plant; few of these tests are of value in demonstrating allelopathy under natural conditions. The veracity of the bioassay for evaluating naturally occurring compounds for phytotoxicity depends upon the physiological and biochemical response capacity of the bioassay organism and the mechanism(s) of action of the allelochemicals. The possibility that more than one allelochemical, acting in concert at very low concentrations, may be responsible for an observed allelopathic effect makes it imperative that bioassays be extremely sensitive to chemical growth perturbation agents. Among the many measures of phytotoxicity of allelochemicals, the inhibition (or stimulation) of seed germination, radicle elongation, and/or seedling growth have been the parameters of choice for most investigations. Few of these assays have been selected with the view towards the possible mechanism of the allelopathic effect.

  4. Introduction to naturally occurring radioactive material

    International Nuclear Information System (INIS)

    Egidi, P.

    1997-01-01

    Naturally occurring radioactive material (NORM) is everywhere; we are exposed to it every day. It is found in our bodies, the food we eat, the places where we live and work, and in products we use. Some industrial practices involving natural resources concentrate these radionuclides to a degree that they may pose risk to humans and the environment if they are not controlled. This session will concentrate on diffuse sources of technologically-enhanced (TE) NORM, which are generally large-volume, low-activity waste streams produced by industries such as mineral mining, ore benefication, production of phosphate Fertilizers, water treatment and purification, and oil and gas production. The majority of radionuclides in TENORM are found in the uranium and thorium decay chains. Radium and its subsequent decay products (radon) are the principal radionuclides used in characterizing the redistribution of TENORM in the environment by human activity. We will briefly review other radionuclides occurring in nature (potassium and rubidium) that contribute primarily to background doses. TENORM is found in many waste streams; for example, scrap metal, sludges, slags, fluids, and is being discovered in industries traditionally not thought of as affected by radionuclide contamination. Not only the forms and volumes, but the levels of radioactivity in TENORM vary. Current discussions about the validity of the linear no dose threshold theory are central to the TENORM issue. TENORM is not regulated by the Atomic Energy Act or other Federal regulations. Control and regulation of TENORM is not consistent from industry to industry nor from state to state. Proposed regulations are moving from concentration-based standards to dose-based standards. So when is TENORM a problem? Where is it a problem? That depends on when, where, and whom you talk to exclamation point We will start by reviewing background radioactivity, then we will proceed to the geology, mobility, and variability of these

  5. Naturally occurring flavonoids against human norovirus surrogates.

    Science.gov (United States)

    Su, Xiaowei; D'Souza, Doris H

    2013-06-01

    Naturally occurring plant-derived flavonoids are reported to have antibacterial, antiviral, and pharmacological activities. The objectives of this study were to determine the antiviral effects of four flavonoids (myricetin, L-epicatechin, tangeretin, and naringenin) on the infectivity of food borne norovirus surrogates after 2 h at 37 °C. The lab-culturable surrogates, feline calicivirus (FCV-F9) at titers of ~7 log₁₀ PFU/ml (high titer) or ~5 log₁₀ PFU/ml (low titer) and murine norovirus (MNV-1) at ~5 log₁₀ PFU/ml, were mixed with equal volumes of myricetin, L-epicatechin, tangeretin, or naringenin at concentrations of 0.5 or 1 mM, and incubated for 2 h at 37 °C. Treatments of viruses were neutralized in cell culture medium containing 10 % heat-inactivated fetal bovine serum, serially diluted, and plaque assayed. Each treatment was replicated thrice and assayed in duplicate. FCV-F9 (low titer) was not found to be reduced by tangeretin or naringenin, but was reduced to undetectable levels by myricetin at both concentrations. Low titer FCV-F9 was also decreased by 1.40 log₁₀ PFU/ml with L-epicatechin at 0.5 mM. FCV-F9 at high titers was decreased by 3.17 and 0.72 log₁₀ PFU/ml with myricetin and L-epicatechin at 0.5 mM, and 1.73 log10 PFU/ml with myricetin at 0.25 mM, respectively. However, MNV-1 showed no significant inactivation by the four tested treatments. The antiviral effects of the tested flavonoids are dependent on the virus type, titer, and dose. Further research will focus on understanding the antiviral mechanism of myricetin and L-epicatechin.

  6. HER2 Genetic Link to Breast Cancer

    Science.gov (United States)

    When researchers discovered the HER2 gene's importance to breast cancer growth, this led to the development of trastuzumab and other treatments that have improved survival for women with HER2-positive breast cancer.

  7. Emerging technologies for assessing HER2 amplification

    NARCIS (Netherlands)

    Penault-Llorca, Frédérique; Bilous, Michael; Dowsett, Mitch; Hanna, Wedad; Osamura, Robert Yoshiyuki; Rüschoff, Josef; van de Vijver, Marc

    2009-01-01

    Patients with human epidermal growth factor receptor-2 (HER2)+ breast cancer are eligible for trastuzumab treatment; therefore, accurate assessment of HER2 status is essential. Until recently, only 2 methods were validated for determining the HER2 status of breast tumors in the routine diagnostic

  8. Naturally Occurring Cinnamic Acid Sugar Ester Derivatives

    Directory of Open Access Journals (Sweden)

    Yuxin Tian

    2016-10-01

    Full Text Available Cinnamic acid sugar ester derivatives (CASEDs are a class of natural product with one or several phenylacrylic moieties linked with the non-anomeric carbon of a glycosyl skeleton part through ester bonds. Their notable anti-depressant and brains protective activities have made them a topic of great interest over the past several decades. In particular the compound 3′,6-disinapoylsucrose, the index component of Yuanzhi (a well-known Traditional Chinese Medicine or TCM, presents antidepressant effects at a molecular level, and has become a hotspot of research on new lead drug compounds. Several other similar cinnamic acid sugar ester derivatives are reported in traditional medicine as compounds to calm the nerves and display anti-depression and neuroprotective activity. Interestingly, more than one third of CASEDs are distributed in the family Polygalaceae. This overview discusses the isolation of cinnamic acid sugar ester derivatives from plants, together with a systematic discussion of their distribution, chemical structures and properties and pharmacological activities, with the hope of providing references for natural product researchers and draw attention to these interesting compounds.

  9. Comparison of HER2 and phospho-HER2 expression between biopsy and resected breast cancer specimens using a quantitative assessment method.

    Directory of Open Access Journals (Sweden)

    Yalai Bai

    Full Text Available BACKGROUND: HER2/Neu (ErbB-2 overexpression, which occurs in 15-20% of breast cancer cases, is associated with better response to treatment with the drug trastuzumab. PhosphoHER2 (pHER2 has been evaluated for prediction of response to trastuzumab. Both markers are heterogeneously detected and are potentially subject to loss as a consequence of delayed time to fixation. Here, we quantitatively assess both markers in core needle biopsies (CNBs and matched tumor resections to assess concordance between the core and the resection and between HER2 and pHER2. METHODS: A selected retrospective collection of archival breast cancer cases yielded 67 cases with both core and resection specimens. Both HER2 and pTyr(1248HER2 were analyzed by the AQUA® method of quantitative immunofluorescence on each specimen pair. RESULTS: Both HER2 immunoreactivity (P<0.0001 and pTyr(1248HER2 immunoreactivity (P<0.0001 were lower in resections relative to CNB specimens. However, clinical implications of this change may not be evident since no case changed from 3+ (CNB to negative (resection. Assessment of pTyr(1248HER2 showed no direct correlation with HER2 in either CNB or resection specimens. CONCLUSIONS: The data suggest that measurement of both HER2 and phospho- Tyr(1248HER2, in formalin-fixed tissue by immunological methods is significantly affected by pre-analytic variables. The current study warrants the adequate handling of resected specimens for the reproducible evaluation of HER2 and pHER2. The level of pTyr(1248HER2, was not correlated to total HER2 protein. Further studies are required to determine the significance of these observations with respect to response to HER2 directed therapies.

  10. Structural studies of naturally occurring toxicogenic compounds

    Energy Technology Data Exchange (ETDEWEB)

    Springer, J. P.

    1977-10-01

    The paralytic shellfish poison (PSP), saxitoxin, is a neurotoxin isolated from Alaska butter clams (Saxidomus giganteus), mussels (Mytilus californianus) and axenic cultures of the dinoflagellate Gonyaulax catenella. The structure of saxitoxin has been determined through the use of single crystal X-ray diffraction. It possesses a unique tricyclic arrangement of atoms containing two guanidinium moieties and also a hydrated ketone. The relative stereochemistry is presented as well as the absolute configuration. The chemical constitution of a tremorgenic metabolite, paxilline, isolated from extracts of the fungus Penicillium paxilli Bainier has been determined. Paxilline represents a previously unreported class of natural compounds formed by the combination of tryptophan and mevalonate subunits. The complete stereostructure of two other fungal metabolites, paspaline and paspalicine, closely related to paxilline but isolated from Claviceps paspali Stammes have also been determined and are presented. The stereochemistries of paxilline, paspaline and paspalicine are identical at corresponding chiral centers.

  11. Naturally occurring antifungal aromatic esters and amides

    International Nuclear Information System (INIS)

    Ali, M.S.; Shahnaz; Tabassum, S.; Ogunwande, I.A.; Pervez, M.K.

    2010-01-01

    During the search of antifungal natural products from terrestrial plants, a new long chained aromatic ester named grandiflorate along with spatazoate from Portulaca grandiflora and N-[2-methoxy-2-(4-methoxyphenyl) ethyl]-trans-cinnamide and aegeline from Solanum erianthum of Nigeria were isolated and tested against six fungal species. The known constituents have not been reported so far from mentioned investigated plants. Structures of the isolated compounds were elucidated with the aid of spectroscopic techniques including two dimensional NMR experiments. Among the compounds, the esters found more potent than amides against Candida albicans and Aspergillus flavus. The new compound grandiflorate gave response against all tested fungal species while aegeline was found to give lowest inhibition during this study. (author)

  12. Naturally occurring antifungal aromatic esters and amides

    Energy Technology Data Exchange (ETDEWEB)

    Ali, M S; Shahnaz,; Tabassum, S; Ogunwande, I A; Pervez, M K [University of Karachi (Pakistan). HEJ Research Inst. of Chemistry, International Centre for Chemical and Biological Sciences

    2010-08-15

    During the search of antifungal natural products from terrestrial plants, a new long chained aromatic ester named grandiflorate along with spatazoate from Portulaca grandiflora and N-[2-methoxy-2-(4-methoxyphenyl) ethyl]-trans-cinnamide and aegeline from Solanum erianthum of Nigeria were isolated and tested against six fungal species. The known constituents have not been reported so far from mentioned investigated plants. Structures of the isolated compounds were elucidated with the aid of spectroscopic techniques including two dimensional NMR experiments. Among the compounds, the esters found more potent than amides against Candida albicans and Aspergillus flavus. The new compound grandiflorate gave response against all tested fungal species while aegeline was found to give lowest inhibition during this study. (author)

  13. tabAnti-HER2 (erbB-2) oncogene effects of phenolic compounds directly isolated from commercial Extra-Virgin Olive Oil (EVOO)

    International Nuclear Information System (INIS)

    Menendez, Javier A; Vazquez-Martin, Alejandro; Garcia-Villalba, Rocio; Carrasco-Pancorbo, Alegria; Oliveras-Ferraros, Cristina; Fernandez-Gutierrez, Alberto; Segura-Carretero, Antonio

    2008-01-01

    The effects of the olive oil-rich Mediterranean diet on breast cancer risk might be underestimated when HER2 (ERBB2) oncogene-positive and HER2-negative breast carcinomas are considered together. We here investigated the anti-HER2 effects of phenolic fractions directly extracted from Extra Virgin Olive Oil (EVOO) in cultured human breast cancer cell lines. Solid phase extraction followed by semi-preparative high-performance liquid chromatography (HPLC) was used to isolate phenolic fractions from commercial EVOO. Analytical capillary electrophoresis coupled to mass spectrometry was performed to check for the composition and to confirm the identity of the isolated fractions. EVOO polyphenolic fractions were tested on their tumoricidal ability against HER2-negative and HER2-positive breast cancer in vitro models using MTT, crystal violet staining, and Cell Death ELISA assays. The effects of EVOO polyphenolic fractions on the expression and activation status of HER2 oncoprotein were evaluated using HER2-specific ELISAs and immunoblotting procedures, respectively. Among the fractions mainly containing the single phenols hydroxytyrosol and tyrosol, the polyphenol acid elenolic acid, the lignans (+)-pinoresinol and 1-(+)-acetoxypinoresinol, and the secoiridoids deacetoxy oleuropein aglycone, ligstroside aglycone, and oleuropein aglycone, all the major EVOO polyphenols (i.e. secoiridoids and lignans) were found to induce strong tumoricidal effects within a micromolar range by selectively triggering high levels of apoptotic cell death in HER2-overexpressors. Small interfering RNA-induced depletion of HER2 protein and lapatinib-induced blockade of HER2 tyrosine kinase activity both significantly prevented EVOO polyphenols-induced cytotoxicity. EVOO polyphenols drastically depleted HER2 protein and reduced HER2 tyrosine autophosphorylation in a dose- and time-dependent manner. EVOO polyphenols-induced HER2 downregulation occurred regardless the molecular mechanism

  14. tabAnti-HER2 (erbB-2 oncogene effects of phenolic compounds directly isolated from commercial Extra-Virgin Olive Oil (EVOO

    Directory of Open Access Journals (Sweden)

    Carrasco-Pancorbo Alegria

    2008-12-01

    occurred regardless the molecular mechanism contributing to HER2 overexpression (i.e. naturally by gene amplification and ectopically driven by a viral promoter. Pre-treatment with the proteasome inhibitor MG132 prevented EVOO polyphenols-induced HER2 depletion. Conclusion The ability of EVOO-derived polyphenols to inhibit HER2 activity by promoting the proteasomal degradation of the HER2 protein itself, together with the fact that humans have safely been ingesting secoiridoids and lignans as long as they have been consuming olives and OO, support the notion that the stereochemistry of these phytochemicals might provide an excellent and safe platform for the design of new HER2-targeting agents.

  15. Emerging technologies for HER2 testing

    NARCIS (Netherlands)

    van de Vijver, Marc

    2002-01-01

    HER2-positive status is the sole criterion for identifying patients with breast cancer for Herceptin therapy, which has known efficacy in women with metastatic breast cancer (MBC). Immunohistochemistry (IHC) and fluorescence in-situ hybridization (FISH), which measure the HER2 protein and gene,

  16. Optimizing HER2 assessment in breast cancer

    DEFF Research Database (Denmark)

    Holten-Rossing, Henrik; Møller Talman, Maj-Lis; Kristensson, Martin

    2015-01-01

    In breast cancer, analysis of HER2 expression is pivotal for treatment decision. This study aimed at comparing digital, automated image analysis with manual reading using the HER2-CONNECT algorithm (Visiopharm) in order to minimize the number of equivocal 2+ scores and the need for reflex...

  17. IMMUNOHISTOCHEMICAL EXPRESSION OF HER2 IN ADENOCARCINOMA OF THE STOMACH

    Directory of Open Access Journals (Sweden)

    Diego Michelon DE CARLI

    2015-06-01

    Full Text Available Background Worldwide, gastric cancer is the fourth cancer in incidence and the second most common cause of cancer death. Gastric cancer is asymptomatic in the early stages and very often diagnosed at advanced stages, determining a dismal prognosis. Expression of the HER2 gene has been identified in about 20% of gastric cancer cases, and its hyper-expression is associated with poor prognosis. Objective To investigate HER2 immunohistochemical expression in gastric adenocarcinoma and its relationship to the histological type and anatomic location. Methods A cross-sectional retrospective study analyzed the immunohistochemical expression of HER2 in a sample of 48 specimens of gastric cancer. Immunohistochemical analysis were performed using avidin-biotin-peroxidase method with C-erb B2 (clone EP1045Y, as a primary antibody (Biocare Medical, USA. Standardized gastric adenocarcinoma‘s HER2 expression criteria has been used in the analysis of samples. Results There were seven cases with reactivity for HER2. Five were of intestinal-type while two cases were of mixed-type in which the expression occurred in the intestinal component. It was identified a significant association of HER2 expression in the intestinal subtype of gastric adenocarcinoma (P=0.003. Regarding the anatomical site, HER2 was positive in only one (16.6% of the six proximal cases and six (14.28% of the 42 distal cases (P=0.88. Conclusion HER2 immunoexpression was identified in 14.6% of the samples, and the expression was significantly associated to Lauren’s intestinal subtype.

  18. Deposition of naturally occurring radioactivity in oil and gas production

    International Nuclear Information System (INIS)

    Lysebo, I.; Strand, T.

    1997-01-01

    This booklet contains general information about naturally occurring radioactive materials, NORM, in production of oil and natural gas, occupational doses, radiation protection procedures and measures, and classification methods of contaminated equipment. 6 refs., 1 fig., 1 tab

  19. Activating HER2 mutations in HER2 gene amplification negative breast cancer.

    Science.gov (United States)

    Bose, Ron; Kavuri, Shyam M; Searleman, Adam C; Shen, Wei; Shen, Dong; Koboldt, Daniel C; Monsey, John; Goel, Nicholas; Aronson, Adam B; Li, Shunqiang; Ma, Cynthia X; Ding, Li; Mardis, Elaine R; Ellis, Matthew J

    2013-02-01

    Data from 8 breast cancer genome-sequencing projects identified 25 patients with HER2 somatic mutations in cancers lacking HER2 gene amplification. To determine the phenotype of these mutations, we functionally characterized 13 HER2 mutations using in vitro kinase assays, protein structure analysis, cell culture, and xenograft experiments. Seven of these mutations are activating mutations, including G309A, D769H, D769Y, V777L, P780ins, V842I, and R896C. HER2 in-frame deletion 755-759, which is homologous to EGF receptor (EGFR) exon 19 in-frame deletions, had a neomorphic phenotype with increased phosphorylation of EGFR or HER3. L755S produced lapatinib resistance, but was not an activating mutation in our experimental systems. All of these mutations were sensitive to the irreversible kinase inhibitor, neratinib. These findings show that HER2 somatic mutation is an alternative mechanism to activate HER2 in breast cancer and they validate HER2 somatic mutations as drug targets for breast cancer treatment. We show that the majority of HER2 somatic mutations in breast cancer patients are activating mutations that likely drive tumorigenesis. Several patients had mutations that are resistant to the reversible HER2 inhibitor lapatinib, but are sensitive to the irreversible HER2 inhibitor, neratinib. Our results suggest that patients with HER2 mutation–positive breast cancers could benefit from existing HER2-targeted drugs.

  20. Phase I clinical trial of HER2-specific immunotherapy with concomitant HER2 kinase inhibtion

    Directory of Open Access Journals (Sweden)

    Hamilton Erika

    2012-02-01

    Full Text Available Abstract Background Patients with HER2-overexpressing metastatic breast cancer, despite initially benefiting from the monoclonal antibody trastuzumab and the EGFR/HER2 tyrosine kinase inhibitor lapatinib, will eventually have progressive disease. HER2-based vaccines induce polyclonal antibody responses against HER2 that demonstrate enhanced anti-tumor activity when combined with lapatinib in murine models. We wished to test the clinical safety, immunogenicity, and activity of a HER2-based cancer vaccine, when combined with lapatinib. Methods We immunized women (n = 12 with metastatic, trastuzumab-refractory, HER2-overexpressing breast cancer with dHER2, a recombinant protein consisting of extracellular domain (ECD and a portion of the intracellular domain (ICD of HER2 combined with the adjuvant AS15, containing MPL, QS21, CpG and liposome. Lapatinib (1250 mg/day was administered concurrently. Peripheral blood antibody and T cell responses were measured. Results This regimen was well tolerated, with no cardiotoxicity. Anti-HER2-specific antibody was induced in all patients whereas HER2-specific T cells were detected in one patient. Preliminary analyses of patient serum demonstrated downstream signaling inhibition in HER2 expressing tumor cells. The median time to progression was 55 days, with the majority of patients progressing prior to induction of peak anti-HER2 immune responses; however, 300-day overall survival was 92% (95% CI: 77-100%. Conclusions dHER2 combined with lapatinib was safe and immunogenic with promising long term survival in those with HER2-overexpressing breast cancers refractory to trastuzumab. Further studies to define the anticancer activity of the antibodies induced by HER2 vaccines along with lapatinib are underway. Trial registry ClinicalTrials.gov NCT00952692

  1. HER-2 Pulsed Dendritic Cell Vaccine Can Eliminate HER-2 Expression and Impact DCIS

    Science.gov (United States)

    Sharma, Anupama; Koldovsky, Ursula; Xu, Shuwen; Mick, Rosemarie; Roses, Robert; Fitzpatrick, Elizabeth; Weinstein, Susan; Nisenbaum, Harvey; Levine, Bruce L; Fox, Kevin; Zhang, Paul; Koski, Gary; Czerniecki, Brian J

    2011-01-01

    Background HER-2/neu over-expression plays a critical role in breast cancer development and its expression in ductal carcinoma in situ (DCIS) is associated with development of invasive breast cancer. A vaccine targeting HER-2/neu expression in DCIS may initiate immunity against invasive cancer. Methods A HER-2/neu dendritic cell (DC) vaccine was administered to 27 patients with HER-2/neu over-expressing DCIS. The HER-2/neu vaccine was administered prior to surgical resection and pre- and post-vaccination analysis was conducted to assess clinical results. Results At surgery, 5 of 27 (18.5%) vaccinated subjects had no evidence of remaining disease, while among 22 subjects with residual DCIS, HER-2/neu expression was eradicated in 11 (50%). When comparing ERneg with ERpos DCIS lesions, vaccination was more effective in hormone-independent DCIS. Following vaccination, no residual DCIS was found in 40% of ERneg subjects compared to 5.9% in ERpos subject. Sustained HER-2/neu expression was found in 10% of ERneg subjects compared to 47.1% in ERpos subjects (p=0.04). Post-vaccination phenotypes were significantly different between ERpos and ERneg subjects (p=0.01), with 7 of 16 (43.8%) initially presenting with ERpos HER-2/neupos Luminal B phenotype finishing with the ERpos HER-2/neuneg Luminal A phenotype, and 3 of 6 (50%) with the ERneg HER-2/neupos phenotype changing to the ERneg HER-2/neuneg phenotype. Conclusions Results suggest vaccination against HER-2/neu is safe, well-tolerated and induces decline and or eradication of HER-2/neu expression. These findings warrant further exploration of HER-2/neu vaccination in estrogen-independent breast cancer and highlight the need to target additional tumor associated antigens and pathways. PMID:22252842

  2. Cardiotoxicity of novel HER2-targeted therapies.

    Science.gov (United States)

    Sendur, Mehmet A N; Aksoy, Sercan; Altundag, Kadri

    2013-08-01

    Trastuzumab, an anti-HER2 humanized monoclonal antibody, is the standard treatment for both early and metastatic HER2-positive breast cancer. In addition to other chemotherapeutic agents, trastuzumab significantly improves response rate and survival in HER2-positive early and metastatic breast cancer. Although it is well known that trastuzumab therapy is closely associated with both symptomatic and asymptomatic cardiotoxicity, less is known about novel HER2-targeted therapies. The aim of this review is to discuss the cardiac safety data from recent studies of novel anti-HER2 drugs other than trastuzumab. Novel HER2-targeted therapies showed favorable results in HER2 positive metastatic breast cancer patients. Pubmed database, ASCO and San Antonio Breast Cancer Symposium Meeting abstracts were searched until January 2013 using the following search keywords; 'trastuzumab, trastuzumab cardiotoxicity, HER-2 targeted therapies, lapatinib, pertuzumab, trastuzumab emtansine, afatinib and neratinib'; papers which were considered relevant for the aim of this review were selected by the authors. Lapatinib, pertuzumab, T-DM1, neratinib and afatinib molecules are evaluated in the study. In a comprehensive analysis, 3689 lapatinib treated patients enrolled in 49 trials; asymptomatic cardiac events were reported in 53 patients (1.4%) and symptomatic grade III and IV systolic dysfunction was observed only in 7 patients (0.2%) treated with lapatinib. In phase I-III trials of pertuzumab, cardiac dysfunction was seen in 4.5-14.5% of patients with pertuzumab treatment and cardiac dysfunction was usually grade I and II. Cardiotoxicity of pertuzumab was usually reported with the trastuzumab combination and no additive cardiotoxicity was reported with addition of pertuzumab to trastuzumab. T-DM1 had a better safety profile compared to trastuzumab, no significant cardiotoxicity was observed with T-DM1 in heavily pre-treated patients. In the EMILIA study, only in 1.7% of patients in the T

  3. HER2 overexpression elicits a proinflammatory IL-6 autocrine signaling loop that is critical for tumorigenesis.

    Science.gov (United States)

    Hartman, Zachary C; Yang, Xiao-Yi; Glass, Oliver; Lei, Gangjun; Osada, Takuya; Dave, Sandeep S; Morse, Michael A; Clay, Timothy M; Lyerly, Herbert K

    2011-07-01

    HER2 overexpression occurs in approximately 25% of breast cancers, where it correlates with poor prognosis. Likewise, systemic inflammation in breast cancer correlates with poor prognosis, although the process is not understood. In this study, we explored the relationship between HER2 and inflammation, comparing the effects of overexpressing wild-type or mutated inactive forms of HER2 in primary human breast cells. Wild-type HER2 elicited a profound transcriptional inflammatory profile, including marked elevation of interleukin-6 (IL-6) expression, which we established to be a critical determinant of HER2 oncogenesis. Mechanistic investigations revealed that IL-6 secretion induced by HER2 overexpression activated Stat3 and altered gene expression, enforcing an autocrine loop of IL-6/Stat3 expression. Both mouse and human in vivo models of HER2-amplified breast carcinoma relied critically on this HER2-IL-6-Stat3 signaling pathway. Our studies offer the first direct evidence linking HER2 to a systemic inflammatory mechanism that orchestrates HER2-mediated tumor growth. We suggest that the HER2-IL-6-STAT3 signaling axis we have defined in breast cancer could prompt new therapeutic or prevention strategies for treatment of HER2-amplified cancers. ©2011 AACR.

  4. Docosahexaenoic Acid Modulates a HER2-Associated Lipogenic Phenotype, Induces Apoptosis, and Increases Trastuzumab Action in HER2-Overexpressing Breast Carcinoma Cells

    OpenAIRE

    Ravacci, Graziela Rosa; Brentani, Maria Mitzi; Tortelli, Tharcisio Citrângulo; Torrinhas, Raquel Suzana M. M.; Santos, Jéssica Reis; Logullo, Angela Flávia; Waitzberg, Dan Linetzky

    2015-01-01

    In breast cancer, lipid metabolic alterations have been recognized as potential oncogenic stimuli that may promote malignancy. To investigate whether the oncogenic nature of lipogenesis closely depends on the overexpression of HER2 protooncogene, the normal breast cell line, HB4a, was transfected with HER2 cDNA to obtain HER2-overexpressing HB4aC5.2 cells. Both cell lines were treated with trastuzumab and docosahexaenoic acid. HER2 overexpression was accompanied by an increase in the expressi...

  5. Long term disease-free survival and T cell and antibody responses in women with high-risk Her2+ breast cancer following vaccination against Her2

    Directory of Open Access Journals (Sweden)

    Anders Carey

    2007-09-01

    Full Text Available Abstract Background The HER2-inhibiting antibody trastuzumab, in combination with chemotherapy, significantly improves survival of women with resected, HER2-overexpressing breast cancers, but is associated with toxicities including a risk of cardiomyopathy. Additionally, the beneficial effect of trastuzumab is expected to decrease once the drug is discontinued. We proposed to address these concerns by using cancer vaccines to stimulate HER2 intracellular domain (ICD-specific T cell and antibody responses. Methods Subjects with stage II (≥ 6 +LN, III, or stage IV breast cancerwith > 50% HER2 overexpressing tumor cells who were disease-free after surgery and adjuvant therapy were eligible. Vaccines consisted of immature, cultured DC (n = 3, mature cultured DC (n = 3, or mature Flt3-ligand mobilized peripheral blood DC (n = 1 loaded with ICD, or tetanus toxoid, keyhole limpet hemocyanin or CMV peptide as controls, and were administered intradermally/subcutaneously four times at 3 week intervals. ICD-specific T cell and antibody responses were measured. Cardiac function was determined by MUGA or ECHO; long term disease status was obtained from patient contact. Results All seven patients successfully underwent DC generation and five received all 4 immunizations. There were no toxicities greater than grade 1 or ejection fraction decrements below normal. Delayed-type hypersensitivity (DTH reactions at the injection site occurred in 6/7 patients and HER2 specificity was detected by cytokine flow cytometry or ELISPOT in 5 patients. At more than 5 years of follow-up, 6/7 had detectable anti-ICD antibodies. One patient experienced a pulmonary recurrence at 4 years from their study immunizations. This recurrence was resected and they are without evidence of disease. All patients are alive and disease-free at 4.6–6.7 years of follow-up. Conclusion Although this was a small pilot study, the well-tolerated nature of the vaccines, the lack of cardiac

  6. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2.

    Science.gov (United States)

    Slamon, D J; Leyland-Jones, B; Shak, S; Fuchs, H; Paton, V; Bajamonde, A; Fleming, T; Eiermann, W; Wolter, J; Pegram, M; Baselga, J; Norton, L

    2001-03-15

    The HER2 gene, which encodes the growth factor receptor HER2, is amplified and HER2 is overexpressed in 25 to 30 percent of breast cancers, increasing the aggressiveness of the tumor. We evaluated the efficacy and safety of trastuzumab, a recombinant monoclonal antibody against HER2, in women with metastatic breast cancer that overexpressed HER2. We randomly assigned 234 patients to receive standard chemotherapy alone and 235 patients to receive standard chemotherapy plus trastuzumab. Patients who had not previously received adjuvant (postoperative) therapy with an anthracycline were treated with doxorubicin (or epirubicin in the case of 36 women) and cyclophosphamide alone (138 women) or with trastuzumab (143 women). Patients who had previously received adjuvant anthracycline were treated with paclitaxel alone (96 women) or paclitaxel with trastuzumab (92 women). The addition of trastuzumab to chemotherapy was associated with a longer time to disease progression (median, 7.4 vs. 4.6 months; P<0.001), a higher rate of objective response (50 percent vs. 32 percent, P<0.001), a longer duration of response (median, 9.1 vs. 6.1 months; P<0.001), a lower rate of death at 1 year (22 percent vs. 33 percent, P=0.008), longer survival (median survival, 25.1 vs. 20.3 months; P=0.01), and a 20 percent reduction in the risk of death. The most important adverse event was cardiac dysfunction of New York Heart Association class III or IV, which occurred in 27 percent of the group given an anthracycline, cyclophosphamide, and trastuzumab; 8 percent of the group given an anthracycline and cyclophosphamide alone; 13 percent of the group given paclitaxel and trastuzumab; and 1 percent of the group given paclitaxel alone. Although the cardiotoxicity was potentially severe and, in some cases, life-threatening, the symptoms generally improved with standard medical management. Trastuzumab increases the clinical benefit of first-line chemotherapy in metastatic breast cancer that

  7. Neratinib Approved for HER2+ Breast Cancer.

    Science.gov (United States)

    2017-09-01

    The FDA approved the tyrosine kinase inhibitor neratinib for extended adjuvant treatment of early-stage HER2-positive breast cancer. The decision adds another treatment option to help prevent recurrence, but its relatively small potential benefit must be weighed against the risk of serious side effects. ©2017 American Association for Cancer Research.

  8. Immunoregulation by naturally occurring and disease-associated autoantibodies

    DEFF Research Database (Denmark)

    Nielsen, Claus H; Bendtzen, Klaus

    2012-01-01

    The role of naturally occurring autoantibodies (NAbs) in homeostasis and in disease manifestations is poorly understood. In the present chapter, we review how NAbs may interfere with the cytokine network and how NAbs, through formation of complement-activating immune complexes with soluble self......-antigens, may promote the uptake and presentation of self-molecules by antigen-presenting cells. Both naturally occurring and disease-associated autoantibodies against a variety of cytokines have been reported, including NAbs against interleukin (IL)-1α, IL-6, IL-8, IL-10, granulocyte-macrophage colony...

  9. The effects of naturally occurring impurities in rock salt

    Indian Academy of Sciences (India)

    In this paper we investigate the effect that naturally occurring impurities in salt mines have both on effective permittivity of the medium and on radio wave propagation at ∼200 MHz. The effective permittivity is determined based on the dielectric properties of salt and the characteristics of the main impurities. We conclude that ...

  10. Transmission of naturally occurring lymphoma in macaque monkeys.

    OpenAIRE

    Hunt, R D; Blake, B J; Chalifoux, L V; Sehgal, P K; King, N W; Letvin, N L

    1983-01-01

    Spontaneously occurring rhesus monkey lymphomas were transmitted into healthy rhesus monkeys by using tumor cell suspensions. The naturally arising tumors included an immunoblastic sarcoma and an undifferentiated lymphoma. Recipient animals developed undifferentiated lymphomas, poorly differentiated lymphomas, or parenchymal lymphoproliferative abnormalities suggestive of early lesions of lymphoma. Some of these animals developed such opportunistic infections as cytomegalovirus hepatitis and ...

  11. Learning by investing: evidence from a naturally occurring auction

    Czech Academy of Sciences Publication Activity Database

    Hanousek, Jan; Kočenda, Evžen

    2011-01-01

    Roč. 19, č. 1 (2011), s. 125-149 ISSN 0967-0750 R&D Projects: GA ČR GA402/09/1595; GA MŠk LC542 Institutional research plan: CEZ:MSM0021620846 Keywords : learning * naturally occurring auction * stock market Subject RIV: AH - Economics Impact factor: 0.679, year: 2011

  12. Adsorption of fluoride ions onto naturally occurring earth materials ...

    African Journals Online (AJOL)

    Batch sorption system using two naturally occurring earth materials (EM) as adsorbents was investigated to remove fluoride ions from aqueous solution. The system variables studied include initial concentration of the sorbate, agitation time, adsorbent dose, pH, co-ions and temperature. The experimental data fitted well to ...

  13. Natural Transformation of Campylobacter jejuni Occurs Beyond Limits of Growth

    Science.gov (United States)

    Vegge, Christina S.; Brøndsted, Lone; Ligowska-Marzęta, Małgorzata; Ingmer, Hanne

    2012-01-01

    Campylobacter jejuni is a human bacterial pathogen. While poultry is considered to be a major source of food borne campylobacteriosis, C. jejuni is frequently found in the external environment, and water is another well-known source of human infections. Natural transformation is considered to be one of the main mechanisms for mediating transfer of genetic material and evolution of the organism. Given the diverse habitats of C. jejuni we set out to examine how environmental conditions and physiological processes affect natural transformation of C. jejuni. We show that the efficiency of transformation is correlated to the growth conditions, but more importantly that transformation occurs at growth-restrictive conditions as well as in the late stationary phase; hence revealing that growth per se is not required for C. jejuni to be competent. Yet, natural transformation of C. jejuni is an energy dependent process, that occurs in the absence of transcription but requires an active translational machinery. Moreover, we show the ATP dependent ClpP protease to be important for transformation, which possibly could be associated with reduced protein glycosylation in the ClpP mutant. In contrast, competence of C. jejuni was neither found to be involved in DNA repair following DNA damage nor to provide a growth benefit. Kinetic studies revealed that several transformation events occur per cell cycle indicating that natural transformation of C. jejuni is a highly efficient process. Thus, our findings suggest that horizontal gene transfer by natural transformation takes place in various habitats occupied by C. jejuni. PMID:23049803

  14. On the noble gas isotopic fractionation in naturally occurring gases

    International Nuclear Information System (INIS)

    Marty, B.

    1984-01-01

    The isotopic composition of neon in the mantle is an important geochemical constraint on the formation of the earth and subsequent degassing. Some deviation of neon isotopic composition in natural gas and rock samples from the atmospheric value which can not be accounted for by the known nuclear process has been reported, and Nagao et al. interpreted the deviation as the result of mass fractionation in natural gas in Japan. The possible cause of such fractionation was investigated. Gaseous diffusion, such as (a) free-molecule diffusion, (b) mutual diffusion and (c) thermal diffusion, is able to cause isotopic fractionation. After the detailed consideration on these three diffusion processes, conclusion that free-molecule diffusion occurs only in very particular condition, and it is questionable that thermal diffusion occurs in nature, were obtained. (b) which means the interaction of two or more gases, is supposed to occur in nature, and is able to confirm experimentally. In mutual diffusion only, gas transfer is concerned, but other form of fractionation should not be neglected. In solid diffusion, gas is trapped by fine grained sedimentary rocks, and may be fractionated by adsorption and communication to exterior through minute channels. Underground water also works as noble gas reservoir. For example, when gas stream is in contact with water, continuous exchange is possible to take place at the interface of gas and liquid, which contributes to the fractionation. (Ishimitsu, A.)

  15. Biological Monitoring of HER-2 Positive Patients Using Serum HER-2 and Circulating Tumor Cells

    National Research Council Canada - National Science Library

    Fournier, Marcia

    2002-01-01

    ...: Blood samples were collected from 55 women with HER-2 positive (lHC+++ and/or FlSH+) metastatic breast cancer and 30 healthy female volunteers Blood samples were collected at baseline, during With the first cycle...

  16. Clinical Significance of HER-2 Splice Variants in Breast Cancer Progression and Drug Resistance

    Directory of Open Access Journals (Sweden)

    Claire Jackson

    2013-01-01

    Full Text Available Overexpression of human epidermal growth factor receptor (HER-2 occurs in 20–30% of breast cancers and confers survival and proliferative advantages on the tumour cells making HER-2 an ideal therapeutic target for drugs like Herceptin. Continued delineation of tumour biology has identified splice variants of HER-2, with contrasting roles in tumour cell biology. For example, the splice variant 16HER-2 (results from exon 16 skipping increases transformation of cancer cells and is associated with treatment resistance; conversely, Herstatin (results from intron 8 retention and p100 (results from intron 15 retention inhibit tumour cell proliferation. This review focuses on the potential clinical implications of the expression and coexistence of HER-2 splice variants in cancer cells in relation to breast cancer progression and drug resistance. “Individualised” strategies currently guide breast cancer management; in accordance, HER-2 splice variants may prove valuable as future prognostic and predictive factors, as well as potential therapeutic targets.

  17. Naturally occuring radiation in the Nordic countries - recommendations

    International Nuclear Information System (INIS)

    1986-01-01

    In the publication ''Report on the Applicability of International Radiation Protection Recommendations in the Nordic Countries'', published in 1976, the radiation protection authorities in Denmark, Finland, Iceland, Norway and Sweden expessed their agreement on the main principles of radiation protection. The general aspects of radiation protection were covered in the recommendations with the exception of exposure of the public from natural sources of radiation. In 1983 a working group published the report ''Naturally Occurring radiation in the Nordic Countries, - Levels'' in the Radiation Protection Information-Series from the Nordic countries. In that report the present knowledge of the population exposure from natural sources of external gamma-radiation and from radon and thoron daughters in air was reviewed as a basis for the development of the radiation protection recommendations for natural radiation. During preparation of these recommendations due account has also been taken of ICRP publication no. 39: ''Principles for Limiting Exposure of the Public to Natural Sources of Radiation'', which was published in 1984 and in which ICRP for the first time has issued more specific recommendations for natural sources. The recommendations may serve as a basis for more formal rules and regulations within each country, if this is seemed necessary. However, no attempt has been made to formulate identical rules for all the five countries since the exposure levels from natural sources, methods of application and the legal frameworks differ between the countries. (EG)

  18. Naturally occurring crystalline phases: analogues for radioactive waste forms

    International Nuclear Information System (INIS)

    Haaker, R.F.; Ewing, R.C.

    1981-01-01

    Naturally occurring mineral analogues to crystalline phases that are constituents of crystalline radioactive waste forms provide a basis for comparison by which the long-term stability of these phases may be estimated. The crystal structures and the crystal chemistry of the following natural analogues are presented: baddeleyite, hematite, nepheline; pollucite, scheelite;sodalite, spinel, apatite, monazite, uraninite, hollandite-priderite, perovskite, and zirconolite. For each phase in geochemistry, occurrence, alteration and radiation effects are described. A selected bibliography for each phase is included

  19. Naturally occurring crystalline phases: analogues for radioactive waste forms

    Energy Technology Data Exchange (ETDEWEB)

    Haaker, R.F.; Ewing, R.C.

    1981-01-01

    Naturally occurring mineral analogues to crystalline phases that are constituents of crystalline radioactive waste forms provide a basis for comparison by which the long-term stability of these phases may be estimated. The crystal structures and the crystal chemistry of the following natural analogues are presented: baddeleyite, hematite, nepheline; pollucite, scheelite;sodalite, spinel, apatite, monazite, uraninite, hollandite-priderite, perovskite, and zirconolite. For each phase in geochemistry, occurrence, alteration and radiation effects are described. A selected bibliography for each phase is included.

  20. An Update on Antitumor Activity of Naturally Occurring Chalcones

    Directory of Open Access Journals (Sweden)

    En-Hui Zhang

    2013-01-01

    Full Text Available Chalcones, which have characteristic 1,3-diaryl-2-propen-1-one skeleton, are mainly produced in roots, rhizomes, heartwood, leaves, and seeds of genera Angelica, Sophora, Glycyrrhiza, Humulus, Scutellaria, Parartocarpus, Ficus, Dorstenia, Morus, Artocarpus, and so forth. They have become of interest in the research and development of natural antitumor agents over the past decades due to their broad range of mechanisms including anti-initiation, induction of apoptosis, antiproliferation, antimetastasis, antiangiogenesis, and so forth. This review summarizes the studies on the antitumor activity of naturally occurring chalcones and their underlying mechanisms in detail during the past decades.

  1. Naturally Occurring Anthraquinones: Chemistry and Therapeutic Potential in Autoimmune Diabetes

    Directory of Open Access Journals (Sweden)

    Shih-Chang Chien

    2015-01-01

    Full Text Available Anthraquinones are a class of aromatic compounds with a 9,10-dioxoanthracene core. So far, 79 naturally occurring anthraquinones have been identified which include emodin, physcion, cascarin, catenarin, and rhein. A large body of literature has demonstrated that the naturally occurring anthraquinones possess a broad spectrum of bioactivities, such as cathartic, anticancer, anti-inflammatory, antimicrobial, diuretic, vasorelaxing, and phytoestrogen activities, suggesting their possible clinical application in many diseases. Despite the advances that have been made in understanding the chemistry and biology of the anthraquinones in recent years, research into their mechanisms of action and therapeutic potential in autoimmune disorders is still at an early stage. In this paper, we briefly introduce the etiology of autoimmune diabetes, an autoimmune disorder that affects as many as 10 million worldwide, and the role of chemotaxis in autoimmune diabetes. We then outline the chemical structure and biological properties of the naturally occurring anthraquinones and their derivatives with an emphasis on recent findings about their immune regulation. We discuss the structure and activity relationship, mode of action, and therapeutic potential of the anthraquinones in autoimmune diabetes, including a new strategy for the use of the anthraquinones in autoimmune diabetes.

  2. Leaching Properties of Naturally Occurring Heavy Metals from Soils

    Science.gov (United States)

    Zhang, M.; Hoshino, M.; Yoshikawa, M.; Hara, J.; Sugita, H.

    2014-12-01

    The major threats to human health from heavy metals are associated with exposure to arsenic, lead, cadmium, chromium, mercury, as well as some other elements. The effects of such heavy metals on human health have been extensively studied and reviewed by international organizations such as WHO. Due to their toxicity, heavy metal contaminations have been regulated by national environmental standards in many countries, and/or laws such as the Soil Contamination Countermeasures Act in Japan. Leaching of naturally occurring heavy metals from the soils, especially those around abandoned metal mines into surrounding water systems, either groundwater or surface water systems, is one of the major pathways of exposure. Therefore, understanding the leaching properties of toxic heavy metals from naturally polluted soils is of fundamentally importance for effectively managing abandoned metal mines, excavated rocks discharged from infrastructure constructions such as tunneling, and/or selecting a pertinent countermeasure against pollution when it is necessary. In this study, soil samples taken from the surroundings of abandoned metal mines in different regions in Japan were collected and analyzed. The samples contained multiple heavy metals such as lead, arsenic and chromium. Standard leaching test and sequential leaching test considering different forms of contaminants, such as trivalent and pentavalent arsenics, and trivalent and hexavalent chromiums, together with standard test for evaluating total concentration, X-ray Fluorescence Analysis (XRF), X-ray diffraction analysis (XRD) and Cation Exchange Capacity (CEC) tests were performed. In addition, sequential leaching tests were performed to evaluate long-term leaching properties of lead from representative samples. This presentation introduces the details of the above experimental study, discusses the relationships among leaching properties and chemical and mineral compositions, indicates the difficulties associated with

  3. Natural transformation of Campylobacter jejuni occurs beyond limits of growth

    DEFF Research Database (Denmark)

    Vegge, Christina Skovgaard; Brøndsted, Lone; Ligowska, Małgorzata

    2012-01-01

    of transformation is correlated to the growth conditions, but more importantly that transformation occurs at growth-restrictive conditions as well as in the late stationary phase; hence revealing that growth per se is not required for C. jejuni to be competent. Yet, natural transformation of C. jejuni is an energy......Campylobacter jejuni is a human bacterial pathogen. While poultry is considered to be a major source of food borne campylobacteriosis, C. jejuni is frequently found in the external environment, and water is another well-known source of human infections. Natural transformation is considered...... to be one of the main mechanisms for mediating transfer of genetic material and evolution of the organism. Given the diverse habitats of C. jejuni we set out to examine how environmental conditions and physiological processes affect natural transformation of C. jejuni. We show that the efficiency...

  4. Virus-like particle display of HER2 induces potent anti-cancer responses

    DEFF Research Database (Denmark)

    Palladini, Arianna; Thrane, Susan; Janitzek, Christoph M

    2018-01-01

    Overexpression of human epidermal growth factor receptor-2 (HER2) occurs in 20-30% of invasive breast cancers. Monoclonal antibody therapy is effective in treating HER2-driven mammary carcinomas, but its utility is limited by high costs, side effects and development of resistance. Active vaccinat...

  5. A virosomal formulated Her-2/neu multi-peptide vaccine induces Her-2/neu-specific immune responses in patients with metastatic breast cancer: a phase I study.

    Science.gov (United States)

    Wiedermann, Ursula; Wiltschke, C; Jasinska, J; Kundi, M; Zurbriggen, R; Garner-Spitzer, E; Bartsch, R; Steger, G; Pehamberger, H; Scheiner, O; Zielinski, C C

    2010-02-01

    We have previously shown in mice that vaccination with three Her-2-peptides representing B-cell epitopes of the extracellular domain of Her-2/neu induces Her-2/neu-specific IgG antibodies with strong anti-tumor activity in vitro and in vivo. We have now finalized a phase I clinical trial with an anti-Her-2/neu vaccine-construct of immunopotentiating reconstituted influenza virosomes with the three peptides in patients with metastatic breast cancer (MBC). Ten MBC patients with low protein overexpression of Her-2/neu of MBC (+ or ++ upon immunohistochemistry, FISH negative) and positive hormone receptor status were enrolled in a single center phase I study. The virosomal formulated vaccine, consisting of 10 microg/peptide, was intramuscularly applied three times on days 1, 28, and 56. The primary endpoint of the study, which lasted 12 weeks, was safety, the secondary endpoint immunogenicity. Local erythema at the injection site was the only vaccine-related side effect occurring in four patients. In 8 of 10 patients an increase in peptide-specific antibody titer measured by ELISA was found. Importantly, the induced antibodies were also directed against the native Her-2/neu protein. Cellular immune responses, as measured by in vitro production of IL-2, IFN-c, and TNF-a of PBMCs showed a marked increase after vaccination in the majority of vaccinees. Notably, the number of CD4+CD25+Foxp3+T regulatory cells, which were significantly increased compared to healthy controls prior to vaccination, was markedly reduced following vaccination. In all, the immunological responses after vaccination indicated that the patients in stage IV of disease were immunocompetent and susceptible to vaccination. The Her-2/neu multipeptide vaccine was safe, well tolerated and effective in overcoming immunological tolerance to Her-2/neu. The induction of anti-Her-2-specific antibodies could result in clinical benefit comparable to passive anti-Her-2 antibody therapy.

  6. Coamplification of miR-4728 protects HER2-amplified breast cancers from targeted therapy

    Science.gov (United States)

    Floros, Konstantinos V.; Hu, Bin; Monterrubio, Carles; Hughes, Mark T.; Wells, Jason D.; Morales, Cristina Bernadó; Ghotra, Maninderjit S.; Costa, Carlotta; Souers, Andrew J.; Boikos, Sosipatros A.; Leverson, Joel D.; Tan, Ming; Serra, Violeta; Koblinski, Jennifer E.; Arribas, Joaquin; Prat, Aleix; Paré, Laia; Miller, Todd W.; Harada, Hisashi; Windle, Brad E.; Scaltriti, Maurizio; Faber, Anthony C.

    2018-01-01

    HER2 (ERBB2) amplification is a driving oncogenic event in breast cancer. Clinical trials have consistently shown the benefit of HER2 inhibitors (HER2i) in treating patients with both local and advanced HER2+ breast cancer. Despite this benefit, their efficacy as single agents is limited, unlike the robust responses to other receptor tyrosine kinase inhibitors like EGFR inhibitors in EGFR-mutant lung cancer. Interestingly, the lack of HER2i efficacy occurs despite sufficient intracellular signaling shutdown following HER2i treatment. Exploring possible intrinsic causes for this lack of response, we uncovered remarkably depressed levels of NOXA, an endogenous inhibitor of the antiapoptotic MCL-1, in HER2-amplified breast cancer. Upon investigation of the mechanism leading to low NOXA, we identified a micro-RNA encoded in an intron of HER2, termed miR-4728, that targets the mRNA of the Estrogen Receptor α (ESR1). Reduced ESR1 expression in turn prevents ERα-mediated transcription of NOXA, mitigating apoptosis following treatment with the HER2i lapatinib. Importantly, resistance can be overcome with pharmacological inhibition of MCL-1. More generally, while many cancers like EGFR-mutant lung cancer are driven by activated kinases that when drugged lead to robust monotherapeutic responses, we demonstrate that the efficacy of targeted therapies directed against oncogenes active through focal amplification may be mitigated by coamplified genes. PMID:29476008

  7. Reference Material IAEA 434: Naturally Occurring Radionuclides in Phosphogypsum

    International Nuclear Information System (INIS)

    2010-01-01

    Phosphogypsum is generated as a by-product of the phosphoric acid based fertilizer industry. The discharge of phosphogypsum on earth surface deposits is a potential source of enhanced natural radiation and heavy metals, and the resulting environmental impact should be considered carefully to ensure safety and compliance with environmental regulations. In addition, phosphogypsum can be used to make several building materials and it is used in agriculture as a conditioner to maintain soil productivity in areas where soils are poor and erode easily. A reliable determination of naturally occurring radionuclides in phosphogypsum is necessary to comply with the radiation protection and environmental regulations. The IAEA-434 will assist laboratories in the IAEA Member States in validating their analytical methods for the determination of naturally occurring radionuclides in phosphogypsum and to control the quality of the produced analytical results. Reference values for the massic activities and associated standard uncertainties were established for: Pb-210, Ra-226, Th-230, U-234 and U-238. During sample production and certification, the requirements for reference material production and certification as stated in ISO guides 34 and 35 were taken into account. This report summarizes the preparation and certification process

  8. Complexes of actinides with naturally occuring organic substances - Literature survey

    International Nuclear Information System (INIS)

    Olofsson, U.; Allard, B.

    1983-02-01

    Properties of naturally occurring humic and fulvic acids and their formation of actinide complexes are reviewed. Actinides in all the oxdation states III, IV, V and VI would form complexes with many humic and fulvic acids, comparable in strength to the hydroxide and carbonate complexes. Preliminary experiments have shown, that the presence of predominantly humic acid complexes would significantly reduce the sorption of americium on geologic media. This does not, however, necessarily lead to a potentially enhanced mobility under environmental conditions, since humic and fulvic acids carrying trace metals also would be strongly bound to e.g. clayish material. (author)

  9. Naturally occurring radioactive materials at New South Wales mines

    International Nuclear Information System (INIS)

    McLaughlin, Robert

    2013-01-01

    Until recently mines in New South Wales have been largely exempt from the provisions of the Radiation Control Act with respect to radioactive ore being mined and processed. Legislative changes and the national harmonisation efforts for mine safety regulation have drawn attention to the emerging issue of naturally occurring radioactive material (NORM). While mine operators are already obliged under their duty of care to manage this hazard, specific control measures are increasingly expected by the community and regulators. This applies throughout the whole mine life cycle from exploration right through to rehabilitation.

  10. Immunomodulatory effects in workers exposed to naturally occurring asbestos fibers.

    Science.gov (United States)

    Ledda, Caterina; Costa, Chiara; Matera, Serena; Puglisi, Beatrice; Costanzo, Valentina; Bracci, Massimo; Fenga, Concettina; Rapisarda, Venerando; Loreto, Carla

    2017-05-01

    Natural asbestiform fibers are defined 'naturally occurring asbestos' (NOA) and refer to the mineral as a natural component of soils or rocks. The release of NOA fibers into the air from rocks or soils by routine human activities or natural weathering processes represents a risk for human beings. Fluoro-edenite (FE) is a NOA fiber detected in the benmoreitic lava in the area of Biancavilla, South-west slope of Mt. Etna. The aim of the present study was to investigate FE immunotoxicity pathways in a group of 38 occupationally exposed construction workers, in order to find any biological markers of its effect. Subjects underwent respiratory function tests and HRCT total chest scanning. Serum IL-1β, IL-6, IL-8 and TNF-α were measured. The presence of PPs was significantly greater in subjects exposed than in the control (25 vs. 2). In subjects exposed to FE, IL-1β and TNF-α values were significantly higher than the controls. The previously observed increase of IL-1β and IL-18 showed a probable involvement of the proteic complex defined inflammosome by FE fibers.

  11. Naturally occurring radionuclides in agricultural products: An overview

    International Nuclear Information System (INIS)

    Hanlon, E.A.

    1994-01-01

    Low levels of naturally occurring radionuclides exist in phosphatic clays, a by-product of phosphatic mining and beneficiation processes. Concerns about these radionuclides entering the human food chain were an immediate research priority before the phosphate clays could be reclaimed for intensive agricultural purposes. Efforts included the assembly of a large body of data from both sons and plants, part of which were produced by the Polk County (Florida) Mined Lands Agricultural Research/Demonstration Project MLAR/DP. Additional detailed studies involving dairy and beef cattle (Bos taurus) were conducted by researchers working with the MLAR/DP. A national symposium was conducted in which data concerning the MLAR/DP work and other research projects also dealing with naturally occurring radionuclides in agriculture could be discussed. The symposium included invited review papers dealing with the identification of radionuclide geological origins, the geochemistry and movement of radionuclides within the environment, mechanisms of plant uptake, entry points into the food chain, and evaluation of dose and risk assessment to the consumer of low levels of radionuclides. The risk to human health of an individual obtaining 0.1 of his or her dietary intake from crops produced on phosphatic clays increased by 1 in 5 x 10 6 /yr above a control individual consuming no food grown on phosphatic clays. Leaf tissues were found to be generally higher than fruit, grain, or root tissues. The natural range in radionuclide content among various food types was greater than the difference in radionuclides content between the same food produced on phosphatic clays vs. natural soils. 19 refs

  12. Regulation of naturally occurring radioactive materials in Australia

    International Nuclear Information System (INIS)

    Jeffries, C.; Akber, R.; Johnston, A.; Cassels, B.

    2011-01-01

    In order to promote uniformity between jurisdictions, the Australian Radiation Protection and Nuclear Safety Agency (ARPANSA) has developed the National Directory for Radiation Protection, which is a regulatory framework that all Australian governments have agreed to adopt. There is a large and diverse range of industries involved in mining or mineral processing, and the production of fossil fuels in Australia. Enhanced levels of naturally occurring radionuclides can be associated with mineral extraction and processing, other industries (e.g. metal recycling) and some products (e.g. plasterboard). ARPANSA, in conjunction with industry and State regulators, has undertaken a review and assessment of naturally occurring radioactive material (NORM) management in Australian industries. This review has resulted in guidance on the management of NORM that will be included in the National Directory for Radiation Protection. The first NORM safety guide provides the framework for NORM management and addresses specific NORM issues in oil and gas production, bauxite, aluminium and phosphate industries. Over time further guidance material for other NORM-related industries will be developed. This presentation will provide an overview of the regulatory approach to managing NORM industries in Australia. (authors)

  13. Interaction between manufactured gold nanoparticles and naturally occurring organic macromolecules

    International Nuclear Information System (INIS)

    Diegoli, Sara; Manciulea, Adriana L.; Begum, Shakiela; Jones, Ian P.; Lead, Jamie R.; Preece, Jon A.

    2008-01-01

    The increasing exploitation of nanomaterials into many consumer and other products is raising concerns as these nanomaterials are likely to be released into the environment. Due to our lack of knowledge about the environmental chemistry, transport and ecotoxicology of nanomaterials, it is of paramount importance to study how natural aquatic colloids can interact with manufactured gold nanoparticles as these interactions will determine their environmental fate and behaviour. In this context, our work aims to quantify the effect of naturally occurring riverine macromolecules - International Humic Substances Society (IHSS) Suwannee River Humic Acid Standard (SRHA) - on citrate- and acrylate-stabilized gold nanoparticles. The influence of SRHA on the stability of the gold colloids was studied as a function of pH by UV-visible absorption spectroscopy, dynamic light scattering (DLS) and transmission electron microscopy (TEM). At high ionic strengths (0.1 M), extensive and rapid aggregation occurred, while more subtle effects were observed at lower ionic strength values. Evidence was found that SRHA enhances particle stability at extreme pH values (ionic strength < 0.01 M) by substituting and/or over-coating the original stabilizer on the gold nanoparticle surface, thus affecting surface charge and chemistry. These findings have important implications for the fate and behaviour of nanoparticles in the environment and their ecotoxicity

  14. Daily intakes of naturally occurring radioisotopes in typical Korean foods

    International Nuclear Information System (INIS)

    Choi, Min-Seok; Lin Xiujing; Lee, Sun Ah; Kim, Wan; Kang, Hee-Dong; Doh, Sih-Hong; Kim, Do-Sung; Lee, Dong-Myung

    2008-01-01

    The concentrations of naturally occurring radioisotopes ( 232 Th, 228 Th, 230 Th, 228 Ra, 226 Ra, and 40 K) in typical Korean foods were evaluated. The daily intakes of these radioisotopes were calculated by comparing concentrations in typical Korean foods and the daily consumption rates of these foods. Daily intakes were as follows: 232 Th, 0.00-0.23; 228 Th, 0.00-2.04; 230 Th, 0.00-0.26; 228 Ra, 0.02-2.73; 226 Ra, 0.01-4.37 mBq/day; and 40 K, 0.01-5.71 Bq/day. The total daily intake of the naturally occurring radioisotopes measured in this study from food was 39.46 Bq/day. The total annual internal dose resulting from ingestion of radioisotopes in food was 109.83 μSv/y, and the radioisotope with the highest daily intake was 40 K. These values were same level compiled in other countries

  15. Regulation of naturally occurring radioactive materials in Australia.

    Science.gov (United States)

    Jeffries, Cameron; Akber, Riaz; Johnston, Andrew; Cassels, Brad

    2011-07-01

    In order to promote uniformity between jurisdictions, the Australian Radiation Protection and Nuclear Safety Agency (ARPANSA) has developed the National Directory for Radiation Protection, which is a regulatory framework that all Australian governments have agreed to adopt. There is a large and diverse range of industries involved in mining or mineral processing, and the production of fossil fuels in Australia. Enhanced levels of naturally occurring radionuclides can be associated with mineral extraction and processing, other industries (e.g. metal recycling) and some products (e.g. plasterboard). ARPANSA, in conjunction with industry and State regulators, has undertaken a review and assessment of naturally occurring radioactive material (NORM) management in Australian industries. This review has resulted in guidance on the management of NORM that will be included in the National Directory for Radiation Protection. The first NORM safety guide provides the framework for NORM management and addresses specific NORM issues in oil and gas production, bauxite, aluminium and phosphate industries. Over time further guidance material for other NORM-related industries will be developed. This presentation will provide an overview of the regulatory approach to managing NORM industries in Australia.

  16. Altered dopamine signaling in naturally occurring maternal neglect.

    Directory of Open Access Journals (Sweden)

    Stephen C Gammie

    2008-04-01

    occurring neglect and that MaD1 mice are a useful model for understanding the basis of naturally occurring neglect.

  17. Naturally occurring dominant drug resistance mutations occur infrequently in the setting of recently acquired hepatitis C.

    Science.gov (United States)

    Applegate, Tanya L; Gaudieri, Silvana; Plauzolles, Anne; Chopra, Abha; Grebely, Jason; Lucas, Michaela; Hellard, Margaret; Luciani, Fabio; Dore, Gregory J; Matthews, Gail V

    2015-01-01

    Direct-acting antivirals (DAAs) are predicted to transform hepatitis C therapy, yet little is known about the prevalence of naturally occurring resistance mutations in recently acquired HCV. This study aimed to determine the prevalence and frequency of drug resistance mutations in the viral quasispecies among HIV-positive and -negative individuals with recent HCV. The NS3 protease, NS5A and NS5B polymerase genes were amplified from 50 genotype 1a participants of the Australian Trial in Acute Hepatitis C. Amino acid variations at sites known to be associated with possible drug resistance were analysed by ultra-deep pyrosequencing. A total of 12% of individuals harboured dominant resistance mutations, while 36% demonstrated non-dominant resistant variants below that detectable by bulk sequencing (that is, Resistance variants (resistance from all classes, with the exception of sofosbuvir. Dominant resistant mutations were uncommonly observed in the setting of recent HCV. However, low-level mutations to all DAA classes were observed by deep sequencing at the majority of sites and in most individuals. The significance of these variants and impact on future treatment options remains to be determined. Clinicaltrials.gov NCT00192569.

  18. HER2 activating mutations are targets for colorectal cancer treatment.

    Science.gov (United States)

    Kavuri, Shyam M; Jain, Naveen; Galimi, Francesco; Cottino, Francesca; Leto, Simonetta M; Migliardi, Giorgia; Searleman, Adam C; Shen, Wei; Monsey, John; Trusolino, Livio; Jacobs, Samuel A; Bertotti, Andrea; Bose, Ron

    2015-08-01

    The Cancer Genome Atlas project identified HER2 somatic mutations and gene amplification in 7% of patients with colorectal cancer. Introduction of the HER2 mutations S310F, L755S, V777L, V842I, and L866M into colon epithelial cells increased signaling pathways and anchorage-independent cell growth, indicating that they are activating mutations. Introduction of these HER2 activating mutations into colorectal cancer cell lines produced resistance to cetuximab and panitumumab by sustaining MAPK phosphorylation. HER2 mutants are potently inhibited by low nanomolar doses of the irreversible tyrosine kinase inhibitors neratinib and afatinib. HER2 gene sequencing of 48 cetuximab-resistant, quadruple (KRAS, NRAS, BRAF, and PIK3CA) wild-type (WT) colorectal cancer patient-derived xenografts (PDX) identified 4 PDXs with HER2 mutations. HER2-targeted therapies were tested on two PDXs. Treatment with a single HER2-targeted drug (trastuzumab, neratinib, or lapatinib) delayed tumor growth, but dual HER2-targeted therapy with trastuzumab plus tyrosine kinase inhibitors produced regression of these HER2-mutated PDXs. HER2 activating mutations cause EGFR antibody resistance in colorectal cell lines, and PDXs with HER2 mutations show durable tumor regression when treated with dual HER2-targeted therapy. These data provide a strong preclinical rationale for clinical trials targeting HER2 activating mutations in metastatic colorectal cancer. ©2015 American Association for Cancer Research.

  19. Quantification of HER2 autoantibodies in the amplification phenomenon of HER2 in breast cancer

    DEFF Research Database (Denmark)

    Lauterlein, Jens-Jacob L; Petersen, Eva R B; Olsen, Dorte Aa

    2011-01-01

    Gene amplification of HER2 (human epidermal growth factor receptor 2) is a well-known phenomenon in various cancers. However, little is known about the mechanism of the gene amplification phenomenon itself. Autoantibodies to cellular receptors have been described in several cancer types. We hypot...

  20. Determination of naturally occurring radionuclides in El-Sin Water

    International Nuclear Information System (INIS)

    Al-Masri, M.S.; Al-Rayyes, A.H.

    2000-01-01

    Naturally occurring radionuclides levels have been determined in El-Sin water for the period of 1995 and 1996. water samples were collected from four sites, which are the main drinking water sources of the area. Radon concentration was found to vary between 0.88 Bq/1 in Lattakia main water supply site and 8.4 Bq/1 in El-Sin springs.The highest values found for other radionuclides were 51.6 mBq/1, 18.6 mB/1 and 24.8 mBq/1 for sup 2 sup 2 sup 6 Ra, sup 2 sup 1 sup 0 Po and total uranium (sup 2 sup 3 sup 4 U and sup 2 sup 3 sup 8 U) respectively. These levels are much lower than the maximum permissible levels in drinking water set by international organization.(author)

  1. Is anyone regulating naturally occurring radioactive material? A state survey

    International Nuclear Information System (INIS)

    Gross, E.M.; Barisas, S.G.

    1993-08-01

    As far as we know, naturally occurring radioactive material (NORM) has surrounded humankind since the beginning of time. However, recent data demonstrating that certain activities concentrate NORM have increased concern regarding its proper handling and disposal and precipitated the development of new NORM-related regulations. The regulation of NORM affects the management of government facilities as well as a broad range of industrial processes. Recognizing that NORM regulation at the federal level is extremely limited, Argonne National Laboratory (ANL) conducted a 50-state survey to determine the extent to which states have assumed the responsibility for regulating NORM as well as the NORM standards that are currently being applied at the state level. Though the survey indicates that NORM regulation comprises a broad spectrum of controls from full licensing requirements to virtually no regulation at afl, a trend is emerging toward recognition of the need for increased regulation of potential NORM hazards, particularly in the absence of federal standards

  2. Discrimination of Naturally Occurring Radioactive Material in Plastic Scintillator Material

    International Nuclear Information System (INIS)

    Ely, James H.; Kouzes, Richard T.; Geelhood, Bruce D.; Schweppe, John E.; Warner, Ray A.

    2003-01-01

    Plastic scintillator material is used in many applications for the detection of gamma-rays from radioactive material, primarily due to the sensitivity per unit cost compared to other detection materials. However, the resolution and lack of full-energy peaks in the plastic scintillator material prohibits detailed spectroscopy. Therefore, other materials such as doped sodium iodide are used for spectroscopic applications. The limited spectroscopic information can however be exploited in plastic scintillator materials to provide some discrimination. The discrimination between man-made and naturally occurring sources would be useful in reducing alarm screening for radiation detection applications which target man-made sources. The results of applying the limited energy information from plastic scintillator material for radiation portal monitors are discussed.

  3. Modification of radiation damage by naturally occurring substances

    International Nuclear Information System (INIS)

    Prasad, K.N.

    1984-01-01

    The major objectives of studying the modification of radiation sensitivity have been (1) to identify a compound that will produce a differential protection or sensitization of the effect of irradiation on normal and tumor tissue, and (2) to understand more about the mechanisms of radiation damage. In spite of massive research on this particular problem since World War II, the first objective remains elusive. During this period, numerous radioprotective and radiosensitizing agents have been identified. These agents have served as important biologic tools for increasing our understanding of radiation injuries. Most of these substances are synthetic compounds and are very toxic to humans. In addition, very few of the compounds provide differential modifications of the effect of radiation on tumor and normal cells. This chapter presents objectives for identifying naturally occurring substances that modify the effect of x-radiation on mammalian cells and discusses the role of physiologic substances in modifying radiation injuries on mammalian normal and tumor cells

  4. Epigenetic variation in mangrove plants occurring in contrasting natural environment.

    Directory of Open Access Journals (Sweden)

    Catarina Fonseca Lira-Medeiros

    2010-04-01

    Full Text Available Epigenetic modifications, such as cytosine methylation, are inherited in plant species and may occur in response to biotic or abiotic stress, affecting gene expression without changing genome sequence. Laguncularia racemosa, a mangrove species, occurs in naturally contrasting habitats where it is subjected daily to salinity and nutrient variations leading to morphological differences. This work aims at unraveling how CpG-methylation variation is distributed among individuals from two nearby habitats, at a riverside (RS or near a salt marsh (SM, with different environmental pressures and how this variation is correlated with the observed morphological variation.Significant differences were observed in morphological traits such as tree height, tree diameter, leaf width and leaf area between plants from RS and SM locations, resulting in smaller plants and smaller leaf size in SM plants. Methyl-Sensitive Amplified Polymorphism (MSAP was used to assess genetic and epigenetic (CpG-methylation variation in L. racemosa genomes from these populations. SM plants were hypomethylated (14.6% of loci had methylated samples in comparison to RS (32.1% of loci had methylated samples. Within-population diversity was significantly greater for epigenetic than genetic data in both locations, but SM also had less epigenetic diversity than RS. Frequency-based (G(ST and multivariate (beta(ST methods that estimate population structure showed significantly greater differentiation among locations for epigenetic than genetic data. Co-Inertia analysis, exploring jointly the genetic and epigenetic data, showed that individuals with similar genetic profiles presented divergent epigenetic profiles that were characteristic of the population in a particular environment, suggesting that CpG-methylation changes may be associated with environmental heterogeneity.In spite of significant morphological dissimilarities, individuals of L. racemosa from salt marsh and riverside presented

  5. 'The NORM Report' : the journal addressing naturally occurring radioactive materials

    International Nuclear Information System (INIS)

    Simmons, C.T.; Tsurikov, N.

    2008-01-01

    Full text: The need for the specific international publication dedicated to the radiation protection and regulatory issues associated with exposures of workers, general public and the environment in situations involving naturally occurring radioactive materials (Norm) has been identified almost ten years ago. In the 1990-s the journal entitled 'the NORM report' was published in the U.S.A. mainly dealt with legislative updates in regard to NORM in different states and at a later stage Canada. The printed journal has a wide following among industries and regulatory authorities concerned with NORM. Unfortunately, the publishing ceased in early 2000-s with the passing of the editor, Dr. Peter Gray. The publication of 'the NORM Report' will re-commence in early 2008 as an internet based publication that is intended to be a resource for: Regulatory authorities exchange information in regards to the 'NORM-specific' regulations and guidelines applicable in their jurisdictions. They are also able to collect details from authorities in other countries/states - to ensure the adoption of the most appropriate regulatory standards to similar levels of radiation exposure and the same industries world-wide (not only within the USA), a) Researches, who will be able to publish the results of their studies in a journal specifically dedicated to naturally occurring radioactive materials and b) Industries that use, process, and generate - to facilitate the information exchange in regards to best practices in controlling radiation exposure and in the disposal or re-use of NORM-containing materials. The intent of the presentation is to obtain the opinion of a wider radiation protection community of the usefulness and the contents of the publication of 'the NORM Report' to ensure the journal meets its state objectives. (author)

  6. Naturally occurring radioactivity in the Nordic countries. Recommendations

    International Nuclear Information System (INIS)

    2000-01-01

    In the publication 'Naturally Occurring Radiation in the Nordic Countries - Recommendations' published in 1986 the radiation protection authorities in Denmark, Finland, Iceland, Norway and Sweden gave radiation protection recommendations for natural radiation in the Nordic countries. The exposure of the populations in the Nordic countries to natural radiation sources is among the highest in the world and much effort has been devoted during the last 10 to 20 years to characterising, assessing and, where feasible, to reduce these exposures. The exposure of workers to natural radiation sources has also been an important area of work in the same period. During this period the international recommendations on radiation protection policy have been further developed with ICRP Publication 60: '1990 Recommendations of the International Commission on Radiological Protection', and ICRP Publication 65: 'Protection Against Radon-222 at Home and at Work'. The European Basic Safety Standards Directive from 1996 (96/29/EURATOM), which is based on the ICRP recommendations, differs from the earlier versions in that special provisions have been laid down concerning exposure to natural radiation sources. As Denmark, Finland and Sweden are members of European Union and the EFTA-countries (Iceland and Norway) have close co-operation with the EU, the practical implementation of the EU-BSS will play an important role in all the Nordic countries. In November 1998, a new Drinking Water Directive, 98/83/EC, was adopted. The directive also includes radioactivity in drinking water, excluding potassium-40, radon, and radon decay products. Altogether this means that the Nordic recommendations from 1986 for natural radiation needed to be updated. The Nordic Radiation Protection Authorities therefore decided to set up a working group with the aim of revising the recommendations from 1986. The new revised recommendations will, as before, only deal with the components of the exposure to natural

  7. Naturally occurring Vpr inhibitors from medicinal plants of Myanmar.

    Science.gov (United States)

    Win, Nwet Nwet; Ngwe, Hla; Abe, Ikuro; Morita, Hiroyuki

    2017-10-01

    Human immunodeficiency virus type-1 (HIV-1) is a lentiviral family member that encodes the retroviral Gag, Pol, and Env proteins, along with six additional accessory proteins, Tat, Rev, Vpu, Vif, Nef, and Vpr. The currently approved anti-HIV drugs target the Pol and Env encoded proteins. However, these drugs are only effective in reducing viral replication. Furthermore, the drugs' toxicities and the emergence of drug-resistant strains have become serious worldwide problems. Resistance eventually arises to all of the approved anti-HIV drugs, including the newly approved drugs that target HIV integrase (IN). Drug resistance likely emerges because of spontaneous mutations that occur during viral replication. Therefore, new drugs that effectively block other viral components must be developed to reduce the rate of resistance and suppress viral replication with little or no long-term toxicity. The accessory proteins may expand treatment options. Viral protein R (Vpr) is one of the promising drug targets among the HIV accessory proteins. However, the search for inhibitors continues in anti-HIV drug discovery. In this review, we summarize the naturally occurring compounds discovered from two Myanmar medicinal plants as well as their structure-activity relationships. A total of 49 secondary metabolites were isolated from Kaempferia pulchra rhizomes and Picrasama javanica bark, and the types of compounds were identified as isopimarane diterpenoids and picrasane quassinoids, respectively. Among the isolates, 7 diterpenoids and 15 quassinoids were found to be Vpr inhibitors lacking detectable toxicity, and their potencies varied according to their respective functionalities.

  8. Radiation protection and the naturally occurring radioactive materials (NORM)

    International Nuclear Information System (INIS)

    Paschoa, A.S.; MacDowell, P.

    1996-01-01

    There are many industries dealing with naturally occurring radioactive materials (NORM), some of them without knowing that their industrial processes and/or their regular wastes involve radioactivity. However, an increasing number of industries that produce NORM wastes are being sued, wherever there is a legal framework to do so. In particular, NORM wastes produced for a long time by the oil industry became foci of legal battles in the United States and elsewhere. The ripple effect of these judicial battles will influence the decision making processes of NORM wastes producing industries, mostly because of the costs incurred by remedial and preventive actions concerning NORM contamination. The regulation of NORM will occur sooner or later, and such actions may become mandatory. A foreseeable consequence of such regulation is a change in attitude concerning the sources and materials associated with NORM. Among those industries likely to be affected one can mention: niobium; rare earth processing; oil production; phosphate; uranium mining and milling; zircon; water treatment; and waste water treatment. The paper will briefly review data on exempt concentration activities, as suggested by the basic safety standards based on realistic environmental and dosimetric models. These activity concentrations are compared with those found in a number of extractive industries, and may be used to establish derived limits from a pre-established dose limit. (author)

  9. HER2 overexpression elicits a pro-inflammatory IL-6 autocrine signaling loop that is critical for tumorigenesis

    Science.gov (United States)

    Hartman, Zachary C.; Yang, Xiao-Yi; Glass, Oliver; Lei, Gangjun; Osada, Takuya; Dave, Sandeep S.; Morse, Michael A.; Clay, Timothy M.; Lyerly, Herbert Kim

    2011-01-01

    HER2 overexpression occurs in ~25% of breast cancers where it correlates with poor prognosis. Likewise, systemic inflammation in breast cancer correlates with poor prognosis although the process is not understood. In this study, we explored the relationship between HER2 and inflammation, comparing the effects of overexpressing wild-type or mutated inactive forms of HER2 in primary human breast cells. Wild-type HER2 elicited a profound transcriptional inflammatory profile, including marked elevation of IL-6 expression, which we established to be a critical determinant of HER2 oncogenesis. Mechanistic investigations revealed that IL-6 secretion induced by HER2 overexpression activated Stat3 and altered gene expression, enforcing an autocrine loop of IL-6/Stat3 expression. Both mouse and human in vivo models of HER2 amplified breast carcinoma relied critically on this HER2-IL-6-Stat3 signaling pathway. Our studies offer the first direct evidence linking HER2 to a systemic inflammatory mechanism that orchestrates HER2-mediated tumor growth. We suggest that the HER2-IL6-STAT3 signaling axis we have defined in breast cancer could prompt new therapeutic or prevention strategies for treatment of HER2-amplified cancers. PMID:21518778

  10. Emerging treatments for HER2-positive early-stage breast cancer: focus on neratinib.

    Science.gov (United States)

    Kourie, Hampig Raphael; El Rassy, Elie; Clatot, Florian; de Azambuja, Evandro; Lambertini, Matteo

    2017-01-01

    Over the last decades, a better understanding of breast cancer heterogeneity provided tools for a biologically based personalization of anticancer treatments. In particular, the overexpression of the human epidermal growth factor receptor 2 (HER2) by tumor cells provided a specific target in these HER2-positive tumors. The development of the monoclonal antibody trastuzumab, and its approval in 1998 for the treatment of patients with metastatic disease, radically changed the natural history of this aggressive subtype of breast cancer. These findings provided strong support for the continuous research in targeting the HER2 pathway and implementing the development of new anti-HER2 targeted agents. Besides trastuzumab, a series of other anti-HER2 agents have been developed and are currently being explored for the treatment of breast cancer patients, including those diagnosed with early-stage disease. Among these agents, neratinib, an oral tyrosine kinase inhibitor that irreversibly inhibits HER1, HER2, and HER4 at the intracellular level, has shown promising results, including when administered to patients previously exposed to trastuzumab-based treatment. This article aims to review the available data on the role of the HER2 pathway in breast cancer and on the different targeted agents that have been studied or are currently under development for the treatment of patients with early-stage HER2-positive disease with a particular focus on neratinib.

  11. Committed effective dose from naturally occuring radionuclides in shellfish

    International Nuclear Information System (INIS)

    Khandaker, Mayeen Uddin; Wahib, Norfadira Binti; Amin, Yusoff Mohd.; Bradley, D.A.

    2013-01-01

    Recognizing their importance in the average Malaysian daily diet, the radioactivity concentrations in mollusc- and crustacean-based food have been determined for key naturally occuring radionuclides. Fresh samples collected from various maritime locations around peninsular Malaysia have been processed using standard procedures; the radionuclide concentrations being determined using an HPGe γ-ray spectrometer. For molluscs, assuming secular equilibrium, the range of activities of 238 U ( 226 Ra), 232 Th ( 228 Ra) and 40 K were found to be 3.28±0.35 to 5.34±0.52, 1.20±0.21 to 2.44±0.21 and 118±6 to 281±14 Bq kg −1 dry weight, respectively. The respective values for crustaceans were 3.02±0.57 to 4.70±0.52, 1.38±0.21 to 2.40±0.35 and 216±11 to 316±15 Bq kg −1 . The estimated average daily intake of radioactivity from consumption of molluscs are 0.37 Bq kg −1 for 238 U ( 226 Ra), 0.16 Bq kg −1 for 232 Th ( 228 Ra) and 18 Bq kg −1 for 40 K; the respective daily intake values from crustaceans are 0.36 Bq kg −1 , 0.16 Bq kg −1 and 23 Bq kg −1 . Associated annual committed effective doses from molluscs are estimated to be in the range 21.3 to 34.7 μSv for 226 Ra, 19.3 to 39.1 μSv for 228 Ra and 17.0 to 40.4 μSv for 40 K. For crustaceans, the respective dose ranges are 19.6 to 30.5 μSv, 22.0 to 38.4 μSv and 31.1 to 45.5 μSv, being some several times world average values. - Highlights: ► Activity concentrations of naturally occuring radionuclides were assessed for shellfish. ► 238 U, 232 Th, 40 K intake via shellfish showed several times higher than world averages. ► Committed effective doses due to the ingestions of 238 U, 232 Th, 40 K are the first report in Malaysia. ► Estimated committed effective dose also showed higher values than the world average

  12. Naturally occurring mastitis disrupts developmental competence of bovine oocytes.

    Science.gov (United States)

    Roth, Z; Dvir, A; Kalo, D; Lavon, Y; Krifucks, O; Wolfenson, D; Leitner, G

    2013-10-01

    We examined the effects of naturally occurring mastitis on bovine oocyte developmental competence in vitro. Specifically, we investigated the effects of intramammary infection on the ovarian pool of oocytes (i.e., follicle-enclosed oocytes) and their ability to undergo in vitro maturation, fertilization, and further development to the blastocyst stage. Culled Holstein cows (n=50) from 9 commercial dairy farms in Israel were allotted to 3 groups according to somatic cell count (SCC) records of the last 3 monthly milk tests as well as of quarter samples collected before slaughter: (1) low SCC (n=7), (2) medium SCC (n=16), or (3) high SCC (n=27). Means of SCC values differed among low-, medium-, and high-SCC groups: 148,000, 311,000 and 1,813,000 cell/mL milk, respectively. Milk yield and days in milk did not differ among the 3 groups. Bacterial isolates included coagulase-negative staphylococci, Escherichia coli, Streptococcus dysgalactiae, or no bacteria found. Ovaries were collected at the abattoir and brought to the laboratory. Cumulus oocyte complexes were recovered separately from each cow and subjected individually to in vitro maturation and fertilization, followed by 8d in culture. The number of aspirated oocytes did not differ among groups, with a range of 17 to 21 oocytes per cow. The proportion of oocytes that cleaved into 2- to 4-cell-stage embryos (86.1 ± 3.4%) did not differ among groups. In contrast, mean percentages of embryos developed to the blastocyst stage on d 7 and 8 after fertilization were less in both medium- and-high SCC groups than in the low-SCC group (5.6 ± 2.3 and 4.1 ± 1.8 vs. 18.1 ± 4.6%, respectively). Additional analysis indicated that cleavage and blastocyst-formation rates did not differ among the bacterial types in the low-, medium-, and high-SCC groups. These are the first results to demonstrate that naturally occurring mastitis disrupts the developmental competence of the ovarian pool of oocytes, (i.e., oocytes at the

  13. Intravenous Topiramate: Pharmacokinetics in Dogs with Naturally-Occurring Epilepsy

    Directory of Open Access Journals (Sweden)

    Irene Vuu

    2016-12-01

    Full Text Available Barriers to developing treatments for human status epilepticus (SE include the inadequacy of experimental animal models. In contrast, naturally-occurring canine epilepsy is similar to the human condition and can serve as a platform to translate research from rodents to humans. The objectives of this study were to characterize the pharmacokinetics (PK of an intravenous (IV dose of topiramate (TPM in dogs with epilepsy, and evaluate its effect on intracranial electroencephalographic (iEEG features. Five dogs with naturally occurring epilepsy were used for this study. Three were getting at least one antiseizure drug as maintenance therapy including phenobarbital (PB. Four (ID 1-4 were used for the 10 mg/kg IV TPM + PO TPM study, and three (ID 3-5 were used for the 20 mg/kg IV TPM study. IV TPM was infused over 5 minutes at both doses. The animals were observed for vomiting, diarrhea, ataxia, and lethargy. Blood samples were collected at scheduled pre- and post-dose times. Plasma concentrations were measured using a validated HPLC-MS method. Non-compartmental and population compartmental modeling were performed (Phoenix WinNonLin and NLME using plasma concentrations from all dogs in the study. Intracranial EEG (iEEG was acquired in one dog. The difference between averaged iEEG energy levels at 15 minutes pre- and post-dose was assessed using a Kruskal-Wallis test. No adverse events were noted. Topiramate concentration-time profiles were best fit by a two-compartment model. PB co-administration was associated with a 5.6 fold greater clearance and a ~4 fold shorter elimination half-life. iEEG data showed that TPM produced a significant energy increase at frequencies >4 Hz across all 16 electrodes within 15 minutes of dosing. Simulations suggested that dogs on an enzyme inducer would require 25 mg/kg, while dogs on non-inducing drugs would need 20 mg/kg to attain the target concentration (20-30 µg/mL at 30-minutes post-dose.This study shows that IV

  14. Naturally occurring minichromosome platforms in chromosome engineering: an overview.

    Science.gov (United States)

    Raimondi, Elena

    2011-01-01

    Artificially modified chromosome vectors are non-integrating gene delivery platforms that can shuttle very large DNA fragments in various recipient cells: theoretically, no size limit exists for the chromosome segments that an engineered minichromosome can accommodate. Therefore, genetically manipulated chromosomes might be potentially ideal vector systems, especially when the complexity of higher eukaryotic genes is concerned. This review focuses on those chromosome vectors generated using spontaneously occurring small markers as starting material. The definition and manipulation of the centromere domain is one of the main obstacles in chromosome engineering: naturally occurring minichromosomes, due to their inherent small size, were helpful in defining some aspects of centromere function. In addition, several distinctive features of small marker chromosomes, like their appearance as supernumerary elements in otherwise normal karyotypes, have been successfully exploited to use them as gene delivery vectors. The key technologies employed for minichromosome engineering are: size reduction, gene targeting, and vector delivery in various recipient cells. In spite of the significant advances that have been recently achieved in all these fields, several unsolved problems limit the potential of artificially modified chromosomes. Still, these vector systems have been exploited in a number of applications where the investigation of the controlled expression of large DNA segments is needed. A typical example is the analysis of genes whose expression strictly depends on the chromosomal environment in which they are positioned, where engineered chromosomes can be envisaged as epigenetically regulated expression systems. A novel and exciting advance concerns the use of engineered minichromosomes to study the organization and dynamics of local chromatin structures.

  15. Canine osteosarcoma: a naturally occurring disease to inform pediatric oncology.

    Science.gov (United States)

    Fenger, Joelle M; London, Cheryl A; Kisseberth, William C

    2014-01-01

    Osteosarcoma (OSA) is the most common form of malignant bone cancer in children and dogs, although the disease occurs in dogs approximately 10 times more frequently than in people. Multidrug chemotherapy and aggressive surgical techniques have improved survival; however, new therapies for OSA are critical, as little improvement in survival times has been achieved in either dogs or people over the past 15 years, even with significant efforts directed at the incorporation of novel therapeutic approaches. Both clinical and molecular evidence suggests that human and canine OSA share many key features, including tumor location, presence of microscopic metastatic disease at diagnosis, development of chemotherapy-resistant metastases, and altered expression/activation of several proteins (e.g. Met, ezrin, phosphatase and tensin homolog, signal transducer and activator of transcription 3), and p53 mutations, among others. Additionally, canine and pediatric OSA exhibit overlapping transcriptional profiles and shared DNA copy number aberrations, supporting the notion that these diseases are similar at the molecular level. This review will discuss the similarities between pediatric and canine OSA with regard to histology, biologic behavior, and molecular genetic alterations that indicate canine OSA is a relevant, spontaneous, large animal model of the pediatric disease and outline how the study of naturally occurring OSA in dogs will offer additional insights into the biology and future treatment of this disease in both children and dogs. © The Author 2014. Published by Oxford University Press on behalf of the Institute for Laboratory Animal Research. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  16. Combustion of crude oil sludge containing naturally occurring radioactive material

    International Nuclear Information System (INIS)

    Mohamad Puad Abu; Muhd Noor Muhd Yunus; Shamsuddin, A.H.; Sopian, K.

    2000-01-01

    The characteristics of crude oil sludge fi-om the crude oil terminal are very unique because it contains both heavy metals and also Naturally Occurring Radioactive Material (NORM). As a result, the Department of Environmental (DOE) and the Atomic Energy Licensing Board (AELB) considered it as Scheduled Wastes and Low Level Radioactive Waste (LLRW) respectively. As a Scheduled Wastes, there is no problem in dealing with the disposal of it since there already exist a National Center in Bukit Nanas to deal with this type of waste. However, the Center could not manage this waste due to the presence of NORM by which the policy regarding the disposal of this kind of waste has not been well established. This situation is unclear to certain parties, especially with respect to the relevant authorities having final jurisdiction over the issue as well as the best practical method of disposal of this kind of waste. Existing methods of treatment viewed both from literature and current practice include that of land farming, storing in plastic drum, re-injection into abandoned oil well, recovery, etc., found some problems. Due to its organic nature, very low level in radioactivity and the existence of a Scheduled Waste incineration facility in Bukit Nanas, there is a potential to treat this sludge by using thermal treatment technology. However, prior to having this suggestion to be put into practice, there are issues that need to be addressed. This paper attempts to discuss the potentials and the related issues of combusting crude oil sludge based on existing experimental data as well as mathematical modeling

  17. Public Health Goal for Naturally Occurring Radionuclides in Groundwater

    International Nuclear Information System (INIS)

    Kamel, N.H.M.; Omar, H.A.; El-Baset, L.A.

    2008-01-01

    Naturally occurring and man-made radionuclide in groundwater may have a health hazardous to some residents. The objective of this work is to provide criteria for safety of drinking-water with respect to the chemical parameters and the radionuclide content. The annual effective dose for the consumption of drinking water was considered. Ground water samples were selected from different sites in Egypt, that have the most population, it were taken from aquifer regions along Giza sites in Egypt. Chemical analyses for the major anions, cations, and the radiological analyses were tested . Activity concentrations (Bq/l) of the gross alpha and the gross beta activities of our investigated samples were compared with the maximum contaminant level (MCL) of the world health organization (WHO). Some of the water samples were found to have a higher of gross beta and alpha particles than the MCL. Alpha activity were found depending on to the total dissolved solids (TDS) content of the water samples. Gamma activity concentrations were analyzed using low background germanium detector, the higher of activity values was found in some investigated samples is due to increasing of 226 Ra and 228 Ra activities. Tritium activity concentrations also were measured using soft beta liquid scintillation counter, it was found lower than the MCL. Our investigated samples were found to have a higher concentrations of the phosphate, nitrites, iron, and manganese contents than the maximum permissible limit, all the ground water samples were found to have a higher of silica and alumina content. Commercial carbon powder and natural clay materials were tested as ion exchangers for the removal of inorganic contaminants in the ground water samples. Clay materials was found to have a higher selectivity than activated carbon for the removal of radionuclides, phosphates, nitrites, and manganese content at the ground water samples

  18. Divisional role of quantitative HER2 testing in breast cancer.

    Science.gov (United States)

    Yamamoto-Ibusuki, Mutsuko; Yamamoto, Yutaka; Fu, Peifen; Yamamoto, Satoko; Fujiwara, Saori; Honda, Yumi; Iyama, Ken-ichi; Iwase, Hirotaka

    2015-03-01

    Human epidermal growth factor receptor 2 (HER2) is amplified in human breast cancers in which therapy targeted to HER2 significantly improves patient outcome. We re-visited the use of real-time quantitative polymerase chain reaction (qPCR)-based assays using formalin-fixed paraffin-embedded (FFPE) tissues as alternative methods and investigated their particular clinical relevance. DNA and RNA were isolated from FFPE specimens and HER2 status was assessed by qPCR in 249 consecutive patients with primary breast cancer. Concordance with results forg immunohistochemistry (IHC) and in situ hybridization (ISH), clinical characteristics and survival was assessed. HER2 gene copy number had a stronger correlation with clinicopathological characteristics and excellent concordance with IHC/ISH results (Sensitivity: 96.7 %; concordance: 99.2 %). HER2 gene expression showed inadequate sensitivity, rendering it unsuitable to determine HER2 status (Sensitivity: 46.7 %; concordance: 92.1 %), but lower HER2 gene expression, leading to the classification of many cases as "false negative", contributed to a prediction of better prognosis within the HER2-amplified subpopulation. Quantitative HER2 assessments are suggested to have evolved their accuracy in this decade, which can be a potential alternative for HER2 diagnosis in line with the in situ method, while HER2 gene expression levels could provide additional information regarding prognosis or therapeutic strategy within a HER2-amplified subpopulation.

  19. Naturally Occurring Radioactive Material (NORM) in oil and gas industry

    International Nuclear Information System (INIS)

    Algalhoud, K. A.; AL-Fawaris, B. H.

    2008-01-01

    Oil and gas industry in the Great Jamahiriya is one of those industries that were accompanied with generation of some solid and liquid waste, which associated with risks that might lead to harmful effects to the man and the environment. Among those risks the continuous increase of radioactivity levels above natural radioactive background around operating oil fields, due to accumulation of solid and liquid radioactive scales and sludge as well as contaminated produced water that contain some naturally occurring radioactive materials ( NORM/TE-NORM). Emergence of NORM/TE-NORM in studied area noticed when the natural background radioactivity levels increased around some oil fields during end of 1998, For this study, six field trips and a radiation surveys were conducted within selected oil fields that managed and owned by six operating companies under NOC, in order to determine the effective radiation dose in contrast with dose limits set by International Counsel of Radiation Protection(ICRP),and International Atomic Energy Agency(IAEA) Additionally solid samples in a form of scales and liquid samples were also taken for further investigation and laboratory analysis. Results were tabulated and discussed within the text .However to be more specific results pointed out to the fact that existence of NORM/TE-NORM as 226 Ra, 228 Ra, within some scale samples from surface equipment in some oil and gas fields in Jamahiriya were significant. As a result of that, the workers might receive moderate radiation dose less than the limits set by ICRP,IAEA, and other parts of the world producing oil and gas. Results predicted that within the investigated oil fields if workers receive proper training about handling of NORM/TE-NORM and follow the operating procedure of clean ups, work over and maintenance plane carefully, their committed exposure from NORM/TE-NORM will be less than the set limits by ICRP and IAEA. In a trend to estimate internal radiation dose as a result of possible

  20. HER2 specific delivery of methotrexate by dendrimer conjugated anti-HER2 mAb

    International Nuclear Information System (INIS)

    Shukla, Rameshwer; Thomas, Thommey P; Desai, Ankur M; Kotlyar, Alina; Park, Steve J; Baker, James R Jr

    2008-01-01

    Herceptin, a humanized monoclonal antibody that binds to human growth factor receptor-2 (HER2), was covalently attached to a fifth-generation (G5) polyamidoamine dendrimer containing the cytotoxic drug methotrexate. The specific binding and internalization of this conjugate labeled with FITC was clearly demonstrated in cell lines overexpressing HER2 by flow cytometry as well as confocal microscopic analysis. In addition, binding and uptake of antibody conjugated dendrimers was completely blocked by excess non-conjugated herceptin. The dendrimer conjugate was also shown to inhibit the dihydrofolate reductase with similar activity to methotrexate. Co-localization experiments with lysotracker red indicate that antibody conjugate, although internalized efficiently into cells, has an unusually long residence time in the lysosome. Somewhat lower cytotoxicity of the conjugate in comparison to free methotrexate was attributed to the slow release of methotrexate from the conjugate and its long retention in the lysosomal pocket

  1. GROWTH OF NATURALLY OCCURING Listeria innocua IN COPPA DI TESTA

    Directory of Open Access Journals (Sweden)

    G. Merialdi

    2010-06-01

    Full Text Available Coppa di testa is a traditional cooked pork salami produced in different Italian regions. The main raw material is deboned meat of pork head with the addition of tongue and rind. After a long (3-5 h high temperature (97°C cooking, additives and flavourings are added and the salami is prepared. After cooling the salami is often portioned and vacuum- packaged. In this study the growth of naturally occurring contamination of Listeria innocua in three batches of vacuum packaged Coppa di testa, stored at 4°C for 80 days, is described. The average max was 0.24 (days-1 and the average doubling time was 2.87 days. The maximum growth level ranged from 4.90 to 8.17 (log10 cfu/g. These results indicate that Coppa di testa definitely supports the growth of Listeria innocua in the considered storage conditions. Taking into account that at 4°C Listeria monocytogenes strains are associated with higher grow rates than L. innocua, these results emphasize the importance of preventing Listeria monocytogenes contamination in the production stages following cooking.

  2. Naturally occurring and accelerator-produced radioactive materials: 1987 review

    International Nuclear Information System (INIS)

    Austin, J.H.

    1988-03-01

    From time to time, the issue as to whether the US Nuclear Regulatory Commission (NRC) should seek legislative authority to regulate naturally occurring and accelerator-produced radioactive materials (NARM) is raised. Because NARM exists in the environment, in homes, in workplaces, in medical institutions, and in consumer products, the issue of Federal controls over NARM is very old and very complex. This report presents a review of NARM sources and uses as well as incidents and problems associated with those materials. A review of previous congressional and Federal agency actions on radiation protection matters, in general, and on NARM, in particular, is provided to develop an understanding of existing Federal regulatory activity in ionizing radiation and in control of NARM. In addition, State controls over NARM are reviewed. Eight questions are examined in terms of whether the NRC should seek legislative authority to regulate NARM. The assessment of these questions serves as the basis for developing and evaluating five options. The evaluation of those options leads to two recommendations

  3. Naturally occurring radioactive material in the oil and gas industry

    International Nuclear Information System (INIS)

    Steingraber, W.A.

    1994-01-01

    Naturally occurring radioactive material (NORM) has been found in the Earth's crust and soil, the water we drink, the food we eat, the air we breathe, and the tissues of every living organism. It is relatively easy to determine open-quotes concentrationsclose quotes, or specific activity levels, in the range of 1 part per trillion for radioactive materials. With radioactive elements so abundant and detection possible at such low levels, the presence of NORM in oil and gas operations shouldn't be surprising. In fact, this presence has been recognized since at least the 1930's, but the phenomenon received only minimal attention in the United States until the mid-1980's. At that time regulatory agencies in several oil- and gas-producing states began to focus on NORM in the exploration and production segment of the industry, expressing concern over potential health and safety implications. The most significant aspects of NORM in oil production operations include original source, transport media, composition/radionuclides present, measurement methods, health/safety issues, waste classification, and waste disposal. In addition, I will summarize industry-sponsored NORM data collection and analysis efforts being conducted to aid in development of sound policies and procedures to address environmental, health, and safety issues. Current activities by state and federal regulatory agencies relevant to NORM in the oil and gas industry will also be reviewed

  4. Regulation of naturally occurring radioactive material (NORM) -- an international perspective

    International Nuclear Information System (INIS)

    Davis, M.W.

    1997-01-01

    Naturally Occurring Radioactive Material (NORM) was first recognized as a potential problem as long ago as 1904 in the oil fields of Canada. NORM later became an issue in the North Sea oil and gas production facilities in the early 1980's and became more widely recognized in the United States in 1986 during a routine well workover in the state of Mississippi. NORM contamination of oil and gas industry production equipment has since been identified world wide. The United States, including Alaska and the Gulf of Mexico region, the North Sea region, the United Kingdom, Canada, Australia and several Middle Eastern countries have all reported NORM contamination. The purpose of this paper is to discuss some of the international regulations or guidelines that have been promulgated concerning NORM in the oil and gas industry. Additionally, the impact of these regulations or guidelines on non-oil and gas industries will also be discussed. A comparison of these regulations or guidelines to those generally found in the United States shall be drawn

  5. The dynamics of HER2 status in esophageal adenocarcinoma.

    Science.gov (United States)

    Creemers, Aafke; Ebbing, Eva A; Hooijer, Gerrit K J; Stap, Lisanne; Jibodh-Mulder, Rajni A; Gisbertz, Susanne S; van Berge Henegouwen, Mark I; van Montfoort, Maurits L; Hulshof, Maarten C C M; Krishnadath, Kausilia K; van Oijen, Martijn G H; Bijlsma, Maarten F; Meijer, Sybren L; van Laarhoven, Hanneke W M

    2018-06-01

    Trastuzumab, a monoclonal antibody against HER2, has become standard of care for metastatic HER2-overexpressing esophagogastric adenocarcinoma and is currently investigated as (neo)adjuvant treatment option in HER2-positive esophagogastric adenocarcinoma. The HER2 status is commonly determined on archived material of the primary tumor. However, this status may change over the course of treatment or disease progression. The aim of this study was to assess the dynamics of HER2 status in esophageal adenocarcinoma (EAC) in patients with resectable and recurrent disease, and to determine the associations of these changes with clinical outcome. Discordance, defined as any change in HER2 status between matched biopsy and post-neoadjuvant chemoradiation therapy resection specimen ( N = 170), or between matched resection specimen and recurrence of patients not eligible for curative treatment ( N = 61), was determined using the standardized HER2 status scoring system. Clinically relevant positive discordance was defined as a change to HER2 positive status, as this would imply eligibility for HER2-targeted therapy. A difference in HER2 status between biopsy and resection specimen and resection specimen and metachronous recurrence was observed in 2.1% ( n = 3) and 3.3% ( n = 2) of the paired cases, respectively. Clinically relevant discordance was detected in 1.4% ( n = 2) of the resectable patients and 1.6% ( n = 1) of the patients with recurrent disease. Patients with HER2-positive status tumors before start of neoadjuvant treatment showed better overall survival, but not statistically significant. No association between HER2 status discordance and survival was found. Clinically relevant HER2 status discordance was observed and in order to prevent under-treatment of patients, the assessment of HER2 status in the metastatic setting should preferably be performed on the most recently developed lesions if the previous HER2 assessment on archival material of the primary tumor

  6. Human epidermal growth factor receptor 2 (HER2) immunoreactivity

    DEFF Research Database (Denmark)

    Rasmussen, Anne-Sofie Schrohl; Pedersen, Hans Christian; Jensen, Sussie Steen

    2011-01-01

    The availability of specific antibody-based test systems is essential to testing of HER2 protein expression. Here, we mapped epitopes recognized by three pharmacodiagnostic HER2 antibodies and investigated their specificity towards peptides and fusion proteins homologous to the intracellular doma...... domains of HER1, HER2, HER3 and HER4. The investigated antibodies were PATHWAY(®) HER2 (clone 4B5; Ventana Medical Systems Inc., Tucson, AZ, USA), HercepTest™ (Dako Denmark A/S, Glostrup, Denmark), and Oracle(®) HER2 (clone CB11; Leica Microsystems GmbH, Wetzlar, Germany)....

  7. Microenvironment-Mediated Mechanisms of Resistance to HER2 Inhibitors Differ between HER2+ Breast Cancer Subtypes.

    Science.gov (United States)

    Watson, Spencer S; Dane, Mark; Chin, Koei; Tatarova, Zuzana; Liu, Moqing; Liby, Tiera; Thompson, Wallace; Smith, Rebecca; Nederlof, Michel; Bucher, Elmar; Kilburn, David; Whitman, Matthew; Sudar, Damir; Mills, Gordon B; Heiser, Laura M; Jonas, Oliver; Gray, Joe W; Korkola, James E

    2018-03-28

    Extrinsic signals are implicated in breast cancer resistance to HER2-targeted tyrosine kinase inhibitors (TKIs). To examine how microenvironmental signals influence resistance, we monitored TKI-treated breast cancer cell lines grown on microenvironment microarrays composed of printed extracellular matrix proteins supplemented with soluble proteins. We tested ∼2,500 combinations of 56 soluble and 46 matrix microenvironmental proteins on basal-like HER2+ (HER2E) or luminal-like HER2+ (L-HER2+) cells treated with the TKIs lapatinib or neratinib. In HER2E cells, hepatocyte growth factor, a ligand for MET, induced resistance that could be reversed with crizotinib, an inhibitor of MET. In L-HER2+ cells, neuregulin1-β1 (NRG1β), a ligand for HER3, induced resistance that could be reversed with pertuzumab, an inhibitor of HER2-HER3 heterodimerization. The subtype-specific responses were also observed in 3D cultures and murine xenografts. These results, along with bioinformatic pathway analysis and siRNA knockdown experiments, suggest different mechanisms of resistance specific to each HER2+ subtype: MET signaling for HER2E and HER2-HER3 heterodimerization for L-HER2+ cells. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

  8. Uranium occurence in nature: Geophysical prospecting, and its occurence in Syria

    International Nuclear Information System (INIS)

    Al-Haj Rasheed, Zaki

    1985-01-01

    A general idea about naturaly occured uranium minerals such as uranite, pechblende, carnotite, coffinit, and bronnerit is given. At the same time, different geophysical methods and detecting devices applied for uranium exploration have been demonstrated. Investigations and studies carried out in Syria point to a uranium content of 100 ppm in the exploited Syrian phosphorite. 1 fig., 1 tab

  9. Can breast cancer patients with HER2 dual-equivocal tumours be managed as HER2-negative disease?

    Science.gov (United States)

    Tong, Yiwei; Chen, Xiaosong; Fei, Xiaochun; Lin, Lin; Wu, Jiayi; Huang, Ou; He, Jianrong; Zhu, Li; Chen, Weiguo; Li, Yafen; Shen, Kunwei

    2018-01-01

    Increasing human epidermal growth factor receptor 2 (HER2) immunohistochemistry (IHC)/fluorescence in situ hybridisation (FISH) dual-equivocal breast tumours are reported after the 2013 American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) guideline update. The aim of this study is to investigate the clinico-pathologic characteristics, treatment patterns and disease outcome of these patients with HER2 dual-equivocal tumours. Patients with HER2 IHC 2+ and available FISH results were retrospectively analysed from the Comprehensive Breast Health Center, Shanghai Ruijin Hospital. The 2013 ASCO/CAP guideline was applied to define HER2-positive, dual-equivocal and -negative groups. Patient characteristics, systemic treatment patterns and survival were compared among these groups. Reverse transcriptase-polymerase chain reaction-based assays were applied to test HER2 mRNA expression level. Among 691 patients included, 133 (19.25%) were HER2 positive, 25 (3.62%) were HER2 dual-equivocal and 533 (77.13%) were HER2 negative. Univariate and multivariate analyses stated that HER2 dual-equivocal tumours shared more similarity with HER2-negative tumours, whereas HER2-positive tumours had rather different clinico-pathologic features. HER2 dual-equivocal tumours had similar HER2 mRNA levels compared with HER2-negative tumours (P = 0.26), which were much less compared with HER2-positive breast cancer. Besides, adjuvant systemic treatment patterns were comparable between HER2-negative and dual-equivocal tumours, and none of HER2 dual-equivocal patients received anti-HER2 treatment. There was no survival difference among these three groups (P = 0.43). HER2 dual-equivocal tumours share more similarity with HER2-negative disease in terms of clinico-pathologic features, HER2 mRNA levels, adjuvant systemic treatment patterns and disease outcome, which deserves further clinical evaluation. Copyright © 2017 Elsevier Ltd. All rights reserved.

  10. Naturally occurring asbestos-A recurring public policy challenge

    Energy Technology Data Exchange (ETDEWEB)

    Lee, R.J.; Strohmeier, B.R. [RJ Lee Group, Inc., 350 Hochberg Road, Monroeville, PA 15146 (United States); Bunker, K.L. [RJ Lee Group, Inc., 350 Hochberg Road, Monroeville, PA 15146 (United States)], E-mail: klbunker@rjlg.com; Van Orden, D.R. [RJ Lee Group, Inc., 350 Hochberg Road, Monroeville, PA 15146 (United States)

    2008-05-01

    The potential environmental hazards and associated public health issues related to exposure to respirable dusts from the vicinity of natural in-place asbestos deposits (commonly referred to as naturally occurring asbestos, NOA) have gained the regulatory and media spotlight in many areas around the United States, such as Libby, MT, Fairfax County, VA, and El Dorado Hills, CA, among others. NOA deposits may be present in a variety of geologic formations. It has been suggested that airborne asbestos may be released from NOA deposits, and absent appropriate engineering controls, may pose a potential health hazard if these rocks are crushed or exposed to natural weathering and erosion or to human activities that create dust. The issue that needs to be addressed at a policy level is the method of assessing exposures to elongated rock fragments ubiquitous in dust clouds in these same environments and the associated risk. Elongated rock fragments and single crystal minerals present in NOA have been construed by some as having attributes, including the health effects, of asbestos fibers. However, the Occupational Safety and Health Administration (OSHA), Mine Safety and Health Administration (MSHA), and the Consumer Products Safety Commission (CPSC) found that the scientific evidence did not support this assumption. As in many environmental fields of study, the evidence is often disputed. Regulatory policy is not uniform on the subject of rock fragments, even within single agencies. The core of the issue is whether the risk parameters associated with exposures to commercial asbestos can or should be applied to rock fragments meeting an arbitrary set of particle dimensions used for counting asbestos fibers. Inappropriate inclusion of particles or fragments results in dilution of risk and needless expenditure of resources. On the other hand, inappropriate exclusion of particles or fragments may result in increased and unnecessary risk. Some of the fastest growing counties in

  11. Naturally occurring asbestos-A recurring public policy challenge

    International Nuclear Information System (INIS)

    Lee, R.J.; Strohmeier, B.R.; Bunker, K.L.; Van Orden, D.R.

    2008-01-01

    The potential environmental hazards and associated public health issues related to exposure to respirable dusts from the vicinity of natural in-place asbestos deposits (commonly referred to as naturally occurring asbestos, NOA) have gained the regulatory and media spotlight in many areas around the United States, such as Libby, MT, Fairfax County, VA, and El Dorado Hills, CA, among others. NOA deposits may be present in a variety of geologic formations. It has been suggested that airborne asbestos may be released from NOA deposits, and absent appropriate engineering controls, may pose a potential health hazard if these rocks are crushed or exposed to natural weathering and erosion or to human activities that create dust. The issue that needs to be addressed at a policy level is the method of assessing exposures to elongated rock fragments ubiquitous in dust clouds in these same environments and the associated risk. Elongated rock fragments and single crystal minerals present in NOA have been construed by some as having attributes, including the health effects, of asbestos fibers. However, the Occupational Safety and Health Administration (OSHA), Mine Safety and Health Administration (MSHA), and the Consumer Products Safety Commission (CPSC) found that the scientific evidence did not support this assumption. As in many environmental fields of study, the evidence is often disputed. Regulatory policy is not uniform on the subject of rock fragments, even within single agencies. The core of the issue is whether the risk parameters associated with exposures to commercial asbestos can or should be applied to rock fragments meeting an arbitrary set of particle dimensions used for counting asbestos fibers. Inappropriate inclusion of particles or fragments results in dilution of risk and needless expenditure of resources. On the other hand, inappropriate exclusion of particles or fragments may result in increased and unnecessary risk. Some of the fastest growing counties in

  12. Naturally occurring asbestos: a recurring public policy challenge.

    Science.gov (United States)

    Lee, R J; Strohmeier, B R; Bunker, K L; Van Orden, D R

    2008-05-01

    The potential environmental hazards and associated public health issues related to exposure to respirable dusts from the vicinity of natural in-place asbestos deposits (commonly referred to as naturally occurring asbestos, NOA) have gained the regulatory and media spotlight in many areas around the United States, such as Libby, MT, Fairfax County, VA, and El Dorado Hills, CA, among others. NOA deposits may be present in a variety of geologic formations. It has been suggested that airborne asbestos may be released from NOA deposits, and absent appropriate engineering controls, may pose a potential health hazard if these rocks are crushed or exposed to natural weathering and erosion or to human activities that create dust. The issue that needs to be addressed at a policy level is the method of assessing exposures to elongated rock fragments ubiquitous in dust clouds in these same environments and the associated risk. Elongated rock fragments and single crystal minerals present in NOA have been construed by some as having attributes, including the health effects, of asbestos fibers. However, the Occupational Safety and Health Administration (OSHA), Mine Safety and Health Administration (MSHA), and the Consumer Products Safety Commission (CPSC) found that the scientific evidence did not support this assumption. As in many environmental fields of study, the evidence is often disputed. Regulatory policy is not uniform on the subject of rock fragments, even within single agencies. The core of the issue is whether the risk parameters associated with exposures to commercial asbestos can or should be applied to rock fragments meeting an arbitrary set of particle dimensions used for counting asbestos fibers. Inappropriate inclusion of particles or fragments results in dilution of risk and needless expenditure of resources. On the other hand, inappropriate exclusion of particles or fragments may result in increased and unnecessary risk. Some of the fastest growing counties in

  13. Probabilities of Natural Events Occurring at Savannah River Plant

    Energy Technology Data Exchange (ETDEWEB)

    Huang, J.C.

    2001-07-17

    This report documents the comprehensive evaluation of probability models of natural events which are applicable to Savannah River Plant. The probability curves selected for these natural events are recommended to be used by all SRP/SRL safety analysts. This will ensure a consistency in analysis methodology for postulated SAR incidents involving natural phenomena.

  14. HER2 amplification, overexpression and score criteria in esophageal adenocarcinoma

    Science.gov (United States)

    Hu, Yingchuan; Bandla, Santhoshi; Godfrey, Tony E.; Tan, Dongfeng; Luketich, James D.; Pennathur, Arjun; Qiu, Xing; Hicks, David G.; Peters, Jeffrey; Zhou, Zhongren

    2011-01-01

    The HER2 oncogene was recently reported to be amplified and overexpressed in esophageal adenocarcinoma. However, the relationship of HER2 amplification in esophageal adenocarcinoma with prognosis has not been well defined. The scoring systems for clinically evaluating HER2 in esophageal adenocarcinoma are not established. The aims of the study were to establish a HER2 scoring system and comprehensively investigate HER2 amplification and overexpression in esophageal adenocarcinoma and its precursor lesion. Using a tissue microarray, containing 116 cases of esophageal adenocarcinoma, 34 cases of BE, 18 cases of low grade dysplasia and 15 cases of high grade dysplasia, HER2 amplification and overexpression were analyzed by HercepTest and CISH methods. The amplification frequency in an independent series of 116 esophageal adenocarcinoma samples was also analyzed using Affymetrix SNP 6.0 microarrays. In our studies, we have found that HER2 amplification does not associate with poor prognosis in total 232 esophageal adenocarcinoma patients by CISH and high density microarrays. We further confirm the similar frequency of HER2 amplification by CISH (18.10%; 21/116) and SNP 6.0 microarrays (16.4%, 19/116) in esophageal adenocarcinoma. HER2 protein overexpression was observed in 12.1 % (14/116) of esophageal adenocarcinoma and 6.67% (1/15) of HGD. No HER2 amplification or overexpression was identified in BE or LGD. All HER2 protein overexpression cases showed HER2 gene amplification. Gene amplification was found to be more frequent by CISH than protein overexpression in esophageal adenocarcinoma (18.10% vs 12.9%). A modified two-step model for esophageal adenocarcinoma HER-2 testing is recommend for clinical esophageal adenocarcinoma HER-2 trial. PMID:21460800

  15. Single-cell quantitative HER2 measurement identifies heterogeneity and distinct subgroups within traditionally defined HER2-positive patients.

    Science.gov (United States)

    Onsum, Matthew D; Geretti, Elena; Paragas, Violette; Kudla, Arthur J; Moulis, Sharon P; Luus, Lia; Wickham, Thomas J; McDonagh, Charlotte F; MacBeath, Gavin; Hendriks, Bart S

    2013-11-01

    Human epidermal growth factor receptor 2 (HER2) is an important biomarker for breast and gastric cancer prognosis and patient treatment decisions. HER2 positivity, as defined by IHC or fluorescent in situ hybridization testing, remains an imprecise predictor of patient response to HER2-targeted therapies. Challenges to correct HER2 assessment and patient stratification include intratumoral heterogeneity, lack of quantitative and/or objective assays, and differences between measuring HER2 amplification at the protein versus gene level. We developed a novel immunofluorescence method for quantitation of HER2 protein expression at the single-cell level on FFPE patient samples. Our assay uses automated image analysis to identify and classify tumor versus non-tumor cells, as well as quantitate the HER2 staining for each tumor cell. The HER2 staining level is converted to HER2 protein expression using a standard cell pellet array stained in parallel with the tissue sample. This approach allows assessment of HER2 expression and heterogeneity within a tissue section at the single-cell level. By using this assay, we identified distinct subgroups of HER2 heterogeneity within traditional definitions of HER2 positivity in both breast and gastric cancers. Quantitative assessment of intratumoral HER2 heterogeneity may offer an opportunity to improve the identification of patients likely to respond to HER2-targeted therapies. The broad applicability of the assay was demonstrated by measuring HER2 expression profiles on multiple tumor types, and on normal and diseased heart tissues. Copyright © 2013 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

  16. Committed effective dose from naturally occuring radionuclides in shellfish

    Science.gov (United States)

    Khandaker, Mayeen Uddin; Wahib, Norfadira Binti; Amin, Yusoff Mohd.; Bradley, D. A.

    2013-07-01

    Recognizing their importance in the average Malaysian daily diet, the radioactivity concentrations in mollusc- and crustacean-based food have been determined for key naturally occuring radionuclides. Fresh samples collected from various maritime locations around peninsular Malaysia have been processed using standard procedures; the radionuclide concentrations being determined using an HPGe γ-ray spectrometer. For molluscs, assuming secular equilibrium, the range of activities of 238U (226Ra), 232Th (228Ra) and 40K were found to be 3.28±0.35 to 5.34±0.52, 1.20±0.21 to 2.44±0.21 and 118±6 to 281±14 Bq kg-1 dry weight, respectively. The respective values for crustaceans were 3.02±0.57 to 4.70±0.52, 1.38±0.21 to 2.40±0.35 and 216±11 to 316±15 Bq kg-1. The estimated average daily intake of radioactivity from consumption of molluscs are 0.37 Bq kg-1 for 238U (226Ra), 0.16 Bq kg-1 for 232Th (228Ra) and 18 Bq kg-1 for 40K; the respective daily intake values from crustaceans are 0.36 Bq kg-1, 0.16 Bq kg-1 and 23 Bq kg-1. Associated annual committed effective doses from molluscs are estimated to be in the range 21.3 to 34.7 μSv for 226Ra, 19.3 to 39.1 μSv for 228Ra and 17.0 to 40.4 μSv for 40K. For crustaceans, the respective dose ranges are 19.6 to 30.5 μSv, 22.0 to 38.4 μSv and 31.1 to 45.5 μSv, being some several times world average values.

  17. A Naturally Occurring Recombinant Enterovirus Expresses a Torovirus Deubiquitinase.

    Science.gov (United States)

    Shang, Pengcheng; Misra, Saurav; Hause, Ben; Fang, Ying

    2017-07-15

    identified a special case of cross-order recombination between enterovirus G (order Picornavirales ) and torovirus (order Nidovirales ). This naturally occurring recombination event may have broad implications for other picornaviral and/or nidoviral species. Importantly, we demonstrated that the exogenous ToV-PLP gene that was inserted into the EVG genome encodes a deubiquitinase/deISGylase and potentially suppresses host cellular innate immune responses. Our results provide insights into how a gain of function through genetic recombination, in particular cross-order recombination, may improve the ability of a virus to evade host immunity. Copyright © 2017 American Society for Microbiology.

  18. Phase I Study of 68Ga-HER2-Nanobody for PET/CT Assessment of HER2 Expression in Breast Carcinoma.

    Science.gov (United States)

    Keyaerts, Marleen; Xavier, Catarina; Heemskerk, Johannes; Devoogdt, Nick; Everaert, Hendrik; Ackaert, Chloé; Vanhoeij, Marian; Duhoux, Francois P; Gevaert, Thierry; Simon, Philippe; Schallier, Denis; Fontaine, Christel; Vaneycken, Ilse; Vanhove, Christian; De Greve, Jacques; Lamote, Jan; Caveliers, Vicky; Lahoutte, Tony

    2016-01-01

    Human epidermal growth factor receptor 2 (HER2) status is one of the major tumor characteristics in breast cancer to guide therapy. Anti-HER2 treatment has clear survival advantages in HER2-positive breast carcinoma patients. Heterogeneity in HER2 expression between primary tumor and metastasis has repeatedly been described, resulting in the need to reassess HER2 status during the disease course. To avoid repeated biopsy with potential bias due to tumor heterogeneity, Nanobodies directed against HER2 have been developed as probes for molecular imaging. Nanobodies, which are derived from unique heavy-chain-only antibodies, are the smallest antigen-binding antibody fragments and have ideal characteristics for PET imaging. The primary aims were assessment of safety, biodistribution, and dosimetry. The secondary aim was to investigate tumor-targeting potential. In total, 20 women with primary or metastatic breast carcinoma (score of 2+ or 3+ on HER2 immunohistochemical assessment) were included. Anti-HER2-Nanobody was labeled with (68)Ga via a NOTA derivative. Administered activities were 53-174 MBq (average, 107 MBq). PET/CT scans for dosimetry assessment were obtained at 10, 60, and 90 min after administration. Physical evaluation and blood analysis were performed for safety evaluation. Biodistribution was analyzed for 11 organs using MIM software; dosimetry was assessed using OLINDA/EXM. Tumor-targeting potential was assessed in primary and metastatic lesions. No adverse reactions occurred. A fast blood clearance was observed, with only 10% of injected activity remaining in the blood at 1 h after injection. Uptake was seen mainly in the kidneys, liver, and intestines. The effective dose was 0.043 mSv/MBq, resulting in an average of 4.6 mSv per patient. The critical organ was the urinary bladder wall, with a dose of 0.406 mGy/MBq. In patients with metastatic disease, tracer accumulation well above the background level was demonstrated in most identified sites of

  19. Improved tumor targeting of anti-HER2 nanobody through N-succinimidyl 4-guanidinomethyl-3-iodobenzoate radiolabeling.

    Science.gov (United States)

    Pruszynski, Marek; Koumarianou, Eftychia; Vaidyanathan, Ganesan; Revets, Hilde; Devoogdt, Nick; Lahoutte, Tony; Lyerly, H Kim; Zalutsky, Michael R

    2014-04-01

    Nanobodies are approximately 15-kDa proteins based on the smallest functional fragments of naturally occurring heavy chain-only antibodies and represent an attractive platform for the development of molecularly targeted agents for cancer diagnosis and therapy. Because the human epidermal growth factor receptor type 2 (HER2) is overexpressed in breast and ovarian carcinoma, as well as in other malignancies, HER2-specific Nanobodies may be valuable radiodiagnostics and therapeutics for these diseases. The aim of the present study was to evaluate the tumor-targeting potential of anti-HER2 5F7GGC Nanobody after radioiodination with the residualizing agent N-succinimidyl 4-guanidinomethyl 3-(125/131)I-iodobenzoate (*I-SGMIB). The 5F7GGC Nanobody was radiolabeled using *I-SGMIB and, for comparison, with N(ε)-(3-*I-iodobenzoyl)-Lys(5)-N(α)-maleimido-Gly(1)-GEEEK (*I-IB-Mal-d-GEEEK), another residualizing agent, and by direct radioiodination using IODO-GEN ((125)I-Nanobody). The 3 labeled Nanobodies were evaluated in affinity measurements, and paired-label internalization assays were performed on HER2-expressing BT474M1 breast carcinoma cells and in paired-label tissue distribution measurements in mice bearing subcutaneous BT474M1 xenografts. *I-SGMIB-Nanobody was produced in 50.4% ± 3.6% radiochemical yield and exhibited a dissociation constant of 1.5 ± 0.5 nM. Internalization assays demonstrated that intracellular retention of radioactivity was up to 1.5-fold higher for *I-SGMIB-Nanobody than for coincubated (125)I-Nanobody or *I-IB-Mal-d-GEEEK-Nanobody. Peak tumor uptake for *I-SGMIB-Nanobody was 24.50% ± 9.89% injected dose/g at 2 h, 2- to 4-fold higher than observed with other labeling methods, and was reduced by 90% with trastuzumab blocking, confirming the HER2 specificity of localization. Moreover, normal-organ clearance was fastest for *I-SGMIB-Nanobody, such that tumor-to-normal-organ ratios greater than 50:1 were reached by 24 h in all tissues except lungs

  20. Emerging treatments for HER2-positive early-stage breast cancer: focus on neratinib

    Directory of Open Access Journals (Sweden)

    Kourie HR

    2017-07-01

    Full Text Available Hampig Raphael Kourie,1 Elie El Rassy,1 Florian Clatot,2,3 Evandro de Azambuja,4 Matteo Lambertini3,4 1Department of Oncology, Faculty of Medicine, Saint Joseph University, Beirut, Lebanon; 2Department of Medical Oncology and IRON/U1245, Centre Henri Becquerel, Rouen, France; 3Breast Cancer Translational Research Laboratory, 4Department of Medicine, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium Abstract: Over the last decades, a better understanding of breast cancer heterogeneity provided tools for a biologically based personalization of anticancer treatments. In particular, the overexpression of the human epidermal growth factor receptor 2 (HER2 by tumor cells provided a specific target in these HER2-positive tumors. The development of the monoclonal antibody trastuzumab, and its approval in 1998 for the treatment of patients with metastatic disease, radically changed the natural history of this aggressive subtype of breast cancer. These findings provided strong support for the continuous research in targeting the HER2 pathway and implementing the development of new anti-HER2 targeted agents. Besides trastuzumab, a series of other anti-HER2 agents have been developed and are currently being explored for the treatment of breast cancer patients, including those diagnosed with early-stage disease. Among these agents, neratinib, an oral tyrosine kinase inhibitor that irreversibly inhibits HER1, HER2, and HER4 at the intracellular level, has shown promising results, including when administered to patients previously exposed to trastuzumab-based treatment. This article aims to review the available data on the role of the HER2 pathway in breast cancer and on the different targeted agents that have been studied or are currently under development for the treatment of patients with early-stage HER2-positive disease with a particular focus on neratinib. Keywords: breast cancer, HER2-positive, neratinib, early-stage, targeted

  1. NATURALLY OCCURRING MELLEIN-TYPE 3,4 ...

    African Journals Online (AJOL)

    Dr Mdachi

    isolation, characterization and bioassay studies of melleins, a number of synthetic studies have also been ... from Cashew Nut Shell Liquid (CNSL) - a readily available natural resource. Utilization of ...... of the currently available methods.

  2. Naturally Occurring Wound Healing Agents: An Evidence-Based Review.

    Science.gov (United States)

    Karapanagioti, E G; Assimopoulou, A N

    2016-01-01

    Nature constitutes a pool of medicines for thousands of years. Nowadays, trust in nature is increasingly growing, as many effective medicines are naturally derived. Over the last decades, the potential of plants as wound healing agents is being investigated. Wounds and ulcers affect the patients' life quality and often lead to amputations. Approximately 43,000,000 patients suffer from diabetic foot ulcers worldwide. Annually, $25 billion are expended for the treatment of chronic wounds, with the number growing due to aging population and increased incidents of diabetes and obesity. Therefore a timely, orderly and effective wound management and treatment is crucial. This paper aims to systematically review natural products, mainly plants, with scientifically well documented wound healing activity, focusing on articles based on animal and clinical studies performed worldwide and approved medicinal products. Moreover, a brief description of the wound healing mechanism is presented, to provide a better understanding. Although a plethora of natural products are in vitro and in vivo evaluated for wound healing activity, only a few go through clinical trials and even fewer launch the market as approved medicines. Most of them rely on traditional medicine, indicating that ethnopharmacology is a successful strategy for drug development. Since only 6% of plants have been systematically investigated pharmacologically, more intensified efforts and emerging advancements are needed to exploit the potentials of nature for the development of novel medicines. This paper aims to provide a reliable database and matrix for thorough further investigation towards the discovery of wound healing agents.

  3. Developing Anti-HER2 Vaccines: Breast Cancer Experience.

    Science.gov (United States)

    Al-Awadhi, Aydah; Murray, James Lee; Ibrahim, Nuhad K

    2018-04-25

    Breast cancer accounts for more than one million new cases annually and is the leading cause of death in women globally. HER2 overexpression induces cellular and humoral immune responses against the HER2 protein and is associated with higher tumour proliferation rates. Trastuzumab-based therapies are effectively and widely used as standard of care in HER2-amplified/overexpressed breast cancer patients; one cited mechanism of action is the induction of passive immunity and antibody-dependent cellular cytotoxicity against malignant breast cancer cells. These findings drove the efforts to generate antigen-specific immunotherapy to trigger the patient's immune system to target HER2-overexpressing tumour cells, which led to the development of various vaccines against the HER2 antigen. This manuscript discusses the various anti-HER2 vaccine formulations and strategies and their potential role in the metastatic and adjuvant settings. This article is protected by copyright. All rights reserved. © 2018 UICC.

  4. The role of neratinib in HER2-driven breast cancer.

    Science.gov (United States)

    Cherian, Mathew A; Ma, Cynthia X

    2017-06-30

    Up to 25% of patients with early-stage HER2+ breast cancer relapse despite adjuvant trastuzumab-based regimens and virtually all patients with metastatic disease eventually die from resistance to existing treatment options. In addition, recent studies indicate that activating HER2 mutations without gene amplification could drive tumor growth in a subset of HER2-ve breast cancer that is not currently eligible for HER2-targeted agents. Neratinib is an irreversible HER kinase inhibitor with activity as extended adjuvant therapy following standard trastuzumab-based adjuvant treatment in a Phase III trial. Phase II trials of neratinib demonstrate promising activity in combination with cytotoxic agents in trastuzumab resistant metastatic HER2+ breast cancer, and either as monotherapy or in combination with fulvestrant for HER2-mutated breast cancers. We anticipate a potential role for neratinib in the therapy of these patient populations.

  5. Pharmacodynamics, pharmacokinetics and clinical efficacy of neratinib in HER2-positive breast cancer and breast cancer with HER2 mutations.

    Science.gov (United States)

    Kourie, Hampig Raphael; Chaix, Marie; Gombos, Andrea; Aftimos, Phillippe; Awada, Ahmad

    2016-08-01

    Despite the availability of several potent HER2-directed targeted agents, primary and acquired resistance continues to influence patient outcomes in HER2-positive breast cancer. Neratinib is an irreversible pan-HER tyrosine kinase inhibitor in late-phase clinical development. This review article focuses on neratinib in the treatment of HER2-positive breast cancer - early and metastatic stage - and HER2-mutant breast cancer, with particular emphasis on the pharmacokinetics and pharmacodynamics of the drug. The phase III ExteNET trial shows that neratinib improves 2-year invasive disease-free survival after trastuzumab-based adjuvant therapy in early-stage HER2-positive breast cancer, and in particular HER2+/HR+ tumors. Survival data are awaited. The investigational role of neratinib in high-risk patients or conversely in de-escalation dual regimens with other anti-HER2 therapies and without chemotherapy are of interest. Phase II trials show that neratinib has efficacy, either as monotherapy or in combination with other chemotherapeutic or endocrine agents, in patients with HER2-positive metastatic breast cancer and in tumors harboring HER2 mutations. The role of neratinib in therapeutic algorithms of HER2-positive patients, as well as delaying CNS events, awaits the results of ongoing trials such as NALA. Diarrhea, the main toxicity of neratinib, can be effectively managed with early loperamide prophylaxis.

  6. The HER2-binding affibody molecule (Z(HER2∶342₂ increases radiosensitivity in SKBR-3 cells.

    Directory of Open Access Journals (Sweden)

    Lina Ekerljung

    Full Text Available We have previously shown that the HER2-specific affibody molecule (Z(HER2∶342₂ inhibits proliferation of SKBR-3 cells. Here, we continue to investigate its biological effects in vitro by studying receptor dimerization and clonogenic survival following irradiation. We found that (Z(HER2∶342₂ sensitizes the HER2-overexpressing cell line SKBR-3 to ionizing radiation. The survival after exposure to (Z(HER2∶342₂ and 8 Gy (S(8Gy 0.006 was decreased by a factor four compared to the untreated (S(8Gy 0.023. The low HER2-expressing cell line MCF-7 was more radiosensitive than SKBR-3 but did not respond to (Z(HER2∶342₂. Treatment by (Z(HER2∶342₂ strongly increased the levels of dimerized and phosphorylated HER2 even after 5 minutes of stimulation. The monomeric Z(HER2∶342 does not seem to be able to induce receptor phosphorylation and dimerization or sensitize cells to irradiation.

  7. Dual blockade of HER2 in HER2-overexpressing tumor cells does not completely eliminate HER3 function.

    Science.gov (United States)

    Garrett, Joan T; Sutton, Cammie R; Kuba, María Gabriela; Cook, Rebecca S; Arteaga, Carlos L

    2013-02-01

    Dual blockade of HER2 with trastuzumab and lapatinib or with pertuzumab is a superior treatment approach compared with single-agent HER2 inhibitors. However, many HER2-overexpressing breast cancers still escape from this combinatorial approach. Inhibition of HER2 and downstream phosphoinositide 3-kinase (PI3K)/AKT causes a transcriptional and posttranslational upregulation of HER3 which, in turn, counteracts the antitumor action of the HER2-directed therapies. We hypothesized that suppression of HER3 would synergize with dual blockade of HER2 in breast cancer cells sensitive and refractory to HER2 antagonists. Inhibition of HER2/HER3 in HER2(+) breast cancer cell lines was evaluated by Western blotting. We analyzed drug-induced apoptosis and two- and three-dimensional growth in vitro. Growth inhibition of PI3K was examined in vivo in xenografts treated with combinations of trastuzumab, lapatinib, and the HER3-neutralizing monoclonal antibody U3-1287. Treatment with U3-1287 blocked the upregulation of total and phosphorylated HER3 that followed treatment with lapatinib and trastuzumab and, in turn, enhanced the antitumor action of the combination against trastuzumab-sensitive and -resistant cells. Mice bearing HER2(+) xenografts treated with lapatinib, trastuzumab, and U3-1287 exhibited fewer recurrences and better survival than mice treated with lapatinib and trastuzumab. Dual blockade of HER2 with trastuzumab and lapatinib does not eliminate the compensatory upregulation of HER3. Therapeutic inhibitors of HER3 should be considered as part of multidrug combinations aimed at completely and rapidly disabling the HER2 network in HER2-overexpressing breast cancers.

  8. Natural occurring radioactivity in Palmyra and its surrounding

    International Nuclear Information System (INIS)

    Al-Masri, M. S.; Shwekani, R.; Raja, G.; Hushari, M.; Al-Hent, R.; Issa, M.

    2006-06-01

    In this work, the natural radiation background has been carried out for Palmyra city and its surroundings area. The study has covered gamma radiation measurements, indoor radon gas concentration and radionuclides levels in environmental samples (soil, water, plat). The results showed that indoor radon gas concentrations and radiation exposure rates are within the background levels. Also, the results showed that there is no artificial radiation in the area and there is no correlation between the natural radiation levels and the reported cancer cases. Therefore, the reported cancer cases in this area may be due to non-radiation cases, which must be investigated, or they are within the natural levels in Syria unless accurate statistics proves the opposite. (author)

  9. Shear strength properties of naturally occurring bituminous sands

    CSIR Research Space (South Africa)

    Anochie-Boateng, Joseph

    2009-06-01

    Full Text Available because of the cohesive nature of bitumen contents. However, results from the direct shear tests were comparable to properties of oil sands reported earlier from various other laboratory tests. Based on the direct shear test results, Mohr-Coulomb failure...

  10. Assessment of terrestrial naturally occurring radioactive Material in ...

    African Journals Online (AJOL)

    The levels of natural radioactivity of 40K, 238U and 232Th in soils and mine tailings of Awo and Ede areas of Osunstate, Nigeria have been measured using a portable, advanced survey meter 992 Fluke Victoreen Gamma Scout Model for in-situ investigation and a 1 inch by 1 inch Cesium Iodide detector system.

  11. Overview of naturally occurring Earth materials and human health concerns

    Science.gov (United States)

    Ernst, W. G.

    2012-10-01

    The biosphere and the Earth's critical zone have maintained a dynamic equilibrium for more than 3.5 billion years. Except for solar energy, almost all terrestrial substances necessary for life have been derived from near-surface portions of the land, hydrosphere, and atmosphere. If aggregate biological activities are less than the rate of nutrient supply and/or resource renewal, sustained population growth is possible. Where the replenishment rate of a life-sustaining Earth material is finite, usage may reach a condition of dynamic equilibrium in which biological consumption equals but on average cannot exceed the overall supply. Although large, most natural resources are present in finite abundances; for such commodities, excessive present-day human utilization reduces future availability, and thus the ultimate planetary carrying capacity for civilization. Intensive use of Earth materials has enhanced the quality of life, especially in the developed nations. Still, natural background levels, and Earth processes such as volcanic eruptions, as well as human activities involving agriculture, construction, and the extraction, refining, and transformation of mineral resources have led to harmful side effects involving environmental degradation and public health hazards. Among naturally and anthropogenically induced risks are bioaccessible airborne dusts and gases, soluble pollutants in agricultural, industrial, and residential waters, and toxic chemical species in foods and manufactured products. At appropriate levels of ingestion, many Earth materials are necessary for existence, but underdoses and overdoses have mild to serious consequences for human health and longevity. This overview briefly sketches several natural resource health hazards. Included are volcanic ash + aerosols + gases, mineral dusts, non-volcanic aerosols + nanoparticles, asbestos + fibrous zeolites, arsenic, fluorine, iodine, uranium + thorium + radium + radon + polonium, selenium, mercury, copper

  12. Complex forming properties of natural occurring fulvic acids

    International Nuclear Information System (INIS)

    Marinsky, J.A.; Mathuthu, A.; Bicking, M.; Ephraim, J.

    1985-07-01

    The experimental program developed in our earlier investigations of the protonation equilibria encountered with Armadale Horizons Bh and Suwannee River fulvic-acid has been employed in the present investigation of a Swedish fulvic acid source. Complications introduced by the polyelectrolyte nature and the degree of heterogeneity in the functional unit content of this natural organic acid molecule have been resolved as they were with the previous fulvic acid samples. The physical chemical properties of this fulvic acid have been compared with those resolved for the Armadale Horizons Bh and the Suwannee River fulvic acid as well. The insight gained from these protonation studies and metal ion binding studies, also carried out in the course of this investigation, has led to the development of a model for interpretation of the binding of metal ions to fulvic acid at any fulvic acid concentration level. With 12 refs. (Author)

  13. Technically enhanced naturally occurring radioactive materials; identification, characterization and treatment

    International Nuclear Information System (INIS)

    Aly, H.F.

    2001-01-01

    Radioactive materials (TENORM) is produced in a relatively large amount with relatively small radioactivity, however in many instances the radioactivity levels exceeds that permissible. In this presentation, the different industries where enhanced levels of natural radioactivity is identified and characterized will be given. The different approaches for treatment of this enhanced radioactivity will be addressed. Finally, our research and development activities in characterization and treatment of TENORM produced from the oil fields in Egypt will be presented. (authors)

  14. Deposits of naturally occurring radioactivity in production of oil and natural gas

    International Nuclear Information System (INIS)

    Strand, T.; Lysebo, I.; Kristensen, D.; Birovljev, A.

    1997-01-01

    Deposits of naturally occurring radioactive materials is an increasing problem in Norwegian oil and gas production. Activity concentration in solid-state samples and production water, and doses to workers involved in different operations off-shore, have been measured. The report also includes a discussion of different methods of monitoring and alternatives for final disposal of wastes. 154 refs

  15. Novel HER2 Aptamer Selectively Delivers Cytotoxic Drug to HER2-positive Breast Cancer Cells in Vitro

    Directory of Open Access Journals (Sweden)

    Liu Zhe

    2012-07-01

    Full Text Available Abstract Background Aptamer-based tumor targeted drug delivery system is a promising approach that may increase the efficacy of chemotherapy and reduce the related toxicity. HER2 protein is an attractive target for tumor-specific drug delivery because of its overexpression in multiple malignancies, including breast, gastric, ovarian, and lung cancers. Methods In this paper, we developed a new HER2 aptamer (HB5 by using systematic evolution of ligands by exponential enrichment technology (SELEX and exploited its role as a targeting ligand for delivering doxorubicin (Dox to breast cancer cells in vitro. Results The selected aptamer was an 86-nucleotide DNA molecule that bound to an epitope peptide of HER2 with a Kd of 18.9 nM. The aptamer also bound to the extracellular domain (ECD of HER2 protein with a Kdof 316 nM, and had minimal cross reactivity to albumin or trypsin. In addition, the aptamer was found to preferentially bind to HER2-positive but not HER2-negative breast cancer cells. An aptamer-doxorubicin complex (Apt-Dox was formulated by intercalating Dox into the DNA structure of HB5. The Apt-Dox complex could selectively deliver Dox to HER2-positive breast cancer cells while reducing the drug intake by HER2-negative cells in vitro. Moreover, Apt-Dox retained the cytotoxicity of Dox against HER2-positive breast cancer cells, but reduced the cytotoxicity to HER2-negative cells. Conclusions The results suggest that the selected HER2 aptamer may have application potentials in targeted therapy against HER2-positive breast cancer cells.

  16. Expression of Her-2/neu in extrahepatic cholangiocarcinoma

    Directory of Open Access Journals (Sweden)

    Shamekh R

    2017-02-01

    Full Text Available Rania Shamekh,1,* Marilin Rosa,2,* Zena Sayegh,2 Masoumeh Ghayouri,2 Richard Kim,3 Mokenge P Malafa,3 Domenico Coppola2 1Department of Pathology, University of South Florida, 2Department of Anatomic Pathology, 3Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA *These authors contributed equally to this work Background: Receptor tyrosine-protein kinase erbB-2, which is also frequently called human epidermal growth factor receptor-2 (Her-2 or Her-2/neu, has been found to be overexpressed in various human cancers.Hypothesis: The aim of this pilot study was to explore the frequency of Her-2/neu gene amplification and protein expression in extrahepatic cholangiocarcinoma (EHBC. We used the World Health Organization classification criteria for EHBC.Materials and methods: This was a retrospective study using 88 tissue samples, including 45 samples from non-neoplastic biliary tissue (NNB and 43 samples of extrahepatic cholangiocarcinoma (EHBC. A tissue microarray including NNB and EHBC was constructed and analyzed by immunohistochemistry (IHC and dual in situ hybridization for Her-2/neu protein expression and amplification, respectively. The Her-2/neu expression was scored following the guidelines used for the ToGA study.Results: All NNB samples and all but one EHBC samples showed no expression of Her-2/neu by IHC. The one EHBC case immunohistochemically positive for Her-2/neu had an IHC score of 3+. Her-2/neu gene amplification was present in two EHBC samples only and included the case found to be positive by IHC.Conclusion: Our findings are similar to those reported in the literature. Although Her-2/neu overexpression has been documented in many types of cancer, Her-2/neu protein overexpression tends to have no role in the development and/or progression of EHBC. Keywords: extrahepatic, cholangiocarcinoma, Her-2/neu, ToGA, immunohistochemistry

  17. Neratinib overcomes trastuzumab resistance in HER2 amplified breast cancer.

    Science.gov (United States)

    Canonici, Alexandra; Gijsen, Merel; Mullooly, Maeve; Bennett, Ruth; Bouguern, Noujoude; Pedersen, Kasper; O'Brien, Neil A; Roxanis, Ioannis; Li, Ji-Liang; Bridge, Esther; Finn, Richard; Siamon, Dennis; McGowan, Patricia; Duffy, Michael J; O'Donovan, Norma; Crown, John; Kong, Anthony

    2013-10-01

    Trastuzumab has been shown to improve the survival outcomes of HER2 positive breast cancer patients. However, a significant proportion of HER2-positive patients are either inherently resistant or develop resistance to trastuzumab. We assessed the effects of neratinib, an irreversible panHER inhibitor, in a panel of 36 breast cancer cell lines. We further assessed its effects with or without trastuzumab in several sensitive and resistant breast cancer cells as well as a BT474 xenograft model. We confirmed that neratinib was significantly more active in HER2-amplified than HER2 non-amplified cell lines. Neratinib decreased the activation of the 4 HER receptors and inhibited downstream pathways. However, HER3 and Akt were reactivated at 24 hours, which was prevented by the combination of trastuzumab and neratinib. Neratinib also decreased pHER2 and pHER3 in acquired trastuzumab resistant cells. Neratinib in combination with trastuzumab had a greater growth inhibitory effect than either drug alone in 4 HER2 positive cell lines. Furthermore, trastuzumab in combination with neratinib was growth inhibitory in SKBR3 and BT474 cells which had acquired resistance to trastuzumab as well as in a BT474 xenograft model. Innately trastuzumab resistant cell lines showed sensitivity to neratinib, but the combination did not enhance response compared to neratinib alone. Levels of HER2 and phospho-HER2 showed a direct correlation with sensitivity to neratinib. Our data indicate that neratinib is an effective anti-HER2 therapy and counteracted both innate and acquired trastuzumab resistance in HER2 positive breast cancer. Our results suggest that combined treatment with trastuzumab and neratinib is likely to be more effective than either treatment alone for both trastuzumab-sensitive breast cancer as well as HER2-positive tumors with acquired resistance to trastuzumab.

  18. Total syntheses of naturally occurring diacetylenic spiroacetal enol ethers.

    Science.gov (United States)

    Miyakoshi, Naoki; Aburano, Daisuke; Mukai, Chisato

    2005-07-22

    A highly stereoselective method for constructing a (2E)-methoxymethylidene-1,6-dioxaspiro[4.5]decane skeleton has been developed on the basis of the palladium(II)-catalyzed ring-closing reaction of the 3,4-dioxygenated-9-hydroxy-1-nonyn-5-one derivatives as a crucial step. The newly developed procedures could be successfully applied to the first total synthesis of five diacetylenic spiroacetal enol ether natural products starting from commercially available (R,R)- or (S,S)-diethyl tartrate.

  19. Thermodynamic characterization of tandem mismatches found in naturally occurring RNA

    Science.gov (United States)

    Christiansen, Martha E.; Znosko, Brent M.

    2009-01-01

    Although all sequence symmetric tandem mismatches and some sequence asymmetric tandem mismatches have been thermodynamically characterized and a model has been proposed to predict the stability of previously unmeasured sequence asymmetric tandem mismatches [Christiansen,M.E. and Znosko,B.M. (2008) Biochemistry, 47, 4329–4336], experimental thermodynamic data for frequently occurring tandem mismatches is lacking. Since experimental data is preferred over a predictive model, the thermodynamic parameters for 25 frequently occurring tandem mismatches were determined. These new experimental values, on average, are 1.0 kcal/mol different from the values predicted for these mismatches using the previous model. The data for the sequence asymmetric tandem mismatches reported here were then combined with the data for 72 sequence asymmetric tandem mismatches that were published previously, and the parameters used to predict the thermodynamics of previously unmeasured sequence asymmetric tandem mismatches were updated. The average absolute difference between the measured values and the values predicted using these updated parameters is 0.5 kcal/mol. This updated model improves the prediction for tandem mismatches that were predicted rather poorly by the previous model. This new experimental data and updated predictive model allow for more accurate calculations of the free energy of RNA duplexes containing tandem mismatches, and, furthermore, should allow for improved prediction of secondary structure from sequence. PMID:19509311

  20. Preparation and properties of natural nanocomposites based on natural rubber and naturally occurring halloysite nanotubes

    International Nuclear Information System (INIS)

    Rooj, Sandip; Das, Amit; Thakur, Varun; Mahaling, R.N.; Bhowmick, Anil K.; Heinrich, Gert

    2010-01-01

    A 'green' composite based on natural halloysite nanotubes (HNTs) and natural rubber (NR) was prepared by mechanical mixing. A silane coupling agent, bis (triethoxysilylpropyl)-tetrasulphide, was utilized to enhance the properties of these composites. It was observed that the reinforcing activity of HNTs was superior to commercial silica coupled with the same amount of silane coupling agent. Moreover the on-set thermal degradation decomposition temperature was improved by ∼64 o C with the addition of 10 parts HNTs per hundred of rubber. Transmission electron microscopic images confirmed the good dispersion of the HNTs in the rubber matrix, whereas X-ray diffraction studies showed a little change in interlayer spacing between the two silicate layers of HNTs.

  1. Polyomavirus and Naturally Occuring Neuroglial Tumors in Raccoons (Procyon Lotor).

    Science.gov (United States)

    Pesavento, Patricia A; Brostoff, Terza; Church, Molly E; Dela Cruz, Florante N; Woolard, Kevin D

    2016-01-01

    Polyomavirus (PyV) infections are widespread in human populations and, although generally associated with silent persistence, rarely cause severe disease. Among diseases convincingly associated with natural PyV infections of humans, there are remarkably different tissue tropisms and outcomes, including progressive multifocal leukoencephalopathy, transient or progressive nephropathy, and cancer. The variable character and unpredictable outcomes of infection attest to large gaps in our basic understanding of PyV biology. In particular, the rich history of research demonstrating the oncogenic potential of PyVs in laboratory animals begs the question of why cancer is not more often associated with infection. Raccoon polyomavirus (RacPyV), discovered in 2010, is consistently identified in neuroglial tumors in free-ranging raccoons in the western United States. Exposure to RacPyV is widespread, and RacPyV is detected in tissues of raccoons without tumors. Studying the relationship of RacPyV with its natural host is a unique opportunity to uncover cogent cellular targets and protein interactions between the virus and its host. Our hypothesis is that RacPyV, as an intact episome, alters cellular pathways within neural progenitor cells and drives oncogenesis. © The Author 2016. Published by Oxford University Press on behalf of the Institute for Laboratory Animal Research. All rights reserved. For permissions, please email: journals.permissions@oup.com.

  2. Virological and serological findings in dogs with naturally occurring distemper.

    Science.gov (United States)

    Elia, Gabriella; Camero, Michele; Losurdo, Michele; Lucente, Maria Stella; Larocca, Vittorio; Martella, Vito; Decaro, Nicola; Buonavoglia, Canio

    2015-03-01

    Canine distemper virus (CDV) is the cause of a severe and highly contagious disease in dogs. The unpredictable and variable course of CDV-related disease may hamper correct diagnosis of infection and makes it crucial the collection of samples suitable for laboratory confirmation. In the present study we were able to follow the disease in two dogs infected naturally, collecting different biological matrices during the entire period of infection. By real time RT-PCR, viral RNA was detected and quantified, suggesting that urine and rectal swabs would be useful for ante-mortem diagnosis of distemper in dogs, regardless of the clinical stage and form of the illness. Copyright © 2015 Elsevier B.V. All rights reserved.

  3. Structures and properties of naturally occurring polyether antibiotics.

    Science.gov (United States)

    Rutkowski, Jacek; Brzezinski, Bogumil

    2013-01-01

    Polyether ionophores represent a large group of natural, biologically active substances produced by Streptomyces spp. They are lipid soluble and able to transport metal cations across cell membranes. Several of polyether ionophores are widely used as growth promoters in veterinary. Polyether antibiotics show a broad spectrum of bioactivity ranging from antibacterial, antifungal, antiparasitic, antiviral, and tumour cell cytotoxicity. Recently, it has been shown that some of these compounds are able to selectively kill cancer stem cells and multidrug-resistant cancer cells. Thus, they are recognized as new potential anticancer drugs. The biological activity of polyether ionophores is strictly connected with their molecular structure; therefore, the purpose of this paper is to present an overview of their formula, molecular structure, and properties.

  4. Relative leach behavior of waste glasses and naturally occurring glasses

    International Nuclear Information System (INIS)

    Adams, P.B.

    1979-01-01

    Simulated nuclear waste glasses of the sodium-borosilicate type with a low waste loading and of the zinc-borosilicate type with a high waste loading have been compared with obsidians. The resuls indicate that the waste glasses would corrode in normal natural environments at a rate of about 0.1 μm per year at 30 0 C and about 5 μm per year at 90 0 C, compared with obsidians which seem to corrode at, or less than, about 0.01 μm per year at 30 0 C and less than 1 μm per year at 90 0 C. Activation energies for reactions of the two waste glasses with pure water are about 20 kcal/g-mol. 3 figures, 7 tables

  5. Immunohistochemical detection of Her-2/neu overexpression in ...

    African Journals Online (AJOL)

    Materials and Methods: Immunohistochemical staining for Her-2/neu was performed on 10% formalin-fixed, paraffinembedded primary carcinoma of the breast from 83 patients, between 2003 and 2007 using anti-Her-2/neu rabbit polyclonal antibody (DakoCytomation, CA, USA) and reactivity detected by an avidin-biotin ...

  6. Cosmos 954. The occurence and nature of recovered debris

    International Nuclear Information System (INIS)

    Gummer, W.K.; Campbell, F.R.; Knight, G.B.; Ricard, J.L.

    1980-05-01

    The Russian nuclear-powered satellite, Cosmos 954, re-entered the earth's atmosphere early on 24 January 1978. Concern about radioactive debris, whose presence was quickly verified on the frozen surfaces of lakes and land, led to a massive airborne and ground search and recovery program that lasted from re-entry date to the middle of October, 1978, interrupted only by the spring break-up period. The search area extended from Great Slave Lake northeastward towards Baker Lake. Only about 65 kilograms of material were found, although it is probable that the satellite weighed several tons. All fragments but one - itself weighing over 18 kg - were radioactive; many showed clear evidence of melting and erosion. A wide area stretching southwards from Great Slave Lake was affected by a scattered shower of minute particles representing the enriched fuel of the satellite's power source. Intensive searches were carried out in the Territories and adjacent Alberta and Saskatchewan in an effort to find and remove as much as possible of such material. Laboratory studies were carried out on particles to learn their chemical and physical nature, in order to understand their probable behaviour in the general environment. Search and recovery continued until it could be concluded that 1) it was most unlikely that highly raidoactive fragments had been missed; 2) all obvious large fragments had been located and removed; 3) the risk to people from particles remaining in unfrequented areas was not great because of the particles' tiny size, their general insolubility, and their scattered distribution. Residual radiological risks were also fading rapidly relative to the natural radiation background. (auth)

  7. Current therapeutic strategies of anti-HER2 treatment in advanced breast cancer patients

    Directory of Open Access Journals (Sweden)

    Joanna Huszno

    2016-03-01

    Full Text Available The HER2/neu ( ERBB2 oncogene is amplified and/or overexpressed in approximately 20% of breast cancers, and is a strong prognostic factor for relapse and poor overall survival, particularly in node-positive patients. It is also an important predictor for response to trastuzumab, which has established efficacy against breast cancer with overexpression or amplification of the HER2 oncogene. Treatment with the anti-HER2 humanized monoclonal antibody – trastuzumab significantly improves progression-free and overall survival among patients with HER2-positive breast cancer. However, in most patients with HER2-positive metastatic breast cancer, the disease progresses occurred, what cause the need for new targeted therapies for advanced disease. In clinical trials, there are tested new drugs to improve the results of treatment for this group of patients. This paper presents new drugs introduced into clinical practice for treatment of advanced breast cancer, whose molecular target are receptors of the HER2 family. In addition, new therapeutic strategies and drugs that are currently in clinical researches are discussed.

  8. Naturally Occurring Off-Switches for CRISPR-Cas9.

    Science.gov (United States)

    Pawluk, April; Amrani, Nadia; Zhang, Yan; Garcia, Bianca; Hidalgo-Reyes, Yurima; Lee, Jooyoung; Edraki, Alireza; Shah, Megha; Sontheimer, Erik J; Maxwell, Karen L; Davidson, Alan R

    2016-12-15

    CRISPR-Cas9 technology would be enhanced by the ability to inhibit Cas9 function spatially, temporally, or conditionally. Previously, we discovered small proteins encoded by bacteriophages that inhibit the CRISPR-Cas systems of their host bacteria. These "anti-CRISPRs" were specific to type I CRISPR-Cas systems that do not employ the Cas9 protein. We posited that nature would also yield Cas9 inhibitors in response to the evolutionary arms race between bacteriophages and their hosts. Here, we report the discovery of three distinct families of anti-CRISPRs that specifically inhibit the CRISPR-Cas9 system of Neisseria meningitidis. We show that these proteins bind directly to N. meningitidis Cas9 (NmeCas9) and can be used as potent inhibitors of genome editing by this system in human cells. These anti-CRISPR proteins now enable "off-switches" for CRISPR-Cas9 activity and provide a genetically encodable means to inhibit CRISPR-Cas9 genome editing in eukaryotes. VIDEO ABSTRACT. Copyright © 2016 Elsevier Inc. All rights reserved.

  9. Treatment of Gravel Contaminated with Naturally Occurring Radioactive Element

    International Nuclear Information System (INIS)

    Sohsah, M. A.; Kamal, S. M.; Mamoon, A.

    2004-01-01

    Environmental protection primarily means controlling the releases of radioactive and non-radioactive wastes to the environment and involves treatment, storage, cleanup and disposal of these wastes. The present study concerns the cleanup of gravel that has been contaminated with 2 26 R a. Aqueous solutions of different compositions including water and various concentrations of calcium chloride and barium chloride were used to leach the contaminated gravel. The leaching experiments were carried out in glass column. In some leaching experiments, samples of sandy soil were placed below the gravel to test the sorption of the leached 2 26 R a by the soil. The relative efficiencies of the leachant and the extent of sorption of the leached radionuclide were determined both by the liquid scintillation counting and by the thermoluminescent chips. The TLD chips record the dose before and after decontamination of the gravel and before and after contamination of the soil samples when used. The results obtained indicated that acidified barium chloride was relatively the most effective leachant of 2 26 R a contamination. It reduced the dose from the contaminated gravel to almost half. The soil sample used adsorbs the leached radionuclides efficiently, increasing the soil naturally low dose to about six folds

  10. Isolation and Spectral Analysis of Naturally Occurring Thiarubrine A

    Science.gov (United States)

    Reyes, Juan; Morton, Melita; Downum, Kelsey; O'Shea, Kevin E.

    2001-06-01

    We have designed an experiment in which students isolate and characterize thiarubrine A, a pseudo-antiaromatic 1,2-dithia-3,5-cyclohexadiene derivative. Thiarubrines are an important class of compounds which have recently received attention because of their unusual reactivity, unique biological activity, and potential medicinal applications. They possess a distinctive red color and structure features that are particularly useful for demonstrating UV-vis, NMR, and IR spectral analyses. A crude mixture containing thiarubrine A is obtained by methanol (liquid-solid) extraction of the roots of short ragweed, Ambrosia artemisiifolia. Alternatively, these compounds can be isolated from numerous taxa within the family Asteraceae. Thiarubrine A possesses alkyl, alkenyl, and alkynyl functionality, which is useful in illustrating the utility of IR and NMR in the characterization of natural products. The long wavelength UV-vis absorption band of thiarubrine is indication of the nonplanarity of dithiin ring and provides an excellent opportunity to discuss the concepts of aromaticity, conjugation, and molecular orbital theory.

  11. Mycoflora and naturally occurring mycotoxins in poultry feeds in Argentina.

    Science.gov (United States)

    Dalcero, A; Magnoli, C; Luna, M; Ancasi, G; Reynoso, M M; Chiacchiera, S; Miazzo, R; Palacio, G

    1998-01-01

    The purpose of this work was to determine the mycoflora and mycotoxins natural incidence in poultry feeds from 2 factories in Río Cuarto, Córdoba. One hundred and thirty samples were taken from May/1996 to May/1997. The most dominant species isolated of poultry feed samples belonged to the genera Aspergillus spp 85% and Fusarium spp 70%. From Aspergillus genus eleven species were identified and A. flavus was the most frequent. Nine species were identified from the Fusarium genus and the predominant was F. moniliforme. Penicillium ranked third in the number of isolated cases. From this genus twelve species were collected of which P. brevicompactum (15%), P. restrictum (14%) and P. purpurogenum (12%) were the most common. The most significant mycotoxin from poultry feeds was aflatoxin B1 (AFB1) found in 48% of the samples, with levels ranging from 10 to 123 ng/g. For zearalenone (ZEA) the levels were 327 to 5, 850 ng/g and DON was not detected from the samples. Due to the fact that in Argentina there is little information about this topic, these data on poultry feeds in our region would be of worldwide interest.

  12. Population doses from naturally occurring radiation in Norway

    International Nuclear Information System (INIS)

    Stranden, E.

    The main purpose of this work was to study the radiological consequences of the introduction of building materials with high concentrations of radioactivity and to analyse the impact of a reduction of the ventilation rates in houses on the population dose from inhalation of natural airborne radioactivity. The general problems of radioactivity in building materials are discussed. Measurements of radioactivity in building materials from different parts of the country are reported, together with theoretical calculations of the gamma doses in houses. These calculations are compared with experimental results and earlier measurements of the indoor gamma radiation in Norway. Measurements of the outdoor gamma radiation in different parts of Norway are presented. These results are used together with earlier measurements of the gamma radiation inside houses to calculate the average, and variations of population dose from this radiation. An experimental study on the radon concentrations inside different types of dwellings, and a discussion of the respiratory dose received by the inhalation of radon daughters is presented. Some factors that may have influence upon the radon concentrations are also discussed. A method for measurement of radon and thoron daughters in air is discussed. The possible radiological effects of an increased radon concentration in houses are discussed. (Auth.)

  13. Naturally occurring compounds affect glutamatergic neurotransmission in rat brain.

    Science.gov (United States)

    Martini, Lucia Helena; Jung, Fernanda; Soares, Felix Antunes; Rotta, Liane Nanci; Vendite, Deusa Aparecida; Frizzo, Marcos Emilio dos Santos; Yunes, Rosendo A; Calixto, João Batista; Wofchuk, Susana; Souza, Diogo O

    2007-11-01

    Natural products, including those derived from plants, have largely contributed to the development of therapeutic drugs. Glutamate is the main excitatory neurotransmitter in the central nervous system and it is also considered a nociceptive neurotransmitter, by acting on peripheral nervous system. For this reason, in this study we investigated the effects of the hydroalcoholic extracts from Drymis winteri (polygodial and drimanial), Phyllanthus (rutin and quercetine), Jathopha elliptica (jatrophone), Hedyosmum brasiliense (13HDS), Ocotea suaveolens (Tormentic acid), Protium kleinii (alphabeta-amyrin), Citrus paradise (naringin), soybean (genistein) and Crataeva nurvala (lupeol), described as having antinociceptive effects, on glutamatergic transmission parameters, such as [(3)H]glutamate binding, [(3)H]glutamate uptake by synaptic vesicles and astrocyte cultures, and synaptosomal [(3)H]glutamate release. All the glutamatergic parameters were affected by one or more of these compounds. Specifically, drimanial and polygodial presented more broad and profound effects, requiring more investigation on their mechanisms. The putative central side effects of these compounds, via the glutamatergic system, are discussed.

  14. Natural occurring radioactivity materials (NORM) in Ecuadorian oil fields

    International Nuclear Information System (INIS)

    Vasquez, R.; Enriquez, F.; Reinoso, T.

    2008-01-01

    Full text: Many natural elements contain radioactive isotopes, and most of them are present in the soil. In the gas and oil industries the most important radio nuclides are Ra-226 from the decay series of U-238, and in lower grade Ra-228 from the decay series of Th-232. Water exit from the perforation and perforation mud in the Oil towers drowns the NORM materials. Changes in temperature and pressure, allows the presence of sulphates and carbonates in pipes and internal areas of equipment. A Ra and Ba similarity leads to the selective co-precipitation in mud and incrustations of radioisotopes. A measure made in the pipe lines show that these industries generate important doses overcoming the levels of exemption and even the limits of established doses. The research was done by finding a pipe at Shushufindi 52 B well of production near by Coca city in the Ecuadorian jungle. The 'Comision Ecuatoriana de Energia Atomica' (CEEA), supervises the pipe line and accessories that are used in PETROPRODUCION fields accomplishing the radiological characterization, identifying the useless pipes and separate them in order of take care the good ones. Meanwhile the identification of the radioactive isotopes the CEEA proceed with the isolation of the radioactive disposals. From 57.830 pipes and accessories there were 1.607 useless ones, 56.223 didn't show radioactivity. Those pipes were monitored from the PETRODUCCION'S warehouses in Coca, Lago Agrio and Guarumo from September 12 th 2005 to September 12 th 2006. The CEEA is interested in NORMS because inadvertent workers may get high levels of radioactivity exposition. The Oil industries should have a manual about the complete handling of these materials. (author)

  15. Potent In Vitro Antifungal Activities of Naturally Occurring Acetylenic Acids▿

    Science.gov (United States)

    Li, Xing-Cong; Jacob, Melissa R.; Khan, Shabana I.; Ashfaq, M. Khalid; Babu, K. Suresh; Agarwal, Ameeta K.; ElSohly, Hala N.; Manly, Susan P.; Clark, Alice M.

    2008-01-01

    Our continuing effort in antifungal natural product discovery has led to the identification of five 6-acetylenic acids with chain lengths from C16 to C20: 6-hexadecynoic acid (compound 1), 6-heptadecynoic acid (compound 2), 6-octadecynoic acid (compound 3), 6-nonadecynoic acid (compound 4), and 6-icosynoic acid (compound 5) from the plant Sommera sabiceoides. Compounds 2 and 5 represent newly isolated fatty acids. The five acetylenic acids were evaluated for their in vitro antifungal activities against Candida albicans, Candida glabrata, Candida krusei, Candida tropicalis, Candida parapsilosis, Cryptococcus neoformans, Aspergillus fumigatus, Aspergillus flavus, Aspergillus niger, Trichophyton mentagrophytes, and Trichophyton rubrum by comparison with the positive control drugs amphotericin B, fluconazole, ketoconazole, caspofungin, terbinafine, and undecylenic acid. The compounds showed various degrees of antifungal activity against the 21 tested strains. Compound 4 was the most active, in particular against the dermatophytes T. mentagrophytes and T. rubrum and the opportunistic pathogens C. albicans and A. fumigatus, with MICs comparable to several control drugs. Inclusion of two commercially available acetylenic acids, 9-octadecynoic acid (compound 6) and 5,8,11,14-eicosatetraynoic acid (compound 7), in the in vitro antifungal testing further demonstrated that the antifungal activities of the acetylenic acids were associated with their chain lengths and positional triple bonds. In vitro toxicity testing against mammalian cell lines indicated that compounds 1 to 5 were not toxic at concentrations up to 32 μM. Furthermore, compounds 3 and 4 did not produce obvious toxic effects in mice at a dose of 34 μmol/kg of body weight when administered intraperitoneally. Taking into account the low in vitro and in vivo toxicities and significant antifungal potencies, these 6-acetylenic acids may be excellent leads for further preclinical studies. PMID:18458131

  16. Potent in vitro antifungal activities of naturally occurring acetylenic acids.

    Science.gov (United States)

    Li, Xing-Cong; Jacob, Melissa R; Khan, Shabana I; Ashfaq, M Khalid; Babu, K Suresh; Agarwal, Ameeta K; Elsohly, Hala N; Manly, Susan P; Clark, Alice M

    2008-07-01

    Our continuing effort in antifungal natural product discovery has led to the identification of five 6-acetylenic acids with chain lengths from C(16) to C(20): 6-hexadecynoic acid (compound 1), 6-heptadecynoic acid (compound 2), 6-octadecynoic acid (compound 3), 6-nonadecynoic acid (compound 4), and 6-icosynoic acid (compound 5) from the plant Sommera sabiceoides. Compounds 2 and 5 represent newly isolated fatty acids. The five acetylenic acids were evaluated for their in vitro antifungal activities against Candida albicans, Candida glabrata, Candida krusei, Candida tropicalis, Candida parapsilosis, Cryptococcus neoformans, Aspergillus fumigatus, Aspergillus flavus, Aspergillus niger, Trichophyton mentagrophytes, and Trichophyton rubrum by comparison with the positive control drugs amphotericin B, fluconazole, ketoconazole, caspofungin, terbinafine, and undecylenic acid. The compounds showed various degrees of antifungal activity against the 21 tested strains. Compound 4 was the most active, in particular against the dermatophytes T. mentagrophytes and T. rubrum and the opportunistic pathogens C. albicans and A. fumigatus, with MICs comparable to several control drugs. Inclusion of two commercially available acetylenic acids, 9-octadecynoic acid (compound 6) and 5,8,11,14-eicosatetraynoic acid (compound 7), in the in vitro antifungal testing further demonstrated that the antifungal activities of the acetylenic acids were associated with their chain lengths and positional triple bonds. In vitro toxicity testing against mammalian cell lines indicated that compounds 1 to 5 were not toxic at concentrations up to 32 muM. Furthermore, compounds 3 and 4 did not produce obvious toxic effects in mice at a dose of 34 mumol/kg of body weight when administered intraperitoneally. Taking into account the low in vitro and in vivo toxicities and significant antifungal potencies, these 6-acetylenic acids may be excellent leads for further preclinical studies.

  17. Comparison of central HER2 testing with quantitative total HER2 expression and HER2 homodimer measurements using a novel proximity-based assay.

    Science.gov (United States)

    Huang, Weidong; Reinholz, Monica; Weidler, Jodi; Yolanda, Lie; Paquet, Agnes; Whitcomb, Jeannette; Lingle, Wilma; Jenkins, Robert B; Chen, Beiyun; Larson, Jeffrey S; Tan, Yuping; Sherwood, Thomas; Bates, Michael; Perez, Edith A

    2010-08-01

    The accuracy and reliability of immunohistochemical analysis and in situ hybridization for the assessment of HER2 status remains a subject of debate. We developed a novel assay (HERmark Breast Cancer Assay, Monogram Biosciences, South San Francisco, CA) that provides precise quantification of total HER2 protein expression (H2T) and HER2 homodimers (H2D) in formalin-fixed, paraffin-embedded tissue specimens. H2T and H2D results of 237 breast cancers were compared with those of immunohistochemical studies and fluorescence in situ hybridization (FISH) centrally performed at the Mayo Clinic, Rochester, MN. H2T described a continuum across a wide dynamic range ( approximately 2.5 log). Excluding the equivocal cases, HERmark showed 98% concordance with immunohistochemical studies for positive and negative assay values. For the 94 immunohistochemically equivocal cases, 67% and 39% concordance values were observed between HERmark and FISH for positive and negative assay values, respectively. Polysomy 17 in the absence of HER2 gene amplification did not result in HER2 overexpression as evaluated quantitatively using the HERmark assay.

  18. Hungarian situation of the technologically enhanced naturally occuring radioactive materials

    International Nuclear Information System (INIS)

    Juhasz, L.; Szerbin, P.; Czoch, I.

    2003-01-01

    Full text: In Hungary, the main goal is that the Hungarian regulations should meet with the EU Directive No. 96/29. For this aim, a surveying project has been launched in order to collect all relevant information about the Hungarian TENORM situation. This surveying programme covers a lot of data collection (work activities, disposal places, residue quantities) and radiological measurements on the TENORM site. The Hungarian situation of TENORM definitely differs from other countries in the aspect of occurrence forms of natural sources (or in the imported raw materials), in the quantities of exploitation, in the level of the radioactivity and in the applied technological processes. Firstly, those work activities have been choosen where the huge amount of residues have been produced. The other criteria is that the activity concentration in a great portion of the given residues is much higher than the average activity concentration of the typical Hungarian soil. After filtering and ranking, the following main activities enhanced the radioactivity level are left: uranium mining and milling, coal mining, coal firing in power plants, bauxite mining and aluminous earth production. At the uranium mining and milling area the uranium content of residues ranges from 20 to 70 g t -1 , and above those the dose rate is 0.4-10 μSv h -1 . The waste rock piles and heaps for leaching were restored and the remediation of tailings ponds is still under way. In the mountain Mecsek and on the territory from the highland Balaton to the mountain Vertes, the radioactivity level of the coals is 10-50 times higher than the worldwide average. The coal fired plants have piled up in the order of magnitude of 10 million tons of fly ash, bottom ash and slag in ponds around the plants. The radioactivity of U-238 series of ash and slag is in the range from 200 to 2000 Bq·kg -1 . The radionuclide concentrations of bauxite ores range from 200 to 300 Bq·kg -1 . At the refining factories, a lot of red

  19. Interaction of CDCP1 with HER2 Enhances HER2-Driven Tumorigenesis and Promotes Trastuzumab Resistance in Breast Cancer

    Directory of Open Access Journals (Sweden)

    Abdullah Alajati

    2015-04-01

    Full Text Available Understanding the molecular pathways that contribute to the aggressive behavior of HER2-positive breast cancers may aid in the development of novel therapeutic interventions. Here, we show that CDCP1 and HER2 are frequently co-overexpressed in metastatic breast tumors and associated with poor patient prognosis. HER2 and CDCP1 co-overexpression leads to increased transformation ability, cell migration, and tumor formation in vivo, and enhanced HER2 activation and downstream signaling in different breast cancer cell lines. Mechanistically, we demonstrate that CDCP1 binds to HER2 through its intracellular domain, thereby increasing HER2 interaction with the non-receptor tyrosine kinase c-SRC (SRC, leading to trastuzumab resistance. Taken together, our findings establish that CDCP1 is a modulator of HER2 signaling and a biomarker for the stratification of breast cancer patients with poor prognosis. Our results also provide a rationale for therapeutic targeting of CDCP1 in HER2-positive breast cancer patients.

  20. Actinomycetes, an Inexhaustible Source of Naturally Occurring Antibiotics

    Directory of Open Access Journals (Sweden)

    Yōko Takahashi

    2018-05-01

    Full Text Available Global public health faces a desperate situation, due to the lack of effective antibiotics. Coordinated steps need to be taken, worldwide, to rectify this situation and protect the advances in modern medicine made over the last 100 years. Work at Japan’s Kitasato Institute has been in the vanguard of many such advances, and work is being proactively tailored to promote the discovery of urgently needed antimicrobials. Efforts are being concentrated on actinomycetes, the proven source of most modern antibiotics. We devised a novel physicochemical screening mechanism, whereby simple physico-chemical properties, in conjunction with related detection methods, such as LC/MS, LC/UV, and polarity, could be used to identify or predict new compounds in a culture broth, simply by comparing results with existing databases. New compounds are isolated, purified, and their structure determined before being tested for any bioactivity. We used lyophilized actinomycete strains from the Kitasato Microbial Library, most more than 35 years old, and found 330 strains were producers of useful bioactive substances. We also tested organisms found in fresh samples collected in the complex environments from around plant roots, as well as from sediments of mangrove forests and oceans, resulting in the discovery of 36 novel compounds from 11 actinomycete strains. A compound, designated iminimycin, containing an iminium ion in the structure was discovered from the culture broth of Streptomyces griseus OS-3601, which had been stored for a long time as a streptomycin-producing strain. This represented the first iminium ion discovery in actinomycetes. Compounds with a cyclopentadecane skeleton containing 5,6-dihydro-4-hydroxyl-2-pyrone ring and tetrahydrofuran ring, designated mangromicins, were isolated from the culture broth of Lechevalieria aerocolonigenes K10-0216 obtained from sediment in a mangrove forest. These structures are extremely unique among natural compounds

  1. HER 2/neu protein expression in colorectal cancer

    International Nuclear Information System (INIS)

    Schuell, B; Gruenberger, T; Scheithauer, W; Zielinski, Ch; Wrba, F

    2006-01-01

    Conflicting data exist about the prevalence of HER-2/neu overexpression in colorectal cancer ranging from 0 to 83 %. In our study we tried to clarify the extent of expression and its relationship to clinicopathological parameters. This study involved 77 specimens of malignant colorectal cancer lesions of surgically resected patients. HER-2/neu immunohistochemistry was performed using the Hercep-Test Kit. Out of 77 specimens, 56 were Her-2/neu negative (70%), 20 (26%) showed a barely immunostaining (1+), only 1 (1%) was moderately (2+) and 2 (3%) were strongly positive (3+). Her-2/neu staining (moderately and strongly positive) was only detected in primary tumours of patients with confirmed metastases. No relationship was found between membranous HER-2 expression and patients' gender or differentiation. The median survival time of patients with positive HER-2/neu immunostaining was 21 versus 39 months in patients without HER-2/neu expression (p = 0.088). The c-erbB protein expression was observed in colorectal cancer but rarely in the therapeutic range (2+ and 3+). There was no significant association with tumour grade, gender, localization of the primary tumour or survival. These data indicate that c-erbB-2 is unlikely to play a major role in the therapeutic management of colorectal cancer

  2. Salivary expression of soluble HER2 in breast cancer patients with positive and negative HER2 status

    Directory of Open Access Journals (Sweden)

    Laidi F

    2014-07-01

    Full Text Available Fatna Laidi,1 Amal Bouziane,2 Amina Lakhdar,3 Samira Khabouze,3 Brahim Rhrab,3 Fatima Zaoui1 1Oral Biomechanics and Biotechnology Research Unit, Faculty of Dental Medicine, 2Department of Periodontology, Faculty of Dental Medicine, Biostatistical, Clinical and Epidemiological Research Laboratory, Faculty of Medicine and Pharmacy, 3Department of Obstetrics and Gynecology, Ibn Sina University Hospital, Rabat, Morocco Background: The aim of this study was to investigate the relationship between salivary concentration of the soluble fragment of the HER2 (human epidermal growth factor receptor protein and its status in mammary tissues. Methods: This case-control study was done in 27 breast cancer patients with no visible metastatic disease treated at the gynecology service, Maternity Souissi Hospital, Rabat, Morocco. Two groups were selected, ie, patients with positive and negative HER2 status in mammary tissue. The salivary HER2 protein concentration was assessed by enzyme-linked immunosorbent assay. The salivary HER2 concentration was compared between the HER2-positive and HER2-negative groups using the Mann-Whitney U test. A P-value <0.05 was considered to be statistically significant. Results: No statistically significant difference in salivary HER2 protein expression was found between the case and control groups. There was also no significant difference in clinical characteristics according to positive and negative HER2 status (P>0.05, except for the progesterone hormone receptor which was statistically significant in both the case and control groups (P=0.047. Conclusion: According to our data, salivary expression of the HER2 receptor may not be a reliable alternative to tissue assessment. Keywords: breast cancer, HER2, saliva, diagnosis

  3. Quantifying HER-2 expression on circulating tumor cells by ACCEPT.

    Directory of Open Access Journals (Sweden)

    Leonie Zeune

    Full Text Available Circulating tumor cells (CTCs isolated from blood can be probed for the expression of treatment targets. Immunofluorescence is often used for both the enumeration of CTC and the determination of protein expression levels related to treatment targets. Accurate and reproducible assessment of such treatment target expression levels is essential for their use in the clinic. To enable this, an open source image analysis program named ACCEPT was developed in the EU-FP7 CTCTrap and CANCER-ID programs. Here its application is shown on a retrospective cohort of 132 metastatic breast cancer patients from which blood samples were processed by CellSearch® and stained for HER-2 expression as additional marker. Images were digitally stored and reviewers identified a total of 4084 CTCs. CTC's HER-2 expression was determined in the thumbnail images by ACCEPT. 150 of these images were selected and sent to six independent investigators to score the HER-2 expression with and without ACCEPT. Concordance rate of the operators' scoring results for HER-2 on CTCs was 30% and could be increased using the ACCEPT tool to 51%. Automated assessment of HER-2 expression by ACCEPT on 4084 CTCs of 132 patients showed 8 (6.1% patients with all CTCs expressing HER-2, 14 (10.6% patients with no CTC expressing HER-2 and 110 (83.3% patients with CTCs showing a varying HER-2 expression level. In total 1576 CTCs were determined HER-2 positive. We conclude that the use of image analysis enables a more reproducible quantification of treatment targets on CTCs and leads the way to fully automated and reproducible approaches.

  4. Quantifying HER-2 expression on circulating tumor cells by ACCEPT.

    Science.gov (United States)

    Zeune, Leonie; van Dalum, Guus; Decraene, Charles; Proudhon, Charlotte; Fehm, Tanja; Neubauer, Hans; Rack, Brigitte; Alunni-Fabbroni, Marianna; Terstappen, Leon W M M; van Gils, Stephan A; Brune, Christoph

    2017-01-01

    Circulating tumor cells (CTCs) isolated from blood can be probed for the expression of treatment targets. Immunofluorescence is often used for both the enumeration of CTC and the determination of protein expression levels related to treatment targets. Accurate and reproducible assessment of such treatment target expression levels is essential for their use in the clinic. To enable this, an open source image analysis program named ACCEPT was developed in the EU-FP7 CTCTrap and CANCER-ID programs. Here its application is shown on a retrospective cohort of 132 metastatic breast cancer patients from which blood samples were processed by CellSearch® and stained for HER-2 expression as additional marker. Images were digitally stored and reviewers identified a total of 4084 CTCs. CTC's HER-2 expression was determined in the thumbnail images by ACCEPT. 150 of these images were selected and sent to six independent investigators to score the HER-2 expression with and without ACCEPT. Concordance rate of the operators' scoring results for HER-2 on CTCs was 30% and could be increased using the ACCEPT tool to 51%. Automated assessment of HER-2 expression by ACCEPT on 4084 CTCs of 132 patients showed 8 (6.1%) patients with all CTCs expressing HER-2, 14 (10.6%) patients with no CTC expressing HER-2 and 110 (83.3%) patients with CTCs showing a varying HER-2 expression level. In total 1576 CTCs were determined HER-2 positive. We conclude that the use of image analysis enables a more reproducible quantification of treatment targets on CTCs and leads the way to fully automated and reproducible approaches.

  5. HER-2-positive metastatic breast cancer: new possibilities for therapy

    Directory of Open Access Journals (Sweden)

    E. V. Artamonova

    2013-01-01

    Full Text Available This article is devoted to modern approaches in HER-2-positive metastatic breast cancer therapy. Recently treatment algorithm for this type of cancer included trastuzumab plus cytostatic in first line, continuation of trastuzumab with another chemotherapy regimen in second line, further switch to lapatinib and eventual return to trastuzumab after progression. Nowadays our options are broader owing to new anti-HER-2 agents which are pertruzumab and T-DM1. Now the most effective therapy regimen in first line is double HER-2 blockade (trastuzumab + pertuzumab in combination with docetaxel. Benefit of new agent T-DM1 versus combination of lapatinib and capecitabin is proved in patients progressed on trastuzumab and taxanes. T-DM1 also showed high efficacy as salvage therapy in intensively pretreated patients with meta- static HER-2-positive breast cancer who progressed on taxanes, trastuzumab and lapatinib.

  6. Regulation of naturally occurring radioactive materials in non-nuclear industries

    International Nuclear Information System (INIS)

    Scott, L.M.

    1997-01-01

    The volume and concentrations of naturally occurring radioactive material is large across a variety of industries commonly thought not to involve radioactive material. The regulation of naturally occurring radioactive material in the United States is in a state of flux. Inventory of naturally occurring radioactive materials is given, along with a range of concentrations. Current and proposed regulatory limits are presented. (author)

  7. Differences in radiosensitivity between three HER2 overexpressing cell lines

    International Nuclear Information System (INIS)

    Steffen, Ann-Charlott; Tolmachev, Vladimir; Stenerloew, Bo; Goestring, Lovisa; Palm, Stig; Carlsson, Joergen

    2008-01-01

    HER2 is a potential target for radionuclide therapy, especially when HER2 overexpressing breast cancer cells are resistant to Herceptin registered treatment. Therefore, it is of interest to analyse whether HER2 overexpressing tumour cells have different inherent radiosensitivity. The radiosensitivity of three often used HER2 overexpressing cell lines, SKOV-3, SKBR-3 and BT-474, was analysed. The cells were exposed to conventional photon irradiation, low linear energy transfer (LET), to characterise their inherent radiosensitivity. The analysis was made with clonogenic survival and growth extrapolation assays. The cells were also exposed to alpha particles, high LET, from 211 At decays using the HER2-binding affibody molecule 211 At-(Z HER2:4 ) 2 as targeting agent. Assays for studies of internalisation of the affibody molecule were applied. SKOV-3 cells were most radioresistant, SKBR-3 cells were intermediate and BT-474 cells were most sensitive as measured with the clonogenic and growth extrapolation assays after photon irradiation. The HER2 dependent cellular uptake of 211 At was qualitatively similar for all three cell lines. However, the sensitivity to the alpha particles from 211 At differed; SKOV-3 was most resistant, SKBR-3 intermediate and BT-474 most sensitive. These differences were unexpected because it is assumed that all types of cells should have similar sensitivity to high-LET radiation. The sensitivity to alpha particle exposure correlated with internalisation of the affibody molecule and with size of the cell nucleus. There can be differences in radiosensitivity, which, if they also exist between patient breast cancer cells, are important to consider for both conventional radiotherapy and for HER2-targeted radionuclide therapy. (orig.)

  8. Neratinib overcomes trastuzumab resistance in HER2 amplified breast cancer.

    OpenAIRE

    Canonici, A; Gijsen, M; Mullooly, M; Bennett, R; Bouguern, N; Pedersen, K; O'Brien, NA; Roxanis, I; Li, J-L; Bridge, E; Finn, R; Siamon, D; McGowan, P; Duffy, MJ; O'Donovan, N

    2013-01-01

    Trastuzumab has been shown to improve the survival outcomes of HER2 positive breast cancer patients. However, a significant proportion of HER2-positive patients are either inherently resistant or develop resistance to trastuzumab. We assessed the effects of neratinib, an irreversible panHER inhibitor, in a panel of 36 breast cancer cell lines. We further assessed its effects with or without trastuzumab in several sensitive and resistant breast cancer cells as well as a BT474 xenograft model. ...

  9. Selective anti-proliferation of HER2-positive breast cancer cells by anthocyanins identified by high-throughput screening.

    Directory of Open Access Journals (Sweden)

    Weihua Liu

    Full Text Available Overexpressed Human epidermal growth factor receptor 2 (HER2 drives the biology of 20% breast cancer and is a prediction of a poor prognosis for patients. HER2-targeted therapies significantly improve outcomes for HER2-positive patients. Traditional Chinese herbs/medicines have been used to treat breast cancer patients including HER2-positive patients in Asia for decades. Although the traditional medicines demonstrate efficacy in clinics for HER2-positive patients, the mechanism is largely unknown. In this article, we screened a 10,000 natural product library in 6 different cell lines representing breast cancer, and assessed the ability of each drug to cause cytotoxicity through a high-throughput screening approach. We have identified eight natural compounds that selectively inhibit the proliferation of HER2-positive cells. Two of the hit compounds, peonidin-3-glucoside and cyaniding-3-glucoside, are both extracts from black rice. They inhibit the phospho-HER2 and phospho-AKT and were confirmed to induce HER2-psotive breast cancer cells apoptosis both in vitro and in vivo. Peonidin-3-glucoside and cyaniding-3-glucoside treatments significantly reduced the tumor size and volume in vivo compared to the control group. There is no significant difference of antitumorgenic effects between peonidin-3-glucoside and cyaniding-3-glucoside treatments.

  10. Docosahexaenoic Acid Modulates a HER2-Associated Lipogenic Phenotype, Induces Apoptosis, and Increases Trastuzumab Action in HER2-Overexpressing Breast Carcinoma Cells

    Directory of Open Access Journals (Sweden)

    Graziela Rosa Ravacci

    2015-01-01

    Full Text Available In breast cancer, lipid metabolic alterations have been recognized as potential oncogenic stimuli that may promote malignancy. To investigate whether the oncogenic nature of lipogenesis closely depends on the overexpression of HER2 protooncogene, the normal breast cell line, HB4a, was transfected with HER2 cDNA to obtain HER2-overexpressing HB4aC5.2 cells. Both cell lines were treated with trastuzumab and docosahexaenoic acid. HER2 overexpression was accompanied by an increase in the expression of lipogenic genes involved in uptake (CD36, transport (FABP4, and storage (DGAT of exogenous fatty acids (FA, as well as increased activation of “de novo” FA synthesis (FASN. We further investigate whether this lipogenesis reprogramming might be regulated by mTOR/PPARγ pathway. Inhibition of the mTORC1 pathway markers, p70S6 K1, SREBP1, and LIPIN1, as well as an increase in DEPTOR expression (the main inhibitor of the mTOR was detected in HB4aC5.2. Based on these results, a PPARγ selective antagonist, GW9662, was used to treat both cells lines, and the lipogenic genes remained overexpressed in the HB4aC5.2 but not HB4a cells. DHA treatment inhibited all lipogenic genes (except for FABP4 in both cell lines yet only induced death in the HB4aC5.2 cells, mainly when associated with trastuzumab. Neither trastuzumab nor GW9662 alone was able to induce cell death. In conclusion, oncogenic transformation of breast cells by HER2 overexpression may require a reprogramming of lipogenic genetic that is independent of mTORC1 pathway and PPARγ activity. This reprogramming was inhibited by DHA.

  11. Docosahexaenoic Acid Modulates a HER2-Associated Lipogenic Phenotype, Induces Apoptosis, and Increases Trastuzumab Action in HER2-Overexpressing Breast Carcinoma Cells.

    Science.gov (United States)

    Ravacci, Graziela Rosa; Brentani, Maria Mitzi; Tortelli, Tharcisio Citrângulo; Torrinhas, Raquel Suzana M M; Santos, Jéssica Reis; Logullo, Angela Flávia; Waitzberg, Dan Linetzky

    2015-01-01

    In breast cancer, lipid metabolic alterations have been recognized as potential oncogenic stimuli that may promote malignancy. To investigate whether the oncogenic nature of lipogenesis closely depends on the overexpression of HER2 protooncogene, the normal breast cell line, HB4a, was transfected with HER2 cDNA to obtain HER2-overexpressing HB4aC5.2 cells. Both cell lines were treated with trastuzumab and docosahexaenoic acid. HER2 overexpression was accompanied by an increase in the expression of lipogenic genes involved in uptake (CD36), transport (FABP4), and storage (DGAT) of exogenous fatty acids (FA), as well as increased activation of "de novo" FA synthesis (FASN). We further investigate whether this lipogenesis reprogramming might be regulated by mTOR/PPARγ pathway. Inhibition of the mTORC1 pathway markers, p70S6 K1, SREBP1, and LIPIN1, as well as an increase in DEPTOR expression (the main inhibitor of the mTOR) was detected in HB4aC5.2. Based on these results, a PPARγ selective antagonist, GW9662, was used to treat both cells lines, and the lipogenic genes remained overexpressed in the HB4aC5.2 but not HB4a cells. DHA treatment inhibited all lipogenic genes (except for FABP4) in both cell lines yet only induced death in the HB4aC5.2 cells, mainly when associated with trastuzumab. Neither trastuzumab nor GW9662 alone was able to induce cell death. In conclusion, oncogenic transformation of breast cells by HER2 overexpression may require a reprogramming of lipogenic genetic that is independent of mTORC1 pathway and PPARγ activity. This reprogramming was inhibited by DHA.

  12. Neratinib Efficacy and Circulating Tumor DNA Detection of HER2 Mutations in HER2 Nonamplified Metastatic Breast Cancer.

    Science.gov (United States)

    Ma, Cynthia X; Bose, Ron; Gao, Feng; Freedman, Rachel A; Telli, Melinda L; Kimmick, Gretchen; Winer, Eric; Naughton, Michael; Goetz, Matthew P; Russell, Christy; Tripathy, Debu; Cobleigh, Melody; Forero, Andres; Pluard, Timothy J; Anders, Carey; Niravath, Polly Ann; Thomas, Shana; Anderson, Jill; Bumb, Caroline; Banks, Kimberly C; Lanman, Richard B; Bryce, Richard; Lalani, Alshad S; Pfeifer, John; Hayes, Daniel F; Pegram, Mark; Blackwell, Kimberly; Bedard, Philippe L; Al-Kateb, Hussam; Ellis, Matthew J C

    2017-10-01

    Purpose: Based on promising preclinical data, we conducted a single-arm phase II trial to assess the clinical benefit rate (CBR) of neratinib, defined as complete/partial response (CR/PR) or stable disease (SD) ≥24 weeks, in HER2 mut nonamplified metastatic breast cancer (MBC). Secondary endpoints included progression-free survival (PFS), toxicity, and circulating tumor DNA (ctDNA) HER2 mut detection. Experimental Design: Tumor tissue positive for HER2 mut was required for eligibility. Neratinib was administered 240 mg daily with prophylactic loperamide. ctDNA sequencing was performed retrospectively for 54 patients (14 positive and 40 negative for tumor HER2 mut ). Results: Nine of 381 tumors (2.4%) sequenced centrally harbored HER2 mut (lobular 7.8% vs. ductal 1.6%; P = 0.026). Thirteen additional HER2 mut cases were identified locally. Twenty-one of these 22 HER2 mut cases were estrogen receptor positive. Sixteen patients [median age 58 (31-74) years and three (2-10) prior metastatic regimens] received neratinib. The CBR was 31% [90% confidence interval (CI), 13%-55%], including one CR, one PR, and three SD ≥24 weeks. Median PFS was 16 (90% CI, 8-31) weeks. Diarrhea (grade 2, 44%; grade 3, 25%) was the most common adverse event. Baseline ctDNA sequencing identified the same HER2 mut in 11 of 14 tumor-positive cases (sensitivity, 79%; 90% CI, 53%-94%) and correctly assigned 32 of 32 informative negative cases (specificity, 100%; 90% CI, 91%-100%). In addition, ctDNA HER2 mut variant allele frequency decreased in nine of 11 paired samples at week 4, followed by an increase upon progression. Conclusions: Neratinib is active in HER2 mut , nonamplified MBC. ctDNA sequencing offers a noninvasive strategy to identify patients with HER2 mut cancers for clinical trial participation. Clin Cancer Res; 23(19); 5687-95. ©2017 AACR . ©2017 American Association for Cancer Research.

  13. NSCLC and HER2: between lights and shadows.

    Science.gov (United States)

    Ricciardi, Giuseppina Rosaria Rita; Russo, Alessandro; Franchina, Tindara; Ferraro, Giuseppa; Zanghì, Mariangela; Picone, Antonio; Scimone, Antonino; Adamo, Vincenzo

    2014-12-01

    The therapeutic landscape of non-small-cell lung cancer (NSCLC) has dramatically changed in the last few years with the introduction of molecularly targeted agents, leading to unprecedented results in lung tumors with a paradigmatic shift from a "one size fits all" approach to an histologic and molecular-based approach. The discovery of epidermal growth factor receptor (EGFR) mutations in NSCLC in 2004 and the marked response to the EGFR tyrosine kinase inhibitor gefitinib, in a small subset of patients harboring these genetic abnormalities, stimulated the study of other kinase mutants involvement in NSCLC. The incredible story of ALK rearranged tumors, with the rapid Food and Drug Administration approval of Crizotinib after only 4 years from the discovery of EML4-ALK translocation in NSCLC, has profoundly influenced the concept of drug development in NSCLC, paving the way to a novel series of molecularly selected studies with specific inhibitors. The identification of these oncogenic drivers has dramatically changed the genetic landscape of NSCLC moving away from the old concept of a large indistinct histological entity to a combination of rare clinically relevant molecular subsets. Recently, a renewed interest has been emerging on the human epidermal growth factor-2 (HER2) pathway. Genetic aberrations of this signaling pathway have been reported over time to be associated in NSCLC with different sensitivity to the EGFR tyrosine kinase inhibitors, to have a possible prognostic role and more recently HER2 amplification has been emerged as a possible mechanism in EGFR-mutated tumors of acquired resistance to the EGFR tyrosine kinase inhibitors. In addition, dysregulation of the HER2 pathway, in particular HER2 mutations (mostly, in-frame exon 20 insertions), may represent a possible novel therapeutic target in NSCLC, paving the way for a new generation of targeted agents in NSCLC. Since anecdotal case reports of clinical activity of anti-HER2 agents in NSCLC

  14. Label-free LC-MS analysis of HER2+ breast cancer cell line response to HER2 inhibitor treatment.

    Science.gov (United States)

    Di Luca, Alessio; Henry, Michael; Meleady, Paula; O'Connor, Robert

    2015-08-04

    Human epidermal growth-factor receptor (HER)-2 is overexpressed in 25 % of breast-cancers and is associated with an aggressive form of the disease with significantly shortened disease free and overall survival. In recent years, the use of HER2-targeted therapies, monoclonal-antibodies and small molecule tyrosine-kinase inhibitors has significantly improved the clinical outcome for HER2-positive breast-cancer patients. However, only a fraction of HER2-amplified patients will respond to therapy and the use of these treatments is often limited by tumour drug insensitivity or resistance and drug toxicities. Currently there is no way to identify likely responders or rational combinations with the potential to improve HER2-focussed treatment outcome. In order to further understand the molecular mechanisms of treatment-response with HER2-inhibitors, we used a highly-optimised and reproducible quantitative label-free LC-MS strategy to characterize the proteomes of HER2-overexpressing breast-cancer cell-lines (SKBR3, BT474 and HCC1954) in response to drug-treatment with HER2-inhibitors (lapatinib, neratinib or afatinib). Following 12 ours treatment with different HER2-inhibitors in the BT474 cell-line; compared to the untreated cells, 16 proteins changed significantly in abundance following lapatinib treatment (1 μM), 21 proteins changed significantly following neratinib treatment (150 nM) and 38 proteins changed significantly following afatinib treatment (150 nM). Whereas following 24 hours treatment with neratinib (200 nM) 46 proteins changed significantly in abundance in the HCC1954 cell-line and 23 proteins in the SKBR3 cell-line compared to the untreated cells. Analysing the data we found that, proteins like trifunctional-enzyme subunit-alpha, mitochondrial; heterogeneous nuclear ribonucleoprotein-R and lamina-associated polypeptide 2, isoform alpha were up-regulated whereas heat shock cognate 71 kDa protein was down-regulated in 3 or more comparisons. This proteomic

  15. EVALUATION OF IMMUNOHISTOCHEMISTRY (IHC MARKER HER2 IN BREAST CANCER

    Directory of Open Access Journals (Sweden)

    Prasanna G. Shete

    2016-08-01

    Full Text Available The paper discusses a novel approach involving algorithm implementation and hardware Devkit processing for estimating the extent of cancer in a breast tissue sample. The process aims at providing a reliable, repeatable, and fast method that could replace the traditional method of manual examination and estimation. Immunohistochemistry (IHC and Fluorescence in situ Hybridization (FISH are the two main methods used to detect the marker status in clinical practice. FISH is though more reliable than IHC, but IHC is widely used as it is cheaper, convenient to operate and conserve, the morphology is clear. The IHC markers are Estrogen receptor (ER, Progesterone receptor (PR, Human Epidermal Growth Factor (HER2 that give clear indications of the presence of cancer cells in the tissue sample. HER2 remains the most reliable marker for the detection of breast cancer. The Human Epidermal Growth Factor Receptor (HER2 markers are discussed in the paper, as it gives clear indications of the presence of cancer cells in the tissue sample. HER2 is identified based on the color and intensity of the cell membrane staining. The color and intensity is obviously based on the thresholding for classifying the cancerous cells into severity levels in terms of score to estimate the extent of spread of cancer in breast tissue. For HER2 evaluation, the percentage of staining is calculated in terms of ratio of stain pixel count to the total pixel count. The evaluation of HER2 is obtained through simulation software (MATLAB using intensity based algorithm and same is run on embedded processor evaluation board Devkit 8500. The results are validated with doctors.

  16. Heterologous human/rat HER2-specific exosome-targeted T cell vaccine stimulates potent humoral and CTL responses leading to enhanced circumvention of HER2 tolerance in double transgenic HLA-A2/HER2 mice.

    Science.gov (United States)

    Xie, Yufeng; Wu, Jie; Xu, Aizhang; Ahmeqd, Shahid; Sami, Amer; Chibbar, Rajni; Freywald, Andrew; Zheng, Changyu; Xiang, Jim

    2018-03-07

    DNA vaccines composed of heterologous human HER2 and rat neu sequences induce stronger antibody response and protective antitumor immunity than either HER2 or neu DNA vaccines in transgenic mice. We previously developed HER2-specific exosome-targeted T-cell vaccine HER2-T EXO capable of stimulating HER2-specific CD8 + T-cell responses, but only leading to partial protective immunity in double-transgenic HLA-A2/HER2 mice with self-immune tolerance to HER2. Here, we constructed an adenoviral vector AdV HuRt expressing HuRt fusion protein composed of NH 2 -HER2 1-407 (Hu) and COOH-neu 408-690 (Rt) fragments, and developed a heterologous human/rat HER2-specific exosome-targeted T-cell vaccine HuRt-T EXO using polyclonal CD4 + T-cells uptaking exosomes released by AdV HuRt -transfected dendritic cells. We found that the HuRt-T EXO vaccine stimulates enhanced CD4 + T-cell responses leading to increased induction of HER2-specific antibody (∼70 µg/ml) compared to that (∼40 µg/ml) triggered by the homologous HER2-T EXO vaccine. By using PE-H-2K d /HER2 23-71 tetramer, we determined that HuRt-T EXO stimulates stronger HER2-specific CD8 + T-cell responses eradicating 90% of HER2-specific target cells, while HER2-T EXO -induced CD8 + T-cell responses only eliminating 53% targets. Furthermore, HuRt-T EXO , but not HER2-T EXO vaccination, is capable of suppressing early stage-established HER2-expressing 4T1 HER2 breast cancer in its lung metastasis or subcutaneous form in BALB/c mice, and of completely protecting transgenic HLA-A2/HER2 mice from growth of HLA-A2/HER2-expressing BL6-10 A2/HER2 melanoma. HuRt-T EXO -stimulated HER2-specific CD8 + T-cells not only are cytolytic to trastuzumab-resistant HLA-A2/HER2-expressing BT474/A2 breast tumor cells in vitro but also eradicates pre-established BT474/A2 tumors in athymic nude mice. Therefore, our novel heterologous human/rat HER2-specific T-cell vaccine HuRt-T EXO, circumventing HER2 tolerance, may provide a new

  17. From phenotypic to molecular polymorphisms involved in naturally occurring variation for plant development

    NARCIS (Netherlands)

    Alonso-Blanco, C.; Mendez-Vigo, B.; Koornneef, M.

    2005-01-01

    An enormous amount of naturally occurring genetic variation affecting development is found within wild and domesticated plant species. This diversity is presumably involved in plant adaptation to different natural environments or in human preferences. In addition, such intraspecific variation

  18. An Acquired HER2T798I Gatekeeper Mutation Induces Resistance to Neratinib in a Patient with HER2 Mutant-Driven Breast Cancer.

    Science.gov (United States)

    Hanker, Ariella B; Brewer, Monica Red; Sheehan, Jonathan H; Koch, James P; Sliwoski, Gregory R; Nagy, Rebecca; Lanman, Richard; Berger, Michael F; Hyman, David M; Solit, David B; He, Jie; Miller, Vincent; Cutler, Richard E; Lalani, Alshad S; Cross, Darren; Lovly, Christine M; Meiler, Jens; Arteaga, Carlos L

    2017-06-01

    We report a HER2 T798I gatekeeper mutation in a patient with HER2 L869R -mutant breast cancer with acquired resistance to neratinib. Laboratory studies suggested that HER2 L869R is a neratinib-sensitive, gain-of-function mutation that upon dimerization with mutant HER3 E928G , also present in the breast cancer, amplifies HER2 signaling. The patient was treated with neratinib and exhibited a sustained partial response. Upon clinical progression, HER2 T798I was detected in plasma tumor cell-free DNA. Structural modeling of this acquired mutation suggested that the increased bulk of isoleucine in HER2 T798I reduces neratinib binding. Neratinib blocked HER2-mediated signaling and growth in cells expressing HER2 L869R but not HER2 L869R/T798I In contrast, afatinib and the osimertinib metabolite AZ5104 strongly suppressed HER2 L869R/T798I -induced signaling and cell growth. Acquisition of HER2 T798I upon development of resistance to neratinib in a breast cancer with an initial activating HER2 mutation suggests HER2 L869R is a driver mutation. HER2 T798I -mediated neratinib resistance may be overcome by other irreversible HER2 inhibitors like afatinib. Significance: We found an acquired HER2 gatekeeper mutation in a patient with HER2 -mutant breast cancer upon clinical progression on neratinib. We speculate that HER2 T798I may arise as a secondary mutation following response to effective HER2 tyrosine kinase inhibitors (TKI) in other cancers with HER2 -activating mutations. This resistance may be overcome by other irreversible HER2 TKIs, such as afatinib. Cancer Discov; 7(6); 575-85. ©2017 AACR. This article is highlighted in the In This Issue feature, p. 539 . ©2017 American Association for Cancer Research.

  19. Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer.

    Science.gov (United States)

    Slamon, D J; Godolphin, W; Jones, L A; Holt, J A; Wong, S G; Keith, D E; Levin, W J; Stuart, S G; Udove, J; Ullrich, A

    1989-05-12

    Carcinoma of the breast and ovary account for one-third of all cancers occurring in women and together are responsible for approximately one-quarter of cancer-related deaths in females. The HER-2/neu proto-oncogene is amplified in 25 to 30 percent of human primary breast cancers and this alteration is associated with disease behavior. In this report, several similarities were found in the biology of HER-2/neu in breast and ovarian cancer, including a similar incidence of amplification, a direct correlation between amplification and over-expression, evidence of tumors in which overexpression occurs without amplification, and the association between gene alteration and clinical outcome. A comprehensive study of the gene and its products (RNA and protein) was simultaneously performed on a large number of both tumor types. This analysis identified several potential shortcomings of the various methods used to evaluate HER-2/neu in these diseases (Southern, Northern, and Western blots, and immunohistochemistry) and provided information regarding considerations that should be addressed when studying a gene or gene product in human tissue. The data presented further support the concept that the HER-2/neu gene may be involved in the pathogenesis of some human cancers.

  20. Tailoring DNA vaccines: designing strategies against HER2 positive cancers

    Directory of Open Access Journals (Sweden)

    Cristina eMarchini

    2013-05-01

    Full Text Available The crucial role of HER2 in epithelial transformation and its selective overexpression on cancer tissues makes it an ideal target for cancer immunotherapies such as passive immunotherapy with Trastuzumab. There are, however, a number of concerns regarding the use of monoclonal antibodies which include resistance, repeated treatments, considerable costs and side effects that make active immunotherapies against HER2 desirable alternative approaches. The efficacy of anti-HER2 DNA vaccination has been widely demonstrated in transgenic cancer-prone mice, which recapitulate several features of human breast cancers. Nonetheless, the rational design of a cancer vaccine able to trigger a long lasting immunity, and thus prevent tumor recurrence in patients, would require the understanding of how tolerance and immunosuppression regulate antitumor immune responses and, at the same time, the identification of the most immunogenic portions of the target protein. We herein retrace the findings that led to our most promising DNA vaccines that, by encoding human/rat chimeric forms of HER2, are able to circumvent peripheral tolerance. Preclinical data obtained with these chimeric DNA vaccines have provided the rationale for their use in an ongoing phase I clinical trial (EudraCT 2011-001104-34.

  1. Deep bilinear features for Her2 scoring in digital pathology

    Directory of Open Access Journals (Sweden)

    Rodner Erik

    2017-09-01

    Full Text Available We present an automated approach for rating HER2 over-expressions in given whole-slide images of breast cancer histology slides. The slides have a very high resolution and only a small part of it is relevant for the rating.

  2. Serum HER 2 extracellular domain level is correlated with tissue HER 2 status in metastatic gastric or gastro-oesophageal junction adenocarcinoma.

    Directory of Open Access Journals (Sweden)

    Shu-Qin Dai

    Full Text Available BACKGROUND: To explore the association between serum human epidermal growth factor receptor 2 (HER 2 extracellular domain (ECD levels and tissue HER 2 status in metastatic gastric cancer. PATIENTS AND METHODS: HER 2 status was retrospectively analyzed in 219 advanced gastric or gastroesophageal junction (GEJ patients. Serum HER 2 ECD was measured by chemiluminescent assay and tissue HER 2 was assessed by fluorescent in situ hybridisation (FISH and immunohistochemistry (IHC assay. RESULTS: Significant associations were found between serum HER 2 ECD levels and tissue HER 2 status. Twenty-four patients had HER 2 ECD levels >16.35 ng/mL, which has a sensitivity of 51.4% and a specificity of 97.3% to predict tissue HER 2 status. When the cut-off value was increased to 22 ng/mL, then all 12 patients with serum HER 2 ECD levels>22 ng/mL were tissue HER 2 positive, corresponding to a specificity of 100% and a sensitivity of 32.4%. High serum HER 2 ECD levels were strongly associated with the intestinal histological type (Lauren's classification, liver metastasis, multiple metastasis (>2 and increased LDH levels, but not with overall survival. CONCLUSIONS: The high specificity of the serum HER 2 ECD assay in predicting tissue HER 2 status suggests its potential as a surrogate marker of the HER 2 status in gastric cancer.

  3. Serum HER-2 predicts response and resistance to trastuzumab treatment in breast cancer

    DEFF Research Database (Denmark)

    Petersen, Eva Rabing Brix; Sørensen, Patricia Diana; Jakobsen, Erik Hugger

    2013-01-01

    Serum HER2 (S-HER2) was approved in 2003 by the US Food and Drug Administration (FDA) for monitoring trastuzumab treatment in tissue HER2 positive breast cancer patients. Information of the value of S-HER2 is scarce. We hypothesised that S-HER2 would reflect the clinical effect of trastuzumab....

  4. Neratinib for the treatment of HER2-positive early stage breast cancer.

    Science.gov (United States)

    Echavarria, Isabel; López-Tarruella, Sara; Márquez-Rodas, Iván; Jerez, Yolanda; Martin, Miguel

    2017-08-01

    Despite the advances in the treatment of HER2-positive breast cancer, resistance to actual chemotherapeutic regimens eventually occurs. Neratinib, an orally available pan-inhibitor of the ERBB family, represents an interesting new option for early-stage HER2-positive breast cancer. Areas covered: In this article, the development of neratinib, with a special focus on its potential value in the treatment of early-stage HER2-positive breast cancer, has been reviewed. For this purpose, a literature search was conducted, including preclinical studies, early-phase trials in advanced cancer with neratinib in monotherapy and in combination, and phase II and large phase III trials in the early setting. Management of neratinib-induced toxicity, future perspectives for the drug, and ongoing trials are also discussed in this review. Expert commentary: Neratinib is emerging as a promising oral drug for the treatment of HER2-positive breast cancer. Although FDA and EMA approval is derived from the extended adjuvant treatment, this setting may not be the ideal scenario to obtain the beneficial effects of neratinib. Confirmatory data in the neoadjuvant setting and subgroup analysis from the ExTENET trial might bring some light into the best setting for neratinib therapy. Data from confirmatory trials in the metastatic setting are also required.

  5. High p95HER2/HER2 Ratio Associated With Poor Outcome in Trastuzumab-Treated HER2-Positive Metastatic Breast Cancer NCCTG N0337 and NCCTG 98-32-52 (Alliance).

    Science.gov (United States)

    Chumsri, Saranya; Sperinde, Jeff; Liu, Heshan; Gligorov, Joseph; Spano, Jean-Philippe; Antoine, Martine; Moreno Aspitia, Alvaro; Tan, Winston; Winslow, John; Petropoulos, Christos J; Chenna, Ahmed; Bates, Michael; Weidler, Jodi Marie; Huang, Weidong; Dueck, Amylou; Perez, Edith A

    2018-03-12

    Purpose: p95HER2 is a truncated form of HER2 that confers resistance to trastuzumab in vitro , but clinical results have been conflicting to date. Given that p95HER2 levels correlate with total HER2 expression levels, which confer better outcomes, we sought to evaluate the p95HER2/HER2 ratio in the North Central Cancer Treatment Group N0337 and N98-32-52 trials. Experimental Design: The HERmark assay and VeraTag technology (Monogram Biosciences) were used to measure total HER2 and p95HER2 expression levels in 91 patient samples. Results: In the multivariate model, increasing total HER2 level was significantly associated with longer (OS; HR, 0.33; P = 0.002) and decreasing p95HER2 level was significantly associated with longer OS (HR, 4.2; P = 0.01). Total HER2 expression level was significantly associated with longer progression-free survival (PFS) (HR, 0.57; P = 0.04), whereas p95HER2 level was not (HR, 1.7; P = 0.25). However, there was a positive association between p95HER2 and total HER2 expression levels ( R 2 = 0.48; P < 0.001). Consistent with our hypothesis, the ratio of p95HER2/HER2 was significantly associated with worsening PFS (HR, 1.7; P = 0.04) and OS (HR, 2.8; P = 0.002). Patients with the highest tertile of p95HER2/HER2 values had significantly less favorable PFS (HR, 1.8; P = 0.06) and OS (HR, 2.3; P = 0.02). Conclusions: A high p95HER2/HER2 ratio identified patients with metastatic breast cancer with poor outcomes on trastuzumab-based therapies. Further investigation of the p95HER2/HER2 ratio as a potential prognostic or predictive biomarker for HER2-targeted therapy is warranted. Clin Cancer Res; 1-6. ©2018 AACR. ©2018 American Association for Cancer Research.

  6. Content of naturally occurring radionuclides in samples taken from world historical sites

    International Nuclear Information System (INIS)

    Nikolic, J.; Jankovic, M.; Todorovic, D.; Sarap, N.

    2011-01-01

    This paper presents the results of the investigation of naturally occurring radionuclides content in different samples taken from the historical sites in Iran, China, Syria and Jordan. Samples contained different natural materials used in masonry, for making artefacts for personal use as well as water, sand and mud from the Dead sea. The aim was to ascertain the content of naturally occurring radionuclides, calculation of hazard indexes and their comparison to the values recommended and obtained in modern days materials [sr

  7. Long-term hazard of recurrence in HER2+ breast cancer patients untreated with anti-HER2 therapy

    DEFF Research Database (Denmark)

    Strasser-Weippl, Kathrin; Horick, Nora; Smith, Ian E

    2015-01-01

    INTRODUCTION: Worldwide, many patients with HER2+ (human epidermal growth factor receptor 2-positive) early breast cancer (BC) do not receive adjuvant trastuzumab. Hazards of recurrence of these patients with respect to hormone receptor status of the primary tumor have not been described. METHODS...

  8. A single-domain antibody-linked Fab bispecific antibody Her2-S-Fab has potent cytotoxicity against Her2-expressing tumor cells.

    Science.gov (United States)

    Li, Aifen; Xing, Jieyu; Li, Li; Zhou, Changhua; Dong, Bin; He, Ping; Li, Qing; Wang, Zhong

    2016-12-01

    Her2, which is frequently overexpressed in breast cancer, is one of the most studied tumor-associated antigens for cancer therapy. Anti-HER2 monoclonal antibody, trastuzumab, has achieved significant clinical benefits in metastatic breast cancer. In this study, we describe a novel bispecific antibody Her2-S-Fab targeting Her2 by linking a single domain anti-CD16 VHH to the trastuzumab Fab. The Her2-S-Fab antibody can be efficiently expressed and purified from Escherichia coli, and drive potent cancer cell killing in HER2-overexpressing cancer cells. In xenograft model, the Her2-S-Fab suppresses tumor growth in the presence of human immune cells. Our results suggest that the bispecific Her2-S-Fab may provide a valid alternative to Her2 positive cancer therapy.

  9. Targeting breast carcinoma with radioiodinated anti-HER2 Nanobody

    International Nuclear Information System (INIS)

    Pruszynski, Marek; Koumarianou, Eftychia; Vaidyanathan, Ganesan; Revets, Hilde; Devoogdt, Nick; Lahoutte, Tony; Zalutsky, Michael R.

    2013-01-01

    Introduction: With a molecular weight an order of magnitude lower than antibodies but possessing comparable affinities, Nanobodies (Nbs) are attractive as targeting agents for cancer diagnosis and therapy. An anti-HER2 Nb could be utilized to determine HER2 status in breast cancer patients prior to trastuzumab treatment. This provided motivation for the generation of HER2-specific 5F7GGC Nb, its radioiodination and evaluation for targeting HER2 expressing tumors. Methods: 5F7GGC Nb was radioiodinated with 125 I using Iodogen and with 131 I using the residualizing agent N ε -(3-[ 131 I]iodobenzoyl)-Lys 5 -N α -maleimido-Gly 1 -GEEEK ([ 131 I]IB-Mal-D-GEEEK) used previously successfully with intact antibodies. Paired-label internalization assays using BT474M1 cells and tissue distribution experiments in athymic mice bearing BT474M1 xenografts were performed to compare the two labeled Nb preparations. Results: The radiochemical yields for Iodogen and [ 131 I]IB-Mal-D-GEEEK labeling were 83.6 ± 5.0% (n = 10) and 59.6 ± 9.4% (n = 15), respectively. The immunoreactivity of labeled proteins was preserved as confirmed by in vitro and in vivo binding to tumor cells. Biodistribution studies showed that Nb radiolabeled using [ 131 I]IB-Mal-D-GEEEK, compared with the directly labeled Nb, had a higher tumor uptake (4.65 ± 0.61% ID/g vs. 2.92 ± 0.24% ID/g at 8 h), faster blood clearance, lower accumulation in non-target organs except kidneys, and as a result, higher concomitant tumor-to-blood and tumor-to-tissue ratios. Conclusions: Taken together, these results demonstrate that 5F7GGC anti-HER2 Nb labeled with residualizing [ 131 I]IB-Mal-D-GEEEK had better tumor targeting properties compared to the directly labeled Nb suggesting the potential utility of this Nb conjugate for SPECT ( 129 I) and PET imaging ( 124 I) of patients with HER2-expressing tumors.

  10. Targeting HER2-positive cancer using multifunctional nanoparticles

    DEFF Research Database (Denmark)

    Juul, Christian Ammitzbøll

    Advanced delivery of chemotherapeutics to tumor tissue is an active field of research, as it offers several benefits over conventional cancer therapies. In the three introductory chapters of this thesis, the development of liposomes as drug carriers, including novel strategies to improve delivery...... efficiency, is thoroughly reviewed. Chapter 4 encompasses a comprehensive manuscript, which describes the in vitro and in vivo evaluation of a novel liposomal delivery platform designed to target the HER2 receptor on cancer cells and be activated by enzyme activity in the tumor. In Chapter 5, an alternative...... HER2-targeted liposome formulation was assessed in vitro. Rather than being enzyme-sensitive, these liposomes were responsive to reducing conditions. Such conditions are found in several cancers due to hypoxia as well as in endocytic compartments. The progressive in vitro optimization of a complex...

  11. Neratinib, A Novel HER2-Targeted Tyrosine Kinase Inhibitor.

    Science.gov (United States)

    Tiwari, Shruti Rakesh; Mishra, Prasun; Abraham, Jame

    2016-10-01

    HER2 gene amplification and receptor overexpression is identified in 20% to 25% of human breast cancers. Use of targeted therapy for HER2-amplified breast cancer has led to improvements in disease-free and overall survival in this subset of patients. Neratinib is an oral pan HER inhibitor, that irreversibly inhibits the tyrosine kinase activity of epidermal growth factor receptor (EGFR or HER1), HER2, and HER4, which leads to reduced phosphorylation and activation of downstream signaling pathways. Neratinib is currently being tested in a number of clinical trials for its safety and efficacy in lung cancer, and colorectal, bladder, and breast cancers. In this review we discuss the available phase I, II, and III data for use of neratinib in the metastatic, adjuvant, neoadjuvant, and extended adjuvant settings along with the ongoing clinical trials of neratinib in breast cancer. We also elaborate on the side effect profile of this relatively new drug and provide guidelines for its use in clinical practice. Copyright © 2016 Elsevier Inc. All rights reserved.

  12. Correlation between quantitative HER-2 protein expression and risk for brain metastases in HER-2+ advanced breast cancer patients receiving trastuzumab-containing therapy.

    Science.gov (United States)

    Duchnowska, Renata; Biernat, Wojciech; Szostakiewicz, Barbara; Sperinde, Jeff; Piette, Fanny; Haddad, Mojgan; Paquet, Agnes; Lie, Yolanda; Czartoryska-Arłukowicz, Bogumiła; Wysocki, Piotr; Jankowski, Tomasz; Radecka, Barbara; Foszczynska-Kłoda, Małgorzata; Litwiniuk, Maria; Debska, Sylwia; Weidler, Jodi; Huang, Weidong; Buyse, Marc; Bates, Michael; Jassem, Jacek

    2012-01-01

    Patients with human epidermal growth factor receptor (HER)-2+ breast cancer are at particularly high risk for brain metastases; however, the biological basis is not fully understood. Using a novel HER-2 assay, we investigated the correlation between quantitative HER-2 expression in primary breast cancers and the time to brain metastasis (TTBM) in HER-2+ advanced breast cancer patients treated with trastuzumab. The study group included 142 consecutive patients who were administered trastuzumab-based therapy for HER-2+ metastatic breast cancer. HER-2/neu gene copy number was quantified as the HER-2/centromeric probe for chromosome 17 (CEP17) ratio by central laboratory fluorescence in situ hybridization (FISH). HER-2 protein was quantified as total HER-2 protein expression (H2T) by the HERmark® assay (Monogram Biosciences, Inc., South San Francisco, CA) in formalin-fixed, paraffin-embedded tumor samples. HER-2 variables were correlated with clinical features and TTBM was measured from the initiation of trastuzumab-containing therapy. A higher H2T level (continuous variable) was correlated with shorter TTBM, whereas HER-2 amplification by FISH and a continuous HER-2/CEP17 ratio were not predictive (p = .013, .28, and .25, respectively). In the subset of patients that was centrally determined by FISH to be HER-2+, an above-the-median H2T level was significantly associated with a shorter TTBM (hazard ratio, [HR], 2.4; p = .005), whereas this was not true for the median HER-2/CEP17 ratio by FISH (p = .4). Correlation between a continuous H2T level and TTBM was confirmed on multivariate analysis (HR, 3.3; p = .024). These data reveal a strong relationship between the quantitative HER-2 protein expression level and the risk for brain relapse in HER-2+ advanced breast cancer patients. Consequently, quantitative assessment of HER-2 protein expression may inform and facilitate refinements in therapeutic treatment strategies for selected subpopulations of patients in this

  13. Naturally occurring and radiation-induced tumors in SPF mice, and genetic influence in radiation leukemogenesis

    International Nuclear Information System (INIS)

    Kasuga, T.

    1979-01-01

    The data obtained so far in this study point to a strong genetic influence not only on the types and incidence of naturally occurring and radiation-induced tumors but also on radiation leukemogenesis. (Auth.)

  14. APPLICATION OF THE NATURALLY-OCCURRING DEUTERIUM ISOTOPE TO TRACING THE CAPILLARY FRINGE

    Science.gov (United States)

    Naturally-occurring deuterium is a useful tracer of subsurface hydrologic processes. A possible application includes the identification of capillary fringes in the vadose zone. Multiple and discontinuous water tables persist in many temperate regions, under various hydrogeologi...

  15. Synthesis of the naturally occurring prenylated coumarins balsamiferone and cedrelopsin by domino reactions

    Digital Repository Service at National Institute of Oceanography (India)

    Patre, R.E.; Parameswaran, P.S.; Tilve, S.G.

    Regioselective one step synthesis of naturally occurring prenyl coumarin balsamiferone is described using domino Wittig reaction, 3,3-sigmatropic rearrangements and deprenylation, while regioselective synthesis of cedrelopsin is described via domino...

  16. Estimates of naturally occurring pools of thorium, uranium and iodine in boreal forests of southeast Sweden

    International Nuclear Information System (INIS)

    Loefgren, A.; Kautsky, U.

    2009-01-01

    The distribution patterns of naturally occurring radionuclides or their stable isotopes have been used to study the long-term behaviour of the radionuclides that may originate from nuclear waste. The Swedish Nuclear Fuel and Waste Management Company is performing investigations at two potential sites for nuclear waste disposal in southern Sweden. Here is the distribution and total content of the three naturally occurring radionuclides/stable isotopes, thorium, uranium and iodine, described for six forest localities at those sites. (LN)

  17. Detection of Naturally Occurring Gear and Bearing Faults in a Helicopter Drivetrain

    Science.gov (United States)

    2014-01-01

    Detection of Naturally Occurring Gear and Bearing Faults in a Helicopter Drivetrain by Kelsen E. LaBerge, Eric C. Ames, and Brian D. Dykas...5066 ARL-TR-6795 January 2014 Detection of Naturally Occurring Gear and Bearing Faults in a Helicopter Drivetrain Kelsen E. LaBerge...ELEMENT NUMBER 6. AUTHOR(S) Kelsen E. LaBerge, Eric C. Ames, and Brian D. Dykas 5d. PROJECT NUMBER 5e. TASK NUMBER 5f. WORK UNIT NUMBER

  18. Change in HER2 (ERBB2) gene status after taxane-based chemotherapy for breast cancer: polyploidization can lead to diagnostic pitfalls with potential impact for clinical management.

    Science.gov (United States)

    Valent, Alexander; Penault-Llorca, Frédérique; Cayre, Anne; Kroemer, Guido

    2013-01-01

    The status of the HER2 (ERBB2) gene in breast cancer is not static and may change among the primary tumor, lymph node metastases, and distant metastases. This status change can be a consequence of the natural evolution of the tumor or can be induced by therapy. The HER2 gene status is, in the majority of cases, established at the moment of diagnosis. After chemotherapy, monitoring HER2 status can be a challenge because of ploidy changes induced by drugs. The cytogeneticist or the pathologist can face real difficulties in distinguishing between a true HER2 amplification and HER2 copy number increase by polyploidization. We performed a HER2 genetic examination by fluorescence in situ hybridization (FISH) of invasive breast cancers before and after taxane treatment. The majority of patients (91%) were HER2-negative both at diagnosis and after treatment. Thirty of 344 patients (9%) whose tumors were initially HER2-negative were found by FISH to have supernumerary HER2 gene copies (up to 15 copies) after neoadjuvant chemotherapy. This HER2 copy increase could not be attributed to true gene amplifications and instead reflected polyploidization events, which presumably affected all chromosomes. Indeed, when we used other FISH probes, we found other gene copy numbers to parallel those of HER2. We recommend careful checking of invasive breast carcinomas by supplementary FISH probes if the copy number of the HER2 gene is >6. This procedure allows the discrimination of specific HER2 gene amplifications and global increases in ploidy. Copyright © 2013 Elsevier Inc. All rights reserved.

  19. Phase II Study of HER-2/neu Intracellular Domain Peptide-Based Vaccine Administered to Stage IV HER2 Positive Breast Cancer Patients Receiving Trastuzumab

    National Research Council Canada - National Science Library

    Disis, Mary L

    2007-01-01

    The primary purpose of this grant is to determine the overall survival benefit in Stage IV HER2 positive breast cancer patients vaccinated with a HER2 ICD peptide-based vaccine while receiving maintenance trastuzumab...

  20. Phase II Study of HER-2/neu Intracellular Domain Peptide-Based Vaccine Administered to Stage IV HER2 Positive Breast Cancer Patients Receiving Trastuzumab

    National Research Council Canada - National Science Library

    Disis, Mary L

    2006-01-01

    The primary purpose of this grant is to determine the overall survival benefit in Stage IV HER2 positive breast cancer patients vaccinated with a HER2 ICD peptide-based vaccine while receiving maintenance trastuzumab...

  1. A systematic review of trastuzumab and lapatinib in the treatment of women with brain metastases from HER2-positive breast cancer

    DEFF Research Database (Denmark)

    Larsen, Pia Bükmann; Kümler, Iben; Nielsen, Dorte Lisbet

    2013-01-01

    Patients with HER2-positive breast cancer are living still longer and increasingly experiencing brain metastases. Current HER2-targeted therapies have limited potential to cross the blood-brain-barrier. We performed a systematic review to investigate data on HER2-targeting therapies in the treatm......, it is still not evident which HER2-targeting agent should be preferred when brain metastases occur. The choice of chemotherapy to accompany the blockade is not obvious and we do not know if dual is better than single blockade. Further clinical trials are urgently needed....

  2. Fluorescent ratiometric pH indicator SypHer2: applications in neuroscience and regenerative biology

    Science.gov (United States)

    Matlashov, Mikhail E.; Bogdanova, Yulia A.; Ermakova, Galina V.; Mishina, Natalia M.; Ermakova, Yulia G.; Nikitin, Evgeny S.; Balaban, Pavel M.; Okabe, Shigeo; Lukyanov, Sergey; Enikolopov, Grigori; Zaraisky, Andrey G.; Belousov, Vsevolod V.

    2015-01-01

    Background SypHer is a genetically encoded fluorescent pH-indicator with a ratiometric readout, suitable for measuring fast intracellular pH shifts. However, a relatively low brightness of the indicator limits its use. Methods Here we designed a new version of pH-sensor - SypHer-2, that has up to three times brighter fluorescence signal in cultured mammalian cells compared to the SypHer. Results Using the new indicator we registered activity-associated pH oscillations in neuronal cell culture. We observed prominent temporal neuronal cytoplasm acidification that occurs in parallel with calcium entry. Furthermore, we monitored pH in presynaptic and postsynaptic termini by targeting SypHer-2 directly to these compartments and revealed marked differences in pH dynamics between synaptic boutons and dendritic spines. Finally, we were able to reveal for the first time the intracellular pH drop which occurs within an extended region of the amputated tail of the Xenopus laevis tadpole before it begins to regenerate. Conclusions SypHer2 is suitable for quantitative monitoring of pH in biological systems of different scales, from small cellular subcompartments to animal tissues in vivo. General significance The new pH-sensor will help to investigate pH-dependent processes in both in vitro and in vivo studies. PMID:26259819

  3. Fluorescent ratiometric pH indicator SypHer2: Applications in neuroscience and regenerative biology.

    Science.gov (United States)

    Matlashov, Mikhail E; Bogdanova, Yulia A; Ermakova, Galina V; Mishina, Natalia M; Ermakova, Yulia G; Nikitin, Evgeny S; Balaban, Pavel M; Okabe, Shigeo; Lukyanov, Sergey; Enikolopov, Grigori; Zaraisky, Andrey G; Belousov, Vsevolod V

    2015-11-01

    SypHer is a genetically encoded fluorescent pH-indicator with a ratiometric readout, suitable for measuring fast intracellular pH shifts. However, the relatively low brightness of the indicator limits its use. Here we designed a new version of pH-sensor called SypHer-2, which has up to three times brighter fluorescence in cultured mammalian cells compared to the SypHer. Using the new indicator we registered activity-associated pH oscillations in neuronal cell culture. We observed prominent transient neuronal cytoplasm acidification that occurs in parallel with calcium entry. Furthermore, we monitored pH in presynaptic and postsynaptic termini by targeting SypHer-2 directly to these compartments and revealed marked differences in pH dynamics between synaptic boutons and dendritic spines. Finally, we were able to reveal for the first time the intracellular pH drop that occurs within an extended region of the amputated tail of the Xenopus laevis tadpole before it begins to regenerate. SypHer2 is suitable for quantitative monitoring of pH in biological systems of different scales, from small cellular subcompartments to animal tissues in vivo. The new pH-sensor will help to investigate pH-dependent processes in both in vitro and in vivo studies. Copyright © 2015 Elsevier B.V. All rights reserved.

  4. HER2 mutated breast cancer responds to treatment with single agent neratinib, a second generation HER2/EGFR tyrosine kinase inhibitor

    Science.gov (United States)

    Ben–Baruch, Noa Efrat; Bose, Ron; Kavuri, Shyam M.; Ma, Cynthia X.; Ellis, Matthew J.

    2015-01-01

    Activating mutations in the HER2 tyrosine kinase have been identified in human breast cancers that lack HER2 gene amplification. These patients are not candidates for HER2 targeted drugs under current standards of care, but preclinical data strongly suggest that these patients will benefit from anti-HER2 drugs. In this case report, we describe a young woman with metastatic breast cancer whose tumor was found to carry a HER2 L755S mutation, which is in the kinase domain of HER2. Treatment with the second generation HER2/EGFR tyrosine kinase inhibitor, neratinib, resulted in partial response and dramatic improvement in the patient’s function status. This partial response lasted 11 months and when the patient’s cancer progressed, she was treated with neratinib plus capecitabine and her cancer again responded. This second response parallels the benefit seen with continuing trastuzumab in HER2 amplified breast cancer after disease progression. This case is the first report, to our knowledge, of successful single agent treatment of HER2 mutated breast cancer. Two clinical trials of neratinib for HER2 mutated, metastatic breast cancer are currently enrolling patients. Further, data from The Cancer Genome Atlas project have identified HER2 mutations in a wide range of solid tumors, including bladder, colorectal, and non-small cell lung cancer, suggesting that clinical trials of neratinib or neratinib-based combinations for HER2 mutated solid tumors is warranted. PMID:26358790

  5. HER2-Mutated Breast Cancer Responds to Treatment With Single-Agent Neratinib, a Second-Generation HER2/EGFR Tyrosine Kinase Inhibitor.

    Science.gov (United States)

    Ben-Baruch, Noa Efrat; Bose, Ron; Kavuri, Shyam M; Ma, Cynthia X; Ellis, Matthew J

    2015-09-01

    Activating mutations in the HER2 tyrosine kinase have been identified in human breast cancers that lack HER2 gene amplification. These patients are not candidates for HER2-targeted drugs under current standards of care, but preclinical data strongly suggest that these patients will benefit from anti-HER2 drugs. This case report describes a young woman with metastatic breast cancer whose tumor was found to carry a HER2 L755S mutation, which is in the kinase domain of HER2. Treatment with the second-generation HER2/EGFR tyrosine kinase inhibitor neratinib resulted in partial response and dramatic improvement in the patient's functional status. This partial response lasted 11 months, and when the patient's cancer progressed, she was treated with neratinib plus capecitabine and her cancer again responded. This second response parallels the benefit seen with continuing trastuzumab in HER2-amplified breast cancer after disease progression. This case represents the first report, to our knowledge, of successful single-agent treatment of HER2-mutated breast cancer. Two clinical trials of neratinib for HER2-mutated metastatic breast cancer are currently enrolling patients. Further, data from The Cancer Genome Atlas project have identified HER2 mutations in a wide range of solid tumors, including bladder, colorectal, and non-small cell lung cancers, suggesting that clinical trials of neratinib or neratinib-based combinations for HER2-mutated solid tumors is warranted. Copyright © 2015 by the National Comprehensive Cancer Network.

  6. HER-2 Protein Overexpression in Patients with Gastric and Oesophageal Adenocarcinoma at a Tertiary Care Facility in Ghana

    Directory of Open Access Journals (Sweden)

    David Larbi Simpong

    2018-01-01

    Full Text Available The prognosis of gastric and oesophageal adenocarcinoma remains generally poor. However, mounting evidence suggests a positive role of human epidermal growth factor receptor-2 (HER-2 expression in the prognosis of patients with these cancers. In this work, the patterns of HER-2 protein expression were determined in patients with gastric or oesophageal adenocarcinoma. Retrospectively, we reviewed records of gastric and oesophageal biopsies received from 2008 to 2012 and their corresponding archived formalin-fixed paraffin-embedded tissue blocks selected for immunohistochemical analysis. The prevalence of gastric and oesophageal adenocarcinomas and their association with HER-2 protein overexpression were evaluated. Gastric adenocarcinoma made up 18.79% of the gastric biopsies reviewed, and majority of these cancers occurred in males. Regarding the tumour type, HER-2 overexpression was common in the intestinal subtype compared to the diffuse type. Although squamous cell carcinoma was observed to be the commonest (31% tumour type in the oesophagus compared to adenocarcinoma (8.79%, HER-2 was overexpressed in 42.9% of oesophageal adenocarcinomas, like gastric adenocarcinoma (41.4%. There is a high prevalence of gastric and oesophageal adenocarcinoma, with significant overexpression of HER-2 in these tumours, a window of hope for the management of patients with these cancers.

  7. Targeting GPR110 in HER2-Overexpressing Breast Cancers

    Science.gov (United States)

    2015-10-01

    34assay"using"the"transwell" inserts"with" (A)"or"without" (B)"matrigel" for"SKBR3" cells "transfected"with"nonAtarge1ng"( NT1 )"orŗ"independent"GPR110"siRNAs...HER2 drug resistant cells and in tumorigenic population using a broad panel of cell line models. We have successfully generated inducible lentiviral...plasmids with GPR110 cDNA and cell lines that inducibly overexpress GPR110. Generation of cell lines with lentiviral plasmids containing GPR110

  8. HER-2-PET imaging with Zr-89-trastuzumab in metastatic breast cancer patients

    NARCIS (Netherlands)

    Munnink, T. Oude; Dijkers, E.; Hooge, M. Lub-de; Kosterink, J.; Brouwers, A.; de Jong, J. R.; van Dongen, G.; de Vries, E.

    2009-01-01

    1045 Background: Non-invasive diagnostic tools can optimize and evaluate HER2 directed therapy in HER2 positive breast cancer patients. HER2 imaging with (111)In-trastuzumab SPECT showed promising results (Perik et al, J Clin Oncol. 2006). To further optimize HER2 imaging, we developed

  9. Microwave enhancement of CISH for HER2 oncogene.

    Science.gov (United States)

    Leong, Anthony S Y; Haffajee, Zenobia; Clarke, Megan

    2007-03-01

    We describe a modification to the prescribed procedure for the Zymed Spot-Light HER2 chromogenic in situ hybridization kit (84-0146, Zymed Laboratories, San Francisco, CA) by substituting the heat pretreatment step with MW irradiation in citrate buffer 10 mmol/L at pH 6.0 at 98 degrees C for 10 minutes and repeating the procedure afterenzyme digestion with time and temperature controlled in the Mega T/ T oven (Milestone s.r.l., Sorisole, Italy). The subsequent procedure leading up to hybridized was as per manufacturer's instructions. Invasive breast carcinoma previously scored by immunohistochemistry for HER2, comprising 18 cases of 3+, 18 cases of 2+, and 12 cases of 1+, were examined by chromogenic in situ hybridization using this modified procedure, with a parallel set of cases examined by the prescribed Zymed method. The introduction of the "MW retrieval" steps resulted in consistently a greater number of hybridization signals in amplified tumor cells with benign epithelial cells and lymphocytes displaying 2 clear dots compared with the weaker and less consistent signals obtained with the standard procedure. MW exposed sections showed larger numbers of large and small clusters that often allowed identification of amplified tumors without having to count single dots with crisp staining and absence of background precipitation.

  10. Silencing of the HER2/neu Gene by siRNA Inhibits Proliferation and Induces Apoptosis in HER2/neu-Overexpressing Breast Cancer Cells

    Directory of Open Access Journals (Sweden)

    Timo Faltus

    2004-11-01

    Full Text Available In eukaryotes, double-stranded (ds RNA induces sequence-specific inhibition of gene expression referred to as RNA interference (RNAi. We exploited RNAi to define the role of HER2/neu in the neoplastic proliferation of human breast cancer cells. We transfected SK-BR-3, BT-474, MCF-7, and MDA-MB-468 breast cancer cells with short interfering RNA (siRNA targeted against human HER2/neu and analyzed the specific inhibition of HER2/neu expression by Northern and Western blots. Transfection with HER2/neu-specific siRNA resulted in a sequence-specific decrease in HER2/neu mRNA and protein levels. Moreover, transfection with HER2/neu siRNA caused cell cycle arrest at G0/G1 in the breast cancer cell lines SKBR-3 and BT-474, consistent with a powerful RNA silencing effect. siRNA treatment resulted in an antiproliferative and apoptotic response in cells overexpressing HER2/neu, but had no influence in cells with almost no expression of HER2/neu proteins like MDA-MB-468 cells. These data indicate that HER2/neu function is essential for the proliferation of HER2/neuoverexpressing breast cancer cells. Our observations suggest that siRNA targeted against human HER2/neu may be valuable tools as anti proliferative agents that display activity against neoplastic cells at very low doses.

  11. Naturally occurring BRCA2 alternative mRNA splicing events in clinically relevant samples

    DEFF Research Database (Denmark)

    Fackenthal, James D; Yoshimatsu, Toshio; Zhang, Bifeng

    2016-01-01

    patterns and thereby disrupt gene function. mRNA analyses are therefore among the tests used to interpret the clinical significance of some genetic variants. However, these could be confounded by the appearance of naturally occurring alternative transcripts unrelated to germline sequence variation...... to characterise the spectrum of naturally occurring BRCA2 mRNA alternate-splicing events. METHODS: mRNA was prepared from several blood and breast tissue-derived cells and cell lines by contributing ENIGMA laboratories. cDNA representing BRCA2 alternate splice sites was amplified and visualised using capillary...... or agarose gel electrophoresis, followed by sequencing. RESULTS: We demonstrate the existence of 24 different BRCA2 mRNA alternate-splicing events in lymphoblastoid cell lines and both breast cancer and non-cancerous breast cell lines. CONCLUSIONS: These naturally occurring alternate-splicing events...

  12. Survival benefit of anti-HER2 therapy after whole-brain radiotherapy in HER2-positive breast cancer patients with brain metastasis.

    Science.gov (United States)

    Zhang, Qian; Chen, Jian; Yu, Xiaoli; Cai, Gang; Yang, Zhaozhi; Cao, Lu; Hu, Chaosu; Guo, Xiaomao; Sun, Jing; Chen, Jiayi

    2016-09-01

    We aimed to assess the survival benefit of epidermal growth factor receptor 2 (HER2)-positive breast cancer patients with brain metastasis (BM) after whole-brain radiotherapy (WBRT) in combination with systemic treatments, especially anti-HER2 therapy. This retrospective study analyzed the overall survival (OS) of 60 HER2-positive breast cancer patients with BM after WBRT in combination with systemic treatments. Among them, 42 patients received chemotherapy while 18 patients did not receive after WBRT. With regard to anti-HER2 therapy, after WBRT, 17 patients received anti-HER2 treatment without prior adjuvant trastuzumab-based therapy, 7 patients received anti-HER2 treatment with prior adjuvant trastuzumab-based therapy, and 36 patients did not receive further anti-HER2 treatment. All patients were followed up regularly until January 23, 2013. The median OS of patients with BM was 12 months. Patients who received anti-HER2 therapy and chemotherapy after WBRT had significantly better survival compared with patients who did not receive further treatment. Patients who received anti-HER2 treatment after WBRT but did not receive adjuvant trastuzumab-based therapy for early breast cancer had better OS, followed by patients who received anti-HER2 agent both in adjuvant treatment and after WBRT and patients who did not receive anti-HER2 treatment. Multivariate analysis showed that Karnofsky Performance Status, control of extracranial metastases, chemotherapy after WBRT, and anti-HER2 therapy combined with WBRT were all independent predictors for OS. Both chemotherapy and anti-HER2 therapy after WBRT could improve OS. Moreover, patients without prior exposure to adjuvant anti-HER2 treatment may have survival benefit superior to those of patients with prior exposure.

  13. Elemental and Microscopic Analysis of Naturally Occurring C-O-Si Hetero-Fullerene-Like Structures.

    Science.gov (United States)

    Hullavarad, Nilima V; Hullavarad, Shiva S; Fochesatto, Javier

    2015-03-01

    Carbon exhibits an ability to form a wide range of structures in nature. Under favorable conditions, carbon condenses to form hollow, spheroid fullerenes in an inert atmosphere. Using high resolution FESEM, we have concealed the existence of giant hetero-fullerene like structures in the natural form. Clear, distinct features of connected hexagons and pentagons were observed. Energy dispersive X-ray analysis depth-profile of natural fullerene structures indicates that Russian-doll-like configurations composed of C, 0, and Si rings exist in nature. The analysis is based on an outstanding molecular feature found in the size fraction of aerosols having diameters 150 nm to 1.0 µm. The fullerene like structures, which are ~ 150 nm in diameter, are observed in large numbers. To the best of our knowledge, this is the first direct detailed observation of natural fullerene-like structures. This article reports inadvertent observation of naturally occurring hetero-fullerene-like structures in the Arctic.

  14. Naturally occurring radionuclides in pasture soil, feed ingredients and milk of dairy cattle

    Energy Technology Data Exchange (ETDEWEB)

    Turtiainen, T.; Kostiainen, E.; Solatie, D. [STUK-Radiation and Nuclear Safety Authority (Finland)

    2014-07-01

    Naturally occurring radionuclides are generally considered being respective part of the environment and hence no statutory monitoring of their levels are required in food products. Therefore, limited data are available on the naturally occurring radionuclides in food. Dairy products constitute a significant portion of Finnish diet (400-500 g/d) and hence it is reasonable to study radionuclide levels in milk in more detail. Contrary to caesium, strontium and iodine, few transfer coefficients are available in the literature for naturally occurring radionuclide transfer to cow's milk. The renaissance of mining industry in Finland has raised a question among the public about the baseline values of naturally occurring radionuclides in Finnish agricultural products. The objective of this study was to investigate naturally occurring radionuclides in the components of dairy cattle diet and milk and calculate their transfer to milk. This information is needed for regulating the permitted discharges to the environment and for setting up monitoring programs if any unplanned discharges are released. In modern dairy farming, cattle are fed a precise diet in order to maximize milk production and quality and to achieve cost-effectiveness. Therefore, several different components are found in dairy cattle's diet and pasture grass concentrations are not sufficient for calculating radionuclide transfer to cow's milk. In this study, we carried out comprehensive sampling at four dairy farms each representing different areas of natural radiation background. The pasture soils were characterized and measured for natural radioactivity. Samples were taken from cattle's total diet (including e.g. pasture grass, water, silage, mineral forage) and milk. Document available in abstract form only. (authors)

  15. The encounter and analysis of naturally occurring radionuclides in gas and oil production and processing

    International Nuclear Information System (INIS)

    Hartog, F.A.; Jonkers, G.; Knaepen, W.A.I.

    1996-01-01

    As a result of oil and gas production, radioactive daughter elements from the uranium and thorium decay series can be mobilized and transported away from the reservoir. Due to changes in flow regime, temperature, pressure or chemical environment NORs (Naturally Occurring Radionuclides) may build up in products, by-products or waste streams from gas and oil production and processing facilities. Products containing NORs are commonly denoted by the acronym NORM (Naturally Occurring Radioactive Materials). Main topics of this paper are: E and P (Exploration and Production) NORM characteristics; incentives for NORM analysis; NORM analysis; interlaboratory test programme; analysis techniques; results and conclusions of the test programme. 4 figs., 2 tabs

  16. Radioactivity in papers: the concentration and source of naturally occurring radionuclides

    International Nuclear Information System (INIS)

    Kobashi, Asaya

    2005-01-01

    The radioactivities of naturally occurring radionuclides ( 226 Ra, 228 Ra, 228 Th and 40 K) in papers such as magazines, newspapers, and copying papers produced in Japan were determined by gamma-ray spectrometry to obtain information on radioactivity level of papers. The X-ray diffraction measurement of the samples was also carried out to elucidate the source of radionuclides contained in them. The average 226 Ra, 228 Ra, 228 Th, and 40 K contents of pocket-sized books were 6.4, 21.5, 23.7, and 18.8 Bq kg -1 , respectively, and those of other kinds of samples were near to or less than the values. The 228 Th content was generally somewhat higher than the 228 Ra content. Possibly 228 Ra was leached from the raw materials of the papers to water during their production in preference to 228 Th. The concentrations of the naturally occurring radionuclides were correlated to each other. The X-ray diffraction study showed that kaolinite, talc, and calcite were contained in the papers. The kaolinite content of the samples was correlated to the concentrations of the naturally occurring radionuclides, indicating that the naturally occurring radionuclides in the paper samples were mainly brought with kaolinite used as filler or coating pigment in the papers. The regression analysis of the data showed that the natural radioactivity content of filler kaolinite was higher than that of pigment kaolinite. (author)

  17. Standardization of sequential separation of naturally occurring radionuclides in drinking water

    International Nuclear Information System (INIS)

    Nair, Madhu G.; Rao, D.D.; Sathyapriya, R.S.; Sarkar, P.K.

    2012-01-01

    Human are constantly exposed to radiation originating from natural or manmade sources. The main contribution for internal dose is due to radionuclides from uranium and thorium series in drinking water. The distribution of these elements varies depending on the geological and physiological characteristics of the aquifer. With increased concern for radiological safety of public, it is necessary to evaluate the naturally occurring radionuclides in the drinking water

  18. Scenarios identified internationally for occupational and public exposure to naturally occurring radioactive materials

    International Nuclear Information System (INIS)

    Fernandez Gomez, Isis Maria

    2012-01-01

    Natural radiation for decades was considered a normal phenomenon that existed in nature, so that man was conditioned to ignore; unlike artificial ionizing radiation. This mindset has changed, in the late seventies of the last century, because it has became aware of the danger that exposure to natural radiation could pose health. Studies on it have been initiated to conduct and publish. All humans are exposed to natural radiation; but, this exposure is not uniform, has depended on where they live and work, whether they have been in areas with rocks or soils particularly radioactive, their way of life, of the use of certain building materials in their homes, the use of natural gas, the use of home heating with coal. Air travel also have increased exposure to natural radiation. Ionizing radiation, whether natural or artificial, have interacted with the human body in the same way, there fore have failed to say that the natural are less or more harmful than artificial. Natural sources are grouped into two major categories. The first are the external sources: from abroad as cosmic radiation (the sun and interstellar spaces of the universe), terrestrial radiation (emitted by rocks and soil), the radiation of some buildings (e.g. granite, which can emit radon gas) and radiation contained in some foods. The second category are the internal resources: due to the presence in the human body from the environment radionuclides that are able to ionize (potassium-40, carbon-14). The naturally occurring radioactive materials (NORM for its acronym in English) have been referred to those naturally occurring radioactive materials on which any human technological activity has increased its exposure potential compared with the situation unchanged. (author) [es

  19. A FISH-based method for assessment of HER-2 amplification status in breast cancer circulating tumor cells following CellSearch isolation

    Directory of Open Access Journals (Sweden)

    Frithiof H

    2016-11-01

    Full Text Available Henrik Frithiof,1 Kristina Aaltonen,1 Lisa Rydén2,3 1Division of Oncology and Pathology, 2Division of Surgery, Department of Clinical Sciences Lund, Lund University, Lund, 3Department of Surgery, Skåne University Hospital, Malmö, Sweden Introduction: Amplification of the HER-2/neu (HER-2 proto-oncogene occurs in 10%–15% of primary breast cancer, leading to an activated HER-2 receptor, augmenting growth of cancer cells. Tumor classification is determined in primary tumor tissue and metastatic biopsies. However, malignant cells tend to alter their phenotype during disease progression. Circulating tumor cell (CTC analysis may serve as an alternative to repeated biopsies. The Food and Drug Administration-approved CellSearch system allows determination of the HER-2 protein, but not of the HER-2 gene. The aim of this study was to optimize a fluorescence in situ hybridization (FISH-based method to quantitatively determine HER-2 amplification in breast cancer CTCs following CellSearch-based isolation and verify the method in patient samples. Methods: Using healthy donor blood spiked with human epidermal growth factor receptor 2 (HER-2-positive breast cancer cell lines, SKBr-3 and BT-474, and a corresponding negative control (the HER-2-negative MCF-7 cell line, an in vitro CTC model system was designed. Following isolation in the CellSearch system, CTC samples were further enriched and fixed on microscope slides. Immunocytochemical staining with cytokeratin and 4',6-diamidino-2'-phenylindole dihydrochloride identified CTCs under a fluorescence microscope. A FISH-based procedure was optimized by applying the HER2 IQFISH pharmDx assay for assessment of HER-2 amplification status in breast cancer CTCs. Results: A method for defining the presence of HER-2 amplification in single breast cancer CTCs after CellSearch isolation was established using cell lines as positive and negative controls. The method was validated in blood from breast cancer patients

  20. Trastuzumab for HER-2-Positive Advanced Salivary Gland Cancer

    Directory of Open Access Journals (Sweden)

    Yi-Tsung Yang

    2014-12-01

    Full Text Available Salivary gland adenocarcinoma is a rare type of head and neck cancer and often has aggressive behavior with propensity to recur and metastasize. Currently, there are no standard treatment guidelines. Surgery is however, the mainstay of treatment in resectable disease and radiation is also considered for most patients after surgery. Systemic chemotherapy is reserved for metastatic cases, but its results are often disappointing. Recent development of molecular biology has shown that salivary gland caner has several molecular changes which may guide potential therapeutic targets. Here, we report a 67 year-old man diagnosed to have metastasized minor salivary gland adenocarcinoma with diffuse human epidermal growth factor receptor-2 (HER-2-positive, by the immunohistochemical (IHC stain. He was treated with a trastuzumab-containing chemotherapeutic regimen with encouraging results.

  1. Polymer–lipid hybrid anti-HER2 nanoparticles for targeted salinomycin delivery to HER2-positive breast cancer stem cells and cancer cells

    Directory of Open Access Journals (Sweden)

    Li J

    2017-09-01

    Full Text Available Jun Li,1,* Wenqing Xu,2,* Xiaoli Yuan,3,* Huaiwen Chen,3 Hao Song,1,4 Bingquan Wang,5 Jun Han5 1College of Pharmacy, Liaocheng University, Liaocheng, Shandong, 2Railway Police College, Zhengzhou, 3Department of Cadre Health Care, Nanjing General Hospital of Nanjing Military Command, Nanjing, Jiangsu, 4Centre for Stem Cell & Regenerative Medicine, Liaocheng People’s Hospital, 5Institute of Biopharmaceutical Research, Liaocheng University, Liaocheng, Shandong, China *These authors contributed equally to this work Purpose: Breast cancer stem cells (CSCs are responsible for the initiation, recurrence, and metastasis of breast cancer. Sufficient evidence has established that breast cancer cells can spontaneously turn into breast CSCs. Thus, it is essential to simultaneously target breast CSCs and cancer cells to maximize the efficacy of breast cancer therapy. HER2 has been found to be overexpressed in both breast CSCs and cancer cells. We developed salinomycin-loaded polymer–lipid hybrid anti-HER2 nanoparticles (Sali-NP-HER2 to target both HER2-positive breast CSCs and cancer cells.Methods: The antitumor activity of Sali-NP-HER2 constructed by conjugating anti-HER2 antibodies to polymer–lipid salinomycin nanoparticles was evaluated in vitro and in vivo.Results: Sali-NP-HER2 efficiently bound to HER2-positive breast CSCs and cancer cells, resulting in enhanced cytotoxic effects compared with non-targeted nanoparticles or salinomycin. In mice bearing breast cancer xenografts, administration of Sali-NP-HER2 exhibited superior efficacy in inhibiting tumor growth. Sali-NP-HER2 reduced the breast tumorsphere formation rate and the proportion of breast CSCs more effectively than non-targeted nanoparticles or salinomycin alone.Conclusion: Sali-NP-HER2 represents a promising approach in treating HER2-positive breast cancer by targeting both breast CSCs and cancer cells. Keywords: nanoparticles, breast cancer, cancer stem cells, salinomycin, HER2

  2. Naturally occurring products of proglucagon 111-160 in the porcine and human small intestine

    DEFF Research Database (Denmark)

    Buhl, T; Thim, L; Kofod, Hans

    1988-01-01

    to release proglucagon 111-123 (designated spacer peptide 2), which, like proglucagon 126-158 must be considered a potential hormonal entity. By isocratic high pressure liquid chromatography human spacer peptide 2 was indistinguishable from synthetic proglucagon 111-122 amide, suggesting...... that this is the structure of the naturally occurring human peptide....

  3. Radiological dose assessment related to management of naturally occurring radioactive materials generated by the petroleum industry

    International Nuclear Information System (INIS)

    Smith, K.P.; Blunt, D.L.; Williams, G.P.; Tebes, C.L.

    1995-01-01

    A preliminary radiological dose assessment related to equipment decontamination, subsurface disposal, landspreading, equipment smelting, and equipment burial was conducted to address concerns regarding the presence of naturally occurring radioactive materials in production waste streams. The assessment evaluated the relative dose of these activities and included a sensitivity analysis of certain input parameters. Future studies and potential policy actions are recommended

  4. What Are Naturally Occurring School Lotteries and How Do We Identify Them? Reflections on Methodology

    Science.gov (United States)

    Unterman, Rebecca

    2018-01-01

    This post is one in a series highlighting MDRC's methodological work. In the past decade, rapid growth in the number of charter schools and school district choice systems has provided education researchers with exciting opportunities to use naturally occurring pockets of randomization to rigorously study the effects of policy-relevant education…

  5. Predicting Emotions in Facial Expressions from the Annotations in Naturally Occurring First Encounters

    DEFF Research Database (Denmark)

    Navarretta, Costanza

    2014-01-01

    This paper deals with the automatic identification of emotions from the manual annotations of the shape and functions of facial expressions in a Danish corpus of video recorded naturally occurring first encounters. More specifically, a support vector classified is trained on the corpus annotations...... to identify emotions in facial expressions. In the classification experiments, we test to what extent emotions expressed in naturally-occurring conversations can be identified automatically by a classifier trained on the manual annotations of the shape of facial expressions and co-occurring speech tokens. We...... also investigate the relation between emotions and the communicative functions of facial expressions. Both emotion labels and their values in a three dimensional space are identified. The three dimensions are Pleasure, Arousal and Dominance. The results of our experiments indicate that the classifiers...

  6. Deposits of naturally occurring radioactivity in production of oil and natural gas; Radioaktive avleiringer i olje- og gassproduksjon

    Energy Technology Data Exchange (ETDEWEB)

    Strand, T; Lysebo, I; Kristensen, D; Birovljev, A

    1997-01-01

    Deposits of naturally occurring radioactive materials is an increasing problem in Norwegian oil and gas production. Activity concentration in solid-state samples and production water, and doses to workers involved in different operations off-shore, have been measured. The report also includes a discussion of different methods of monitoring and alternatives for final disposal of wastes. 154 refs.

  7. Trastuzumab has preferential activity against breast cancers driven by HER2 homodimers

    Science.gov (United States)

    Ghosh, Ritwik; Narasanna, Archana; Wang, Shizhen Emily; Liu, Shuying; Chakrabarty, Anindita; Balko, Justin M.; González-Angulo, Ana María; Mills, Gordon B.; Penuel, Elicia; Winslow, John; Sperinde, Jeff; Dua, Rajiv; Pidaparthi, Sailaja; Mukherjee, Ali; Leitzel, Kim; Kostler, Wolfgang J.; Lipton, Allan; Bates, Michael; Arteaga, Carlos L.

    2011-01-01

    In breast cancer cells with HER2 gene amplification, HER2 receptors exist on the cell surface as monomers, homodimers and heterodimers with EGFR/HER3. The therapeutic antibody trastuzumab, an approved therapy for HER2+ breast cancer, cannot block ligand-induced HER2 heterodimers, suggesting it cannot effectively inhibit HER2 signaling. Hence, HER2 oligomeric states may predict the odds of a clinical response to trastuzumab in HER2-driven tumors. To test this hypothesis, we generated non-transformed human MCF10A mammary epithelial cells stably expressing a chimeric HER2-FKBP molecule that could be conditionally induced to homodimerize by adding the FKBP ligand AP1510, or instead induced to heterodimerize with EGFR or HER3 by adding the heterodimer ligands EGF/TGFα or heregulin. AP1510, EGF, and heregulin each induced growth of MCF10A cells expressing HER2-FKBP. As expected, trastuzumab inhibited homodimer-mediated but not heterodimer-mediated cell growth. In contrast, the HER2 antibody pertuzumab, which blocks HER2 heterodimerization, inhibited growth induced by heregulin but not AP1510. Lastly, HER2/EGFR tyrosine kinase inhibitor lapatinib blocked both homodimer- and heterodimer-induced growth. AP1510 triggered phosphorylation of Erk1/2 but not AKT, whereas trastuzumab inhibited AP1510-induced Erk1/2 phosphorylation and Shc-HER2 homodimer binding, but not TGFα-induced AKT phosphorylation. Consistent with these observations, high levels of HER2 homodimers correlated with longer time to progression following trastuzumab therapy in a cohort of HER2-overexpressing patients. Together, our findings corroborate the hypothesis that HER2 oligomeric states regulate HER2 signaling, also arguing that trastuzumab sensitivity of homodimers reflects an inability to activate the PI3K/AKT pathway. One of the most important clinical implications of our results is that high levels of HER2 homodimers may predict a positive response to trastuzumab. PMID:21324925

  8. Is the skin a sanctuary for breast cancer cells during treatment with anti-HER2 antibodies?

    Science.gov (United States)

    Graziano, Vincenzo; Scognamiglio, Maria Teresa; Zilli, Marinella; Giampietro, Jamara; Vici, Patrizia; Natoli, Clara; Grassadonia, Antonino

    2015-01-01

    The occurrence of skin metastases is a common event in patients affected by advanced breast cancer, usually associated with systemic disease progression. Here we describe 2 cases of diffuse cutaneous metastases from HER2-overexpressing breast cancer occurring despite a dramatic response in liver and bone, respectively, during treatment with anti-HER2 antibodies Trastuzumab and Pertuzumab. We discuss the reasons for this discrepancy and suggest a possible implication of impaired immune response in the skin. Future research should provide strategies to overcome the induction of immune privilege in the skin in order to avoid discontinuation of effective treatments.

  9. HER2 overexpression and amplification as a potential therapeutic target in colorectal cancer: analysis of 3256 patients enrolled in the QUASAR, FOCUS and PICCOLO colorectal cancer trials.

    Science.gov (United States)

    Richman, Susan D; Southward, Katie; Chambers, Philip; Cross, Debra; Barrett, Jennifer; Hemmings, Gemma; Taylor, Morag; Wood, Henry; Hutchins, Gordon; Foster, Joseph M; Oumie, Assa; Spink, Karen G; Brown, Sarah R; Jones, Marc; Kerr, David; Handley, Kelly; Gray, Richard; Seymour, Matthew; Quirke, Philip

    2016-03-01

    HER2 overexpression/amplification is linked to trastuzumab response in breast/gastric cancers. One suggested anti-EGFR resistance mechanism in colorectal cancer (CRC) is aberrant MEK-AKT pathway activation through HER2 up-regulation. We assessed HER2-amplification/overexpression in stage II-III and IV CRC patients, assessing relationships to KRAS/BRAF and outcome. Pathological material was obtained from 1914 patients in the QUASAR stage II-III trial and 1342 patients in stage IV trials (FOCUS and PICCOLO). Tissue microarrays were created for HER2 immunohistochemistry. HER2-amplification was assessed using FISH and copy number variation. KRAS/BRAF mutation status was assessed by pyrosequencing. Progression-free survival (PFS) and overall survival (OS) data were obtained for FOCUS/PICCOLO and recurrence and mortality for QUASAR; 29/1342 (2.2%) stage IV and 25/1914 (1.3%) stage II-III tumours showed HER2 protein overexpression. Of the HER2-overexpressing cases, 27/28 (96.4%) stage IV tumours and 20/24 (83.3%) stage II-III tumours demonstrated HER2 amplification by FISH; 41/47 (87.2%) also showed copy number gains. HER2-overexpression was associated with KRAS/BRAF wild-type (WT) status at all stages: in 5.2% WT versus 1.0% mutated tumours (p < 0.0001) in stage IV and 2.1% versus 0.2% in stage II-III tumours (p = 0.01), respectively. HER2 was not associated with OS or PFS. At stage II-III, there was no significant correlation between HER2 overexpression and 5FU/FA response. A higher proportion of HER2-overexpressing cases experienced recurrence, but the difference was not significant. HER2-amplification/overexpression is identifiable by immunohistochemistry, occurring infrequently in stage II-III CRC, rising in stage IV and further in KRAS/BRAF WT tumours. The value of HER2-targeted therapy in patients with HER2-amplified CRC must be tested in a clinical trial. © 2015 The Authors. Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society

  10. Interaction of flavonoids, the naturally occurring antioxidants with different media: A UV-visible spectroscopic study

    Science.gov (United States)

    Naseem, Bushra; Shah, S. W. H.; Hasan, Aurangzeb; Sakhawat Shah, S.

    2010-04-01

    Quantitative parameters for interaction of flavonoids—the naturally occurring antioxidants, with solvents and surfactants are determined using UV-visible absorption spectroscopy. The availability of flavonoids; kaempferol, apigenin, kaempferide and rhamnetin in micelles of sodium dodecyl sulfate (SDS) is reflected in terms of partition coefficient, Kc. Thermodynamic calculations show that the process of transfer of flavonoid molecules to anionic micelles of SDS is energy efficient. A distortion in flavonoid's morphology occurs in case of kaempferol and apigenin in surfactant and water, exhibited in terms of a new band in the UV region of electronic spectra of these flavonoids. The partition coefficients of structurally related flavonoids are correlated with their antioxidant activities.

  11. Determination of naturally occurring radionuclides in soil samples of Ayranci, Turkey

    Science.gov (United States)

    Agar, Osman; Eke, Canel; Boztosun, Ismail; Emin Korkmaz, M.

    2015-04-01

    The specific activity, radiation hazard index and the annual effective dose of the naturally occurring radioactive elements (238U, 232Th and 40K) were determined in soil samples collected from 12 different locations in Ayranci region by using a NaI(Tl) gamma-ray spectrometer. The measured activity concentrations of the natural radionuclides in studied soil samples were compared with the corresponding results of different countries and the internationally reported values. From the analysis, it is found that these materials may be safely used as construction materials and do not pose significant radiation hazards.

  12. POSSIBILITIES OF THERAPY OF HER-2-POSITIVE REGIONAL BREAST CANCER

    Directory of Open Access Journals (Sweden)

    A. S. Belokhvostova

    2015-01-01

    Full Text Available Breast cancer heads the list of malignant neoplasms in women. In this connection the regional forms of cancer are diagnosed in one fourth of the patients. The treatment of regional cancer begins with systemic therapy and aimed at gaining of state fit for operation. The choice of modern treatment strategy is based on determination of molecular subtype of the tumor. One of them is referred to HER-2-positive cancer, requiring the administration of additional targeted therapy. This form of cancer is referred to prognostically pejorative tumors, as it’s more aggressive, leads to fast metastasis and early death of the patients. The “golden standard” of systemic chemotherapy is defined as administration of docetaxel and trastuzumab,  and antracyclic drugs, which also prove to be efficient. However concomitant administration of trastuzumab and antracyclines is limited due to their cardiotoxicity. Chemotherapy is not always efficient and, upon recommendations both of Russian and international oncologists, radiotherapy is the next stage of treatment. The question about radiosensibility of HER-2-positive tumors is still open and worth studying. Addition of radiotherapy to regional cancer treatment regimen in combination with the targeted therapy and chemotherapy may contribute to obtaining better survival rate and disease control. There are still no clearly defined standard for the sequence of chemo-radiation therapy. Simultaneous  chemo-radiatiojn  therapy results in  reliably better loco-regional control of tumor and  enables to gain a  higher degree of pathomorphological response on the one hand, and it may result in development of serious adverse effects on the other hand. Striving for improvement of immediate results of antineoplastic therapy, including that of regional cancer, by combining various methods, one should keep in mind the increasing action toxicity, which may have a considerable impact on the patients’ quality of living

  13. Assessment of radiological significance of naturally occurring radionuclides in soil and rock matrices around Kakrapar environment

    International Nuclear Information System (INIS)

    Patra, A.K.; Jaison, T.J.; Baburajan, A.; Hegde, A.G.

    2008-01-01

    The activity and gamma-absorbed dose rate due to the naturally occurring radionuclides in the terrestrial environment such as 238 U, 232 Th and 40 K were determined in soil and rock samples collected around Kakrapar Atomic Power Plant site, using gamma-ray spectrometry. The mean concentration levels measured in Kakrapar soil from naturally occurring radioisotopes such as 238 U, 232 Th and 40 K are lower than the corresponding global average values obtained in worldwide soil. The external hazard index (Hex) and absorbed gamma dose rate in air outdoors is observed to be 0.04-0.18 and 3.1-14.1 nGy h -1 , respectively. (authors)

  14. Left atrial volume and function in dogs with naturally occurring myxomatous mitral valve disease

    DEFF Research Database (Denmark)

    Höllmer, M.; Willesen, J. L.; Tolver, A.

    2017-01-01

    stroke volume increased, whereas LA reservoir and contractile function decreased with increasing disease severity. A maximal LA volume heart failure in dogs with chronic MMVD with a sensitivity of 96% and a specificity of 100......%. An active LA emptying fraction heart failure in dogs with chronic MMVD with a sensitivity of 77% and a specificity of 89% and a sensitivity of 82% and a specificity of 82%, respectively. CONCLUSION: Dogs with MMVD appear to have larger LA...... of cardiac compensation. Left atrial function in dogs with naturally occurring MMVD remains largely unexplored. The objective of this study was to evaluate LA volume and function in dogs with naturally occurring MMVD. ANIMALS: This prospective study included 205 client-owned dogs of different breeds, 114...

  15. Behavioral changes in freestall-housed dairy cows with naturally occurring clinical mastitis

    DEFF Research Database (Denmark)

    Fogsgaard, Katrine Kop; Bennedsgaard, Torben Werner; Herskin, Mette S

    2015-01-01

    Dairy cows exhibit classic signs of sickness behavior during mastitis. However, knowledge about the consequences of naturally occurring mastitis in freestall-housed dairy cows, milked in automatic milking systems, is lacking. The aim of the present study was to describe the behavior of dairy cows...... after diagnosis and antibiotic treatment of mastitis. In the days before and after antibiotic treatment, the milking behavior, feeding, and activity were examined in 30 mastitic and 30 control Danish Holstein-Friesian cows kept in freestalls and milked by an automatic milking system. Sickness behavior...... milking, as seen by a higher frequency of tripping and kicking. Mastitic cows continued to show increased kicking during milking even after the antibiotic treatment period. These results show that the behavioral changes induced by naturally occurring mastitis persisted beyond the days of antibiotic...

  16. Monitoring of increased natural occuring radiation exposure; Arbeitsplatzueberwachung bei erhoehter natuerlicher Strahlenexposition

    Energy Technology Data Exchange (ETDEWEB)

    Guhr, Andreas [ALTRAC Radon-Messtechnik, Berlin (Germany); Leissring, Nick [Bergtechnisches Ingenieurbuero GEOPRAX, Chemnitz (Germany)

    2015-07-01

    The radiation exposure due to natural occurring sources is a special challenge for the health and safety protection at workplaces. The monitoring of the radon exposure of employees in mines, radon-spa and in water works is regulated by prescription of radiation protection. The relevant compounds of the radiation exposure are the inhalation of radon and radon daughter products; terrestrial irradiation; ingestion of radioactive contaminated materials and the inhalation of contaminated dust. The monitoring of the radiation workers is realized essentially by measurements by radiation safety officer of the performing company, by an external engineering firm as well as by control measurements of experts of local authorities. The experiences in the practice have shown that in the field of operational radiation protection only a combination of personal- and operational dosimetry is suitable to avoid health hazards by work in fields with increased natural occurring radiation exposures.

  17. Naturally Occurring Radionuclides in Pottery, Ceramic and Glasswares Produced in Bangladesh

    International Nuclear Information System (INIS)

    Chowdhury, M.I.; Reaz, Rafia; Kamal, M.; Alam, M.N.; Mustafa, M.N.

    2005-01-01

    The concentrations of naturally occurring radionuclides were measured using gamma spectrometry in the finished products of pottery, glass, ceramic and tiles. Ceramic and pottery utensils, tiles, basin and glassware contained naturally occurring radionuclides. Pottery is produced from local clay materials, but ceramic, tiles, basin and glassware's are made from both local and imported raw materials. Radium and thorium radionuclides are concentrated during the making of pottery from the clay materials due to calcination. Radionuclides concentrated more in the highly calcined pottery products than the low calcined products. Glassware products contained very low quantities of radionuclides comparing with the ceramic and pottery products. Study on radioactivity in the pottery, ceramic and glassware products is important in the assessment of possible radiological hazards to human health. The knowledge is essential for the development of standards and guidelines for the use and management of these materials. (author)

  18. A theoretical model of naturally occurring cell death in the nervous system

    OpenAIRE

    Galli, Resta; Resta, Giovanni

    1991-01-01

    Throughout the animal kingdom, the formation of the nervous system involves the elimination of many cells, soon after their generation. This phenomenon, known as naturally occurring cell death, has precise time schedules, is observed in the vast majority of nervous structures and causes the 1oss of 15 - 85% of the neurones generated initially. Elimination of erroneous projections, as well as proper size matching between connecting structures can be achieved through cell death. However if elim...

  19. Individual and collective dose rates from naturally-occurring radionuclides in seafood

    International Nuclear Information System (INIS)

    Pentreath, R.J.; Camplin, W.C.; Allington, D.J.

    1989-01-01

    Although seafoods are not a large item in the UK diet, they are of interest because of the above-average quantities of naturally-occurring radionuclides which they contain -particularly shellfish. The single most important contributor is 210 Po; studies have therefore been made to examine the contribution which this nuclide makes to the dose received, both collectively and to individual high-rate consumers of shellfish. (author)

  20. Benford’s Law and Naturally Occurring Prices in Certain ebaY Auctions

    OpenAIRE

    David E. Giles

    2005-01-01

    We show that certain the winning bids for certain ebaY auctions obey Benford’s Law. One implication of this is that it is unlikely that these bids are subject to collusion among bidders, or “shilling” on the part of sellers. Parenthetically, we also show that numbers from the naturally occurring Fibonacci and Lucas sequences also obey Benford’s Law.

  1. Emissions of naturally occurring radioactivity from aluminum and copper facilities. Report No. 6 (final)

    International Nuclear Information System (INIS)

    Andrews, V.E.

    1982-11-01

    This report summarizes five surveys which were conducted at a Bauxite mining operation, an alumina reduction plant, an aluminum reduction plant, an underground copper mine and mill, and an open pit copper mine and concentrator. Process components and controlled source releases were sampled for naturally occurring radioactivity. Particular emphasis was given to radon-222, lead-210, and polonium-210 emissions from crushing and drying processes

  2. Inhibition and kinetic studies of lignin degrading enzymes of Ganoderma boninense by naturally occurring phenolic compounds.

    Science.gov (United States)

    Surendran, Arthy; Siddiqui, Yasmeen; Saud, Halimi Mohd; Ali, Nusaibah Syd; Manickam, Sivakumar

    2018-05-22

    Lignolytic (Lignin degrading) enzyme, from oil palm pathogen Ganoderma boninense Pat. (Syn G. orbiforme (Ryvarden), is involved in the detoxification and the degradation of lignin in the oil palm and is the rate-limiting step in the infection process of this fungus. Active inhibition of lignin degrading enzymes secreted by G. boninense by various naturally occurring phenolic compounds and estimation of efficiency on pathogen suppression was aimed at. In our work, ten naturally occurring phenolic compounds were evaluated for their inhibitory potential towards the lignolytic enzymes of G.boninense. Additionally, the lignin degrading enzymes were characterised. Most of the peholic compounds exhibited an uncompetitive inhibition towards the lignin degrading enzymes. Benzoic acid was the superior inhibitor to the production of lignin degrading enzymes, when compared between the ten phenolic compounds. The inhibitory potential of the phenolic compounds toward the lignin degrading enzymes are higher than that of the conventional metal ion inhibitor. The lignin degrading enzymes were stable in a wide range of pH but were sensitive to higher to temperature. The study demonstrated the inhibitor potential of ten naturally occurring phenolic compounds toward the lignin degrading enzymes of G. boninense with different efficacies. The study has shed a light towards a new management strategy to control BSR in oil palm. It serves as replacement for the existing chemical control. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

  3. Finding the traces of behavioral and cognitive processes in big data and naturally occurring datasets.

    Science.gov (United States)

    Paxton, Alexandra; Griffiths, Thomas L

    2017-10-01

    Today, people generate and store more data than ever before as they interact with both real and virtual environments. These digital traces of behavior and cognition offer cognitive scientists and psychologists an unprecedented opportunity to test theories outside the laboratory. Despite general excitement about big data and naturally occurring datasets among researchers, three "gaps" stand in the way of their wider adoption in theory-driven research: the imagination gap, the skills gap, and the culture gap. We outline an approach to bridging these three gaps while respecting our responsibilities to the public as participants in and consumers of the resulting research. To that end, we introduce Data on the Mind ( http://www.dataonthemind.org ), a community-focused initiative aimed at meeting the unprecedented challenges and opportunities of theory-driven research with big data and naturally occurring datasets. We argue that big data and naturally occurring datasets are most powerfully used to supplement-not supplant-traditional experimental paradigms in order to understand human behavior and cognition, and we highlight emerging ethical issues related to the collection, sharing, and use of these powerful datasets.

  4. Comparative genome and evolutionary analysis of naturally occurring Beilong virus in brown and black rats.

    Science.gov (United States)

    Woo, Patrick C Y; Wong, Annette Y P; Wong, Beatrice H L; Lam, Carol S F; Fan, Rachel Y Y; Lau, Susanna K P; Yuen, Kwok-Yung

    2016-11-01

    Recently, we reported the presence of Beilong virus in spleen and kidney samples of brown rats and black rats, suggesting that these rodents could be natural reservoirs of Beilong virus. In this study, four genomes of Beilong virus from brown rats and black rats were sequenced. Similar to the Beilong virus genome sequenced from kidney mesangial cell line culture, those of J-virus from house mouse and Tailam virus from Sikkim rats, these four genomes from naturally occurring Beilong virus also contain the eight genes (3'-N-P/V/C-M-F-SH-TM-G-L-5'). In these four genomes, the attachment glycoprotein encoded by the G gene consists of 1046 amino acids; but for the original Beilong virus genome sequenced from kidney mesangial cell line, the G CDS was predicted to be prematurely terminated at position 2205 (TGG→TAG), resulting in a 734-amino-acid truncated G protein. This phenomenon of a lack of nonsense mutation in naturally occurring Beilong viruses was confirmed by sequencing this region of 15 additional rodent samples. Phylogenetic analyses showed that the cell line and naturally occurring Beilong viruses were closely clustered, without separation into subgroups. In addition, these viruses were further clustered with J-virus and Tailam virus, with high bootstrap supports of >90%, forming a distinct group in Paramyxoviridae. Brown rats and black rats are natural reservoirs of Beilong virus. Our results also supports that the recently proposed genus, Jeilongvirus, should encompass Beilong virus, J-virus and Tailam virus as members. Copyright © 2016 Elsevier B.V. All rights reserved.

  5. Optimal specific radioactivity of anti-HER2 Affibody molecules enables discrimination between xenografts with high and low HER2 expression levels

    Energy Technology Data Exchange (ETDEWEB)

    Tolmachev, Vladimir [Uppsala University, Biomedical Radiation Sciences, Rudbeck Laboratory, Uppsala (Sweden); Uppsala University, Department of Medical Sciences, Nuclear Medicine, Uppsala (Sweden); Waallberg, Helena [Royal Institute of Technology, School of Biotechnology, Stockholm (Sweden); Sandstroem, Mattias [Uppsala University Hospital, Section of Hospital Physics, Department of Oncology, Uppsala (Sweden); Hansson, Monika; Wennborg, Anders [Affibody AB, Stockholm (Sweden); Orlova, Anna [Uppsala University, Biomedical Radiation Sciences, Rudbeck Laboratory, Uppsala (Sweden)

    2011-03-15

    Overexpression of the HER2 receptor is a biomarker for predicting those patients who may benefit from trastuzumab therapy. Radiolabelled Affibody molecules can be used to visualize HER2 expression in tumour xenografts with high sensitivity. However, previous studies demonstrated that the difference in uptake in xenografts with high and low HER2 expression levels is not proportional to the difference in expression levels. We hypothesized that discrimination between tumours with high and low HER2 expression may be improved by increasing the injected dose (reducing the specific activity) of the tracer. The influence of injected dose of anti-HER2 {sup 111}In-DOTA-Z{sub HER2} {sub 342} Affibody molecule on uptake in SKOV-3 (high HER2 expression) and LS174T (low expression) xenografts was investigated. The optimal range of injected doses enabling discrimination between xenografts with high and low expression was determined. To verify this, tumour uptake was measured in mice carrying both SKOV-3 and LS174T xenografts after injection of either 1 or 15 {mu}g {sup 111}In-DOTA-Z{sub HER2:342}. An increase in the injected dose caused a linear decrease in the radioactivity accumulation in the LS174T xenografts (low HER2 expression). For SKOV-3 xenografts, the dependence of the tumour uptake on the injected dose was less dramatic. The injection of 10-30 {mu}g {sup 111}In-DOTA-Z{sub HER2:342} per mouse led to the largest difference in uptake between the two types of tumour. Experiments in mice bearing two xenografts confirmed that the optimized injected dose enabled better discrimination of expression levels. Careful optimization of the injected dose of Affibody molecules is required for maximum discrimination between xenografts with high and low levels of HER2 expression. This information has potential relevance for clinical imaging applications. (orig.)

  6. Naturally occurring radioactive materials in construction integrating radiation protection in Reuse

    CERN Document Server

    Schroeyers, Wouter

    2017-01-01

    Naturally Occurring Radioactive Materials in Construction (COST Action NORM4Building) discusses the depletion of energy resources and raw materials and its huge impact not only on the building market, but also in the development of new synthetic building materials, whereby the reuse of various (waste) residue streams becomes a necessity. It is based on the outcome of COST Action TU 1301, where scientists, regulators, and representatives from industry have come together to present new findings, sharing knowledge, experiences, and technologies to stimulate research on the reuse of residues containing enhanced concentrates of natural radionuclides (NORM) in tailor-made building materials. Chapters address legislative issues, measurement, and assessment of building materials, physical and chemical aspects, from raw materials, to residues with enhanced concentrations of natural radionuclides (NORM), processes, building products containing NORM, and end-of-life and reuse requirements. Presents a holistic app...

  7. Gamma ray doses proceeding from natural occurring radionuclides in closed environments

    International Nuclear Information System (INIS)

    Aguiar, Vitor Angelo P. de; Medina, Nilberto H.; Silveira, Marcilei A. Guazzelli da; Moreira, Ramon H.

    2009-01-01

    In this work we report on the application of gamma-ray spectrometry in the study of the effective dose coming from terrestrial natural elements present in building materials such as sand, cement, lime (CaO) and milled granitic stones. The major contribution to annual gamma-ray radiation effective dose is due to the natural occurring radionuclides 40 K, 232 Th and 238 U. Two spectrometry systems were employed to measure the gamma radiation: one with a 60% efficient GeHP detector and the second one with a 2''x2'' NaI(Tl) scintillator. The estimated effective dose coming from the three reference rooms assumed is 0.63 mSv/yr, proceeding from terrestrial natural elements. The principal gamma radiation sources are cement, sand and bricks. (author)

  8. Serum HER2 levels are increased in patients with chronic heart failure.

    NARCIS (Netherlands)

    Perik, P.J.; Vries, E.G.F. de; Gietema, J.A.; Graaf, W.T.A. van der; Smilde, T.D.; Sleijfer, D.Th.; Veldhuisen, D.J. van

    2007-01-01

    BACKGROUND: The use of trastuzumab, an antibody against the human epidermal growth factor receptor 2 (HER2), in patients with HER2 positive metastatic breast cancer, is related to cardiotoxicity. AIMS: To investigate whether serum HER2 is increased in heart failure patients and related to disease

  9. Status of Her2 over expression in muscle invasive urothelial bladder carcinoma: Report of 21 cases

    Directory of Open Access Journals (Sweden)

    Nesrine Mejri

    2014-01-01

    Four patients died from disease, one of them had Her2 3+ score. Conclusion: Her2 overexpression can be observed in muscle invasive urothelial bladder carcinoma in an important number of patients. Evaluation criteria must be standardized, especially with heterogeneous cases. Metastases tests can also readdress the expression of Her2, which gives the patient a supplementary therapeutic tool.

  10. Overcoming resistance and restoring sensitivity to HER2-targeted therapies in breast cancer.

    LENUS (Irish Health Repository)

    Mohd Sharial, M S N

    2012-12-01

    Approximately 15%-23% of breast cancers overexpress human epidermal growth factor receptor 2 (HER2), which leads to the activation of signaling pathways that stimulate cell proliferation and survival. HER2-targeted therapy has substantially improved outcomes in patients with HER2-positive breast cancer. However, both de novo and acquired resistance are observed.

  11. Evaluation of HER2/neu oncoprotein in serum & tissue samples of women with breast cancer

    Directory of Open Access Journals (Sweden)

    Shailaja Shukla

    2016-01-01

    Interpretation & conclusions: The results suggest that elevated serum HER2 level was associated with a clinicopathological aggressive phenotype of breast carcinoma and was related to tissue HER2 overexpression. Therefore, serum HER2 may be useful for monitoring the course of the disease and response to treatment.

  12. The mannosylated extracellular domain of Her2/neu produced in P. pastoris induces protective antitumor immunity

    International Nuclear Information System (INIS)

    Dimitriadis, Alexios; Gontinou, Chrysanthi; Baxevanis, Constantin N; Mamalaki, Avgi

    2009-01-01

    Her2/neu is overexpressed in various human cancers of epithelial origin and is associated with increased metastatic potential and poor prognosis. Several attempts have been made using the extracellular domain of Her2/neu (ECD/Her2) as a prophylactic vaccine in mice with no success in tumor prevention. The extracellular domain of Her2/neu (ECD/Her2) was expressed in yeast P. pastoris, in a soluble highly mannosylated form. The immune response of the immunization with this recombinant ECD/Her2 was analyzed using immunoprecipitation and western blot analysis, proliferation and cytotoxicity assays as well as specific tumor growth assays. Mannosylated ECD/Her2 elicited a humoral response with HER2/neu specific antibodies in vaccinated mice, which were able to reduce the proliferation rate of cancer cells in vitro. Moreover, it elicited a cellular response with Her2/neu-specific CTL capable of lysing tumor cells, in vitro. When immunized Balb/c and HHD mice were challenged with Her2/neu-overexpressing cells, tumor growth was inhibited. Here we report on the efficacy of the extracellular domain of human Her2/neu produced in yeast P. pastoris, which confers mannosylation of the protein, to act as a potent anti-tumor vaccine against Her2/neu overexpressing tumors. Specific cellular and humoral responses were observed as well as efficacy

  13. {sup 186}Re-maSGS-Z{sub HER2:342}, a potential affibody conjugate for systemic therapy of HER2-expressing tumours

    Energy Technology Data Exchange (ETDEWEB)

    Orlova, Anna; Tran, Thuy A. [Uppsala University, Division of Biomedical Radiation Sciences, Rudbeck Laboratory, Uppsala (Sweden); Ekblad, Torun; Karlstroem, Amelie Eriksson [Royal Institute of Technology, School of Biotechnology, Division of Molecular Biotechnology, Stockholm (Sweden); Tolmachev, Vladimir [Uppsala University, Division of Biomedical Radiation Sciences, Rudbeck Laboratory, Uppsala (Sweden); Uppsala University, Division of Nuclear Medicine, Department of Medical Sciences, Uppsala (Sweden)

    2010-02-15

    Affibody molecules are a novel class of tumour-targeting proteins, which combine small size (7 kDa) and picomolar affinities. The Affibody molecule Z{sub HER2:342} has been suggested for imaging of HER2 expression in order to select patients for trastuzumab therapy. When optimizing chelators for {sup 99m}Tc-labelling, we have found that synthetic Z{sub HER2:342} conjugated with mercaptoacetyl-glycyl-glycyl-glycyl (maGGG) and mercaptoacetyl-glycyl-seryl-glycyl (maGSG) chelators provides relatively low renal uptake of radioactivity and could be suitable for therapy. maGGG-Z{sub HER2:342} and maGSG-Z{sub HER2:342} were labelled with {sup 186}Re and their biodistribution was studied in normal mice. Dosimetric evaluation and tumour targeting to HER2-overexpressed xenografts (SKOV-3) by {sup 186}Re-maGSG-Z{sub HER2:342} were studied. Gluconate-mediated labelling of maGGG-Z{sub HER2:342} and maGSG-Z{sub HER2:342} with {sup 186}Re provided a yield of more than 95% within 60 min. The conjugates were stable and demonstrated specific binding to HER2-expressing SKOV-3 cells. Biodistribution in normal mice demonstrated rapid blood clearance, low accumulation of radioactivity in the kidney and other organs, accumulating free perrhenate. Both {sup 186}Re-maGGG-Z{sub HER2:342} and {sup 186}Re-maGSG-Z{sub HER2:342} demonstrated lower renal uptake than their {sup 99m}Tc-labelled counterparts. {sup 186}Re-maGSG-Z{sub HER2:342} provided the lowest uptake in healthy tissues. Biodistribution of {sup 186}Re-maGSG-Z{sub HER2:342} in nude mice bearing SKOV-3 xenografts showed specific targeting of tumours. Tumour uptake 24 h after injection (5.84{+-}0.54%ID/g) exceeded the concentration in blood by more than 500-fold, and uptake in kidneys by about 8-fold. Preliminary dosimetric evaluation showed that dose-to-tumour should exceed dose-to-kidney by approximately 5-fold. Optimization of chelators improves biodistribution properties of rhenium-labelled small scaffold proteins and enables

  14. Upregulation of ER signaling as an adaptive mechanism of cell survival in HER2-positive breast tumors treated with anti-HER2 therapy

    Science.gov (United States)

    Giuliano, Mario; Hu, Huizhong; Wang, Yen-Chao; Fu, Xiaoyong; Nardone, Agostina; Herrera, Sabrina; Mao, Sufeng; Contreras, Alejandro; Gutierrez, Carolina; Wang, Tao; Hilsenbeck, Susan G.; De Angelis, Carmine; Wang, Nicholas J.; Heiser, Laura M.; Gray, Joe W.; Lopez-Tarruella, Sara; Pavlick, Anne C.; Trivedi, Meghana V.; Chamness, Gary C.; Chang, Jenny C.; Osborne, C. Kent; Rimawi, Mothaffar F.; Schiff, Rachel

    2015-01-01

    Purpose To investigate the direct effect and therapeutic consequences of epidermal growth factor receptor 2 (HER2)-targeting therapy on expression of estrogen receptor (ER) and Bcl2 in preclinical models and clinical tumor samples. Experimental design Archived xenograft tumors from two preclinical models (UACC812 and MCF7/HER2-18) treated with ER and HER2-targeting therapies, and also HER2+ clinical breast cancer specimens collected in a lapatinib neoadjuvant trial (baseline and week 2 post treatment), were used. Expression levels of ER and Bcl2 were evaluated by immunohistochemistry and western blot. The effects of Bcl2 and ER inhibition, by ABT-737 and fulvestrant respectively, were tested in parental versus lapatinib-resistant UACC812 cells in vitro. Results Expression of ER and Bcl2 was significantly increased in xenograft tumors with acquired resistance to anti-HER2 therapy, compared with untreated tumors, in both preclinical models (UACC812: ER p=0.0014; Bcl2 p<0.001. MCF7/HER2-18: ER p=0.0007; Bcl2 p=0.0306). In the neoadjuvant clinical study, lapatinib treatment for two weeks was associated with parallel upregulation of ER and Bcl2 (Spearman’s coefficient: 0.70; p=0.0002). Importantly, 18% of tumors originally ER-negative (ER−) converted to ER+ upon anti-HER2 therapy. In ER−/HER2+ MCF7/HER2-18 xenografts, ER re-expression was primarily observed in tumors responding to potent combination of anti-HER2 drugs. Estrogen deprivation added to this anti-HER2 regimen significantly delayed tumor progression (p=0.018). In the UACC812 cells, fulvestrant, but not ABT-737, was able to completely inhibit anti-HER2-resistant growth (p<0.0001). Conclusion HER2 inhibition can enhance or restore ER expression with parallel Bcl2 upregulation, representing an ER-dependent survival mechanism potentially leading to anti-HER2 resistance. PMID:26015514

  15. Restoring Lost Anti-HER-2 Th1 Immunity in Breast Cancer: A Crucial Role for Th1 Cytokines in Therapy and Prevention.

    Science.gov (United States)

    Nocera, Nadia F; Lee, M Catherine; De La Cruz, Lucy M; Rosemblit, Cinthia; Czerniecki, Brian J

    2016-01-01

    The ErbB/B2 (HER-2/neu) oncogene family plays a critical role in the development and metastatic spread of several tumor types including breast, ovarian and gastric cancer. In breast cancer, HER-2/neu is expressed in early disease development in a large percentage of DCIS lesions and its expression is associated with an increased risk of invasion and recurrence. Targeting HER-2 with antibodies such as trastuzumab or pertuzumab has improved survival, but patients with more extensive disease may develop resistance to therapy. Interestingly, response to HER-2 targeted therapies correlates with presence of immune response genes in the breast. Th1 cell production of the cytokines interferon gamma (IFNγ) and TNFα can enhance MHC class I expression, PD-L1 expression, augment apoptosis and tumor senescence, and enhances growth inhibition of many anti-breast cancer agents, including anti-estrogens and HER-2 targeted therapies. Recently, we have identified that a loss of anti-HER-2 CD4 Th1 in peripheral blood occurs during breast tumorigenesis and is dramatically diminished, even in Stage I breast cancers. The loss of anti-HER-2 Th1 response is specific and not readily reversed by standard therapies. In fact, this loss of anti-HER-2 Th1 response in peripheral blood correlates with lack of complete response to neoadjuvant therapy and diminished disease-free survival. This defect can be restored with HER-2 vaccinations in both DCIS and IBC. Correcting the anti-HER-2 Th1 response may have significant impact in improving response to HER-2 targeted therapies. Development of immune monitoring systems for anti-HER-2 Th1 to identify patients at risk for recurrence could be critical to improving outcomes, since the anti-HER-2 Th1 response can be restored by vaccination. Correction of the cellular immune response against HER-2 may prevent recurrence in high-risk patients with DCIS and IBC at risk of developing new or recurrent breast cancer.

  16. Prolyl isomerase Pin1 is highly expressed in Her2-positive breast cancer and regulates erbB2 protein stability

    Directory of Open Access Journals (Sweden)

    Lu Kun

    2008-12-01

    Full Text Available Abstract Overexpression of HER-2/Neu occurs in about 25–30% of breast cancer patients and is indicative of poor prognosis. While Her2/Neu overexpression is primarily a result of erbB2 amplification, it has recently been recognized that erbB2 levels are also regulated on the protein level. However, factors that regulate Her2/Neu protein stability are less well understood. The prolyl isomerase Pin1 catalyzes the isomerization of specific pSer/Thr-Pro motifs that have been phosphorylated in response to mitogenic signaling. We have previously reported that Pin1-catalyzed post-phosphorylational modification of signal transduction modulates the oncogenic pathways downstream from c-neu. The goal of this study was to examine the expression of prolyl isomerase Pin1 in human Her2+ breast cancer, and to study if Pin1 affects the expression of Her2/Neu itself. Methods Immunohistochemistry for Her2 and Pin1 were performed on two hundred twenty-three human breast cancers, with 59% of the specimen from primary cancers and 41% from metastatic sites. Pin1 inhibition was achieved using siRNA in Her2+ breast cancer cell lines, and its effects were studied using cell viability assays, immunoblotting and immunofluorescence. Results Sixty-four samples (28.7% stained positive for Her2 (IHC 3+, and 54% (122/223 of all breast cancers stained positive for Pin1. Of the Her2-positive cancers 40 (62.5% were also Pin1-positive, based on strong nuclear or nuclear and cytoplasmic staining. Inhibition of Pin1 via RNAi resulted in significant suppression of Her2-positive tumor cell growth in BT474, SKBR3 and AU565 cells. Pin1 inhibition greatly increased the sensitivity of Her2-positive breast cancer cells to the mTOR inhibitor Rapamycin, while it did not increase their sensitivity to Trastuzumab, suggesting that Pin1 might act on Her2 signaling. We found that Pin1 interacted with the protein complex that contains ubiquitinated erbB2 and that Pin1 inhibition accelerated erbB2

  17. Activity, specificity, and titer of naturally occurring canine anti-DEA 7 antibodies.

    Science.gov (United States)

    Spada, Eva; Proverbio, Daniela; Baggiani, Luciana; Canzi, Ilaria; Perego, Roberta

    2016-11-01

    The reported prevalence of naturally occurring anti-dog erythrocyte antigen (DEA) 7 antibodies in DEA 7-negative dogs is as high as 50%. Characterization of these antibodies may better define their importance in canine transfusion medicine. We determined in vitro activity, specificity, and titer of anti-DEA 7 antibodies in DEA 7-negative dogs. Plasma samples from 317 DEA 7-negative dogs were cross-matched with DEA 7-positive red blood cells (RBCs) using gel column technology. Agglutination occurred with DEA 7-positive RBCs but not with DEA 7-negative RBCs in 73 samples (23%), which were hence classified as containing anti-DEA 7 antibodies. These samples were evaluated for hemolytic and agglutinating activity, strength of agglutination, and antibody specificity and titers. All samples showed agglutination but none showed hemolysis. Gel agglutination was graded as 1+ for 20 samples (27%), 2+ for 49 samples (67%), 3+ for 4 samples (6%); no samples were graded 4+. The agglutination titer was DEA 7 antibodies were found in 23% of DEA 7-negative dogs. The presence of naturally occurring anti-DEA 7 antibodies suggests that cross-matching of canine blood recipients is advisable, even at first transfusion, to minimize delayed transfusion reactions. © 2016 The Author(s).

  18. Differentiation of naturally-occurring vs. artificial hydrocarbons in a landfill groundwater investigation

    International Nuclear Information System (INIS)

    Beaver, J.L.; Hartness, J.A.; Breeding, L.B.; Buchanan, D.M.

    1994-01-01

    Interpretation of groundwater sampling data at a large municipal/industrial landfill indicates contamination by both artificial and naturally-occurring hydrocarbons. Site hydrogeology consists of three different water bearing zones. The uppermost (shallow) aquifer is an unconfined unit consisting of silt, clay, and sand deposits. An intermediate depth semiconfined aquifer underlies the unconfined unit, and consists of a chert rubble zone and the upper portion of a fractured and solution-enhanced limestone formation. A regionally-extensive organic-rich shale underlies the semiconfined aquifer and separates it from the deep confined aquifer, which also consists of limestone. Groundwater investigations at the landfill have detected chlorinated and non-chlorinated hydrocarbons in the different aquifer intervals. Chlorinated hydrocarbons detected include tetrachloroethene, dichloroethene, and vinyl chloride and occur almost exclusively in the shallow aquifer. Aromatic hydrocarbons detected include benzene, toluene, ethylbenzene, and xylene (BTEX) and-occur in the intermediate and deep aquifers. The landfill was originally interpreted as the source of the contaminants. The observation of free-phase liquid hydrocarbons in the intermediate aquifer at the site, and high dissolved BTEX levels in the deep and intermediate aquifers upgradient of the landfill suggest that the aromatics were derived from a source other than the landfill. A potential source of BTEX contamination may be abandoned (pre-1930) natural gas wells located near the landfill. An additional BTEX source may be the organic-rich shale formation (a documented petroleum source rock)

  19. Naturally occurring arsenic in the groundwater at the Kansas City Plant

    Energy Technology Data Exchange (ETDEWEB)

    Korte, N.E.

    1990-12-01

    This report describes an investigation concerning the presence of arsenic in concentrations exceeding 0.4 mg/L in the groundwater under the Department of Energy's Kansas City Plant (KCP). The study consisted of four distinct phases: a thorough review of the technical literature, a historical survey of arsenic use at the facility, a laboratory study of existing techniques for determining arsenic speciation, and a field program including water, soil, and sediment sampling. The historical survey and literature review demonstrated that plant activities had not released significant quantities of arsenic to the environment but that similar occurrences of arsenic in alluvial groundwater are widespread in the midwestern United States. Laboratory studies showed that a chromatographic separation technique was necessary to accurately determine arsenic speciation for the KCP groundwater samples. Field studies revealed that naturally occurring reducing conditions prevalent in the subsurface are responsible for dissolving arsenic previously sorbed by iron oxides. Indeed, the data demonstrated that the bulk arsenic concentration of site subsoils and sediments is {approximately}7 mg/kg, whereas the arsenic content of iron oxide subsamples is as high as 84 mg/kg. Literature showed that similar concentrations of arsenic in sediments occur naturally and are capable of producing the levels of arsenic found in groundwater monitoring wells at the KCP. The study concludes, therefore, that the arsenic present in the KCP groundwater is the result of natural phenomena. 44 refs., 8 figs., 14 tabs.

  20. Preclinical characterization of naturally occurring polyketide cyclophilin inhibitors from the sanglifehrin family.

    Science.gov (United States)

    Gregory, Matthew A; Bobardt, Michael; Obeid, Susan; Chatterji, Udayan; Coates, Nigel J; Foster, Teresa; Gallay, Philippe; Leyssen, Pieter; Moss, Steven J; Neyts, Johan; Nur-e-Alam, Mohammad; Paeshuyse, Jan; Piraee, Mahmood; Suthar, Dipen; Warneck, Tony; Zhang, Ming-Qiang; Wilkinson, Barrie

    2011-05-01

    Cyclophilin inhibitors currently in clinical trials for hepatitis C virus (HCV) are all analogues of cyclosporine (CsA). Sanglifehrins are a group of naturally occurring cyclophilin binding polyketides that are structurally distinct from the cyclosporines and are produced by a microorganism amenable to biosynthetic engineering for lead optimization and large-scale production by fermentation. Preclinical characterization of the potential utility of this class of compounds for the treatment of HCV revealed that the natural sanglifehrins A to D are all more potent than CsA at disrupting formation of the NS5A-CypA, -CypB, and -CypD complexes and at inhibition of CypA, CypB, and CypD isomerase activity. In particular, sanglifehrin B (SfB) was 30- to 50-fold more potent at inhibiting the isomerase activity of all Cyps tested than CsA and was also shown to be a more potent inhibitor of the 1b subgenomic replicon (50% effective concentrations [EC50s] of 0.070 μM and 0.16 μM in Huh 5-2 and Huh 9-13 cells, respectively). Physicochemical and mouse pharmacokinetic analyses revealed low oral bioavailability (F5 h). These data demonstrate that naturally occurring sanglifehrins are suitable lead compounds for the development of novel analogues that are less immunosuppressive and that have improved metabolism and pharmacokinetic properties.

  1. Preclinical Characterization of Naturally Occurring Polyketide Cyclophilin Inhibitors from the Sanglifehrin Family▿†

    Science.gov (United States)

    Gregory, Matthew A.; Bobardt, Michael; Obeid, Susan; Chatterji, Udayan; Coates, Nigel J.; Foster, Teresa; Gallay, Philippe; Leyssen, Pieter; Moss, Steven J.; Neyts, Johan; Nur-e-Alam, Mohammad; Paeshuyse, Jan; Piraee, Mahmood; Suthar, Dipen; Warneck, Tony; Zhang, Ming-Qiang; Wilkinson, Barrie

    2011-01-01

    Cyclophilin inhibitors currently in clinical trials for hepatitis C virus (HCV) are all analogues of cyclosporine (CsA). Sanglifehrins are a group of naturally occurring cyclophilin binding polyketides that are structurally distinct from the cyclosporines and are produced by a microorganism amenable to biosynthetic engineering for lead optimization and large-scale production by fermentation. Preclinical characterization of the potential utility of this class of compounds for the treatment of HCV revealed that the natural sanglifehrins A to D are all more potent than CsA at disrupting formation of the NS5A-CypA, -CypB, and -CypD complexes and at inhibition of CypA, CypB, and CypD isomerase activity. In particular, sanglifehrin B (SfB) was 30- to 50-fold more potent at inhibiting the isomerase activity of all Cyps tested than CsA and was also shown to be a more potent inhibitor of the 1b subgenomic replicon (50% effective concentrations [EC50s] of 0.070 μM and 0.16 μM in Huh 5-2 and Huh 9-13 cells, respectively). Physicochemical and mouse pharmacokinetic analyses revealed low oral bioavailability (F 5 h). These data demonstrate that naturally occurring sanglifehrins are suitable lead compounds for the development of novel analogues that are less immunosuppressive and that have improved metabolism and pharmacokinetic properties. PMID:21383094

  2. Investigation of the resistance of some naturally occurring and synthetic inorganic ion exchangers against gamma radiation

    International Nuclear Information System (INIS)

    Nilchi, A.; Khanchi, A.; Ghanadi Maragheh, M.; Bagheri, A.

    2003-01-01

    The effect of various doses of gamma radiation on the ion-exchange capacity, distribution coefficient values, elution behaviour, physical effect, pH titration and infrared spectra of some synthetic inorganic ion exchangers, namely the cerium substituted phosphates; and naturally occurring inorganic ion exchangers, zeolites from different parts of Iran, have been studied systematically. No significant change has been observed in the ion-exchange capacity (with the exception of CeP(Na), CeP(Di·Na) and zeolite 5 (deposits of arababad talas)), elution behaviour, physical effect, chemical stability and the infrared spectra of the synthetic ion exchangers irradiated up to a total dose of 200 kGy, while a change has been observed in the pH-titration and distribution behaviour. The increase in pH is sharper for irradiated samples with divalent cations than for the normal samples. Furthermore, the K d values, and hence the selectivity towards certain cations increase with the total dose absorbed, reaching its optimum selectivity with the dose of 50-100 kGy. The natural zeolites chosen for these studies, show, similar pattern to those of synthetic ion exchangers, and in some cases an extremely high selectivity toward certain cations, like Be II . These make, zeolites, which are naturally occurring ion exchangers more viable economically, and extremely useful alternative in this industry

  3. Leptin/HER2 crosstalk in breast cancer: in vitro study and preliminary in vivo analysis

    International Nuclear Information System (INIS)

    Fiorio, Elena; Bonetti, Franco; Giordano, Antonio; Cetto, Gian Luigi; Surmacz, Eva; Mercanti, Anna; Terrasi, Marianna; Micciolo, Rocco; Remo, Andrea; Auriemma, Alessandra; Molino, Annamaria; Parolin, Veronica; Di Stefano, Bruno

    2008-01-01

    Obesity in postmenopausal women is associated with increased breast cancer risk, development of more aggressive tumors and resistance to certain anti-breast cancer treatments. Some of these effects might be mediated by obesity hormone leptin, acting independently or modulating other signaling pathways. Here we focused on the link between leptin and HER2. We tested if HER2 and the leptin receptor (ObR) can be coexpressed in breast cancer cell models, whether these two receptors can physically interact, and whether leptin can transactivate HER2. Next, we studied if leptin/ObR can coexist with HER2 in breast cancer tissues, and if presence of these two systems correlates with specific clinicopathological features. Expression of ObR, HER2, phospo-HER2 was assessed by immonoblotting. Physical interactions between ObR and HER2 were probed by immunoprecipitation and fluorescent immunostaining. Expression of leptin and ObR in breast cancer tissues was detected by immunohistochemistry (IHC). Associations among markers studied by IHC were evaluated using Fisher's exact test for count data. HER2 and ObR were coexpressed in all studied breast cancer cell lines. In MCF-7 cells, HER2 physically interacted with ObR and leptin treatment increased HER2 phosphorylation on Tyr 1248. In 59 breast cancers, the presence of leptin was correlated with ObR (the overall association was about 93%). This result was confirmed both in HER2-positive and in HER2-negative subgroups. The expression of leptin or ObR was numerically more frequent in larger (> 10 mm) tumors. Coexpression of HER2 and the leptin/ObR system might contribute to enhanced HER2 activity and reduced sensitivity to anti-HER2 treatments

  4. HER2 in Breast Cancer Stemness: A Negative Feedback Loop towards Trastuzumab Resistance

    Directory of Open Access Journals (Sweden)

    Babak Nami

    2017-04-01

    Full Text Available HER2 receptor tyrosine kinase that is overexpressed in approximately 20% of all breast cancers (BCs is a poor prognosis factor and a precious target for BC therapy. Trastuzumab is approved by FDA to specifically target HER2 for treating HER2+ BC. However, about 60% of patients with HER2+ breast tumor develop de novo resistance to trastuzumab, partially due to the loss of expression of HER2 extracellular domain on their tumor cells. This is due to shedding/cleavage of HER2 by metalloproteinases (ADAMs and MMPs. HER2 shedding results in the accumulation of intracellular carboxyl-terminal HER2 (p95HER2, which is a common phenomenon in trastuzumab-resistant tumors and is suggested as a predictive marker for trastuzumab resistance. Up-regulation of the metalloproteinases is a poor prognosis factor and is commonly seen in mesenchymal-like cancer stem cells that are risen during epithelial to mesenchymal transition (EMT of tumor cells. HER2 cleavage during EMT can explain why secondary metastatic tumors with high percentage of mesenchymal-like cancer stem cells are mostly resistant to trastuzumab but still sensitive to lapatinib. Importantly, many studies report HER2 interaction with oncogenic/stemness signaling pathways including TGF-β/Smad, Wnt/β-catenin, Notch, JAK/STAT and Hedgehog. HER2 overexpression promotes EMT and the emergence of cancer stem cell properties in BC. Increased expression and activation of metalloproteinases during EMT leads to proteolytic cleavage and shedding of HER2 receptor, which downregulates HER2 extracellular domain and eventually increases trastuzumab resistance. Here, we review the hypothesis that a negative feedback loop between HER2 and stemness signaling drives resistance of BC to trastuzumab.

  5. Determining true HER2 gene status in breast cancers with polysomy by using alternative chromosome 17 reference genes: implications for anti-HER2 targeted therapy.

    Science.gov (United States)

    Tse, Chun Hing; Hwang, Harry C; Goldstein, Lynn C; Kandalaft, Patricia L; Wiley, Jesse C; Kussick, Steven J; Gown, Allen M

    2011-11-01

    The ratio of human epidermal growth factor receptor 2 (HER2) to CEP17 by fluorescent in situ hybridization (FISH) with the centromeric probe CEP17 is used to determine HER2 gene status in breast cancer. Increases in CEP17 copy number have been interpreted as representing polysomy 17. However, pangenomic studies have demonstrated that polysomy 17 is rare. This study tests the hypothesis that the use of alternative chromosome 17 reference genes might more accurately assess true HER2 gene status. In all, 171 patients with breast cancer who had HER2 FISH that had increased mean CEP17 copy numbers (> 2.6) were selected for additional chromosome 17 studies that used probes for Smith-Magenis syndrome (SMS), retinoic acid receptor alpha (RARA), and tumor protein p53 (TP53) genes. A eusomic copy number exhibited in one or more of these loci was used to calculate a revised HER2-to-chromosome-17 ratio by using the eusomic gene locus as the reference. Of 132 cases classified as nonamplified on the basis of their HER2:CEP17 ratios, 58 (43.9%) were scored as amplified by using alternative chromosome 17 reference gene probes, and 13 (92.9%) of 14 cases scored as equivocal were reclassified as amplified. Among the cases with mean HER2 copy number of 4 to 6, 41 (47.7%) of 86 had their HER2 gene status upgraded from nonamplified to amplified, and four (4.7%) of 86 were upgraded from equivocal to amplified. Our results support the findings of recent pangenomic studies that true polysomy 17 is uncommon. Additional FISH studies that use probes to the SMS, RARA, and TP53 genes are an effective way to determine the true HER2 amplification status in patients with polysomy 17 and they have important potential implications for guiding HER2-targeted therapy in breast cancer.

  6. Detection and quantitation of HER-2/neu gene amplification in human breast cancer archival material using fluorescence in situ hybridization.

    Science.gov (United States)

    Pauletti, G; Godolphin, W; Press, M F; Slamon, D J

    1996-07-04

    Amplification and overexpression of the HER-2/neu gene occurs in 25-30% of human breast cancers. This genetic alteration is associated with a poor clinical prognosis in women with either node negative or node positive breast cancers. The initial studies testing this association were somewhat controversial and this controversy was due in large part to significant heterogeneity in both the methods and/or reagents used in testing archival material for the presence of the alteration. These methods included a number of solid matrix blotting techniques for DNA, RNA and protein as well as immunohistochemistry. Fluorescence in situ hybridization (FISH) represents the newest methodologic approach for testing for this genetic alteration. In this study, FISH is compared to Southern, Northern and Western blot analyses as well as immunohistochemistry in a large cohort of archival human breast cancer specimens. FISH was found to be superior to all other methodologies tested in assessing formalin fixed, paraffin embedded material for HER-2/neu amplification. The results from this study also confirm that overexpression of HER-2/neu rarely occurs in the absence of gene amplification in breast cancer (approximately 3% of cases). This method of analysis is rapid, reproducible and extremely reliable in detecting presence of HER-2/neu gene amplification and should have clinical utility.

  7. Validation of a Fully Automated HER2 Staining Kit in Breast Cancer

    Directory of Open Access Journals (Sweden)

    Cathy B. Moelans

    2010-01-01

    Full Text Available Background: Testing for HER2 amplification and/or overexpression is currently routine practice to guide Herceptin therapy in invasive breast cancer. At present, HER2 status is most commonly assessed by immunohistochemistry (IHC. Standardization of HER2 IHC assays is of utmost clinical and economical importance. At present, HER2 IHC is most commonly performed with the HercepTest which contains a polyclonal antibody and applies a manual staining procedure. Analytical variability in HER2 IHC testing could be diminished by a fully automatic staining system with a monoclonal antibody.

  8. The nature and position of processing determines why forgetting occurs in working memory tasks.

    Science.gov (United States)

    Jarrold, Christopher; Tam, Helen; Baddeley, Alan D; Harvey, Caroline E

    2010-12-01

    The effect of potentially distracting processing within working memory was examined by varying the nature and position of processing across conditions of a Brown-Peterson-like task. Separate groups of participants carried out verbal or visuospatial processing operations on identical stimuli, while retaining lists of to-be-remembered words. The number of words presented either before or after the processing interval was varied systematically. Results showed that although verbal processing was no more demanding than visuospatial processing, it led to greater forgetting. However, forgetting was confined to items presented prior to processing, and the difference in degree of forgetting shown by the two groups was maximal when four items occurred before processing. Temporal isolation effects were more marked in the verbal processing group. These findings indicate that individuals can keep active a limited number of items in primary memory during processing, unless processing blocks rehearsal, in which case retrieval occurs from secondary memory.

  9. Interaction of flavonoids, the naturally occurring antioxidants with different media: a UV-visible spectroscopic study.

    Science.gov (United States)

    Naseem, Bushra; Shah, S W H; Hasan, Aurangzeb; Sakhawat Shah, S

    2010-04-01

    Quantitative parameters for interaction of flavonoids-the naturally occurring antioxidants, with solvents and surfactants are determined using UV-visible absorption spectroscopy. The availability of flavonoids; kaempferol, apigenin, kaempferide and rhamnetin in micelles of sodium dodecyl sulfate (SDS) is reflected in terms of partition coefficient, K(c). Thermodynamic calculations show that the process of transfer of flavonoid molecules to anionic micelles of SDS is energy efficient. A distortion in flavonoid's morphology occurs in case of kaempferol and apigenin in surfactant and water, exhibited in terms of a new band in the UV region of electronic spectra of these flavonoids. The partition coefficients of structurally related flavonoids are correlated with their antioxidant activities. Copyright 2010 Elsevier B.V. All rights reserved.

  10. Characteristics of Airborne Particulates Containing Naturally Occurring Radioactive Materials in Monazite Industry

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Yong Geon; Choi, Cheol Kyu; Park, Il; Kim, Min Jun; Go, A Ra; Ji, Seung Woo; Kim, Kwang Pyo [Kyunghee University, Yongin (Korea, Republic of); Koo, Bon Cheol [KINS, Daejeon (Korea, Republic of)

    2016-05-15

    The objective of this study was to characterize physicochemical properties of airborne particulates at a monazite pulverization industry. The properties included particulate size distribution, concentration, shape, density, and radioactivity concentration. Monazite is one of the minerals containing naturally occurring radioactive material (NORM). Therefore, external and internal exposure can be occurred to the workers in monazite industry. The major exposure pathway of the workers is internal exposure due to inhalation of airborne particulates. According to International Commission on Radiological Protection (ICRP), radiation dose due to inhaled particulates containing NORM depends on particulate properties. Therefore, ICRP recommended the internal dose assessment using measured physicochemical properties of the airborne particulates. In the absence of specific information, ICRP provided default reference values. In this study, we characterized physicochemical properties of airborne particulates at a monazite pulverization industry. The databases of particulate information can be used for accurate internal dose assessment of worker.

  11. Geologic considerations for the subsurface injection of naturally occurring radioactive materials (NORM): A case study

    International Nuclear Information System (INIS)

    Ladle, G.H.

    1995-01-01

    NORM waste consists of naturally occurring radioactive material associated with oil and gas operations as scale deposited in tubulars, surface piping, pumps, and other producing and processing equipment. NORM also occurs as sludge and produced sands at wellheads, transport vessels and tank bottoms. For disposal, NORM scale and sludge are separated from the tubulars and tank bottoms and ground to less than 100 microns and mixed into a slurry at the surface facility for disposal into a deep well injection interval below the Underground Sources of Drinking Water zone. This paper addresses two primary considerations: (1) subsurface geologic investigations which identify specific geologic horizons that have sufficient porosity and permeability to accept NORM slurries containing high total suspended solids concentrations, and (2) surface facility requirements. Generic and specific information, criteria, and examples are included in the paper to allow the application of the geologic principles to other areas or regions

  12. Automation of a gamma spectrometric analysis method for naturally occuring radionuclides in different materials (NORM)

    International Nuclear Information System (INIS)

    Marzocchi, Olaf

    2009-06-01

    This work presents an improvement over the standard analysis routine used in the Physikalisches Messlabor to detect gamma peaks in spectra from naturally occurring radioactive materials (NORM). The new routine introduces the use of custom libraries of known gamma peaks, in order to ease the work of the software than can therefore detect more peaks. As final result, the user performing the analysis has less chances of making errors and can also analyse more spectra in the same amount of time. A new software, with an optimised interface able to further enhance the productivity of the user, is developed and validated. (orig.)

  13. Remediation plan for contaminated areas by naturally occurring radioactivity materials in Syrian Petroleum Company oil fields

    International Nuclear Information System (INIS)

    Shweikani, R.; Al-Masri, M. S.; Awad, I.

    2006-01-01

    The present report contains a detailed plan for remediation of areas contaminated with naturally occurring radioactive materials in the syrian Petroleum Company Oil fields. This plan includes a description of the contaminated areas and the procedures that will be followed before and during the execution of the project in addition to the final radiation surveys according to the Syrian regulations. In addition, responsibilities of the main personnel who will carry out the work have been defined and the future monitoring program of the remediated areas was determined. (author)

  14. Distribution of naturally occurring radionuclides in soils of the southern districts of Bangladesh

    International Nuclear Information System (INIS)

    Chowdhury, M. I.; Kamal, M.; Alam, M. N.; Yeasmin, S.; Mostafa, M. N.

    2006-01-01

    The activity concentrations of naturally occurring radioactive materials in soil samples of an elevated radiation background area of nine southern districts of Bangladesh were determined using gamma-ray spectrometry with an aim of evaluating the environmental radioactivity. The outdoor and indoor external effective dose rates and the radiation hazard indices from the soil activity were evaluated with an aim of minimising the harmful effects of ionising radiation to the population of the area concerned. The activity of 137 Cs was measured and observed in some of the locations. (authors)

  15. Safety protection suggestion of naturally occurring radioactive materials in the oil and gas industry

    International Nuclear Information System (INIS)

    Zhou Xiaojian; Zhou Qifu; Wang Xiaotao; Xu Zhongyang; Song Peifeng

    2014-01-01

    It's not enough concern about the naturally occurring radioactive materials (NORM) of oil and gas industry in China. NORM with radium and radon mainly exist in the scale, sludge and production water, and they tend to deposit on the pipe wall, wellhead equipment and so on. These materials are a threat to the health of workers, so it is very important to have the safe disposal of them. This paper introduces the radioactive hazards and puts for-ward the safe disposal measures so as to provide the reference for the safe disposal of radioactive materials. Some management and technical advices are presented too. (authors)

  16. Remediation plan for contaminated areas by naturally occurring radioactivity materials in Syrian petroleum company oil fields

    International Nuclear Information System (INIS)

    Shwekani, R.; Al-Masri, M.S.; Awad, I.

    2005-08-01

    The present report contains a detailed plan for remediation of areas contaminated with naturally occurring radioactive materials in the Syrian petroleum company oil fields. This plan includes a description of the contaminated areas and the procedures that will be followed before and during the execution of the project in addition to the final radiation surveys according to the Syrian regulations. In addition, responsibilities of the main personnel who will carry out the work have been defined and the future monitoring program of the remediated areas was determined. (author)

  17. Naturally occurring radioactive materials (NORM) in the oil and gas processing and production facilities

    International Nuclear Information System (INIS)

    Najera F, J.

    1994-01-01

    NORM contamination is produced by concentration in petroleum facilities of naturally occurring radioactive materials. The presence of NORM in petroleum reservoirs and in the oil and gas industry has been widely recognized. It's not a critical technical problem if you proceed timely to solve it. NORM is a great but controllable hazard to the human health and the environment, and represents a severe waste management problem. We suggest to the latino american oil companies to conduct studies to detect NORM contamination in their facilities an use to them to plan the appropriate actions to control the situation. (author). 15 refs

  18. Commentary on guidelines for radiation measurement and treatment of substances including naturally occurring radioactive materials

    International Nuclear Information System (INIS)

    Sakurai, Naoyuki; Ishiguro, Hideharu

    2007-01-01

    Study group on safety regulation on research reactors in Ministry of Education, Culture, Sports, Science and Technology (MEXT) reported the guidelines of 'Guidelines on radiation measurement and treatment of naturally occurring radioactive materials (NORM)' on 6 February 2006. RANDEC made the website contents 'Study on use and safety of the substances including uranium or thorium', based on the contract with MEXT to make theirs contents. This paper describes the outline of the website in MEXT homepage, background and contents of NORM guidelines in order to understand easily and visually the NORM guidelines, adding in some flowcharts and figures. (author)

  19. Assessment of radiation exposures from naturally occurring radioactive materials in the oil and gas industry

    International Nuclear Information System (INIS)

    Hamlat, M.S.; Djeffal, S.; Kadi, H.

    2001-01-01

    Radioactive deposits, often referred to as naturally occurring radioactive material scale, can, because of incompatibility of formation and injection waters, be formed inside production equipment of the oil and gas industry. These scales contain mainly 226 Ra and its daughter products, which can cause an exposure risk. The gamma ray dose rates, with the associated occupational doses in the oil and gas industry, and 226 Ra concentration in production water, crude oil and hard/soft scale samples were determined. Results obtained are discussed and compared to those from other studies

  20. Antioxidant effect of naturally occurring xanthines on the oxidative damage of DNA bases

    International Nuclear Information System (INIS)

    Vieira, A.J.S.C.; Telo, J.P.; Pereira, H.F.; Patrocinio, P.F.; Dias, R.M.B.

    1999-01-01

    The repair of the oxidised radicals of adenine and guanosine by several naturally occurring xanthines was studied. Each pair of DNA purine/xanthine was made to react with the sulphate radical and the decrease of the concentration of both compounds was measured by HPLC as a function of irradiation time. The results show that xanthine efficiently prevents the oxidation of the two DNA purines. Theophylline and para-xanthine repair the oxidizes radical of adenine but not the one from guanosine. Theobromine and caffeine to do not show any protecting effect. An order of the oxidation potentials of all the purines studied is proposed. (authors)

  1. Bacteremia and bacterial translocation in the naturally occurring canine gastric dilatation-volvulus patient.

    Science.gov (United States)

    Winkler, Kevin P; Greenfield, Cathy L; Schaeffer, David J

    2003-01-01

    This prospective study was performed to determine the prevalence of bacteremia in the naturally occurring gastric dilatation-volvulus (GDV) patient, the possible relationship between bacteremia and survival, and whether bacteremia was a result of translocation from the stomach. Blood cultures were collected from each patient. Bacterial cultures were collected from the liver, mesenteric lymph node, and stomach. Forty-three percent of the GDV cases and 40% of the controls developed positive blood cultures. Gram-negative rods were the most frequently isolated organisms. Evidence of bacterial translocation from the stomach could not be demonstrated in GDV patients, and survival was not affected by the presence of bacteremia.

  2. Radiochemical techniques for determining some naturally occurring radionuclides in marine environmental materials

    Energy Technology Data Exchange (ETDEWEB)

    Baker, C W [Ministry of Agriculture, Fisheries and Food, Lowestoft (UK). Fisheries Lab.

    1984-06-15

    The determination of some of the naturally-occurring, alpha-emitting radionuclides in marine environmental materials, is of interest for several reasons. Radium and radon nuclides are potentially useful as oceanographic tracers. Lead and thorium nuclides may be used to study sedimentation rates, mixing processes and bioturbation in sediments. Radium and polonium nuclides are incorporated into food chains and the data may provide a perspective against which to assess the significance, for marine organisms, of exposure to radiation in a marine radioactive waste disposal situation. This paper discusses the manner in which samples are taken, and the radiochemical methods which have been employed to measure the nuclides, together with some data produced.

  3. Corrected simulations for one-dimensional diffusion processes with naturally occurring boundaries.

    Science.gov (United States)

    Shafiey, Hassan; Gan, Xinjun; Waxman, David

    2017-11-01

    To simulate a diffusion process, a usual approach is to discretize the time in the associated stochastic differential equation. This is the approach used in the Euler method. In the present work we consider a one-dimensional diffusion process where the terms occurring, within the stochastic differential equation, prevent the process entering a region. The outcome is a naturally occurring boundary (which may be absorbing or reflecting). A complication occurs in a simulation of this situation. The term involving a random variable, within the discretized stochastic differential equation, may take a trajectory across the boundary into a "forbidden region." The naive way of dealing with this problem, which we refer to as the "standard" approach, is simply to reset the trajectory to the boundary, based on the argument that crossing the boundary actually signifies achieving the boundary. In this work we show, within the framework of the Euler method, that such resetting introduces a spurious force into the original diffusion process. This force may have a significant influence on trajectories that come close to a boundary. We propose a corrected numerical scheme, for simulating one-dimensional diffusion processes with naturally occurring boundaries. This involves correcting the standard approach, so that an exact property of the diffusion process is precisely respected. As a consequence, the proposed scheme does not introduce a spurious force into the dynamics. We present numerical test cases, based on exactly soluble one-dimensional problems with one or two boundaries, which suggest that, for a given value of the discrete time step, the proposed scheme leads to substantially more accurate results than the standard approach. Alternatively, the standard approach needs considerably more computation time to obtain a comparable level of accuracy to the proposed scheme, because the standard approach requires a significantly smaller time step.

  4. Beneficial Effects of Autologous Bone Marrow-Derived Mesenchymal Stem Cells in Naturally Occurring Tendinopathy

    Science.gov (United States)

    Smith, Roger Kenneth Whealands; Werling, Natalie Jayne; Dakin, Stephanie Georgina; Alam, Rafiqul; Goodship, Allen E.; Dudhia, Jayesh

    2013-01-01

    Tendon injuries are a common age-related degenerative condition where current treatment strategies fail to restore functionality and normal quality of life. This disease also occurs naturally in horses, with many similarities to human tendinopathy making it an ideal large animal model for human disease. Regenerative approaches are increasingly used to improve outcome involving mesenchymal stem cells (MSCs), supported by clinical data where injection of autologous bone marrow derived MSCs (BM-MSCs) suspended in marrow supernatant into injured tendons has halved the re-injury rate in racehorses. We hypothesized that stem cell therapy induces a matrix more closely resembling normal tendon than the fibrous scar tissue formed by natural repair. Twelve horses with career-ending naturally-occurring superficial digital flexor tendon injury were allocated randomly to treatment and control groups. 1X107 autologous BM-MSCs suspended in 2 ml of marrow supernatant were implanted into the damaged tendon of the treated group. The control group received the same volume of saline. Following a 6 month exercise programme horses were euthanized and tendons assessed for structural stiffness by non-destructive mechanical testing and for morphological and molecular composition. BM-MSC treated tendons exhibited statistically significant improvements in key parameters compared to saline-injected control tendons towards that of normal tendons and those in the contralateral limbs. Specifically, treated tendons had lower structural stiffness (ptendon repair in enhancing normalisation of biomechanical, morphological, and compositional parameters. These data in natural disease, with no adverse findings, support the use of this treatment for human tendon injuries. PMID:24086616

  5. Molecular- and nm-scale Investigation of the Structure and Compositional Heterogeneity of Naturally Occurring Ferrihydrite

    Science.gov (United States)

    Cismasu, C.; Michel, F. M.; Stebbins, J. F.; Tcaciuc, A. P.; Brown, G. E.

    2008-12-01

    Ferrihydrite is a hydrated Fe(III) nano-oxide that forms in vast quantities in contaminated acid mine drainage environments. As a result of its high surface area, ferrihydrite is an important environmental sorbent, and plays an essential role in the geochemical cycling of pollutant metal(loid)s in these settings. Despite its environmental relevance, this nanomineral remains one of the least understood environmental solids in terms of its structure (bulk and surface), compositional variations, and the factors affecting its reactivity. Under natural aqueous conditions, ferrihydrite often precipitates in the presence of several inorganic compounds such as aluminum, silica, arsenic, etc., or in the presence of organic matter. These impurities can affect the molecular-level structure of naturally occurring ferrihydrite, thus modifying fundamental properties that are directly correlated with solid-phase stability and surface reactivity. Currently there exists a significant gap in our understanding of the structure of synthetic vs. natural ferrihydrites, due to the inherent difficulties associated to the investigation of these poorly crystalline nanophases. In this study, we combined synchrotron- and laboratory-based techniques to characterize naturally occurring ferrihydrite from an acid mine drainage system situated at the New Idria mercury mine in California. We used high-energy X-ray total scattering and pair distribution function analysis to elucidate quantitative structural details of these samples. We have additionally used scanning transmission X-ray microscopy high resolution imaging (30 nm) to evaluate the spatial relationship of major elements Si, Al, and C within ferrihydrite. Al, Si and C K-edge near- edge X-ray absorption fine structure spectroscopy and 27Al nuclear magnetic resonance spectroscopy were used to obtain short-range structural information. By combining these techniques we attain the highest level of resolution permitted by current analytical

  6. Naturally occurring radioactive materials (NORM IV). Proceedings of an international conference

    International Nuclear Information System (INIS)

    2005-10-01

    Radionuclides of natural origin are ubiquitous in both working and public environments, although their activity concentrations vary considerably. Exposures to natural sources are in most cases not a matter for regulatory concern. However, there are situations where exposures to natural sources may warrant consideration as to whether controls should be applied. One such situation is where the conditions are conducive to the buildup of elevated concentrations of radon in air. Another situation is the mining and/or processing of material where the activity concentrations of radionuclides of natural origin in the material itself, or in any material arising from the process, are significantly elevated - such material has come to be referred to as Naturally Occurring Radioactive Material (NORM). In the past, regulatory attention has been focused mostly on exposures arising from the mining and processing of uranium ores because such activities are part of the nuclear fuel cycle. More recently, attention has been broadened to include exposures from other industrial activities involving NORM, in recognition of the potential for such activities to also give rise to significant exposures of workers and members of the public if not adequately controlled. More and more countries are now including provisions in their national legislation and regulations for the control of exposures to natural sources, and the body of radiological data on such exposures is growing rapidly. This international conference, NORM IV, follows three previous conferences dealing with radon and NORM. The first was held in Amsterdam in 1997, the second in Krefeld, Germany in 1998 (NORM II), and the third in Brussels in 2001 (NORM III). In addition, an International Symposium on Technologically Enhanced Natural Radiation was held in Rio de Janeiro in 1999 - the IAEA was involved in the organization of that symposium, and published the proceedings as IAEA-TECDOC-1271. The main topic addressed at NORM IV was

  7. Quantitative Analysis of HER2 Receptor Expression In Vivo by Near-Infrared Optical Imaging

    Directory of Open Access Journals (Sweden)

    Victor Chernomordik

    2010-07-01

    Full Text Available Human epidermal growth factor receptor 2 (HER2 overexpression in breast cancers is associated with poor prognosis and resistance to therapy. Current techniques for estimating this important characteristic use ex vivo assays that require tissue biopsies. We suggest a novel noninvasive method to characterize HER2 expression in vivo, using optical imaging, based on HER2-specific probes (albumin-binding domain–fused-(ZHER2:3422-Cys Affibody molecules [Affibody AB, Solna, Sweden], labeled with Alexa Fluor 750 [Molecular Probes, Invitrogen, Carlsbad, CA] that could be used concomitantly with HER2-targeted therapy. Subcutaneous tumor xenografts, expressing different levels of HER2, were imaged with a near-infrared fluorescence small-animal imaging system at several times postinjection of the probe. The compartmental ligand-receptor model was used to calculate HER2 expression from imaging data. Correlation between HER2 amplification/overexpression in tumor cells and parameters, directly estimated from the sequence of optical images, was observed (eg, experimental data for BT474 xenografts indicate that initial slope, characterizing the temporal dependence of the fluorescence intensity detected in the tumor, linearly depends on the HER2 expression, as measured ex vivo by an enzyme-linked immunosorbent assay for the same tumor. The results obtained from tumors expressing different levels of HER2 substantiate a similar relationship between the initial slope and HER2 amplification/overexpression. This work shows that optical imaging, combined with mathematical modeling, allows noninvasive monitoring of HER2 expression in vivo.

  8. A Single Domain–Based Anti-Her2 Antibody Has Potent Antitumor Activities

    Directory of Open Access Journals (Sweden)

    Xiaoqiong Wu

    2018-04-01

    Full Text Available Human epidermal growth factor receptor 2 (HER2 is overexpressed in approximately 20% to 30% of breast cancers and various other types of cancers, which plays a vital role in the cancer progression. Monoclonal antibodies targeting Her2 are now used in the clinic to treat Her2 overexpression cancer patients. However, relapse or resistance is frequent with the current therapies. To generate a new treatment avenue against Her2, we immunized and selected a specific anti-Her2 single domain antibody C3 for further studies. The C3-Fc antibody drove antibody-dependent cell-mediated cytotoxicity against Her2-positive tumor cells in vitro and resulted in potent antitumor growth in vivo. These data suggest that the C3-Fc antibody may provide an alternative avenue for Her2-positive cancer therapy.

  9. Clinical significance of Mena and Her-2 expression in breast cancer.

    Science.gov (United States)

    Du, J W; Xu, K Y; Fang, L Y; Qi, X L

    2012-01-01

    The aim of this study was to determine the expression patterns of Mena and Her-2 in breast cancer tissues and to explore their clinical significance and correlation with clinicopathological parameters. The expression of Mena and Her-2 was detected in 40 breast cancer tissues and 14 normal breast tissues by immunohistochemistry, and the relationship of Mena and Her-2 expression with clinicopathological parameters was analyzed. Both Mena (70%) and Her-2 (40%) were more commonly expressed in breast cancer than in normal breast tissue (7.1%, 0%, respectively; p Mena and Her-2 expression in breast cancer were positively correlated (r = 0.530, p Mena and Her-2 were both associated with axillary lymph node metastasis and TNM stage (p Mena and Her-2 are related to the malignancy degree and metastasis of breast cancer, and thus may play a coordinating role in the occurrence and progression of breast cancer.

  10. Selective internalization of self-assembled artificial oil bodies by HER2/neu-positive cells

    International Nuclear Information System (INIS)

    Chiang, Chung-Jen; Lin, Che-Chin; Lin, Li-Jen; Chang, Chih-Hsiang; Chao, Yun-Peng

    2011-01-01

    A novel delivery carrier was developed using artificial oil bodies (AOBs). Plant seed oil bodies (OBs) consist of a triacylglycerol matrix surrounded by a monolayer of phospholipids embedded with the storage protein oleosin (Ole). Ole consists of a central hydrophobic domain with two amphiphatic arms that extrude from the surface of OBs. In this study, a bivalent anti-HER2/neu affibody domain (ZH2) was fused with Ole at the C terminus. After overproduction in Escherichia coli, the fusion protein (Ole-ZH2) was recovered to assemble AOBs. The size of self-assembled AOBs was tailored by varying the oil/Ole-ZH2 ratio and pH to reach a nanoscale. Upon co-incubation with tumor cells, the nanoscale AOBs encapsulated with a hydrophobic fluorescence dye were selectively internalized by HER2/neu-overexpressing cells and displayed biocompatibility with the cells. In addition, the ZH2-mediated endosomal entry of AOBs occurred in a time- and AOB dose-dependent manner. The internalization efficiency was as high as 90%. The internalized AOBs disintegrated at the non-permissive pH (e.g. in acidic endosomes) and the cargo dye was released. Results of in vitro study revealed a sustained and prolonged release profile. Taken together, our findings indicate the potential of AOBs as a delivery carrier.

  11. Induction of interleukin 1 by synthetic and naturally occurring muramyl peptides.

    Science.gov (United States)

    Dinarello, C A; Krueger, J M

    1986-10-01

    Like bacterial lipopolysaccharides (endotoxins), synthetic muramyl peptides (MPs) are thought to exert many of their biological effects by inducing the production of various mediators from host cells. Both synthetic muramyl dipeptide (MDP) and naturally occurring sleep factor (SF), which contains an MP structure, stimulate human monocytes to produce interleukin 1 (IL 1). IL 1 is a family of unique polypeptides that mediate a variety of host defense functions and possess several biological properties, many of which are shared with MPs. Endotoxins are potent inducers of IL 1, but polymyxin B, which blocks endotoxin's biological activities, has no effect on MP-induced IL 1 production. SF purified from human urine and SF isolated from the peritoneal fluid of patients undergoing chronic ambulatory peritoneal dialysis (CAPD) induce IL 1 when incubated with human mononuclear cells in vitro. SF from urine or CAPD fluid induces IL 1 production in the picrogram per milliliter range whereas synthetic MDP requires microgram per milliliter concentrations. Thus, both synthetic and naturally occurring MPs exert their biological effects, in part, by inducing IL 1.

  12. Harnessing naturally occurring tumor immunity: a clinical vaccine trial in prostate cancer.

    Directory of Open Access Journals (Sweden)

    Mayu O Frank

    2010-09-01

    Full Text Available Studies of patients with paraneoplastic neurologic disorders (PND have revealed that apoptotic tumor serves as a potential potent trigger for the initiation of naturally occurring tumor immunity. The purpose of this study was to assess the feasibility, safety, and immunogenicity of an apoptotic tumor-autologous dendritic cell (DC vaccine.We have modeled PND tumor immunity in a clinical trial in which apoptotic allogeneic prostate tumor cells were used to generate an apoptotic tumor-autologous dendritic cell vaccine. Twenty-four prostate cancer patients were immunized in a Phase I, randomized, single-blind, placebo-controlled study to assess the safety and immunogenicity of this vaccine. Vaccinations were safe and well tolerated. Importantly, we also found that the vaccine was immunogenic, inducing delayed type hypersensitivity (DTH responses and CD4+ and CD8+ T cell proliferation, with no effect on FoxP3+ regulatory T cells. A statistically significant increase in T cell proliferation responses to prostate tumor cells in vitro (p = 0.002, decrease in prostate specific antigen (PSA slope (p = 0.016, and a two-fold increase in PSA doubling time (p = 0.003 were identified when we compared data before and after vaccination.An apoptotic cancer cell vaccine modeled on naturally occurring tumor immune responses in PND patients provides a safe and immunogenic tumor vaccine.ClinicalTrials.gov NCT00289341.

  13. Radiation and Radioactivity Levels Survey of Naturally Occurring Radioactive Materials (NORM) at PT Caltex Pacific Indonesia

    International Nuclear Information System (INIS)

    Bakri, Jusuf; Siregar, Roland

    2003-01-01

    PT Caltex Pacific Indonesia (CPI) is the largest oil company sharing contractor with Pertamina, located in Riau Province, Central Sumatera, employs about 6,800 employees and works together with 28,000 business partner employees. Currently CPI produces about 510,000 bbls crude oil. The production process mobilizes the naturally occurring radionuclides from deep reservoir rock that are deposited as Naturally Occurring Radioactive Materials (NORM) in well tubes, surface pipes, vessels and other processing equipment. NORM has a potential to be externally exposed during production process due to the accumulation of gamma emitting radionuclides and internal exposure to employees/business partners particularly during maintenance, sludge processing and decontamination of equipment. Understanding of the possible NORM hazards to human life, CPI initiated a NORM survey in order to obtain a clear picture of the magnitude of NORM in CPI operations. The survey has been conducted in 2001 and 2002 involved experts from Chevron Texaco USA, BATAN and BAPETEN Jakarta. The survey covered the determination of gamma exposure rates and the concentration of 238 U, 232 Th, 226 Ra, 228 Ra, 228 Th and 40 K in several samples taken from scale, sludge, tank bottom and sand. To safely management of NORM, the Industrial Health Team of Corporate Health, Environment and Safety in coordination with Training Center Team and BATAN have conducted a NORM training for Industrial Hygienist and employees exposed to NORM, developed Standard Operating Procedure for NORM Handling and Disposal and continuously performed NORM survey and mapping of all suspected areas. (author)

  14. Inhibition of fatty acid amide hydrolase by kaempferol and related naturally occurring flavonoids

    Science.gov (United States)

    Thors, L; Belghiti, M; Fowler, C J

    2008-01-01

    Background and purpose: Recent studies have demonstrated that the naturally occurring isoflavone compounds genistein and daidzein inhibit the hydrolysis of anandamide by fatty acid amide hydrolase (FAAH) in the low micromolar concentration range. The purpose of the present study was to determine whether this property is shared by flavonoids. Experimental approach: The hydrolysis of anandamide in homogenates and intact cells was measured using the substrate labelled in the ethanolamine part of the molecule. Key results: Twenty compounds were tested. Among the commonly occurring flavonoids, kaempferol was the most potent, inhibiting FAAH in a competitive manner with a Ki value of 5 μM. Among flavonoids with a more restricted distribution in nature, the two most active toward FAAH were 7-hydroxyflavone (IC50 value of 0.5–1 μM depending on the solvent used) and 3,7-dihydroxyflavone (IC50 value 2.2 μM). All three compounds reduced the FAAH-dependent uptake of anandamide and its metabolism by intact RBL2H3 basophilic leukaemia cells. Conclusions and implications: Inhibition of FAAH is an additional in vitro biochemical property of flavonoids. Kaempferol, 7-hydroxyflavone and 3,7-dihydroxyflavone may be useful as templates for the synthesis of novel compounds, which target several systems that are involved in the control of inflammation and cancer. PMID:18552875

  15. Doses to the Norwegian population from naturally occuring radiation and from the Chernobyl fallout

    International Nuclear Information System (INIS)

    Strand, T.

    1987-01-01

    The doses to the Norwegian population from naturally occuring radiation are extensively reviewed. The annual population weighted average dose equivalent to the Norwegian population from 222 Rn and its daughters is estimated to be between 3.5 and 4.5 mSv. The average concentration of 220 Rn daughters in Norwegian dwellings is most probably between 1.0 and 1.5 Bq m -3 . The corresponding effective dose equivalent for 220 Rn and its daughters is estimated to be between 0.4 and 0.6 mSv. The total annual collective dose equivalent from naturally occuring radiation in Norway is found to be between 21000 and 27000 man Sv. The doses to the Norwegian population from the Chernobyl fallout are briefly discussed. Based on the results of a ''food basket'' project and supplementary data from about 30000 measurements on food samples the first year after the reactor accident, the total annual effective dose equivalent from foodstuffs to an average Norwegian consumer during this first year is estimated to be 0.15 +-0.002 m Sv at the 95% confidence level. The per caput effective dose equivalent from external fallout gamma radiation in the first year after the Chernobyl accident, is approximately 82 μSv in Norway

  16. Regulation of naturally occurring and accelerator-produced radioactive materials. A Task Force review

    International Nuclear Information System (INIS)

    Nussbaumer, D.A.; Lubenau, J.O.; Cool, W.S.; Cunningham, L.J.; Mapes, J.R.; Schwartz, S.A.; Smith, D.A.

    1977-06-01

    The use of accelerator-produced radioisotopes (NARM), particularly in medicine, is growing rapidly. One NARM radioisotope, 226 Ra, is one of the most hazardous of radioactive materials, and 226 Ra is used by about 1 / 5 of all radioactive material users. Also, there are about 85,000 medical treatments using 226 Ra each year. All of the 25 Agreement States and 5 non-Agreement States have licensing programs covering NARM users. The Agreement States' programs for regulating NARM are comparable to their programs for regulating byproduct, source, and special nuclear materials under agreements with NRC. But there are 7 states who exercise no regulatory control over NARM users, and the remaining States have control programs which are variable in scope. There are no national, uniformly applied programs to regulate the design, fabrication and quality of sources and devices containing NARM or consumer products containing NARM which are distributed in interstate commerce. Naturally occurring radioactive material (except source material) associated with the nuclear fuel cycle is only partially subject to NRC regulation, i.e., when it is associated with source or special nuclear material being used under an active NRC license. The Task Force recommends that the NRC seek legislative authority to regulate naturally occurring and accelerator-produced radioactive materials for the reason that these materials present significant radiation exposure potential and present controls are fragmentary and non-uniform at both the State and Federal level

  17. Identification of manganese as a toxicant in a groundwater treatment system: Addressing naturally occurring toxicants

    International Nuclear Information System (INIS)

    Goodfellow, W. Jr.; Sohn, V.; Richey, M.; Yost, J.

    1995-01-01

    Effluent from a groundwater remediation system at a bulk oil storage and distribution terminal has been chronically toxic to Ceriodaphnia dubia. The remediation system was designed in response to a hydrocarbon plume in the area of the terminal. The remediation system consists of a series of groundwater recovery wells and groundwater intercept trench systems with groundwater treatment and phased-separated hydrocarbon recovery systems. The groundwater treatment and petroleum recovery systems consist of oil/water separators, product recovery tanks, air strippers, filters, and carbon adsorption units. The characteristics of this effluent are low total suspended solids, total dissolved solids, and hardness concentrations as well as meeting stringent NPDES permit requirements for lead, copper, zinc, mercury, total petroleum hydrocarbons, and BTEX. Additional priority pollutant evaluations revealed no compounds of concern. Performance of a Toxicity identification Evaluation (TIE) indicated that manganese was the principle toxicant in the effluent. Manganese is a naturally occurring constituent in this groundwater source and is not added to the treatment system. This paper will present the results of the TIE with a discussion of treatability/control options for manganese control at this facility. Recommendations for addressing naturally occurring toxicants that are not a result of the facility's operations will also be presented

  18. Determination of naturally occurring radionuclides in scales produced in oil industry

    Energy Technology Data Exchange (ETDEWEB)

    Al-Masri, M S; Ali, A F; Kitue, M; Kawash, A [Atomic Energy Commission, Dept. of Radiation Protection and Nuclear Safety, Damascus (Syrian Arab Republic)

    1997-04-01

    Scales produced by Oil production operations contain relatively high concentrations of natural radionuclides especially radium isotopes (Ra-226, Ra-228, Ra-224) and their daughters. These scales deposit in oil surface equipment such as separator tanks, tubular, and storage tanks. In this work, naturally occurring radionuclides and radiation exposure levels in some Syrian oil lines have been determined. Radiation measurements have shown high radiation exposure in some production sites and reached about 23 {mu}Sv/hr (production wellhead) which is higher than the normal background (0.09 - 012 {mu}Sv/hr). The highest value of the exposure around storage tanks was about o.5 {mu}Sv/hr. Moreover, the highest concentration of radionuclides in scales were found to be 47000 Bq/Kg and 55000 Bq/Kg for Ra-226 and Ra-228 respectively while in sludge samples, the Ra-226 concentration was about 24.2 Bq/Kg, a relatively very low activity. In addition, results have shown that soil contamination can occur by disposal of produced water to the surrounding environment. Furthermore, the present paper shows some of protection procedures, which should be followed by workers for radiation protection. (author). 10 refs., 4 tabs.

  19. Ganoderma tsugae Extract Inhibits Growth of HER2-Overexpressing Cancer Cells via Modulation of HER2/PI3K/Akt Signaling Pathway

    Directory of Open Access Journals (Sweden)

    Han-Peng Kuo

    2013-01-01

    Full Text Available Ganoderma, also known as Lingzhi or Reishi, has been used for medicinal purposes in Asian countries for centuries. It is a medicinal fungus with a variety of biological properties including immunomodulatory and antitumor activities. In this study, we investigated the molecular mechanisms by which Ganoderma tsugae (GT, one of the most common species of Ganoderma, inhibits the proliferation of HER2-overexpressing cancer cells. Here, we show that a quality assured extract of GT (GTE inhibited the growth of HER2-overexpressing cancer cells in vitro and in vivo and enhanced the growth-inhibitory effect of antitumor drugs (e.g., taxol and cisplatin in these cells. We also demonstrate that GTE induced cell cycle arrest by interfering with the HER2/PI3K/Akt signaling pathway. Furthermore, GTE curtailed the expression of the HER2 protein by modulating the transcriptional activity of the HER2 gene and the stability/degradation of the HER2 protein. In conclusion, this study suggests that GTE may be a useful adjuvant therapeutic agent in the treatment of cancer cells that highly express HER2.

  20. Reorienting the Fab domains of trastuzumab results in potent HER2 activators.

    Directory of Open Access Journals (Sweden)

    Justin M Scheer

    Full Text Available The structure of the Fab region of antibodies is critical to their function. By introducing single cysteine substitutions into various positions of the heavy and light chains of the Fab region of trastuzumab, a potent antagonist of HER2, and using thiol chemistry to link the different Fabs together, we produced a variety of monospecific F(ab'(2-like molecules with activities spanning from activation to inhibition of breast tumor cell growth. These isomers (or bis-Fabs of trastuzumab, with varying relative spatial arrangements between the Fv-regions, were able to either promote or inhibit cell-signaling activities through the PI3K/AKT and MAPK pathways. A quantitative phosphorylation mapping of HER2 indicated that the agonistic isomers produced a distinct phosphorylation pattern associated with activation. This study suggests that antibody geometric isomers, found both in nature and during synthetic antibody development, can have profoundly different biological activities independent of their affinities for their target molecules.

  1. Reorienting the Fab Domains of Trastuzumab Results in Potent HER2 Activators

    Science.gov (United States)

    Scheer, Justin M.; Sandoval, Wendy; Elliott, J. Michael; Shao, Lily; Luis, Elizabeth; Lewin-Koh, Sock-Cheng; Schaefer, Gabriele; Vandlen, Richard

    2012-01-01

    The structure of the Fab region of antibodies is critical to their function. By introducing single cysteine substitutions into various positions of the heavy and light chains of the Fab region of trastuzumab, a potent antagonist of HER2, and using thiol chemistry to link the different Fabs together, we produced a variety of monospecific F(ab′)2-like molecules with activities spanning from activation to inhibition of breast tumor cell growth. These isomers (or bis-Fabs) of trastuzumab, with varying relative spatial arrangements between the Fv-regions, were able to either promote or inhibit cell-signaling activities through the PI3K/AKT and MAPK pathways. A quantitative phosphorylation mapping of HER2 indicated that the agonistic isomers produced a distinct phosphorylation pattern associated with activation. This study suggests that antibody geometric isomers, found both in nature and during synthetic antibody development, can have profoundly different biological activities independent of their affinities for their target molecules. PMID:23284778

  2. Switching addictions between HER2 and FGFR2 in HER2-positive breast tumor cells: FGFR2 as a potential target for salvage after lapatinib failure

    International Nuclear Information System (INIS)

    Azuma, Koichi; Tsurutani, Junji; Sakai, Kazuko; Kaneda, Hiroyasu; Fujisaka, Yasuhito; Takeda, Masayuki; Watatani, Masahiro; Arao, Tokuzo; Satoh, Taroh; Okamoto, Isamu; Kurata, Takayasu; Nishio, Kazuto; Nakagawa, Kazuhiko

    2011-01-01

    Highlights: → A lapatinib-resistant breast cancer cell line, UACC812 (UACC812/LR), was found to harbor amplification of the FGFR2 gene. → Inhibition of the molecule by a specific inhibitor of FGFR dramatically induced growth inhibition accompanied by cell death. → Immunohistochemical analysis of patients with HER2-positive breast cancer demonstrated an association between FGFR2 expression and poor outcome for lapatinib-containing chemotherapy. -- Abstract: Agents that target HER2 have improved the prognosis of patients with HER2-amplified breast cancers. However, patients who initially respond to such targeted therapy eventually develop resistance to the treatment. We have established a line of lapatinib-resistant breast cancer cells (UACC812/LR) by chronic exposure of HER2-amplified and lapatinib-sensitive UACC812 cells to the drug. The mechanism by which UACC812/LR acquired resistance to lapatinib was explored using comprehensive gene hybridization. The FGFR2 gene in UACC812/LR was highly amplified, accompanied by overexpression of FGFR2 and reduced expression of HER2, and a cell proliferation assay showed that the IC 50 of PD173074, a small-molecule inhibitor of FGFR tyrosine kinase, was 10,000 times lower in UACC812/LR than in the parent cells. PD173074 decreased the phosphorylation of FGFR2 and substantially induced apoptosis in UACC812/LR, but not in the parent cells. FGFR2 appeared to be a pivotal molecule for the survival of UACC812/LR as they became independent of the HER2 pathway, suggesting that a switch of addiction from the HER2 to the FGFR2 pathway enabled cancer cells to become resistant to HER2-targeted therapy. The present study is the first to implicate FGFR in the development of resistance to lapatinib in cancer, and suggests that FGFR-targeted therapy might become a promising salvage strategy after lapatinib failure in patients with HER2-positive breast cancer.

  3. Switching addictions between HER2 and FGFR2 in HER2-positive breast tumor cells: FGFR2 as a potential target for salvage after lapatinib failure

    Energy Technology Data Exchange (ETDEWEB)

    Azuma, Koichi [Department of Medical Oncology, Kinki University Faculty of Medicine, 377-2 Ohnohigashi, Osakasayama, Osaka 589-8511 (Japan); Tsurutani, Junji, E-mail: tsurutani_j@dotd.med.kindai.ac.jp [Department of Medical Oncology, Kinki University Faculty of Medicine, 377-2 Ohnohigashi, Osakasayama, Osaka 589-8511 (Japan); Sakai, Kazuko; Kaneda, Hiroyasu [Department of Genome Biology, Kinki University Faculty of Medicine, 377-2 Ohnohigashi, Osakasayama, Osaka 589-8511 (Japan); Fujisaka, Yasuhito; Takeda, Masayuki [Department of Medical Oncology, Kinki University Faculty of Medicine, 377-2 Ohnohigashi, Osakasayama, Osaka 589-8511 (Japan); Watatani, Masahiro [Department of Surgery, Kinki University Faculty of Medicine, 377-2 Ohnohigashi, Osakasayama, Osaka 589-8511 (Japan); Arao, Tokuzo [Department of Genome Biology, Kinki University Faculty of Medicine, 377-2 Ohnohigashi, Osakasayama, Osaka 589-8511 (Japan); Satoh, Taroh; Okamoto, Isamu; Kurata, Takayasu [Department of Medical Oncology, Kinki University Faculty of Medicine, 377-2 Ohnohigashi, Osakasayama, Osaka 589-8511 (Japan); Nishio, Kazuto [Department of Genome Biology, Kinki University Faculty of Medicine, 377-2 Ohnohigashi, Osakasayama, Osaka 589-8511 (Japan); Nakagawa, Kazuhiko [Department of Medical Oncology, Kinki University Faculty of Medicine, 377-2 Ohnohigashi, Osakasayama, Osaka 589-8511 (Japan)

    2011-04-01

    Highlights: {yields} A lapatinib-resistant breast cancer cell line, UACC812 (UACC812/LR), was found to harbor amplification of the FGFR2 gene. {yields} Inhibition of the molecule by a specific inhibitor of FGFR dramatically induced growth inhibition accompanied by cell death. {yields} Immunohistochemical analysis of patients with HER2-positive breast cancer demonstrated an association between FGFR2 expression and poor outcome for lapatinib-containing chemotherapy. -- Abstract: Agents that target HER2 have improved the prognosis of patients with HER2-amplified breast cancers. However, patients who initially respond to such targeted therapy eventually develop resistance to the treatment. We have established a line of lapatinib-resistant breast cancer cells (UACC812/LR) by chronic exposure of HER2-amplified and lapatinib-sensitive UACC812 cells to the drug. The mechanism by which UACC812/LR acquired resistance to lapatinib was explored using comprehensive gene hybridization. The FGFR2 gene in UACC812/LR was highly amplified, accompanied by overexpression of FGFR2 and reduced expression of HER2, and a cell proliferation assay showed that the IC{sub 50} of PD173074, a small-molecule inhibitor of FGFR tyrosine kinase, was 10,000 times lower in UACC812/LR than in the parent cells. PD173074 decreased the phosphorylation of FGFR2 and substantially induced apoptosis in UACC812/LR, but not in the parent cells. FGFR2 appeared to be a pivotal molecule for the survival of UACC812/LR as they became independent of the HER2 pathway, suggesting that a switch of addiction from the HER2 to the FGFR2 pathway enabled cancer cells to become resistant to HER2-targeted therapy. The present study is the first to implicate FGFR in the development of resistance to lapatinib in cancer, and suggests that FGFR-targeted therapy might become a promising salvage strategy after lapatinib failure in patients with HER2-positive breast cancer.

  4. Determination of natural occurring radionuclide and heavy metals in drinking water in Malaysia

    International Nuclear Information System (INIS)

    Nur Suraya Ahmad

    2012-01-01

    The objective of this study is to ascertain the activity concentration of naturally occurring radionuclide and selected heavy metals selected mineral and drinking waters sample in Malaysia. The activity concentration of natural radionuclide (mBq/ L) was determined by Gamma Spectroscopy Systems while the concentration of heavy metal (mg/ L) was determined by the Induces Couple Plasma Mass Spectrometry (ICP-MS). The mineral and drinking water samples used in this study were Segar UKM, Giant, Ice Mountain (600 ml), Ice Mountain (1600 ml), Spritzer, Reverse Osmosis, and fresh tap water. The results of the study found 3 natural occurring radioactive materials (NORM) found for example - U-238, Ra-226 and Ra-228. The activity concentration determined was 0.00 mBq/ L to 1.71 mBq/ L for U-238, 0.00 - 32.46 mBq/ L for Ra-226 and 0.00 - 12.01 mBq/ L for Ra-228 respectively. The concentration of heavy metals Zn, Fe, As, Cl, Mn, Cu and Pb determined in this study were in the range of 0.000 - 0.003 mg/ L, 0.002-0.018 mg/ L, 0.000 - 0.007 mg/ L, 6.152 - 57.724 mg/ L, 0.000 - 0.016 μg/ L, 0.058 - 0.766 μg/ L and 0.000 - 0.380 μg/ L respectively. In general, the result of this study indicate that the activity concentration NORM and selected heavy metals in the studied mineral and drinking water samples were low and not exceed the limit set by World Organization (WHO) and Malaysian Food Regulations 1985. Thus, all the studied water samples complying the Malaysian drinking standard and safe to be consumed. (author)

  5. NPACT: Naturally Occurring Plant-based Anti-cancer Compound-Activity-Target database.

    Science.gov (United States)

    Mangal, Manu; Sagar, Parul; Singh, Harinder; Raghava, Gajendra P S; Agarwal, Subhash M

    2013-01-01

    Plant-derived molecules have been highly valued by biomedical researchers and pharmaceutical companies for developing drugs, as they are thought to be optimized during evolution. Therefore, we have collected and compiled a central resource Naturally Occurring Plant-based Anti-cancer Compound-Activity-Target database (NPACT, http://crdd.osdd.net/raghava/npact/) that gathers the information related to experimentally validated plant-derived natural compounds exhibiting anti-cancerous activity (in vitro and in vivo), to complement the other databases. It currently contains 1574 compound entries, and each record provides information on their structure, manually curated published data on in vitro and in vivo experiments along with reference for users referral, inhibitory values (IC(50)/ED(50)/EC(50)/GI(50)), properties (physical, elemental and topological), cancer types, cell lines, protein targets, commercial suppliers and drug likeness of compounds. NPACT can easily be browsed or queried using various options, and an online similarity tool has also been made available. Further, to facilitate retrieval of existing data, each record is hyperlinked to similar databases like SuperNatural, Herbal Ingredients' Targets, Comparative Toxicogenomics Database, PubChem and NCI-60 GI(50) data.

  6. NPACT: Naturally Occurring Plant-based Anti-cancer Compound-Activity-Target database

    Science.gov (United States)

    Mangal, Manu; Sagar, Parul; Singh, Harinder; Raghava, Gajendra P. S.; Agarwal, Subhash M.

    2013-01-01

    Plant-derived molecules have been highly valued by biomedical researchers and pharmaceutical companies for developing drugs, as they are thought to be optimized during evolution. Therefore, we have collected and compiled a central resource Naturally Occurring Plant-based Anti-cancer Compound-Activity-Target database (NPACT, http://crdd.osdd.net/raghava/npact/) that gathers the information related to experimentally validated plant-derived natural compounds exhibiting anti-cancerous activity (in vitro and in vivo), to complement the other databases. It currently contains 1574 compound entries, and each record provides information on their structure, manually curated published data on in vitro and in vivo experiments along with reference for users referral, inhibitory values (IC50/ED50/EC50/GI50), properties (physical, elemental and topological), cancer types, cell lines, protein targets, commercial suppliers and drug likeness of compounds. NPACT can easily be browsed or queried using various options, and an online similarity tool has also been made available. Further, to facilitate retrieval of existing data, each record is hyperlinked to similar databases like SuperNatural, Herbal Ingredients’ Targets, Comparative Toxicogenomics Database, PubChem and NCI-60 GI50 data. PMID:23203877

  7. The radiological impact of naturally-occurring radionuclides in foods from the wild

    International Nuclear Information System (INIS)

    Green, N.; Hammond, D.J.; Davidson, M.F.; Wilkins, B.T.; Williams, B.

    2002-01-01

    Habit surveys have been conducted to identify people who make use of foodstuffs collected from the wild (free foods) in two areas of the UK: in the area around Chipping Norton in Oxfordshire, where levels of naturally-occurring radionuclides in soil were expected to be typical of the UK, and in the vicinity of Okehampton in Devon, where levels were known to be elevated. Individuals who make regular use of these foodstuffs were specifically identified, so that an estimate of typical and higher than average consumption rates could be derived. The naturally-occurring radionuclides of interest were 210 Po, 210 Pb, 234 U, 235 U, 238 U, 230 Th, 232 Th and 226 Ra. Samples of important foodstuffs were collected and the radionuclides of interest determined. The consumption rates were combined with the measured activity concentrations and published dose coefficients to estimate doses to average and higher than average consumers. These doses were compared with estimated doses reported in the Food Standards Agency's ongoing monitoring programme and with average doses to the population of the UK reviewed by NRPB. In total, 400 people were identified and between them they collected 54 different types of free food. Blackberries were by far the most common species collected, although various types of mushroom and nuts were also popular. On average, each collector from around Chipping Norton collected 2.1 different foods, and each from around Okehampton collected 2.2. On the basis of the habit survey, therefore, it would be reasonable to expect that any site, nuclear or otherwise, chosen for habit surveys, whether for radiological purposes or for any other contaminant, could have substantial numbers of people collecting free foods. In addition, the pattern of foods collected was very similar to previous studies, indicating similarities across England and Wales. Doses from the consumption of free foods were estimated. The annual doses estimated to have been received by a typical

  8. HER2 gene amplification in patients with prostate cancer: Evaluating a CISH-based method.

    Science.gov (United States)

    Sharifi, Nazanin; Salmaninejad, Arash; Ferdosi, Samira; Bajestani, Abolfazl Nesaei; Khaleghiyan, Malihe; Estiar, Mehrdad Asghari; Jamali, Mansour; Nowroozi, Mohammad Reza; Shakoori, Abbas

    2016-12-01

    Prostate cancer (PCa) is one of the most widespread malignancies in the world. The role of the human epidermal growth factor receptor 2 (HER2) in the pathogenesis and progression of human PCa remains poorly understood. In contradiction with breast cancer, studies on HER2 overexpression and gene amplification in PCa have produced varying results, although the HER2 oncogene has been implicated in the biology of numerous tumor types, and serves as a prognostic marker and therapeutic target in breast cancer. Technical challenges are considered the main reasons for data discrepancies. Amplification of the HER2 gene has previously been reported in PCa, in which it was associated with tumor progression. The present study aimed to evaluate the prevalence and clinical significance of HER2 amplification in PCa. A total of 32 biopsy samples obtained from human prostate adenocarcinomas were evaluated by chromogenic in situ hybridization (CISH) to determine the frequency of patients with HER2 gene amplifications. High copy numbers of HER2 were detected in 19 of the prostate tumors analyzed. The results of the present study suggested that, in patients without amplification of HER2, high levels of prostate-specific antigen or a high Gleason score were not significantly correlated with a high pathologic stage. Furthermore, amplification levels of the HER2 gene were directly associated with pathologic stage in patients with PCa. Therefore, the potential use of HER2 as a prognostic factor or therapeutic target for PCa warrants further study.

  9. Impact of somatic PI3K pathway and ERBB family mutations on pathological complete response (pCR) in HER2-positive breast cancer patients who received neoadjuvant HER2-targeted therapies.

    LENUS (Irish Health Repository)

    Toomey, Sinead

    2017-07-27

    The Cancer Genome Atlas analysis revealed that somatic EGFR, receptor tyrosine-protein kinase erbB-2 (ERBB2), Erb-B2 receptor tyrosine kinase 3 (ERBB3) and Erb-B2 receptor tyrosine kinase 4 (ERBB4) gene mutations (ERBB family mutations) occur alone or co-occur with somatic mutations in the gene encoding the phosphatidylinositol 3-kinase (PI3K) catalytic subunit (PIK3CA) in 19% of human epidermal growth factor receptor 2 (HER2)-positive breast cancers. Because ERBB family mutations can activate the PI3K\\/AKT pathway and likely have similar canonical signalling effects to PI3K pathway mutations, we investigated their combined impact on response to neoadjuvant HER2-targeted therapies.

  10. Determination of naturally occurring radionuclides in selected rocks from Hetaunda area, Central Nepal

    International Nuclear Information System (INIS)

    Wallova, G.

    2010-01-01

    The specific activities of the naturally occurring radionuclides 238 U, 232 Th, and 40 K were measured in rock samples from the Hetaunda area, central Nepal, by using gamma spectrometry. The specific activities were found to be in the range of 17 - 95 Bq.kg -1 for 238 U, 24 - 260 Bq.kg -1 for 232 Th and 32 - 541 Bq.kg -1 for 40 K. From these data absorbed dose rates in air and annual effective doses were calculated and compared with respective data from the United Nations Scientific Committee on the Effects of Atomic Radiation (UNSCEAR) compilation. The results from our study open the door to the safe applicability of most of the investigated materials as a cheep building material. (author)

  11. Hand-held dynamic visual noise reduces naturally occurring food cravings and craving-related consumption.

    Science.gov (United States)

    Kemps, Eva; Tiggemann, Marika

    2013-09-01

    This study demonstrated the applicability of the well-established laboratory task, dynamic visual noise, as a technique for reducing naturally occurring food cravings and subsequent food intake. Dynamic visual noise was delivered on a hand-held computer device. Its effects were assessed within the context of a diary study. Over a 4-week period, 48 undergraduate women recorded their food cravings and consumption. Following a 2-week baseline, half the participants watched the dynamic visual noise display whenever they experienced a food craving. Compared to a control group, these participants reported less intense cravings. They were also less likely to eat following a craving and consequently consumed fewer total calories following craving. These findings hold promise for curbing unwanted food cravings and craving-driven consumption in real-world settings. Copyright © 2013 Elsevier Ltd. All rights reserved.

  12. Verification of mid-ocean ballast water exchange using naturally occurring coastal tracers

    International Nuclear Information System (INIS)

    Murphy, Kathleen; Boehme, Jennifer; Coble, Paula; Cullen, Jay; Field, Paul; Moore, Willard; Perry, Elgin; Sherrell, Robert; Ruiz, Gregory

    2004-01-01

    We examined methods for verifying whether or not ships have performed mid-ocean ballast water exchange (BWE) on four commercial vessels operating in the Pacific and Atlantic Oceans. During BWE, a ship replaces the coastal water in its ballast tanks with water drawn from the open ocean, which is considered to harbor fewer organisms capable of establishing in coastal environments. We measured concentrations of several naturally occurring chemical tracers (salinity, six trace elements, colored dissolved organic matter fluorescence and radium isotopes) along ocean transects and in ballast tanks subjected to varying degrees of BWE (0-99%). Many coastal tracers showed significant concentration changes due to BWE, and our ability to detect differences between exchanged and unexchanged ballast tanks was greatest under multivariate analysis. An expanded dataset, which includes additional geographic regions, is now needed to test the generality of our results

  13. Regulation of naturally occurring and accelerator-produced radioactive materials: an update

    International Nuclear Information System (INIS)

    Bolling, L.A.; Lubenau, J.O.; Nussbaumer, D.A.

    1984-10-01

    In 1977, NRC published a report (NUREG-0301) of a task force review of the need for, and feasibility of, the Federal government regulating naturally occurring and accelerator-produced radioactive materials (NARM). Since that time, the Federal regulatory role has not significantly changed but State calls for increased Federal involvment have continued. In 1983, a National Governors' Association report on the NRC Agreement State program recommended amendment of the Atomic Energy Act to authorize NRC regulation of these materials. Based on that recommendation, and with the cooperation of the Conference of Radiation Control Program Directors, Inc., NRC staff undertook a review of the current status of use and regulation of NARM. This report contains the results of that review. 10 references

  14. Verification of mid-ocean ballast water exchange using naturally occurring coastal tracers

    Energy Technology Data Exchange (ETDEWEB)

    Murphy, Kathleen; Boehme, Jennifer; Coble, Paula; Cullen, Jay; Field, Paul; Moore, Willard; Perry, Elgin; Sherrell, Robert; Ruiz, Gregory

    2004-04-01

    We examined methods for verifying whether or not ships have performed mid-ocean ballast water exchange (BWE) on four commercial vessels operating in the Pacific and Atlantic Oceans. During BWE, a ship replaces the coastal water in its ballast tanks with water drawn from the open ocean, which is considered to harbor fewer organisms capable of establishing in coastal environments. We measured concentrations of several naturally occurring chemical tracers (salinity, six trace elements, colored dissolved organic matter fluorescence and radium isotopes) along ocean transects and in ballast tanks subjected to varying degrees of BWE (0-99%). Many coastal tracers showed significant concentration changes due to BWE, and our ability to detect differences between exchanged and unexchanged ballast tanks was greatest under multivariate analysis. An expanded dataset, which includes additional geographic regions, is now needed to test the generality of our results.

  15. Systems and methods for facilitating hydrogen storage using naturally occurring nanostructure assemblies

    Science.gov (United States)

    Fliermans,; Carl, B [Augusta, GA

    2012-08-07

    Some or all of the needs above can be addressed by embodiments of the invention. According to embodiments of the invention, systems and methods for facilitating hydrogen storage using naturally occurring nanostructure assemblies can be implemented. In one embodiment, a method for storing hydrogen can be provided. The method can include providing diatoms comprising diatomaceous earth or diatoms from a predefined culture. In addition, the method can include heating the diatoms in a sealed environment in the presence of at least one of titanium, a transition metal, or a noble metal to provide a porous hydrogen storage medium. Furthermore, the method can include exposing the porous hydrogen storage medium to hydrogen. In addition, the method can include storing at least a portion of the hydrogen in the porous hydrogen storage medium.

  16. Extraction and characterization of naturally occurring bioactive peptides from different tissues from Salmon (Salmo salar)

    DEFF Research Database (Denmark)

    Falkenberg, Susan Skanderup; Nielsen, Henrik Hauch

    2011-01-01

    used. Combination of different extraction conditions such as with/without boiling, with/without inhibitor and variation of pH resulted in a total of 36 extracts. The activity of the extracts was analyzed in vitro for ACE (angiotensin-converting enzyme) inhibiting activity, and anti-oxidative activity...... (Free Radical Scavenging assay). A number of extracts showed high ACE inhibiting and anti-oxidative activity. The extracts were then size fractionated by ultrafiltration using a 10 kDa filter, and relevant fractions below 10 kDa from gills, skin and belly flap were further fractionated by gel...... is therefore to extract and identify naturally occurring bioactive peptides from different tissues from salmon. A number of aqueous extracts were made from gills, skin and belly flap. In order to preserve the bioactivity of the peptides mild extraction procedures as acidic, basic and aqueous solutions were...

  17. Determination of radioactive scales in oil industry using naturally occurring radioactive materials

    International Nuclear Information System (INIS)

    Al-Masri, M. S.

    2006-06-01

    In the present study, naturally occurring radioactive materials (Radium isotopes) present in produced water and radiation measurements have been used to study the formation of scales, evaluate their age, determination of geological formations and between wells interactions. Produced water samples were collected and analyzed monthly for 5 months from 11 oil wells in three Syrian oil fields. Analysis includes radium isotopes and anions and cations concentrations in addition to radiation measurements at the well heads. The highest mean values of radium 226, Radium 228 and Radium 224 concentration in produced were 41 Bq/1, 57.1 Bq/1 and 1.1 Bq/1, respectively. The values obtained for Radium 226, Radium 228 and the activity ratio were statistically evaluated and the results were presented using the box plot method. The mean value of the activity ration of Radium 226 and Radium 228 was used to determine the age of scales accumulated inside tubulars. (author)

  18. Naturally Occurring Nrf2 Activators: Potential in Treatment of Liver Injury

    Directory of Open Access Journals (Sweden)

    Ravirajsinh N. Jadeja

    2016-01-01

    Full Text Available Oxidative stress plays a major role in acute and chronic liver injury. In hepatocytes, oxidative stress frequently triggers antioxidant response by activating nuclear erythroid 2-related factor 2 (Nrf2, a transcription factor, which upregulates various cytoprotective genes. Thus, Nrf2 is considered a potential therapeutic target to halt liver injury. Several studies indicate that activation of Nrf2 signaling pathway ameliorates liver injury. The hepatoprotective potential of naturally occurring compounds has been investigated in various models of liver injuries. In this review, we comprehensively appraise various phytochemicals that have been assessed for their potential to halt acute and chronic liver injury by enhancing the activation of Nrf2 and have the potential for use in humans.

  19. Dating of oilfield contamination by Natural Occurring Radioactive Materials (NORM) using isotopic ratios

    International Nuclear Information System (INIS)

    Al-Masri, M. S.; Othman, I.; Aba, A.

    2008-05-01

    In the present work, the possibility of using radium isotope ratios (226, 224, 228) for dating of NORM contaminated sites in the oilfields due to uncontrolled disposal of produced water into the environmental NORM contaminated soil sample were collected from different locations in Syrian Oilfields and radioactivity analysed. In addition, production water samples were collected and analysed to determine the isotopes ratios of the naturally occurring radioactive materials. The results have shown that the 228 Ra/ 226 Ra can be successfully used to date contaminated soil provided that this ratio is determined in production water. Moreover, the 210 Pb/ 226 Ra activity ratios was used for the first time for dating of contaminated soil where all factors affecting the method application have been evaluated. Furthermore, the obtained results for dating using the three methods were compared with the actual contamination dates provided by the oil companies. (Authors)

  20. Naturally occurring radionuclides of paper ashes and their effect in the environment

    International Nuclear Information System (INIS)

    Kobashi, Asaya

    2011-01-01

    The concentrations of naturally occurring radionuclides ( 226 Ra, 228 Ra, 228 Th, and 40 K) in ashes of papers such as magazines and newspapers were determined from the nuclide concentrations in the papers and the ash contents of the papers. The average 226 Ra, 228 Ra, 228 Th, and 40 K concentrations in the 34 ashes were respectively 27, 68, 75, and 75Bq kg -1 . The radium equivalent activities of the ashes were calculated to evaluate the hazard of γ-ray radiation from the ashes in the environment. A copying paper sample showed a high radium equivalent activity of 602Bq kg -1 . However, the average radium equivalent activity was 140Bq kg -1 and was lower than the level that causes an environmental health problem. (author)

  1. Uptake of naturally occurring radioisotopes by vegetation in a region of high radioactivity

    Energy Technology Data Exchange (ETDEWEB)

    Mahon, D C; Mathewes, R W [Simon Fraser Univ., Burnaby, British Columbia (Canada)

    1983-05-01

    The accumulation of four naturally occurring radionuclides of the sup(238)U series, uranium, sup(226)Ra, sup(210)Pb and sup(210)Po, in 15 species of native plants was investigated. Of the plants sampled some accumulated, but none concentrated uranium or sup(226)Ra. Grouseberry (Vaccinium scoparium Leiberg) appeared to concentrate sup(210)Pb and sup(210)Po. There were marked seasonal variations in the accumulation of uranium by grass (Calamagrostis rubescens Buckl.), and of sup(210)Pb and sup(210)Po by grass and fireweed (Epilobium angustifolium L.). High positive correlations between soil and vegetation radionuclide content were found for uranium in fireweed and grouseberry in spring, sup(226)Ra in willow (Salix scouleriana L.) in spring, and uranium in fireweed in summer.

  2. Communicating with the public about the risks of naturally occurring asbestos

    Directory of Open Access Journals (Sweden)

    Claire Hooker

    2017-12-01

    Full Text Available Objectives: To explore the application of evidence based risk communication to community messaging about naturally occurring asbestos (NOA. Type of program or service: Risk communication education about NOA. Methods: We apply principles and determinants of risk communication to the topic of NOA. Results: We emphasise the importance of erring on the side of transparency and trust, even when officials may be concerned about inadvertently heightening needless public concern. We offer a range of practical suggestions for how to lower public concern and outrage relating to the issue of NOA when it arises in local contexts. Lessons learnt: Public concern and outrage can be reduced by favouring early and frequent communication, awareness and use of the ‘rule of threes’ in media communication, open acknowledgement of uncertainty, prioritising response to community concern above narrow myth-busting strategies, and supporting community action.

  3. Implementing a corporate-wide policy for dealing with naturally occurring radioactive material

    International Nuclear Information System (INIS)

    Woods, S.E.; Abernathy, S.E.

    1993-01-01

    With the increased environmental awareness about naturally occurring radioactive materials (NORM), many companies are adopting policies to address the exposure and contamination issues associated with this material. In developing and implementing a NORM policy, every aspect of a business must be thoroughly evaluated to determine at what point the material is encountered and what processes tend to concentrate the material. Once all areas having elevated levels of NORM are identified, the interrelationships between these areas must be evaluated. Corporate policy regarding NORM is discussed, including employee exposure, environmental contamination, facility and equipment contamination, logistics of moving between facilities covered by different regulations, existing and proposed regulations, trends of proposed regulations, disposal of NORM, training and survey equipment. 14 refs., 7 figs

  4. Anomalous deuteron to hydrogen ratio in naturally occuring fission reactions and the possibility of deuteron disintegration

    International Nuclear Information System (INIS)

    Shaheen, M.; Ragheb, M.

    1992-01-01

    A hypothesis is presented for explaining the experimentally determined anomalous D/H ratio observed in the samples from the naturally occuring fission reaction in the Oklo phenomenon. No other explanation has been given, to the best knowledge, for the large difference between the measured D/H ratio in the Oklo samples and the expected values in a fission neutron spectrum. A multicomponent system consisting of hydrogen, deuterium, tritium and helium nuclei is considered. An analytical solution is derived and solved using as boundary conditions the experimentally determined value of the D/H ratio. The solution of the rate equations for hydrogen and deuteron concentrations, assuming a pure fission process without a deuteron sink term, yields a D/H ratio of 445 ppm for a reaction in which the fluence of neutrons is 10 21 n/cm 2 . This exceeds the experimentally observed value of 127 ppm, and the naturally occuring value of 150 ppm. Solving the same rate equations accounting for a deuterium sink term using a hypothesis of deuteron disintegration, and the experimentally observed value of 127 ppm yields a deuteron disintegration constant of 7.47*10 -14 s -1 . Deuteron disintegration would provide a neutron source, in addition to the fission neutrons, driving a subcritical chain reaction over an extended period of time. Relationship of the presented hypothesis to the Vlasov theory of an annihilation meteorite impact explosion explaining the experimentally observed anomalous 235 U/ 238 U ratio, and to the suggestion of deuteron disintegration as a possible explanation of some observations of deuterium dissociation in palladium and titanium electrodes is discussed. The tritium andhelium-3 rate equations are further solved under the deuteron disintegration hypothesis and the relationship of the present work to the work by JONES et al. is discussed. (author) 16 refs.; 7 figs.; 2 tabs

  5. The use of naturally occurring selectively isolated bacteria for inhibiting paraffin deposition

    Energy Technology Data Exchange (ETDEWEB)

    Lazar, I.; Voicu, A.; Dobrota, S.; Petrisor, I.G.; Stefanescu, M.; Sandulescu, L. [Institute of Biology of the Romanian Academy, Spl. Independentei 296, Bucharest (Romania); Nicolescu, C.; Mucenica, D. [PETROSTAR Ploiesti, Bdul Bucuresti 35, Ploiesti (Romania)

    1999-01-01

    One of the most severe problems at any oil fields producing paraffinic oils is that of paraffin depositions. Romania which has a long experience in oil production is also faced with this problem in many oil fields. The microbial treatment, based on the activity of naturally occurring, selectively isolated bacteria, is already proved as an effective alternative to conventional methods to prevent and remove paraffin damage. Using such kind of bacterial products, exciting results for inhibiting paraffin depositions have been obtained. In this paper results concerning the naturally occurring bacteria selectively isolated from hydrocarbon polluted sites as well as from paraffinic oils, semi-solid and solid paraffin depositions are presented. After a laboratory screening, 15 bacterial strains (BS 1-15), three bacterial consortia (BC 1-3) and a Special Bacterial Consortium (SBC1) were selected. For the selection of bacterial consortia, the classical enrichment culture method has been used. The Special Bacterial Consortium resulted from a mixture of BS 1-15 and BC 1-3 following the steps of the classical enrichment culture method. The BS 1-15, BC 1-3 and SBC1 have been tested for their performances in producing biosurfactants and biosolvents as well as for hydrocarbon utilisation. The SBC1 has been tested for its ability in degradation of hydrocarbons contained in several types of paraffinic or non-paraffinic oils, and then for inhibiting paraffin deposition on a `flow equipment` using two types of paraffinic oils. The SBC1 has been also tested for degradation of hydrocarbons contained in semi-solid and solid paraffin depositions. The results obtained could support further applications to prevent and control paraffin depositions

  6. The use of naturally occurring selectively isolated bacteria for inhibiting paraffin deposition

    International Nuclear Information System (INIS)

    Lazar, I.; Voicu, A.; Dobrota, S.; Petrisor, I.G.; Stefanescu, M.; Sandulescu, L.; Nicolescu, C.; Mucenica, D.

    1999-01-01

    One of the most severe problems at any oil fields producing paraffinic oils is that of paraffin depositions. Romania which has a long experience in oil production is also faced with this problem in many oil fields. The microbial treatment, based on the activity of naturally occurring, selectively isolated bacteria, is already proved as an effective alternative to conventional methods to prevent and remove paraffin damage. Using such kind of bacterial products, exciting results for inhibiting paraffin depositions have been obtained. In this paper results concerning the naturally occurring bacteria selectively isolated from hydrocarbon polluted sites as well as from paraffinic oils, semi-solid and solid paraffin depositions are presented. After a laboratory screening, 15 bacterial strains (BS 1-15), three bacterial consortia (BC 1-3) and a Special Bacterial Consortium (SBC1) were selected. For the selection of bacterial consortia, the classical enrichment culture method has been used. The Special Bacterial Consortium resulted from a mixture of BS 1-15 and BC 1-3 following the steps of the classical enrichment culture method. The BS 1-15, BC 1-3 and SBC1 have been tested for their performances in producing biosurfactants and biosolvents as well as for hydrocarbon utilisation. The SBC1 has been tested for its ability in degradation of hydrocarbons contained in several types of paraffinic or non-paraffinic oils, and then for inhibiting paraffin deposition on a 'flow equipment' using two types of paraffinic oils. The SBC1 has been also tested for degradation of hydrocarbons contained in semi-solid and solid paraffin depositions. The results obtained could support further applications to prevent and control paraffin depositions

  7. The radiological impact of naturally-occurring radionuclides in foods from the wild

    International Nuclear Information System (INIS)

    Green, N.; Hammond, D.J.; Davidson, M.F.; Wilkins, B.T.; Williams, B.

    2002-01-01

    Habit surveys have been conducted to identify people who make use of foodstuffs collected from the wild (free foods) in two areas of the UK: in the area around Chipping Norton in Oxfordshire, where levels of naturally-occurring radionuclides in soil were expected to be typical of the UK, and in the vicinity of Okehampton in Devon, where levels were known to be elevated. Individuals who make regular use of these foodstuffs were specifically identified, so that an estimate of typical and higher than average consumption rates could be derived. The naturally-occurring radionuclides of interest were 210 Po, 210 Pb, 234 U, 235 U, 238 U, 230 Th, 232 Th and 226 Ra. Samples of important foodstuffs were collected and the radionuclides of interest determined. The consumption rates were combined with the measured activity concentrations and published dose coefficients to estimate doses to average and higher than average consumers. These doses were compared with estimated doses reported in the Food Standards Agency's ongoing monitoring programme and with average doses to the population of the UK reviewed by NRPB. In total, 400 people were identified and between them they collected 54 different types of free food. Blackberries were by far the most common species collected, although various types of mushroom and nuts were also popular. On average, each collector from around Chipping Norton collected 2.1 different foods, and each from around Okehampton collected 2.2. On the basis of the habit survey, therefore, it would be reasonable to expect that any site, nuclear or otherwise, chosen for habit surveys, whether for radiological purposes or for any other contaminant, could have substantial numbers of people collecting free foods. In addition, the pattern of foods collected was very similar to previous studies, indicating similarities across England and Wales. (author)

  8. Urinary bladder cancer in dogs, a naturally occurring model for cancer biology and drug development.

    Science.gov (United States)

    Knapp, Deborah W; Ramos-Vara, José A; Moore, George E; Dhawan, Deepika; Bonney, Patty L; Young, Kirsten E

    2014-01-01

    Each year more than 65,000 people are diagnosed with urinary bladder cancer, and more than 14,000 people die from the disease in the United States. Studies in relevant animal models are essential to improve the management of bladder cancer. Naturally occurring bladder cancer in dogs very closely mimics human invasive bladder cancer, specifically high-grade invasive transitional cell carcinoma (TCC; also referred to as invasive urothelial carcinoma) in cellular and molecular features; biological behavior, including sites and frequency of metastasis; and response to therapy. Canine bladder cancer complements experimentally induced rodent tumors in regard to animal models of bladder cancer. Results of cellular and molecular studies and -omics analyses in dogs are expected to lead to improved detection of TCC and preneoplastic lesions, earlier intervention, better prediction of patient outcome, and more effective TCC management overall. Studies in dogs are being used to help define heritable risks (through very strong breed-associated risk) and environment risks and to evaluate prevention and treatment approaches that benefit humans as well as dogs. Clinical treatment trials in pet dogs with TCC are considered a win-win scenario by clinician scientists and pet owners. The individual dog benefits from effective treatment, the results are expected to help other dogs, and the findings are expected to ultimately help humans with TCC. This article provides an overview of canine TCC, a summary of the similarities and differences between canine and human invasive TCC, and examples of the types of valuable translational research that can be done using dogs with naturally occurring TCC. © The Author 2014. Published by Oxford University Press on behalf of the Institute for Laboratory Animal Research. All rights reserved. For permissions, please email: journals.permissions@oup.com.

  9. Naturally occurring circadian rhythm and sleep duration are related to executive functions in early adulthood.

    Science.gov (United States)

    Kuula, Liisa; Pesonen, Anu-Katriina; Heinonen, Kati; Kajantie, Eero; Eriksson, Johan Gunnar; Andersson, Sture; Lano, Aulikki; Lahti, Jari; Wolke, Dieter; Räikkönen, Katri

    2018-02-01

    Experimental sleep deprivation studies suggest that insufficient sleep and circadian misalignment associates with poorer executive function. It is not known whether this association translates to naturally occurring sleep patterns. A total of 512 of full-term-born members of the Arvo Ylppö Longitudinal Study [mean age = 25.3, standard deviation (SD) = 0.65] (44.3% men) wore actigraphs to define sleep duration, its irregularity and circadian rhythm (sleep mid-point) during a 1-week period (mean 6.9 nights, SD = 1.7). Performance-based executive function was assessed with the Trail-Making Test, Conners' Continuous Performance Test and Stroop. The self-rated adult version of Behavior Rating Inventory of Executive Function was used to assess trait-like executive function. We found that performance-based and self-reported trait-like executive function correlated only modestly (all correlations ≤0.17). Shorter sleep duration associated with more commission errors. Later circadian rhythm associated with poorer trait-like executive function, as indicated by the Brief Metacognitive Index and the Behavior Regulation Index. Those belonging to the group with the most irregular sleep duration performed slower than others in the Trail-Making Test Part A. All associations were adjusted for sex, age, socioeconomic status and body mass index. In conclusion, naturally occurring insufficient sleep and later circadian rhythm showed modest associations with poorer executive function. Shorter habitual sleep duration was associated with lower scores of performance-based tests of executive function, and later circadian rhythm was associated mainly with poorer trait-like executive function characteristics. Our findings suggest additionally that sleep duration and circadian rhythm associate with different domains of executive function, and there are no additive effects between the two. © 2017 European Sleep Research Society.

  10. The HER2 CISH pharmDx(™) Kit in the assessment of breast cancer patients for anti-HER2 treatment.

    Science.gov (United States)

    Foged, Niels T; Brügmann, Anja; Jørgensen, Jan T

    2013-04-01

    Testing for amplification of the human EGF receptor 2 (HER2) gene by in situ hybridization is a central principle for the identification of breast cancer patients likely to respond to treatments directed toward HER2. However, its application in clinical routine has been somewhat restricted by the typical use of a visualization system based on fluorescence (FISH), which requires skilled, work-intensive, high-magnification quantitative microscopy. The US FDA has recently approved the HER2 CISH pharmDx™ Kit, which is characterized by employing a chromogenic visualization system that allows quantification of the HER2 gene and centromere 17 reference signals by relatively low-magnification brightfield microscopy. It is indicated as an aid in the assessment of patients for whom Herceptin(®) (trastuzumab) treatment is being considered.

  11. Overview of the trastuzumab (Herceptin) anti-HER2 monoclonal antibody clinical program in HER2-overexpressing metastatic breast cancer. Herceptin Multinational Investigator Study Group.

    Science.gov (United States)

    Shak, S

    1999-08-01

    The recombinant humanized anti-HER2 monoclonal antibody trastuzumab (Herceptin; Genentech, San Francisco, CA) was evaluated in human clinical trials for treatment of women with metastatic breast cancer who have tumors that overexpress HER2. The trastuzumab clinical program consisted of a series of phase I, phase II, and phase III clinical trials. Clinical experience with this novel biologic has been obtained in more than 1,000 women with HER2-overexpressing metastatic breast cancer. Two pivotal trials were performed to evaluate trastuzumab efficacy and safety: (1) trastuzumab in combination with chemotherapy as first-line therapy and (2) trastuzumab as a single agent in second- and third-line chemotherapy. Preliminary results of the pivotal clinical trials that have been presented at national meetings are summarized below. The data suggest that trastuzumab will be an important new treatment option for women with HER2-overexpressing metastatic breast cancer.

  12. Quantitative real-time RT-PCR and chromogenic in situ hybridization: precise methods to detect HER-2 status in breast carcinoma

    Directory of Open Access Journals (Sweden)

    Soares Fernando A

    2009-03-01

    Full Text Available Abstract Background HER-2 gene testing has become an integral part of breast cancer patient diagnosis. The most commonly used assay in the clinical setting for evaluating HER-2 status is immunohistochemistry (IHC and fluorescence in situ hybridization (FISH. These procedures permit correlation between HER-2 expression and morphological features. However, FISH signals are labile and fade over time, making post-revision of the tumor difficult. CISH (chromogenic in situ hybridization is an alternative procedure, with certain advantages, although still limited as a diagnostic tool in breast carcinomas. Methods To elucidate the molecular profile of HER-2 status, mRNA and protein expression in 75 invasive breast carcinomas were analyzed by real time quantitative RT-PCR (qRT-PCR and IHC, respectively. Amplifications were evaluated in 43 of these cases by CISH and in 11 by FISH. Results The concordance rate between IHC and qRT-PCR results was 78.9%, and 94.6% for qRT-PCR and CISH. Intratumoral heterogeneity of HER-2 status was identified in three cases by CISH. The results of the three procedures were compared and showed a concordance rate of 83.8%; higher discordances were observed in 0 or 1+ immunostaining cases, which showed high-level amplification (15.4% and HER-2 transcript overexpression (20%. Moreover, 2+ immunostaining cases presented nonamplified status (50% by CISH and HER-2 downexpression (38.5% by qRT-PCR. In general, concordance occurred between qRT-PCR and CISH results. A high concordance was observed between CISH/qRT-PCR and FISH. Comparisons with clinicopathological data revealed a significant association between HER-2 downexpression and the involvement of less than four lymph nodes (P = 0.0350. Conclusion Based on these findings, qRT-PCR was more precise and reproducible than IHC. Furthermore, CISH was revealed as an alternative and useful procedure for investigating amplifications involving the HER-2 gene.

  13. Quantitative real-time RT-PCR and chromogenic in situ hybridization: precise methods to detect HER-2 status in breast carcinoma

    International Nuclear Information System (INIS)

    Rosa, Fabíola E; Silveira, Sara M; Silveira, Cássia GT; Bérgamo, Nádia A; Neto, Francisco A Moraes; Domingues, Maria AC; Soares, Fernando A; Caldeira, José RF; Rogatto, Silvia R

    2009-01-01

    HER-2 gene testing has become an integral part of breast cancer patient diagnosis. The most commonly used assay in the clinical setting for evaluating HER-2 status is immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). These procedures permit correlation between HER-2 expression and morphological features. However, FISH signals are labile and fade over time, making post-revision of the tumor difficult. CISH (chromogenic in situ hybridization) is an alternative procedure, with certain advantages, although still limited as a diagnostic tool in breast carcinomas. To elucidate the molecular profile of HER-2 status, mRNA and protein expression in 75 invasive breast carcinomas were analyzed by real time quantitative RT-PCR (qRT-PCR) and IHC, respectively. Amplifications were evaluated in 43 of these cases by CISH and in 11 by FISH. The concordance rate between IHC and qRT-PCR results was 78.9%, and 94.6% for qRT-PCR and CISH. Intratumoral heterogeneity of HER-2 status was identified in three cases by CISH. The results of the three procedures were compared and showed a concordance rate of 83.8%; higher discordances were observed in 0 or 1+ immunostaining cases, which showed high-level amplification (15.4%) and HER-2 transcript overexpression (20%). Moreover, 2+ immunostaining cases presented nonamplified status (50%) by CISH and HER-2 downexpression (38.5%) by qRT-PCR. In general, concordance occurred between qRT-PCR and CISH results. A high concordance was observed between CISH/qRT-PCR and FISH. Comparisons with clinicopathological data revealed a significant association between HER-2 downexpression and the involvement of less than four lymph nodes (P = 0.0350). Based on these findings, qRT-PCR was more precise and reproducible than IHC. Furthermore, CISH was revealed as an alternative and useful procedure for investigating amplifications involving the HER-2 gene

  14. Natural Competence of Xylella fastidiosa Occurs at a High Frequency Inside Microfluidic Chambers Mimicking the Bacterium's Natural Habitats.

    Science.gov (United States)

    Kandel, Prem P; Lopez, Samantha M; Almeida, Rodrigo P P; De La Fuente, Leonardo

    2016-09-01

    Xylella fastidiosa is a xylem-limited bacterium that is the causal agent of emerging diseases in a number of economically important crops. Genetic diversity studies have demonstrated homologous recombination occurring among X. fastidiosa strains, which has been proposed to contribute to host plant shifts. Moreover, experimental evidence confirmed that X. fastidiosa is naturally competent for recombination in vitro Here, as an approximation of natural habitats (plant xylem vessels and insect mouthparts), recombination was studied in microfluidic chambers (MCs) filled with media amended with grapevine xylem sap. First, different media were screened for recombination in solid agar plates using a pair of X. fastidiosa strains that were previously reported to recombine in coculture. The highest frequency of recombination was obtained with PD3 medium, compared to those with the other two media (X. fastidiosa medium [XFM] and periwinkle wilt [PW] medium) used in previous studies. Dissection of the media components led to the identification of bovine serum albumin as an inhibitor of recombination that was correlated to its previously known effect on inhibition of twitching motility. When recombination was performed in liquid culture, the frequencies were significantly higher under flow conditions (MCs) than under batch conditions (test tubes). The recombination frequencies in MCs and agar plates were not significantly different from each other. Grapevine xylem sap from both susceptible and tolerant varieties allowed high recombination frequency in MCs when mixed with PD3. These results suggest that X. fastidiosa has the ability to be naturally competent in the natural growth environment of liquid flow, and this phenomenon could have implications in X. fastidiosa environmental adaptation. Xylella fastidiosa is a plant pathogen that lives inside xylem vessels (where water and nutrients are transported inside the plant) and the mouthparts of insect vectors. This bacterium

  15. Enhancing arsenic removal from groundwater at household level with naturally occurring iron

    Directory of Open Access Journals (Sweden)

    Anitha Kumari Sharma

    2016-06-01

    Full Text Available A supply of drinking water low in Arsenic (As prevents arsenic poisoning. The presence of high concentrations of iron (Fe in groundwater under the alluvial plains of the large rivers in Southeast Asia is a prerequisite for the simple removal of As. This study investigated the mechanisms and possibilities for enhancing As removal with naturally occurring Fe in a reliable, low cost and sustainable way. The results of the study show that As removal with Fe is greatly enhanced by the addition of an oxidizing agent (preferably KMnO4 immediately after the pumping of groundwater. Further enhancement of As removal in the presence of Fe can be achieved by adding a small volume of a concentrated basic solution of MnO4- and AlO2-, which has a combined oxidation, coagulation and buffering capacity. Best results were obtained when this solution was mixed with the groundwater immediately after its pumping until a pale pink color appeared. Maximum required reaction time was 10 minutes and subsequent filtration of the water was able to reduce the As concentration to near zero. Concentrations of MnO4- and AlO2- can be varied in the solution to achieve sufficient As removal to suit different Fe/As ratios and the presence of interfering co-occurring anions.

  16. Glycosphingolipid analysis in a naturally occurring ovine model of acute neuronopathic Gaucher disease.

    Science.gov (United States)

    Karageorgos, Litsa; Hein, Leanne; Rozaklis, Tina; Adams, Melissa; Duplock, Stephen; Snel, Marten; Hemsley, Kim; Kuchel, Tim; Smith, Nicholas; Hopwood, John J

    2016-07-01

    Gaucher disease arises from mutations in the β-glucocerebrosidase gene which encodes an enzyme required for the lysosomal catabolism of glucosylceramide. We have identified a naturally occurring mutation in the β-glucocerebrosidase gene in sheep that leads to Gaucher disease with acute neurological symptoms. Here we have examined the clinical phenotype at birth and subsequently quantified lipids in Gaucher lamb brain, in order to characterise the disorder. Enzyme activity assessments showed that a reduction in β-glucocerebrosidase activity to 1-5% of wild-type occurs consistently across newborn Gaucher lamb brain regions. We analyzed glucosylceramide, glucosylsphingosine, bis(monoacylglycero)phosphate and ganglioside profiles in brain, liver, and spleen, and observed 30- to 130-fold higher glucosylceramide, and 500- to 2000-fold higher glucosylsphingosine concentrations in Gaucher diseased lambs compared to wild-type. Significant increases of bis(monoacylglycero)phosphate and gangliosides [GM1, GM2, GM3] concentrations were also detected in the brain. As these glycosphingolipids are involved in many cellular events, an imbalance or disruption of the cell membrane lipid homeostasis would be expected to impair normal neuronal function. To our knowledge, this is the first detailed analysis of glycosphingolipids in various brain regions in a large animal model of neuronal disease, which permits the mechanistic investigation of lipid deregulation and their contribution to neurodegenerative process. Copyright © 2016 Elsevier Inc. All rights reserved.

  17. HER2 signaling pathway activation and response of breast cancer cells to HER2-targeting agents is dependent strongly on the 3D microenvironment

    Energy Technology Data Exchange (ETDEWEB)

    Weigelt, Britta; Lo, Alvin T; Park, Catherine C; Gray, Joe W; Bissell, Mina J

    2009-07-27

    Development of effective and durable breast cancer treatment strategies requires a mechanistic understanding of the influence of the microenvironment on response. Previous work has shown that cellular signaling pathways and cell morphology are dramatically influenced by three-dimensional (3D) cultures as opposed to traditional two-dimensional (2D) monolayers. Here, we compared 2D and 3D culture models to determine the impact of 3D architecture and extracellular matrix (ECM) on HER2 signaling and on the response of HER2-amplified breast cancer cell lines to the HER2-targeting agents Trastuzumab, Pertuzumab and Lapatinib. We show that the response of the HER2-amplified AU565, SKBR3 and HCC1569 cells to these anti-HER2 agents was highly dependent on whether the cells were cultured in 2D monolayer or 3D laminin-rich ECM gels. Inhibition of {beta}1 integrin, a major cell-ECM receptor subunit, significantly increased the sensitivity of the HER2-amplified breast cancer cell lines to the humanized monoclonal antibodies Trastuzumab and Pertuzumab when grown in a 3D environment. Finally, in the absence of inhibitors, 3D cultures had substantial impact on HER2 downstream signaling and induced a switch between PI3K-AKT- and RAS-MAPKpathway activation in all cell lines studied, including cells lacking HER2 amplification and overexpression. Our data provide direct evidence that breast cancer cells are able to rapidly adapt to different environments and signaling cues by activating alternative pathways that regulate proliferation and cell survival, events that may play a significant role in the acquisition of resistance to targeted therapies.

  18. Radiological safety and environmental implications in beach mineral industry due to naturally occurring radioactive materials

    International Nuclear Information System (INIS)

    Pillai, P.M.B.; Haridasan, P.P.; Maniyan, C.G.; Khan, A.H.

    2002-01-01

    The presence of monazite (primary ore of Thorium) along with ilmenite and other minerals in the beach sand deposits of coastal regions of South India has made some of these coastal areas prominent among Natural High Background Radiation Areas (NHBRA) in the world. The beach mineral industries are situated in populated areas in these NHBRAs. The radiation background prevailing in these areas due to the presence of the Naturally Occurring Radioactive Materials (NORM) Thorium with traces of Uranium and their decay products had been found to result in estimated percaput annual external exposures ranging from 3 to 25 mSv to the population at NHBRA depending on the monazite content of the soil in the area. The internal exposures estimated are of the order of 1 to 2 mSv per year. The mining of minerals and refilling of the mined out areas with mineral free sand and rehabilitation of the area is found to reduce the external radiation fields by a factor of 3. The notional environmental external radiation exposures to the population occupying this modified NHBRA also reduce correspondingly. (author)

  19. Naturally-Occurring Entomopathogenic Fungi on Three Bark Beetle Species (Coleoptera: Curculionidae in Bulgaria

    Directory of Open Access Journals (Sweden)

    Slavimira A. Draganova

    2010-01-01

    Full Text Available Bark beetles (Coleoptera: Curculionidae: Scolytinae belong to one of the most damaging groups of forest insects and the activity of their natural enemies –pathogens, parasitoids,parasites or predators suppressing their population density,is of great importance. Biodiversity of entomopathogenic fungi on bark beetles in Bulgaria has been investigated sporadically. The aim of this preliminary study was to find, identify and study morphological characteristics of fungal entomopathogens naturally-occurring in populations of three curculionid species – Ips sexdentatus Boern, Ips typographus (L. and Dryocoetes autographus (Ratz.. Dead pest adults were found under the bark of Pinus sylvestris and Picea abies trees collectedfrom forests in the Maleshevska and Vitosha Mountains. Fungal pathogens were isolated into pure cultures on SDAY (Sabouraud dextrose agar with yeast extract and were identified based on morphological characteristics both on the host and in a culture.Morphological characteristics of the isolates were studied by phenotypic methods. The fungal isolates obtained from dead adults of Ips sexdentatus, Ips typographus and D. autographus were found to belong to the species Beauveria bassiana (Bals. – Criv. Vuillemin,Beauveria brongniartii (Saccardo Petch and Isaria farinosa (Holmsk. Fries (anamorph Ascomycota, Sordariomycetes: Hypocreales, Cordycipitaceae. Morphological traits of the isolates are described.

  20. Controls on chemistry and diagenesis of naturally occurring iron-oxide phases

    Energy Technology Data Exchange (ETDEWEB)

    Nancy W. Hinman; J. Michelle Kotler; Beizhan Yan; Aaron Tenesch; Richard V. Morris; Daphne L. Stoner; Jill R. Scott

    2009-07-01

    The purposes of this study were to (i) document chemical and mineralogical compositions in two naturally acidic drainages over a 1 m soil profile, (ii) document organic and inorganic signatures representative of past chemical or biological processes in the soils, and (iii) determine whether mineralogical and chemical differences are a consequence of differences in original composition, depositional conditions, or diagenesis. Two sites were studied: Paymaster Creek in the Heddleston Mining District near Lincoln, Montana and the New World Mining District near Cooke City, Montana. The oldest deposits at both naturally acidic sites pre-date human mining activity by several thousand years, although there is recent human activity at both sites. Both sites have streams with high dissolved Fe and moderately low pH and actively accumulate schwertmannite on streambeds. Soil deposits away from the streambed at Paymaster Creek contained goethite with adsorbed sulfate, but no schwertmannite, suggesting either that the original conditions precluded schwertmannite precipitation or that diagenesis occurred rapidly converting the schwertmannite to goethite. The New World Mining District site showed the expected profile, which is a gradual transition from schwertmannite- and goethite-bearing soils to goethite-only soils. Concentrations of Cr, As and other trace elements shown to retard diagenesis were higher at the New World site than at the Paymaster site.

  1. Levels of naturally occurring gamma radiation measured in British homes and their prediction in particular residences

    Energy Technology Data Exchange (ETDEWEB)

    Kendall, G.M. [University of Oxford, Cancer Epidemiology Unit, Oxford (United Kingdom); Wakeford, R. [University of Manchester, Centre for Occupational and Environmental Health, Institute of Population Health, Manchester (United Kingdom); Athanson, M. [University of Oxford, Bodleian Library, Oxford (United Kingdom); Vincent, T.J. [University of Oxford, Childhood Cancer Research Group, Oxford (United Kingdom); Carter, E.J. [University of Worcester, Earth Heritage Trust, Geological Records Centre, Henwick Grove, Worcester (United Kingdom); McColl, N.P. [Public Health England, Centre for Radiation, Chemical and Environmental Hazards, Chilton, Didcot, Oxon (United Kingdom); Little, M.P. [National Cancer Institute, DHHS, NIH, Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, Bethesda, MD (United States)

    2016-03-15

    Gamma radiation from natural sources (including directly ionising cosmic rays) is an important component of background radiation. In the present paper, indoor measurements of naturally occurring gamma rays that were undertaken as part of the UK Childhood Cancer Study are summarised, and it is shown that these are broadly compatible with an earlier UK National Survey. The distribution of indoor gamma-ray dose rates in Great Britain is approximately normal with mean 96 nGy/h and standard deviation 23 nGy/h. Directly ionising cosmic rays contribute about one-third of the total. The expanded dataset allows a more detailed description than previously of indoor gamma-ray exposures and in particular their geographical variation. Various strategies for predicting indoor natural background gamma-ray dose rates were explored. In the first of these, a geostatistical model was fitted, which assumes an underlying geologically determined spatial variation, superimposed on which is a Gaussian stochastic process with Matern correlation structure that models the observed tendency of dose rates in neighbouring houses to correlate. In the second approach, a number of dose-rate interpolation measures were first derived, based on averages over geologically or administratively defined areas or using distance-weighted averages of measurements at nearest-neighbour points. Linear regression was then used to derive an optimal linear combination of these interpolation measures. The predictive performances of the two models were compared via cross-validation, using a randomly selected 70 % of the data to fit the models and the remaining 30 % to test them. The mean square error (MSE) of the linear-regression model was lower than that of the Gaussian-Matern model (MSE 378 and 411, respectively). The predictive performance of the two candidate models was also evaluated via simulation; the OLS model performs significantly better than the Gaussian-Matern model. (orig.)

  2. Radiological dose assessment of naturally occurring radioactive materials in concrete building materials

    International Nuclear Information System (INIS)

    Amran AB Majid; Aznan Fazli Ismail; Muhamad Samudi Yasir; Redzuwan Yahaya; Ismail Bahari

    2013-01-01

    Previous studies have shown that the natural radioactivity contained in building materials have significantly influenced the dose rates in dwelling. Exposure to natural radiation in building has been of concerned since almost 80 % of our daily live are spend indoor. Thus, the aim of the study is to assess the radiological risk associated by natural radioactivity in soil based building materials to dwellers. A total of 13 Portland cement, 46 sand and 43 gravel samples obtained from manufacturers or bought directly from local hardware stores in Peninsular of Malaysia were analysed for their radioactivity concentrations. The activity concentrations of 226 Ra, 232 Th and 40 K in the studied building materials samples were found to be in the range of 3.7-359.3, 2.0-370.8 and 10.3-1,949.5 Bq kg -1 respectively. The annual radiation dose rates (μSv year -1 ) received by dwellers were evaluated for 1 to 50 years of exposure using Resrad-Build Computer Code based on the activity concentration of 226 Ra, 232 Th and 40 K found in the studied building material samples. The rooms modelling were based on the changing parameters of concrete wall thickness and the room dimensions. The annual radiation dose rates to dwellers were found to increase annually over a period of 50 years. The concrete thicknesses were found to have significantly influenced the dose rates in building. The self-absorption occurred when the concrete thickness was thicker than 0.4 m. Results of this study shows that the dose rates received by the dwellers of the building are proportional to the size of the room. In general the study concludes that concrete building materials; Portland cements, sands, and gravels in Peninsular of Malaysia does not pose radiological hazard to the building dwellers. (author)

  3. Levels of naturally occurring gamma radiation measured in British homes and their prediction in particular residences

    International Nuclear Information System (INIS)

    Kendall, G.M.; Wakeford, R.; Athanson, M.; Vincent, T.J.; Carter, E.J.; McColl, N.P.; Little, M.P.

    2016-01-01

    Gamma radiation from natural sources (including directly ionising cosmic rays) is an important component of background radiation. In the present paper, indoor measurements of naturally occurring gamma rays that were undertaken as part of the UK Childhood Cancer Study are summarised, and it is shown that these are broadly compatible with an earlier UK National Survey. The distribution of indoor gamma-ray dose rates in Great Britain is approximately normal with mean 96 nGy/h and standard deviation 23 nGy/h. Directly ionising cosmic rays contribute about one-third of the total. The expanded dataset allows a more detailed description than previously of indoor gamma-ray exposures and in particular their geographical variation. Various strategies for predicting indoor natural background gamma-ray dose rates were explored. In the first of these, a geostatistical model was fitted, which assumes an underlying geologically determined spatial variation, superimposed on which is a Gaussian stochastic process with Matern correlation structure that models the observed tendency of dose rates in neighbouring houses to correlate. In the second approach, a number of dose-rate interpolation measures were first derived, based on averages over geologically or administratively defined areas or using distance-weighted averages of measurements at nearest-neighbour points. Linear regression was then used to derive an optimal linear combination of these interpolation measures. The predictive performances of the two models were compared via cross-validation, using a randomly selected 70 % of the data to fit the models and the remaining 30 % to test them. The mean square error (MSE) of the linear-regression model was lower than that of the Gaussian-Matern model (MSE 378 and 411, respectively). The predictive performance of the two candidate models was also evaluated via simulation; the OLS model performs significantly better than the Gaussian-Matern model. (orig.)

  4. Worldwide Open Proficiency Test: Determination of Naturally Occurring Radionuclides in Phosphogypsum and Water

    International Nuclear Information System (INIS)

    2010-01-01

    A reliable determination of naturally occurring radionuclides in phosphogypsum is necessary to comply with the radiation protection and environmental regulations. This proficiency test (PT) is one of the series of the world wide proficiency tests organised every year by the IAEA Terrestrial Environment Laboratory. This series of PTs is designed to identify analytical problems, to support Member State laboratories to maintain their accreditation and to provide a forum for discussions regarding the analysis of naturally occurring radionuclides. The range of sample types available for analysis has been mainly at environmental levels. In this PT, the test item set consisted of six samples: one phosphogypsum (the IAEA-434 reference material) and five water samples spiked with natural radionuclides. The main task of the participating laboratories was to identify and traceably quantify the activity levels of radionuclides present in these matrices. The tasks of the IAEA were to prepare and distribute the samples to the participating laboratories, to collect and interpret analysis results and to compile a comprehensive report. The certified massic activity values of all radionuclides used in this PT were traceable to international standards of radioactivity. In this PT, 1800 test items (reference materials) were prepared and distributed to 300 laboratories from 76 countries in November 2008. The deadline for receiving the results from the participants was set at 15 May 2009. The participating laboratories were requested to analyse Ra-226, U-234 and U-238 in water samples 01 and 02, and gross alpha/beta in water samples 03, 04 and 05. In the phosphogypsum sample number 06 the participants were asked to analyse Pb-210, Ra-226, Th-230, U-234 and U-238. The analytical results of the participating laboratories were compared with the reference values assigned to the reference materials, and a rating system was applied. Three National Metrology Institutes (NMI) and six expert

  5. HER-2 positive and p53 negative breast cancers are associated with poor prognosis.

    LENUS (Irish Health Repository)

    2011-06-01

    p53 and HER-2 coexpression in breast cancer has been controversial. These markers were tested using immunohistochemistry and HercepTest. HER-2 expression is related to reduced breast cancer survival (p = .02) . p53 expression relates to HER-2 expression (p = .029). Coexpression between p53 and HER-2 has no relation to prognosis. On univariate and multivariate analysis, combination of HER-2 positive and p53 negative expression was associated with a poor prognosis (p = .018 and p = .027, respectively), while the combination of HER-2 negative and p53 positive expression was associated with a favorable prognosis (p = .022 and p = .010, respectively). Therefore the expression of these markers should be considered collectively.

  6. Circulating HER2 DNA after trastuzumab treatment predicts survival and response in breast cancer

    DEFF Research Database (Denmark)

    Sorensen, Boe S; Mortensen, Lise S; Andersen, Jørn

    2010-01-01

    BACKGROUND: Only a subset of breast cancer patients responds to the HER2 inhibitor trastuzumab, and methods to identify responders are needed. PATIENTS AND METHODS: We studied 28 patients with metastatic breast cancer that had amplified human epidermal growth factor receptor 2 (HER2) genes...... in their primary tumour and were treated with a combination of trastuzumab and chemotherapy. Plasma was collected and amplification of the HER2 gene in circulating DNA and the amounts of the extracellular domain (ECD) of HER2 were measured just before first treatment (n=28) and just before second treatment three...... response (p=0.02), and overall survival (p=0.05). HER2 ECD kinetics did not correlate to clinical data. CONCLUSION: We suggest that a decrease in HER2 gene amplification in the plasma predicts a more favourable response to trastuzumab....

  7. Serum HER-2 concentrations for monitoring women with breast cancer in a routine oncology setting

    DEFF Research Database (Denmark)

    Sørensen, Patricia Diana; Jakobsen, Erik Hugger; Langkjer, Sven Tyge

    2009-01-01

    BACKGROUND: The purpose of this study was to determine the positive predictive value (PPV) of positive serum human epidermal growth factor receptor-2 (HER-2) for monitoring women with breast cancer following diagnosis and treatment in a routine clinical setting. METHODS: Serum HER-2 was measured...... could be determined in ten tissue-positive patients was 3-24 months (mean 11.3 months), when compared to standard clinical imaging methods. CONCLUSIONS: Serum HER-2 is a useful marker for the detection of recurrence of breast cancer and for monitoring the effect of treatment, especially in tissue HER-2...... in 1348 patients with breast cancer: 837 during routine oncology clinic visits and 511 following new diagnosis. All patients with positive serum HER-2, 1/5 of negative patients from the oncology clinic, and all the newly diagnosed were followed; a total of 862 patients. Serum HER-2 was measured using...

  8. HER-2 positive and p53 negative breast cancers are associated with poor prognosis.

    LENUS (Irish Health Repository)

    2012-02-01

    p53 and HER-2 coexpression in breast cancer has been controversial. These markers were tested using immunohistochemistry and HercepTest. HER-2 expression is related to reduced breast cancer survival (p = .02) . p53 expression relates to HER-2 expression (p = .029). Coexpression between p53 and HER-2 has no relation to prognosis. On univariate and multivariate analysis, combination of HER-2 positive and p53 negative expression was associated with a poor prognosis (p = .018 and p = .027, respectively), while the combination of HER-2 negative and p53 positive expression was associated with a favorable prognosis (p = .022 and p = .010, respectively). Therefore the expression of these markers should be considered collectively.

  9. Practical consensus recommendations on Her2 +ve breast cancer with solitary brain mets

    Directory of Open Access Journals (Sweden)

    Nitesh Rohatgi

    2018-01-01

    Full Text Available Breast cancer is a common cause of brain metastases, with metastases occurring in at least 10–16% of patients. Longer survival of patients with metastatic breast cancer and the use of better imaging techniques are associated with an increased incidence of brain metastases. Current therapies include surgery, whole-brain radiation therapy, stereotactic radiosurgery, chemotherapy and targeted therapies. However, the timing and appropriate use of these therapies is controversial and careful patient selection by using available prognostic tools is extremely important. Expert oncologist discussed on the mode of treatment to extend the OS and improve the quality of life ofHER2-positivebreast cancer patients with Solitary brain metastases. This expert group used data from published literature, practical experience and opinion of a large group of academic oncologists to arrive at this practical consensus recommendations for the benefit of community oncologists.

  10. NatHER: protocol for systematic evaluation of trends in survival among patients with HER2-positive advanced breast cancer.

    Science.gov (United States)

    Korner, Eli J; Morris, Anne; Allen, Isabel Elaine; Hurvitz, Sara; Beattie, Mary S; Kalesan, Bindu

    2015-10-01

    Human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) is an aggressive form of breast cancer and is historically associated with poor outcomes compared with HER2-negative MBC. Since 1998, four drugs have been globally approved for the targeted treatment of HER2-positive MBC. Additional advances in patient care-such as improved breast cancer screening, HER2 testing, and supportive care-have also occurred. The objective of this systematic review and meta-analysis is to determine whether there has been a cumulative change in survival over time in patients with HER2-positive advanced breast cancer based on results from interventional clinical trials (ICTs) and observational studies and to compare outcomes across these types of studies. A systematic search of Medline, EMBASE, and the Cochrane Central Register of Controlled Trials will be performed. Two investigators will independently assess each abstract for inclusion. English language reports of ICTs and observational studies that include patients with HER2-positive advanced breast cancer from 1987 onwards will be considered. The primary outcome of interest is overall survival; secondary outcomes include progression-free survival and safety. Data on clinical outcomes, as well as on study design, study population, treatment/intervention, methodological quality, and outcomes, will be extracted using a structured codebook developed by the authors for this study. Standard and cumulative random effects meta-analysis will be performed to derive pooled risk estimates, both overall and by study design, controlling for covariates such as aggregate demographic and clinical characteristics of patients, treatment/intervention, and study characteristics. Heterogeneity of studies will be evaluated using the I(2) statistic. Differences in risk estimates by quality characteristics will be performed using meta-regression. This study will evaluate current and evolving trends in survival associated with

  11. Relationship Between HER2 Status and Prognosis in Women With Brain Metastases From Breast Cancer

    International Nuclear Information System (INIS)

    Xu Zhiyuan; Marko, Nicholas F.; Chao, Sam T.; Angelov, Lilyana; Vogelbaum, Michael A.; Suh, John H.; Barnett, Gene H.; Weil, Robert J.

    2012-01-01

    Purpose: To analyze factors affecting outcomes in breast cancer patients with brain metastases (BM) and characterize the role of HER2 status. Methods and Materials: We identified 264 breast cancer patients treated between 1999 and 2008 for BM. HER2 status was known definitively for 172 patients and was used to define cohorts in which survival and risk factors were analyzed. Results: Kaplan-Meier survival analysis demonstrated improved mean overall survival (105.7 vs. 74.3 months, p < 0.02), survival after diagnosis of BM (neurologic survival, NS) (32.2 vs. 18.9 months, p < 0.01), and survival after treatment with stereotactic radiosurgery (RS) (31.3 vs. 14.1, p < 0.01) in HER2+ patients relative to those with HER2− breast cancer. HER2+ status was an independent, positive prognostic factor for survival on univariate and multivariate hazard analysis (hazard ratio: overall survival = 0.66, 0.18; NS = 0.50, 0.34). Additionally, subgroup analysis suggests that stereotactic radiosurgery may be of particular benefit in patients with HER2+ tumors. Conclusions: Overall survival, NS, and RS are improved in patients with HER2+ tumors, relative to those with HER2− lesions, and HER2 amplification is independently associated with increased survival in patients with BM from breast cancer. Our findings suggest that the prognosis of HER2+ patients may be better than that of otherwise similar patients who are HER2− and that stereotactic radiosurgery may be beneficial for some patients with HER2+ lesions.

  12. New developments in the treatment of HER2-positive breast cancer

    Directory of Open Access Journals (Sweden)

    Nahta R

    2012-05-01

    Full Text Available Rita NahtaDepartments of Pharmacology and Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, USAAbstract: Approximately 20%–30% of metastatic breast cancers show increased expression of the human epidermal growth factor receptor-2 (HER2 tyrosine kinase. Two HER2-specific therapies are currently approved for clinical treatment of patients with HER2-overexpressing metastatic breast cancer. Trastuzumab is a monoclonal antibody against HER2 and is approved for first-line treatment of HER2-positive metastatic breast cancer. Lapatinib is a small molecule dual inhibitor of epidermal growth factor receptor and HER2 tyrosine kinases, and is approved for trastuzumab-refractory disease. Although trastuzumab is a highly effective therapy for patients with HER2-overexpressing metastatic breast cancer, a significant number of patients in the initial clinical trials of trastuzumab monotherapy showed resistance to trastuzumab-based therapy. Further, among those who did respond, the initial trials indicated that the median time to progression was less than 1 year. Similarly, lapatinib is effective in a subset of trastuzumab-refractory cases, but the majority of patients display resistance. This review discusses the multiple molecular mechanisms of resistance that have been proposed in the literature. In addition, novel agents that are being tested for efficacy against HER2-positive breast cancer, including the antibodies pertuzumab and trastuzumab-DM1 and the immunotoxin affitoxin, are reviewed. The introduction of trastuzumab has revolutionized the clinical care of patients with HER2-positive metastatic breast cancer and has resulted in dramatic reductions in recurrences of early-stage HER2-positive breast cancer. The development and implementation of gene- and protein-based assays that measure potential molecular predictors of trastuzumab resistance will allow individualization of HER2-targeted therapeutic approaches

  13. Risk analysis and protective measures for occupationally workers with technologically enhanced naturally occurring radioactive materials

    International Nuclear Information System (INIS)

    Hegazy, R.A.M.

    2011-01-01

    Naturally occurring radionuclides are present in many natural resources. Elevated concentrations of these radionuclides are often found in certain geological materials, namely igneous rocks and ores. Human activities that exploit these resources may lead to enhanced concentrations of radionuclides (often referred to as technologically enhanced naturally occurring radioactive material (TE-NORM). Enhanced levels of natural background radiation are encountered in many occupational industrial activities involving a large number of workers. Uncontrolled activities associated with TE-NORM can contaminate the environment and pose a risk to human health. This risk can be alleviated by the adoption of controls to identify where NORM is present; and cleaning the NORM-contaminated equipment and waste management while protecting workers. The main objective of this study is to investigate the natural radioactivity and the hazard parameters in the TE-NORM samples from different industrial activities. Also to describe the models and develop the computer codes that allow one to estimate the risk of cancer resulting from any specified dose of ionizing radiation for occupationally workers in different industrial activities. The present study deals with 50 different samples. This waste generated from petroleum fields, phosphate fertilizers samples, consumer product samples from China, ceramic and zircon samples. The radon exhalation rates calculated using solid state nuclear track detector (CR-39). The value of radon exhalation rate 58.82±5.3 x10 3 , 4.28±0.49 x10 3 and 0.306±0.025 x10 3 Bq/m 2 h for scale, sludge and sand, respectively. The value of radon exhalation rate 82.67±7.98, 62.58 ±5.7, 46.16 ±3.91 and 198.51±18.68 Bq/m 2 h for phosphate fertilizers samples, consumer product samples from China, ceramic and zircon samples, respectively. The 226 Ra activity concentrations were 301.4±771.5, 52.1±438 and 2.56±55.37 kBq/kg for scale, sludge and sand, respectively. The

  14. Production and Evaluation of 236gNp and Reference Materials for Naturally Occurring Radioactive Materials

    Science.gov (United States)

    Larijani, Cyrus Kouroush

    This thesis is based on the development of a radiochemical separation scheme capable of separating both 236gNp and 236Pu from a uranium target of natural isotopic composition ( 1 g uranium) and 200 MBq of fission decay products. The isobaric distribution of fission residues produced following the bombardment of a natural uranium target with a beam of 25 MeV protons has been evaluated. Decay analysis of thirteen isobarically distinct fission residues were carried out using high-resolution gamma-ray spectrometry at the UK National Physical Laboratory. Stoichiometric abundances were calculated via the determination of absolute activity concentrations associated with the longest-lived members of each isobaric chain. This technique was validated by computational modelling of likely sequential decay processes through an isobaric decay chain. The results were largely in agreement with previously published values for neutron bombardments on natural uranium at energies of 14 MeV. Higher relative yields of products with mass numbers A 110-130 were found, consistent with the increasing yield of these radionuclides as the bombarding energy is increased. Using literature values for the production cross-section for fusion of protons with uranium targets, it is estimated that an upper limit of approximately 250 Bq of activity from the 236Np ground state was produced in this experiment. Using a radiochemical separation scheme, Np and Pu fractions were separated from the produced fission decay products, with analyses of the target-based final reaction products made using Inductively Couple Plasma Mass Spectrometry (ICP-MS) and high-resolution alpha and gamma-ray spectrometry. In a separate research theme, reliable measurement of Naturally Occurring Radioactive Materials is of significance in order to comply with environmental regulations and for radiological protection purposes. The thesis describes the standardisation of three reference materials, namely Sand, Tuff and TiO2 which

  15. Clinicopathological and prognostic significance of HER-2/neu and VEGF expression in colon carcinomas

    Directory of Open Access Journals (Sweden)

    Li Jing

    2011-06-01

    Full Text Available Abstract Background HER-2/neu and VEGF expression is correlated with disease behaviors in various cancers. However, evidence for their expression in colon cancer is rather contradictory both for the protein expression status and prognostic value. HER-2/neu is found to participate in VEGF regulation, and has known correlation with VEGF expression in some tumors. In this study, we investigated HER-2/neu and VEGF expression in Chinese colon patients and explored whether there was any correlation between their expression patterns. Methods HER-2/neu and VEGF were investigated immunohistochemically using tumor samples obtained from 317 colon cancer patients with all tumor stages. Correlation of the degree of staining with clinicopathological parameters and survival was investigated. Results Positive expression rates of HER-2/neu and VEGF in colon cancer were 15.5% and 55.5% respectively. HER-2/neu expression was significantly correlated with tumor size and distant metastases (P (P > 0.05. Expression of VEGF was significantly correlated with tumor size, tumor stage, lymph node metastases, and distant metastases (P (P = 0.146. No correlation between HER-2/neu and VEGF expression was detected (P = 0.151. Conclusions HER-2/neu and VEGF are not important prognostic markers of colon cancer. The present results do not support any association between HER2/neu and VEGF expression in this setting.

  16. Novel anti-HER2 monoclonal antibodies: synergy and antagonism with tumor necrosis factor-α

    Directory of Open Access Journals (Sweden)

    Ceran Ceyhan

    2012-10-01

    Full Text Available Abstract Background One-third of breast cancers display amplifications of the ERBB2 gene encoding the HER2 kinase receptor. Trastuzumab, a humanized antibody directed against an epitope on subdomain IV of the extracellular domain of HER2 is used for therapy of HER2-overexpressing mammary tumors. However, many tumors are either natively resistant or acquire resistance against Trastuzumab. Antibodies directed to different epitopes on the extracellular domain of HER2 are promising candidates for replacement or combinatorial therapy. For example, Pertuzumab that binds to subdomain II of HER2 extracellular domain and inhibits receptor dimerization is under clinical trial. Alternative antibodies directed to novel HER2 epitopes may serve as additional tools for breast cancer therapy. Our aim was to generate novel anti-HER2 monoclonal antibodies inhibiting the growth of breast cancer cells, either alone or in combination with tumor necrosis factor-α (TNF-α. Methods Mice were immunized against SK-BR-3 cells and recombinant HER2 extracellular domain protein to produce monoclonal antibodies. Anti-HER2 antibodies were characterized with breast cancer cell lines using immunofluorescence, flow cytometry, immunoprecipitation, western blot techniques. Antibody epitopes were localized using plasmids encoding recombinant HER2 protein variants. Antibodies, either alone or in combination with TNF-α, were tested for their effects on breast cancer cell proliferation. Results We produced five new anti-HER2 monoclonal antibodies, all directed against conformational epitope or epitopes restricted to the native form of the extracellular domain. When tested alone, some antibodies inhibited modestly but significantly the growth of SK-BR-3, BT-474 and MDA-MB-361 cells displaying ERBB2 amplification. They had no detectable effect on MCF-7 and T47D cells lacking ERBB2 amplification. When tested in combination with TNF-α, antibodies acted synergistically on SK-BR-3 cells

  17. Analysis of molecular subtypes for the increased HER2 equivocal cases caused by application of the updated 2013 ASCO/CAP HER2 testing guidelines in breast cancer.

    Science.gov (United States)

    Guo, Lei; Yuan, Pei; Zhang, Jing; Ling, Yun; Li, Wenbin; Zhao, Bohui; Ying, Jianming; Xuan, Lixue

    2017-11-01

    Accurate testing of the status of human epidermal growth factor receptor type 2 (HER2) is a prerequisite for HER2-directed therapy. The American Society of Clinical Oncology (ASCO) and the College of American Pathologists (CAP) published joint guideline recommendations for HER2 testing in breast cancer in 2007 and it was updated in 2013. We compared the HER2 gene amplification status based on these two guidelines and analyzed the molecular characteristics of the equivocal cases. A total of 1894 patient samples were analyzed for both immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). HER2 FISH amplification was examined and re-assessed using 2013 guidelines. According to the 2013 ASCO/CAP recommendations, 763 (40.3%) cases were classified as HER2 positive compared with 729 (38.5%) cases defined by 2007 guidelines. There was a significant increase of 6.1% in the proportion of HER2 FISH equivocal cases that were interpreted using ASCO/CAP 2013 (7.3%) compared with 2007 (1.2%) guidelines (P guidelines, 125 cases were IHC2+ and 13 cases were IHC1+. These 125 cases included 4 double equivocal cases which were defined as equivocal by both 2007 and 2013 guidelines and 121 cases whose status was changed from negative defined by 2007 guidelines to equivocal defined by 2013 guidelines. Compared with luminal A type and luminal B type respectively, these 121 equivocal cases demonstrated no significant difference with luminal B type in T stage and N stage (P = 0.192, P = 0.421). When we divided the luminal B type into two parts that included HER2 negative cases and HER2 positive cases, the equivocal cases also showed no significant difference with these two subtypes in T stage and N stage. Our study suggested that implementation of the revised ASCO/CAP 2013 guidelines resulted in an increase of 1.7% in overall HER2 positivity rate and of 6.1% in equivocal cases. Pathological analysis revealed that these equivocal cases exhibit similar biological

  18. Mobilization of arsenic and other naturally occurring contaminants in groundwater of the Main Ethiopian Rift aquifers.

    Science.gov (United States)

    Rango, Tewodros; Vengosh, Avner; Dwyer, Gary; Bianchini, Gianluca

    2013-10-01

    This study investigates the mechanisms of arsenic (As) and other naturally occurring contaminants (F(-), U, V, B, and Mo) mobilization from Quaternary sedimentary aquifers of the Main Ethiopian Rift (MER) and their enrichment in the local groundwater. The study is based on systematic measurements of major and trace elements as well as stable oxygen and hydrogen isotopes in groundwater, coupled with geochemical and mineralogical analyses of the aquifer rocks. The Rift Valley aquifer is composed of rhyolitic volcanics and Quaternary lacustrine sediments. X-ray fluorescence (XRF) results revealed that MER rhyolites (ash, tuff, pumice and ignimbrite) and sediments contain on average 72 wt. % and 65 wt. % SiO2, respectively. Petrographic studies of the rhyolites indicate predominance of volcanic glass, sanidine, pyroxene, Fe-oxides and plagioclase. The As content in the lacustrine sediments (mean = 6.6 mg/kg) was higher than that of the rhyolites (mean: 2.5 mg/kg). The lacustrine aquifers of the Ziway-Shala basin in the northern part of MER were identified as high As risk zones, where mean As concentration in groundwater was 22.4 ± 33.5 (range of 0.60-190 μg/L) and 54% of samples had As above the WHO drinking water guideline value of 10 μg/L. Field As speciation measurements showed that most of the groundwater samples contain predominantly (~80%) arsenate-As(V) over arsenite-As(III) species. The As speciation together with field data of redox potential (mean Eh = +73 ± 65 mV) and dissolved-O2 (6.6 ± 2.2 mg/L) suggest that the aquifer is predominantly oxidative. Water-rock interactions, including the dissolution of volcanic glass produces groundwater with near-neutral to alkaline pH (range 6.9-8.9), predominance of Na-HCO3 ions, and high concentration of SiO2 (mean: 85.8 ± 11.3 mg/L). The groundwater data show high positive correlation of As with Na, HCO3, U, B, V, and Mo (R(2) > 0.5; p groundwater indicates that Fe-oxides and oxyhydroxides minerals were saturated

  19. Molecular characterization of a naturally occurring intraspecific recombinant begomovirus with close relatives widespread in southern Arabia

    KAUST Repository

    Al-Saleh, Mohammed A

    2014-06-02

    Background: Tomato leaf curl Sudan virus (ToLCSDV) is a single-stranded DNA begomovirus of tomato that causes downward leaf curl, yellowing, and stunting. Leaf curl disease results in significant yield reduction in tomato crops in the Nile Basin. ToLCSDV symptoms resemble those caused by Tomato yellow leaf curl virus, a distinct and widespread begomovirus originating in the Middle East. In this study, tomato samples exhibiting leaf curl symptoms were collected from Gezira, Sudan. The associated viral genome was molecularly characterized, analyzed phylogenetically, and an infectious clone for one isolate was constructed. Findings. The complete genomes for five newly discovered variants of ToLCSDV, ranging in size from 2765 to 2767-bp, were cloned and sequenced, and subjected to pairwise and phylogenetic analyses. Pairwise analysis indicated that the five Gezira isolates shared 97-100% nucleotide identity with each other. Further, these variants of ToLCSDV shared their highest nucleotide identity at 96-98%, 91-95%, 91-92%, and 91-92% with the Shambat, Gezira, Oman and Yemen strains of ToLCSDV, respectively. Based on the high maximum nucleotide identities shared between these ToLCSDV variants from Gezira and other previously recognized members of this taxonomic group, they are considered isolates of the Shambat strain of ToLCSDV. Analysis of the complete genome sequence for these new variants revealed that they were naturally occurring recombinants between two previously reported strains of ToLCSDV. Finally, a dimeric clone constructed from one representative ToLCSV genome from Gezira was shown to be infectious following inoculation to tomato and N. benthamiana plants. Conclusion: Five new, naturally occurring recombinant begomovirus variants (>96% shared nt identity) were identified in tomato plants from Gezira in Sudan, and shown to be isolates of the Shambat strain of ToLCSDV. The cloned viral genome was infectious in N. benthamiana and tomato plants, and symptoms

  20. Effects of naturally occurring coumarins on hepatic drug-metabolizing enzymes inmice

    International Nuclear Information System (INIS)

    Kleiner, Heather E.; Xia, Xiaojun; Sonoda, Junichiro; Zhang, Jun; Pontius, Elizabeth; Abey, Jane; Evans, Ronald M.; Moore, David D.; DiGiovanni, John

    2008-01-01

    Cytochromes P450 (P450s) and glutathione S-transferases (GSTs) constitute two important enzyme families involved in carcinogen metabolism. Generally, P450s play activation or detoxifying roles while GSTs act primarily as detoxifying enzymes. We previously demonstrated that oral administration of the linear furanocoumarins, isopimpinellin and imperatorin, modulated P450 and GST activities in various tissues of mice. The purpose of the present study was to compare a broader range of naturally occurring coumarins (simple coumarins, and furanocoumarins of the linear and angular type) for their abilities to modulate hepatic drug-metabolizing enzymes when administered orally to mice. We now report that all of the different coumarins tested (coumarin, limettin, auraptene, angelicin, bergamottin, imperatorin and isopimpinellin) induced hepatic GST activities, whereas the linear furanocoumarins possessed the greatest abilities to induce hepatic P450 activities, in particular P450 2B and 3A. In both cases, this corresponded to an increase in protein expression of the enzymes. Induction of P4502B10, 3A11, and 2C9 by xenobiotics often is a result of activation of the pregnane X receptor (PXR) and/or constitutive androstane receptor (CAR). Using a pregnane X receptor reporter system, our results demonstrated that isopimpinellin activated both PXR and its human ortholog SXR by recruiting coactivator SRC-1 in transfected cells. In CAR transfection assays, isopimpinellin counteracted the inhibitory effect of androstanol on full-length mCAR, a Gal4-mCAR ligand-binding domain fusion, and restored coactivator binding. Orally administered isopimpinellin induced hepatic mRNA expression of Cyp2b10, Cyp3a11, and GSTa in CAR(+/+) wild-type mice. In contrast, the induction of Cyp2b10 mRNA by isopimpinellin was attenuated in the CAR(-/-) mice, suggesting that isopimpinellin induces Cyp2b10 via the CAR receptor. Overall, the current data indicate that naturally occurring coumarins have

  1. Characterization of naturally occurring airborne diacetyl concentrations associated with the preparation and consumption of unflavored coffee

    Directory of Open Access Journals (Sweden)

    Jennifer S. Pierce

    2015-01-01

    Full Text Available Diacetyl, a suspected cause of respiratory disorders in some food and flavorings manufacturing workers, is also a natural component of roasted coffee. We characterized diacetyl exposures that would plausibly occur in a small coffee shop during the preparation and consumption of unflavored coffee. Personal (long- and short-term and area (long-term samples were collected while a barista ground whole coffee beans, and brewed and poured coffee into cups. Simultaneously, long-term personal samples were collected as two participants, the customers, drank one cup of coffee each per h. Air sampling and analyses were conducted in accordance with OSHA Method 1012. Diacetyl was detected in all long-term samples. The long-term concentrations for the barista and area samples were similar, and ranged from 0.013–0.016 ppm; long-term concentrations for the customers were slightly lower and ranged from 0.010–0.014 ppm. Short-term concentrations ranged from below the limit of detection (<0.0047 ppm–0.016 ppm. Mean estimated 8 h time-weighted average (8 h TWA exposures for the barista ranged from 0.007–0.013 ppm; these values exceed recommended 8 h TWA occupational exposure limits (OELs for diacetyl and are comparable to long-term personal measurements collected in various food and beverage production facilities. The concentrations measured based on area sampling were comparable to those measured in the breathing zone of the barista, thus exceedances of the recommended OELs may also occur for coffee shop workers who do not personally prepare coffee (e.g., cashier, sanitation/maintenance. These findings suggest that the practicality and scientific basis of the recommended OELs for diacetyl merit further consideration.

  2. Naturally occurring variants of human Α9 nicotinic receptor differentially affect bronchial cell proliferation and transformation.

    Directory of Open Access Journals (Sweden)

    Anna Chikova

    Full Text Available Isolation of polyadenilated mRNA from human immortalized bronchial epithelial cell line BEP2D revealed the presence of multiple isoforms of RNA coded by the CHRNA9 gene for α9 nicotinic acetylcholine receptor (nAChR. BEP2D cells were homozygous for the rs10009228 polymorphism encoding for N442S amino acid substitution, and also contained mRNA coding for several truncated isoforms of α9 protein. To elucidate the biologic significance of the naturally occurring variants of α9 nAChR, we compared the biologic effects of overexpression of full-length α9 N442 and S442 proteins, and the truncated α9 variant occurring due to a loss of the exon 4 sequence that causes frame shift and early termination of the translation. These as well as control vector were overexpressed in the BEP2D cells that were used in the assays of proliferation rate, spontaneous vs. tobacco nitrosamine 4-(methylnitrosamino-1-(3-pyridyl-1-butanone (NNK-induced cellular transformation, and tumorigenicity in cell culture and mice. Overexpression of the S442 variant significantly increased cellular proliferation, and spontaneous and NNK-induced transformation. The N442 variant significantly decreased cellular transformation, without affecting proliferation rate. Overexpression of the truncated α9 significantly decreased proliferation and suppressed cellular transformation. These results suggested that α9 nAChR plays important roles in regulation of bronchial cell growth by endogenous acetylcholine and exogenous nicotine, and susceptibility to NNK-induced carcinogenic transformation. The biologic activities of α9 nAChR may be regulated at the splicing level, and genetic polymorphisms in CHRNA9 affecting protein levels, amino acid sequence and RNA splicing may influence the risk for lung cancer.

  3. Characterization of naturally occurring airborne diacetyl concentrations associated with the preparation and consumption of unflavored coffee.

    Science.gov (United States)

    Pierce, Jennifer S; Abelmann, Anders; Lotter, Jason T; Comerford, Chris; Keeton, Kara; Finley, Brent L

    2015-01-01

    Diacetyl, a suspected cause of respiratory disorders in some food and flavorings manufacturing workers, is also a natural component of roasted coffee. We characterized diacetyl exposures that would plausibly occur in a small coffee shop during the preparation and consumption of unflavored coffee. Personal (long- and short-term) and area (long-term) samples were collected while a barista ground whole coffee beans, and brewed and poured coffee into cups. Simultaneously, long-term personal samples were collected as two participants, the customers, drank one cup of coffee each per h. Air sampling and analyses were conducted in accordance with OSHA Method 1012. Diacetyl was detected in all long-term samples. The long-term concentrations for the barista and area samples were similar, and ranged from 0.013⿿0.016 ppm; long-term concentrations for the customers were slightly lower and ranged from 0.010⿿0.014 ppm. Short-term concentrations ranged from below the limit of detection (barista ranged from 0.007⿿0.013 ppm; these values exceed recommended 8 h TWA occupational exposure limits (OELs) for diacetyl and are comparable to long-term personal measurements collected in various food and beverage production facilities. The concentrations measured based on area sampling were comparable to those measured in the breathing zone of the barista, thus exceedances of the recommended OELs may also occur for coffee shop workers who do not personally prepare coffee (e.g., cashier, sanitation/maintenance). These findings suggest that the practicality and scientific basis of the recommended OELs for diacetyl merit further consideration.

  4. 2-Deoxyadenosine triphosphate restores the contractile function of cardiac myofibril from adult dogs with naturally occurring dilated cardiomyopathy

    OpenAIRE

    Cheng, Yuanhua; Hogarth, Kaley A.; O'Sullivan, M. Lynne; Regnier, Michael; Pyle, W. Glen

    2015-01-01

    1) First report to characterize and define the contractile kinetics and defects associated with naturally occurring dilated cardiomyopathy (DCM) in dogs. 2) Novel findings that dATP is able to reverse the contractile defects associated with naturally occurring canine DCM.

  5. Characterization of Contaminant Transport using Naturally-Occurring U-Series Disequilibria - Final Report

    International Nuclear Information System (INIS)

    Murrell, Michael T.; Ku, Teh-Lung

    2001-01-01

    The interactions of mixed wastes containing radionuclides with solid rock surface and the mobility of the radionuclides in aquifer systems depend not only on the chemistry of the nuclides and the physico-chemical effects of radioactive decay, but also on the site-specific hydrogeology. Thus, to characterize contaminant transport, it is best to cross-check figures derived from any small-scale laboratory experiments over limited times with that obtained from field-oriented, natural analog studies. We propose such a study using the naturally-occurring U and Th decay-series disequilibria. The work of ours and other researchers have shown that the parent/daughter disequilibrium patterns existing in groundwater systems can be modeled in terms of local nuclide mass balance to arrive at such information as the rock-water contact time (fluid flow) and rates of contaminant transport, taking into account the retardation effect due to nuclide/rock interaction contaminants at INEL by grouping them into three categories, represented by isotopes of (1) Th and Pa, (2) U and (3) Ra. Mass spectrometric measurements of these elements will be emphasized in order to minimize sample size requirements and to maximize precision. Results will form the data base for a model code for computing: (1) Fluid residence time (transport rates) in the basalt aquifers at various locations, (2) The in-situ adsorption and desorption rate constants, as well as the retardation factors, of various radionuclide wastes, and (3) Rock dissolution rate and its relation to preferential flow and contamination transport in the fractured rock

  6. Further evidence for GHB naturally occurring in common non-alcoholic beverages.

    Science.gov (United States)

    Elliott, Simon P; Fais, Paolo

    2017-08-01

    GHB has been implicated in many cases of suspected surreptitious administration with the purpose of increasing victim vulnerability to sexual assault. Low amounts of endogenous (or naturally occurring) GHB, which do not reach pharmacologically active levels, have been detected in alcoholic and non-alcoholic beverages. Due to the continued requirement to obtain data on the presence of endogenous GHB in various beverage types, GHB concentrations were measured in a series of non-alcoholic beverages. Tonic water and lemon flavoured tonic water beverages were analysed at 0, 24 and 96h after the bottle opening using gas chromatography coupled to tandem mass spectrometry (GC-MS/MS) on an Agilent 6890/7000C Triple Quadrupole. GHB was detected in all beverages at very low amounts ranging from 89 to 145ng/mL (0.089-0.145mg/L) and did not demonstrate a general trend of variation for concentration along the tested time span (96h). The presented data provide additional evidence for the endogenous nature of GHB in non-alcoholic beverages at very low concentrations, which are many orders of magnitude lower than those described to produce any pharmacological effect on the subject. However, when considering a case of alleged drug-facilitated sexual assault, a low level of GHB detected in a drink may be related both to a surreptitiously GHB administration with subsequent dilution for concealment or to the presence of endogenous GHB. On this basis, a comprehensive analysis of all the available information, including circumstantial data demonstrating possible attempts to conceal GHB administration and an assessment of levels of endogenous GHB in the suspected beverage type, is of the utmost importance for a proper interpretation of the toxicological results. Copyright © 2017 Elsevier B.V. All rights reserved.

  7. Spectral analysis of naturally occurring methylxanthines (theophylline, theobromine and caffeine) binding with DNA.

    Science.gov (United States)

    Johnson, Irudayam Maria; Prakash, Halan; Prathiba, Jeyaguru; Raghunathan, Raghavachary; Malathi, Raghunathan

    2012-01-01

    Nucleic acids exist in a dynamic equilibrium with a number of molecules that constantly interact with them and regulate the cellular activities. The inherent nature of the structure and conformational integrity of these macromolecules can lead to altered biological activity through proper targeting of nucleic acids binding ligands or drug molecules. We studied the interaction of naturally occurring methylxanthines such as theophylline, theobromine and caffeine with DNA, using UV absorption and Fourier transform infrared (FTIR) spectroscopic methods, and especially monitored their binding affinity in the presence of Mg(2+) and during helix-coil transitions of DNA by temperature (T(m)) or pH melting profiles. The study indicates that all these molecules effectively bind to DNA in a dose dependent manner. The overall binding constants of DNA-theophylline = 3.5×10(3) M(-1), DNA-theobromine = 1.1×10(3) M(-1), and DNA-Caffeine = 3.8×10(3) M(-1). On the other hand T(m)/pH melting profiles showed 24-35% of enhanced binding activity of methylxanthines during helix-coil transitions of DNA rather than to its native double helical structure. The FTIR analysis divulged that theophylline, theobromine and caffeine interact with all the base pairs of DNA (A-T; G-C) and phosphate group through hydrogen bond (H-bond) interaction. In the presence of Mg(2+), methylxanthines altered the structure of DNA from B to A-family. However, the B-family structure of DNA remained unaltered in DNA-methylxanthines complexes or in the absence of Mg(2+). The spectral analyses indicated the order of binding affinity as "caffeine≥theophylline>theobromine" to the native double helical DNA, and "theophylline≥theobromine>caffeine to the denatured form of DNA and in the presence of divalent metal ions.

  8. Spectral analysis of naturally occurring methylxanthines (theophylline, theobromine and caffeine binding with DNA.

    Directory of Open Access Journals (Sweden)

    Irudayam Maria Johnson

    Full Text Available Nucleic acids exist in a dynamic equilibrium with a number of molecules that constantly interact with them and regulate the cellular activities. The inherent nature of the structure and conformational integrity of these macromolecules can lead to altered biological activity through proper targeting of nucleic acids binding ligands or drug molecules. We studied the interaction of naturally occurring methylxanthines such as theophylline, theobromine and caffeine with DNA, using UV absorption and Fourier transform infrared (FTIR spectroscopic methods, and especially monitored their binding affinity in the presence of Mg(2+ and during helix-coil transitions of DNA by temperature (T(m or pH melting profiles. The study indicates that all these molecules effectively bind to DNA in a dose dependent manner. The overall binding constants of DNA-theophylline = 3.5×10(3 M(-1, DNA-theobromine = 1.1×10(3 M(-1, and DNA-Caffeine = 3.8×10(3 M(-1. On the other hand T(m/pH melting profiles showed 24-35% of enhanced binding activity of methylxanthines during helix-coil transitions of DNA rather than to its native double helical structure. The FTIR analysis divulged that theophylline, theobromine and caffeine interact with all the base pairs of DNA (A-T; G-C and phosphate group through hydrogen bond (H-bond interaction. In the presence of Mg(2+, methylxanthines altered the structure of DNA from B to A-family. However, the B-family structure of DNA remained unaltered in DNA-methylxanthines complexes or in the absence of Mg(2+. The spectral analyses indicated the order of binding affinity as "caffeine≥theophylline>theobromine" to the native double helical DNA, and "theophylline≥theobromine>caffeine to the denatured form of DNA and in the presence of divalent metal ions.

  9. Potential environmental and regulatory implications of naturally occurring radioactive materials (NORM)

    International Nuclear Information System (INIS)

    Paschoa, A.S.

    1998-01-01

    The immense volume of naturally occurring radioactive materials (NORM) wastes produced annually by extracting industries throughout the world deserves to come to the attention of international and national environmental protection agencies and regulatory bodies. Although a great deal of work has been done in the fields of radiation protection and remedial actions concerning uranium and other mines, the need to dispose of diffuse NORM wastes will have environmental and regulatory implications that thus far are not fully appreciated. NORM wastes constitute, by and large, unwanted byproducts of industrial activities as diverse as thorium and uranium milling, niobium, tin and gold mining extraction, water treatment, and the production of oil, gas, phosphate fertilizer, coal fire and aluminium. The volumes of NORM wastes produced annually could reach levels so high that the existing low level radioactive waste (LLRW) facilities would be readily occupied by NORM if controlled disposal procedures were not adopted. On the other hand, NORM cannot just be ignored as being below radiological concern (BRC) or lower than exempt concentration levels (ECLs), because sometimes NORM concentrations reach levels as high as 1 x 10 3 kBq/kg for 226 Ra, and not much less for 228 Ra. Unfortunately, thus far, there is not enough information available concerning NORM wastes in key industries, though the international scientific community has been concerned, for a long time now, with technologically enhanced natural radiation exposures (TENRE). This article is written with the intention of examining, to the extent possible, the potential environmental and regulatory implications of NORM wastes being produced in selected industries. (Author)

  10. Naturally Occurring Radioactive Materials in Uranium-Rich Coals and Associated Coal Combustion Residues from China.

    Science.gov (United States)

    Lauer, Nancy; Vengosh, Avner; Dai, Shifeng

    2017-11-21

    Most coals in China have uranium concentrations up to 3 ppm, yet several coal deposits are known to be enriched in uranium. Naturally occurring radioactive materials (NORM) in these U-rich coals and associated coal combustion residues (CCRs) have not been well characterized. Here we measure NORM (Th, U, 228 Ra, 226 Ra, and 210 Pb) in coals from eight U-rich coal deposits in China and the associated CCRs from one of these deposits. We compared NORM in these U-rich coals and associated CCRs to CCRs collected from the Beijing area and natural loess sediments from northeastern China. We found elevated U concentrations (up to 476 ppm) that correspond to low 232 Th/ 238 U and 228 Ra/ 226 Ra activity ratios (≪1) in the coal samples. 226 Ra and 228 Ra activities correlate with 238 U and 232 Th activities, respectively, and 226 Ra activities correlate well with 210 Pb activities across all coal samples. We used measured NORM activities and ash yields in coals to model the activities of CCRs from all U-rich coals analyzed in this study. The activities of measured and modeled CCRs derived from U-rich coals exceed the standards for radiation in building materials, particularly for CCRs originating from coals with U > 10 ppm. Since beneficial use of high-U Chinese CCRs in building materials is not a suitable option, careful consideration needs to be taken to limit potential air and water contamination upon disposal of U- and Ra-rich CCRs.

  11. Naturally occurring radionuclides transfer factor on aquatic flora and fauna in Nagarjuna Sagar Dam near proposed uranium mining site

    International Nuclear Information System (INIS)

    Arunachalam, Kantha Deivi

    2015-04-01

    Naturally occurring radioactive element can be found in low levels within all rock, soil, and water. The present work aims to understand the transfer of naturally occurring radionuclides in different compartments of environment reflecting its behaviour in different tropic levels. The understanding and evaluation of the possible interactions of various naturally occurring radionuclides were done in the world's third largest man-made dam, Nagarjuna Sagar, built on river Krishna located in Andhra Pradesh, India. The naturally occurring radionuclides such as Uranium ( 238 U), Polonium ( 210 Po), Radium ( 226 Ra), and Lead ( 210 Pb) were analyzed in different matrices (i.e) sediment, water, and fish. The measurement of the naturally occurring radionuclides in the environment can be used as a reference baseline for long-term monitoring in the entire aquatic ecosystem

  12. Characterization of a naturally occurring breast cancer subset enriched in EMT and stem cell characteristics

    Energy Technology Data Exchange (ETDEWEB)

    Hennessy, Bryan T.; Gonzalez-Angulo, Ana-Maria; Stemke-Hale, Katherine; Gilcrease, Michael Z.; Krishnamurthy, Savitri; Lee, Ju-Seog; Fridlyand, Jane; Sahin, Aysegul; Agarwal, Roshan; Joy, Corwin; Liu, Wenbin; Stivers, David; Baggerly, Keith; Carey, Mark; Lluch, Ana; Monteagudo, Carlos; He, Xiaping; Weigman, Victor; Fan, Cheng; Palazzo, Juan; Hortobagyi, Gabriel N.; Nolden, Laura K.; Wang, Nicholas J.; Valero, Vicente; Gray, Joe W.; Perou, Charles M.; Mills, Gordon B.

    2009-05-19

    Metaplastic breast cancers (MBC) are aggressive, chemoresistant tumors characterized by lineage plasticity. To advance understanding of their pathogenesis and relatedness to other breast cancer subtypes, 28 MBCs were compared with common breast cancers using comparative genomic hybridization, transcriptional profiling, and reverse-phase protein arrays and by sequencing for common breast cancer mutations. MBCs showed unique DNA copy number aberrations compared with common breast cancers. PIK3CA mutations were detected in 9 of 19 MBCs (47.4%) versus 80 of 232 hormone receptor-positive cancers (34.5%; P = 0.32), 17 of 75 HER-2-positive samples (22.7%; P = 0.04), 20 of 240 basal-like cancers (8.3%; P < 0.0001), and 0 of 14 claudin-low tumors (P = 0.004). Of 7 phosphatidylinositol 3-kinase/AKT pathway phosphorylation sites, 6 were more highly phosphorylated in MBCs than in other breast tumor subtypes. The majority of MBCs displayed mRNA profiles different from those of the most common, including basal-like cancers. By transcriptional profiling, MBCs and the recently identified claudin-low breast cancer subset constitute related receptor-negative subgroups characterized by low expression of GATA3-regulated genes and of genes responsible for cell-cell adhesion with enrichment for markers linked to stem cell function and epithelial-to-mesenchymal transition (EMT). In contrast to other breast cancers, claudin-low tumors and most MBCs showed a significant similarity to a 'tumorigenic' signature defined using CD44{sup +}/CD24{sup -} breast tumor-initiating stem cell-like cells. MBCs and claudin-low tumors are thus enriched in EMT and stem cell-like features, and may arise from an earlier, more chemoresistant breast epithelial precursor than basal-like or luminal cancers. PIK3CA mutations, EMT, and stem cell-like characteristics likely contribute to the poor outcomes of MBC and suggest novel therapeutic targets.

  13. Immunotherapy with a HER2-Targeting Listeria Induces HER2-Specific Immunity and Demonstrates Potential Therapeutic Effects in a Phase I Trial in Canine Osteosarcoma.

    Science.gov (United States)

    Mason, Nicola J; Gnanandarajah, Josephine S; Engiles, Julie B; Gray, Falon; Laughlin, Danielle; Gaurnier-Hausser, Anita; Wallecha, Anu; Huebner, Margie; Paterson, Yvonne

    2016-09-01

    Recombinant Listeria vaccines induce tumor-specific T-cell responses that eliminate established tumors and prevent metastatic disease in murine cancer models. We used dogs with HER2/neu(+) appendicular osteosarcoma, a well-recognized spontaneous model for pediatric osteosarcoma, to determine whether a highly attenuated, recombinant Listeria monocytogenes expressing a chimeric human HER2/neu fusion protein (ADXS31-164) could safely induce HER2/neu-specific immunity and prevent metastatic disease. Eighteen dogs that underwent limb amputation or salvage surgery and adjuvant chemotherapy were enrolled in a phase I dose escalation clinical trial and received either 2 × 10(8), 5 × 10(8), 1 × 10(9), or 3.3 × 10(9) CFU of ADXS31-164 intravenously every 3 weeks for 3 administrations. Only low-grade, transient toxicities were observed. ADXS31-164 broke peripheral tolerance and induced antigen-specific IFNγ responses against the intracellular domain of HER2/neu in 15 of 18 dogs within 6 months of treatment. Furthermore, ADXS31-164 reduced the incidence of metastatic disease and significantly increased duration of survival time and 1-, 2-, and 3-year survival rates when compared with a historical control group with HER2/neu(+) appendicular osteosarcoma treated with amputation and chemotherapy alone. These findings demonstrate that ADXS31-164 administered in the setting of minimal residual disease can induce HER2/neu-specific immunity and may reduce the incidence of metastatic disease and prolong overall survival in a clinically relevant, spontaneous, large animal model of cancer. These findings, therefore, have important translational relevance for children with osteosarcoma and adults with other HER2/neu(+) cancers. Clin Cancer Res; 22(17); 4380-90. ©2016 AACR. ©2016 American Association for Cancer Research.

  14. Reciprocal regulation of annexin A2 and EGFR with Her-2 in Her-2 negative and herceptin-resistant breast cancer.

    Directory of Open Access Journals (Sweden)

    Praveenkumar K Shetty

    Full Text Available Alternative survival pathways are commonly seen to be upregulated upon inhibition of receptor tyrosine kinases (RTK, including Her-2. It is established that treatment with Herceptin leads to selective overexpression and activation of epidermal growth factor receptor (EGFR and Src which further contributes to oncogenesis in Herceptin resistant and triple negative breast cancer (TNBC patients. Here, we show a co-regulated upregulation in the expression of Annexin A2 (AnxA2, a known substrate of Src and one of the regulators of EGFR receptor endocytosis, in Herceptin resistant and Her-2 negative breast cancer. Immunohistochemical expression analysis revealed a reciprocal regulation between Her-2 and AnxA2 in breast cancer clinical samples as well as in cell lines as confirmed by protein and RNA analysis. The siRNA and Herceptin mediated downregulation/inhibition of Her-2 in Her-2 amplified cells induced AnxA2 expression and membrane translocation. In this study we report a possible involvement of AnxA2 in maintaining constitutively activated EGFR downstream signaling intermediates and hence in cell proliferation, migration and viability. This effect was consistent in Herceptin resistant JIMT-1 cells as well as in Her-2 negative breast cancer. The siRNA mediated AnxA2 downregulation leads to increased apoptosis, decreased cell viability and migration. Our studies further indicate the role of AnxA2 in EGFR-Src membrane bound signaling complex and ligand induced activation of downstream signaling pathways. Targeting this AnxA2 dependent positive regulation of EGFR signaling cascade may be of therapeutic value in Her-2 negative breast cancer.

  15. Pennsylvania's technologically enhanced, naturally occurring radioactive material experiences and studies of the oil and gas industry.

    Science.gov (United States)

    Allard, David J

    2015-02-01

    This presentation provides an overview of the Commonwealth of Pennsylvania's experiences and ongoing studies related to technologically enhanced, naturally occurring radioactive material (TENORM) in the oil and gas industry. It has been known for many years that Pennsylvania's geology is unique, with several areas having relatively high levels of natural uranium and thorium. In the 1950s, a few areas of the state were evaluated for commercial uranium production. In the late 1970s, scoping studies of radon in homes prompted the Pennsylvania Department of Environmental Protection (DEP) Bureau of Radiation Protection (BRP) to begin planning for a larger state-wide radon study. The BRP and Oil and Gas Bureau also performed a TENORM study of produced water in the early 1990s for a number of conventional oil and gas wells. More recently, BRP and the Bureau of Solid Waste developed radiation monitoring regulations for all Pennsylvania solid waste disposal facilities. These were implemented in 2001, prompting another evaluation of oil and gas operations and sludge generated from the treatment of conventionally produced water and brine but mainly focused on the disposal of TENORM solid waste in the state's Resource Conservation and Recovery Act Subtitle D landfills. However, since 2008, the increase in volumes of gas well wastewater and levels of Ra observed in the unconventional shale gas well flow-back fracking water has compelled DEP to fully re-examine these oil and gas operations. Specifically, with BRP in the lead, a new TENORM study of oil and gas operations and related wastewater treatment operations has been initiated (), supported by an American National Standards Institute standard on TENORM () and a U.S. Government Accountability Office report on shale resource development and risks (). This study began in early 2013 and will examine the potential public and worker radiation exposure and environmental impact as well as re-evaluate TENORM waste disposal. This

  16. Almera Proficiency Test Determination of Naturally Occurring Radionuclides in Phosphogypsum and Water

    International Nuclear Information System (INIS)

    2010-01-01

    Phosphogypsum is generated as a by-product of the phosphoric acid based fertilizer industry. The discharge of phosphogypsum on earth surface deposits is a potential source of enhanced natural radiation and heavy metals, and the resulting environmental impact should be considered carefully to ensure safety and compliance with environmental regulations. A reliable determination of technologically enhanced naturally occurring radioactive materials in phosphogypsum is necessary to comply with the radiation protection and environmental regulations. This proficiency test (PT) is one of the series of the ALMERA network proficiency tests organised on a regular basis by the Chemistry Unit of the IAEA Terrestrial Environment Laboratory. These proficiency tests are designed to identify analytical problems, to support Member States laboratories to maintain their preparedness and to provide rapid and reliable analytical results. In this PT, the test item set consisted of six samples: one phosphogypsum (the IAEA-434 reference material) and five water samples spiked with natural radionuclides. The main task of the participating laboratories was to identify and quantify the activity levels of radionuclides present in these matrices. The tasks of IAEA were to prepare and distribute the samples to the participating laboratories, to collect and interpret analysis results and to compile a comprehensive report. The certified massic activity values of all radionuclides used in this PT were fulfilling the requirements of metrological traceability to international standards of radioactivity. In this PT, 306 test items (reference materials) were prepared and distributed to 52 participants from 40 countries in November 2008. The deadline for receiving the results from the participants was set to15 May 2009. For gross alpha/beta results the deadline was one working day from the date of sample delivery. The participating laboratories were requested to analyse Ra-226, U-234 and U-238 in water

  17. Alternatives for the disposal of NORM [naturally occurring radioactive materials] wastes in Texas

    International Nuclear Information System (INIS)

    Nielson, K.K.; Rogers, V.C.; Pollard, C.G.

    1989-01-01

    Some of the Texas wastes containing naturally occurring radioactive materials (NORM) have been disposed of in a uranium mill tailings impoundment. There is currently no operating disposal facility in Texas to accept these wastes. As a result, some wastes containing extremely small amounts of radioactivity are sent to elaborate disposal sites at extremely high costs. The Texas Low-Level Radioactive Waste Disposal Authority has sponsored a study to investigate lower cost, alternative disposal methods for certain wastes containing small quantities of NORM. This paper presents the results of a multipathway safety analysis of various scenarios for disposing of wastes containing limited quantities of NORM in Texas. The wastes include pipe scales and sludges from oil and gas production, residues from rare-earth mineral processing, and water treatment resins, but exclude large-volume, diffuse wastes (coal fly ash, phosphogypsum). The purpose of the safety analysis is to define concentration and quantity limits for the key nuclides of NORM that will avoid dangerous radiation exposures under different waste disposal scenarios

  18. Studies of two naturally occurring compounds which effect release of acetylcholine from synaptosomes

    International Nuclear Information System (INIS)

    Koenig, M.L.

    1985-01-01

    Two naturally occurring compounds which effect the release of neurotransmitter from synaptosomes have been purified to apparent homogeneity. Iotrochotin (IOT) isolated from wound exudate of the Caribbean purple bleeder sponge promotes release in a manner that is independent of the extracellular Ca 2+ ion concentration. Leptinotarsin (LPT-d), a protein taken from hemolymph of the Colorado potato beetle, Leptinotarsa decemlineata, stimulates Ca 2+ -dependent release. IOT is slightly acidic and has a molecular weight of approximately 18 kD. [ 3 H]acetylcholine which has been introduced into synaptosomes as [ 3 H]choline can be released by IOT. The toxin releasable pool of labelled neurotransmitter is not depleted by depolarization of the synaptosomes with high potassium, and therefore seems to be primarily extravesicular. LPT-d is a larger protein (molecular weight = 45 kD) than IOT, and seems to effect primarily vesicular release by opening at least one type of presynaptic Ca 2+ channel. The facilitatory effects of the toxin on synaptosomal release can be inhibited by inorganic Ca 2+ channel antagonists, but are not generally affected by organic antagonists

  19. Regulatory Initiatives for Control and Release of Technologically Enhanced Naturally-Occurring Radioactive Materials

    Energy Technology Data Exchange (ETDEWEB)

    Egidi, P.V.

    1999-03-02

    Current drafts of proposed standards and suggested State regulations for control and release of technologically-enhanced naturally-occurring radioactive material (TENORM), and standards for release of volumetrically-contaminated material in the US are reviewed. These are compared to the recommendations of the International Atomic Energy Association (IAEA) Safety Series and the European Commission (EC) proposals. Past regulatory efforts with respect to TENORM in the US dealt primarily with oil-field related wastes. Currently, nine states (AK, GA, LA, MS, NM, OH, OR SC, TX) have specific regulations pertaining to TENORM, mostly based on uranium mill tailings cleanup criteria. The new US proposals are dose- or risk-based, as are the IAEA and EC recommendations, and are grounded in the linear no threshold hypothesis (LNT). TENORM wastes involve extremely large volumes, particularly scrap metal and mine wastes. Costs to control and dispose of these wastes can be considerable. The current debate over the validity of LNT at low doses and low dose rates is particularly germane to this discussion. Most standards setting organizations and regulatory agencies base their recommendations on the LNT. The US Environmental Protection Agency has released a draft Federal Guidance Report that recommends calculating health risks from low-level exposure to radionuclides based on the LNT. However, some scientific and professional organizations are openly questioning the validity of LNT and its basis for regulations, practices, and costs to society in general. It is not clear at this time how a non-linear regulatory scheme would be implemented.

  20. Construction of a naturally occurring radioactive material project in the BeAAT hazardous waste facilities.

    Science.gov (United States)

    Abuahmad, H

    2015-06-01

    This paper does not necessarily reflect the views of the International Commission on Radiological Protection. Naturally occurring radioactive material (NORM) is produced during exploration and production operations of subsidiaries of the Abu Dhabi National Oil Company (ADNOC) in the United Arab Emirates, and accumulates in drilling tubulars, plant equipment, and components. These NORM hazardous wastes need to be managed in such a way that they do not damage human health and the environment. The primary radionuclides of concern in the oil and gas industries are radium-226 and radium-228. These radioisotopes are the decay products of uranium and thorium isotopes that are present in subsurface formations from which hydrocarbons are produced. While uranium and thorium are largely immobile, radium is slightly more soluble and may become mobilised in the fluid phases of the formation (International Association of Oil & Gas Producers, 2008). In order to treat and dispose of NORM waste products safely, ADNOC's subsidiary 'TAKREER' is developing a new facility, on behalf of all ADNOC subsidiaries, within the existing Central Environmental Protection Facilities (BeAAT) in Ruwais city. The NORM plant is envisaged to treat, handle, and dispose of NORM waste in the forms of scale, sludge, and contaminated equipment. The NORM treatment facility will cover activities such as decontamination, volume reduction, NORM handling, and concrete immobilisation of NORM waste into packages for designated landfilling. © The International Society for Prosthetics and Orthotics Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.

  1. Assessment of environmental impact models in natural occurring radionuclides solid wastes disposal from the mineral industry

    International Nuclear Information System (INIS)

    Pontedeiro, Elizabeth May Braga Dulley

    2006-07-01

    This work evaluates the behavior of wastes with naturally occurring radionuclides as generated by the mineral industry and their final disposal in landfills. An integrated methodology is used to predict the performance of an industrial landfill for disposal of wastes containing NORM/TENORM, and to define acceptable amounts that can be disposed at the landfill using long-term environmental assessment. The governing equations for radionuclide transport are solved analytically using the generalized integral transform technique. Results obtained for each compartment of the biogeosphere are validated with experimental results or compared to other classes of solutions. An impact analysis is performed in order to define the potential consequences of a landfill to the environment, considering not only the engineering characteristics of the waste deposit but also the exposure pathways and plausible scenarios in which the contaminants could migrate and reach the environment and the human population. The present work permits the development of a safety approach that can be used to derive quantitative waste acceptance criteria for the disposal of NORM/TENORM waste in landfills. (author)

  2. Bismuth solubility through binding by various organic compounds and naturally occurring soil organic matter.

    Science.gov (United States)

    Murata, Tomoyoshi

    2010-01-01

    The present study was performed to examine the effects of soluble organic matter and pH on the solubility of Bi in relation to inference with the behavior of metallic Bi dispersed in soil and water environments using EDTA, citric acid, tartaric acid, L-cysteine, soil humic acids (HA), and dissolved organic matter (DOM) derived from the soil organic horizon. The solubility of Bi by citric acid, tartaric acid, L-cysteine, HA, and DOM showed pH dependence, while that by EDTA did not. Bi solubility by HA seemed to be related to the distribution of pKa (acid dissociation constant) values of acidic functional groups in their molecules. That is, HA extracted at pH 3.2 solubilized Bi preferentially in the acidic range, while HA extracted at pH 8.4 showed preferential solubilization at neutral and alkaline pH. This was related to the dissociation characteristics of functional groups, their binding capacity with Bi, and precipitation of Bi carbonate or hydroxides. In addition to the dissociation characteristics of functional groups, the unique structural configuration of the HA could also contribute to Bi-HA complex formation. The solubility of Bi by naturally occurring DOM derived from the soil organic horizon (Oi) and its pH dependence were different from those associated with HA and varied among tree species.

  3. Use of naturally occurring mercury to determine the importance of cutthroat trout to Yellowstone grizzly bears

    Science.gov (United States)

    Felicetti, L.A.; Schwartz, C.C.; Rye, R.O.; Gunther, K.A.; Crock, J.G.; Haroldson, M.A.; Waits, L.; Robbins, C.T.

    2004-01-01

    Spawning cutthroat trout (Oncorhynchus clarki (Richardson, 1836)) are a potentially important food resource for grizzly bears (Ursus arctos horribilis Ord, 1815) in the Greater Yellowstone Ecosystem. We developed a method to estimate the amount of cutthroat trout ingested by grizzly bears living in the Yellowstone Lake area. The method utilized (i) the relatively high, naturally occurring concentration of mercury in Yellowstone Lake cutthroat trout (508 ± 93 ppb) and its virtual absence in all other bear foods (6 ppb), (ii) hair snares to remotely collect hair from bears visiting spawning cutthroat trout streams between 1997 and 2000, (iii) DNA analyses to identify the individual and sex of grizzly bears leaving a hair sample, (iv) feeding trials with captive bears to develop relationships between fish and mercury intake and hair mercury concentrations, and (v) mercury analyses of hair collected from wild bears to estimate the amount of trout consumed by each bear. Male grizzly bears consumed an average of 5 times more trout/kg bear than did female grizzly bears. Estimated cutthroat trout intake per year by the grizzly bear population was only a small fraction of that estimated by previous investigators, and males consumed 92% of all trout ingested by grizzly bears.

  4. Treatment of Obesity-Related Complications with Novel Classes of Naturally Occurring PPAR Agonists.

    Science.gov (United States)

    Bassaganya-Riera, Josep; Guri, Amir J; Hontecillas, Raquel

    2011-01-01

    The prevalence of obesity and its associated comorbidities has grown to epidemic proportions in the US and worldwide. Thus, developing safe and effective therapeutic approaches against these widespread and debilitating diseases is important and timely. Activation of peroxisome proliferator-activated receptors (PPARs) α, γ, and δ through several classes of pharmaceuticals can prevent or treat a variety of metabolic and inflammatory diseases, including type II diabetes (T2D). Thus, PPARs represent important molecular targets for developing novel and better treatments for a wide range of debilitating and widespread obesity-related diseases and disorders. However, available PPAR γ agonistic drugs such as Avandia have significant adverse side effects, including weight gain, fluid retention, hepatotoxicity, and congestive heart failure. An alternative to synthetic agonists of PPAR γ is the discovery and development of naturally occurring and safer nutraceuticals that may be dual or pan PPAR agonists. The purpose of this paper is to summarize the health effects of three plant-derived PPAR agonists: abscisic acid (ABA), punicic acid (PUA), and catalpic acid (CAA) in the prevention and treatment of chronic inflammatory and metabolic diseases and disorders.

  5. Theoretical simulations on the antioxidant mechanism of naturally occurring flavonoid: A DFT approach

    International Nuclear Information System (INIS)

    Praveena, R.; Sadasivam, K.

    2016-01-01

    Synthetic antioxidants such as butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT) are found to be toxic, hence non-carcinogenic naturally occurring radical scavengers especially flavonoids have gained considerable importance in the past two decades. In the present investigation, the radical scavenging activity of C-glycosyl flavonoids is evaluated using theoretical approach which could broaden its scope in therapeutic applications. Gas and solvent phase studies of structural and molecular characteristics of C-glycosyl flavonoid, isovitexin is investigated through hydrogen atom transfer mechanism (HAT), Electron transfer-proton transfer (ET–PT) and Sequential proton loss electron transfer (SPLET) by Density functional theory (DFT) using hybrid parameters. The computed values of the adiabatic ionization potential, electron affinity, hardness, softness, electronegativity and electrophilic index indicate that isovitexin possess good radical scavenging activity. The behavior of different –OH groups in polyphenolic compounds is assessed by considering electronic effects of the neighbouring groups and the overall geometry of molecule which in turn helps in analyzing the antioxidant capacity of the polyphenolic molecule. The studies indicate that the H–atom abstraction from 4’–OH site is preferred during the radical scavenging process. From Mulliken spin density analysis and FMOs, B–ring is found to be more delocalized center and capable of electron donation. Comparison of antioxidant activity of vitexin and isovitexin leads to the conclusion that isovitexin acts as a better radical scavenger. This is an evidence for the importance of position of glucose unit in the flavonoid.

  6. Characterization of naturally occurring radioactive materials and Cobald-60 contaminated ferrous scraps from steel industries

    International Nuclear Information System (INIS)

    Chao, H.E.; Chiu, H.S.; Hunga, J.Y.; His, H.W.; Chen, Y.B.

    2002-01-01

    Since the occurrence of radioactively contaminated rebar incident in 1992, steel industries in Taiwan were encouraged by Atomic Energy Council (AEC) to install portal monitor to detect the abnormal radiation in shipments of metal scrap feed. From 1994 through 1999, there were 53 discoveries of radioactivity in ferrous scraps by steel companies. These include 15 orphan radioactive sources, 16 cobalt-60 contaminated rebars, 20 Naturally Occurring Radioactive Material (NORM) contaminated scraps, and two unknowns. Most NORM-contaminated scraps were from abroad. The NORM and cobalt-60 contaminated scraps were taken from the steel mills and analyzed in laboratory. The analytical results of scales and sludge sampled from NORM-contaminated scraps combining with the circumstantial evidences indicate that five possible industrial processes may be involved. They are oil production and treatment, heavy mineral sand benefication and rare earth processing, copper mining and processing, recovery of ammonium chloride by lime adsorption in Ammonium-soda process, and tailing of uranium enrichment process. The cobalt-60 activity and trace elements concentrations of contaminated rebars confirm that all of them were produced domestically in the period from Oct. 1982 to Jan. 1983, when the cobalt-60 sources were lost and entered the electric arc furnace to produce the contaminated rebars. (author)

  7. Ocean disposal option for bulk wastes containing naturally occurring radionuclides: an assessment case history

    International Nuclear Information System (INIS)

    Stull, E.A.; Merry-Libby, P.

    1985-01-01

    There are 180,000 m 3 of slightly contaminated radioactive wastes (36 pCi/g radium-226) currently stored at the US Department of Energy's Niagara Falls Storage Site (NFSS), near Lewiston, New York. These wastes resulted from the cleanup of soils that were contaminated above the guidelines for unrestricted use of property. An alternative to long-term management of these wastes on land is dispersal in the ocean. A scenario for ocean disposal is presented for excavation, transport, and emplacement of these wastes in an ocean disposal site. The potential fate of the wastes and impacts on the ocean environment are analyzed, and uncertainties in the development of two worst-case scenarios for dispersion and pathway analyses are discussed. Based on analysis of a worst-case pathway back to man, the incremental dose from ingesting fish containing naturally occurring radionuclides from ocean disposal of the NFSS wastes is insignificant. Ocean disposal of this type of waste appears to be a technically promising alternative to the long-term maintenance costs and eventual loss of containment associated with management in a near-surface land burial facility

  8. Perceived risks of produced water management and naturally occurring radioactive material content in North Dakota.

    Science.gov (United States)

    Torres, Luisa; Yadav, Om Prakash; Khan, Eakalak

    2017-07-01

    Unconventional oil and gas development using hydraulic fracturing has caused conflict and controversy across the globe including the U.S. where some States banned the practice. Nevertheless, North Dakota (ND) has supported the practice because the State perceives the risks to be acceptable and because it has brought growth and opportunities to small communities. However, social acceptance of new technology is based on a number of factors and not contingent on economic benefits. To date, no research has been conducted to understand public risk perception of hazards associated with produced water from hydraulic fracturing in ND. This study focuses on understanding the risk perception of select ND stakeholder groups regarding produced water management and naturally occurring radioactive material. The software Qualtrics was used to create an online survey, collect data, and perform statistical analysis. The most important variables that seem to influence risk perception are the images and thoughts associated with produced water, level of knowledge about produced water handling and content, and knowing how to proceed in case of a spill of produced water. Overall, social risk perception could be in alignment with actual technical risk if availability of objective information is improved. Copyright © 2017 Elsevier Ltd. All rights reserved.

  9. Safe Management of natural Occurring radionuclides Materials (NORM) from Petroleum Industry in Egypt

    International Nuclear Information System (INIS)

    El-Hussany, B.S.

    2015-01-01

    The isolation of radioactive waste from the environment becomes a real problem need to solve in the last half century. Waste management system is created for safe isolation of the waste. Radioactive waste management including all activities, administrative and operational, That are involved in the handling, conditioning, transport, storage and disposal of radioactive wastes. In petroleum and gas industries there are many wastes containing natural occurring radioactive waste (NORM). The concentration of NORM is increased during the different processes. Accumulation of NORM in these areas makes hazard effects on the workers and on the environment. In Egypt, there are many oil and gas industries in different areas of the republic. Most of these exploration sites containing large amounts of NORM waste. The management of this waste is remained unclear for many companies. Some companies have storage designs for the waste. Others are stored the waste on the working site on land without barriers. Additionally final destination of these wastes is not decided. The improper management of this waste lead to hazard effects to workers in the present time and to public in the future. The present work studies the NORM waste management, from petroleum industry, in Egypt. Strategy of NORM is proposed. NORM waste management steps (system) is also proposed, Incineration and deoiling processes for the treatment of NORM waste are compered. Also in this study, human intrusion scenarios were studied for two NORM storage designs, A) above-ground and B) under-ground bunkers

  10. Previous management practices for naturally occurring radionuclide wastes: current radiological status

    International Nuclear Information System (INIS)

    Goldsmith, W.A.; Crawford, D.J.; Haywood, F.F.; Leggett, R.Q.

    1979-01-01

    Many installations used during the early days of the United States atomic energy program have been released in recent years for unrestricted private uses. These installations include lands and buildings used for the storage of radioactive wastes resulting from refining and processing of uranium and thorium. Waste management practices at these sites in the 1940's and 1950's were not conducted with today's emphasis on as-low-as-reasonably-achievable (ALARA) principles. Consequently, many of these older waste storage areas are contaminated with naturally occurring radionuclides in concentrations which are orders of magnitude greater than those found ordinarily in the earth's crust. current and potential elevated human exposures at fifteen of these sites are due primarily to radon daughters and external-gamma radiation. A wide variety of exposure conditions may be found at these sites - ranging from slightly above background to more than thirty times the guidelines recommended for the public. Remedial actions are contemplated for a number of these sites where contamination levels or radiaion exposures exceed current guidelines

  11. Naturally occurring 32 Si and low-background silicon dark matter detectors

    Energy Technology Data Exchange (ETDEWEB)

    Orrell, John L.; Arnquist, Isaac J.; Bliss, Mary; Bunker, Raymond; Finch, Zachary S.

    2018-05-01

    The naturally occurring radioisotope Si-32 represents a potentially limiting background in future dark matter direct-detection experiments. We investigate sources of Si-32 and the vectors by which it comes to reside in silicon crystals used for fabrication of radiation detectors. We infer that the Si-32 concentration in commercial single-crystal silicon is likely variable, dependent upon the specific geologic and hydrologic history of the source (or sources) of silicon “ore” and the details of the silicon-refinement process. The silicon production industry is large, highly segmented by refining step, and multifaceted in terms of final product type, from which we conclude that production of Si-32-mitigated crystals requires both targeted silicon material selection and a dedicated refinement-through-crystal-production process. We review options for source material selection, including quartz from an underground source and silicon isotopically reduced in Si-32. To quantitatively evaluate the Si-32 content in silicon metal and precursor materials, we propose analytic methods employing chemical processing and radiometric measurements. Ultimately, it appears feasible to produce silicon-based detectors with low levels of Si-32, though significant assay method development is required to validate this claim and thereby enable a quality assurance program during an actual controlled silicon-detector production cycle.

  12. Genetic basis of hindlimb loss in a naturally occurring vertebrate model

    Directory of Open Access Journals (Sweden)

    Emily K. Don

    2016-03-01

    Full Text Available Here we genetically characterise pelvic finless, a naturally occurring model of hindlimb loss in zebrafish that lacks pelvic fin structures, which are homologous to tetrapod hindlimbs, but displays no other abnormalities. Using a hybrid positional cloning and next generation sequencing approach, we identified mutations in the nuclear localisation signal (NLS of T-box transcription factor 4 (Tbx4 that impair nuclear localisation of the protein, resulting in altered gene expression patterns during pelvic fin development and the failure of pelvic fin development. Using a TALEN-induced tbx4 knockout allele we confirm that mutations within the Tbx4 NLS (A78V; G79A are sufficient to disrupt pelvic fin development. By combining histological, genetic, and cellular approaches we show that the hindlimb initiation gene tbx4 has an evolutionarily conserved, essential role in pelvic fin development. In addition, our novel viable model of hindlimb deficiency is likely to facilitate the elucidation of the detailed molecular mechanisms through which Tbx4 functions during pelvic fin and hindlimb development.

  13. Radiological dose assessment related to management of naturally occurring radioactive materials generated by the petroleum industry

    International Nuclear Information System (INIS)

    Smith, K.P.; Blunt, D.L.; Williams, G.P.

    1996-09-01

    A preliminary radiological dose assessment of equipment decontamination, subsurface disposal, landspreading, equipment smelting, and equipment burial was conducted to address concerns regarding the presence of naturally occurring radioactive materials (NORM) in production waste streams. The assessment estimated maximum individual dose equivalents for workers and the general public. Sensitivity analyses of certain input parameters also were conducted. On the basis of this assessment, it is concluded that (1) regulations requiring workers to wear respiratory protection during equipment cleaning operations are likely to result in lower worker doses, (2) underground injection and downhole encapsulation of NORM wastes present a negligible risk to the general public, and (3) potential doses to workers and the general public related to smelting NORM-contaminated equipment can be controlled by limiting the contamination level of the initial feed. It is recommended that (1) NORM wastes be further characterized to improve studies of potential radiological doses; (2) states be encouraged to permit subsurface disposal of NORM more readily, provided further assessments support this study; results; (3) further assessment of landspreading NORM wastes be conducted; and (4) the political, economic, sociological, and nonradiological issues related to smelting NORM-contaminated equipment be studied to fully examine the feasibility of this disposal option

  14. Regulatory Initiatives for Control and Release of Technologically Enhanced Naturally-Occurring Radioactive Material

    International Nuclear Information System (INIS)

    Egidi, P.V.

    1999-01-01

    Current drafts of proposed standards and suggested State regulations for control and release of technologically-enhanced naturally-occurring radioactive material (TENORM), and standards for release of volumetrically-contaminated material in the US are reviewed. These are compared to the recommendations of the International Atomic Energy Association (IAEA) Safety Series and the European Commission (EC) proposals. Past regulatory efforts with respect to TENORM in the US dealt primarily with oil-field related wastes. Currently, nine states (AK, GA, LA, MS, NM, OH, OR SC, TX) have specific regulations pertaining to TENORM, mostly based on uranium mill tailings cleanup criteria. The new US proposals are dose- or risk-based, as are the IAEA and EC recommendations, and are grounded in the linear no threshold hypothesis (LNT). TENORM wastes involve extremely large volumes, particularly scrap metal and mine wastes. Costs to control and dispose of these wastes can be considerable. The current debate over the validity of LNT at low doses and low dose rates is particularly germane to this discussion. Most standards setting organizations and regulatory agencies base their recommendations on the LNT. The US Environmental Protection Agency has released a draft Federal Guidance Report that recommends calculating health risks from low-level exposure to radionuclides based on the LNT. However, some scientific and professional organizations are openly questioning the validity of LNT and its basis for regulations, practices, and costs to society in general. It is not clear at this time how a non-linear regulatory scheme would be implemented

  15. Polyhydroxyester films obtained by non-catalyzed melt-polycondensation of natural occurring fatty polyhydroxyacids.

    Directory of Open Access Journals (Sweden)

    Jose Jesus Benitez

    2015-08-01

    Full Text Available Free-standing polyesters films from mono and polyhydroxylated fatty acids (C16 and C18 have been obtained by non-catalyzed melt-condensation polymerization in air at 150°C. Chemical characterization by Fourier Transform Infrared Spectroscopy (FTIR and 13C Magic Angle Spinning Nuclear Magnetic Resonance (13C MAS-NMR has confirmed the formation of the corresponding esters and the occurrence of hydroxyl partial oxidation which extent depends on the type of hydroxylation of the monomer (primary or secondary. Generally, polyester films obtained are hydrophobic, insoluble in common solvents, amorphous and infusible as revealed by X-ray Diffraction (XRD and Differential Scanning Calorimetry (DSC. In -polyhydroxy acids, esterification reaction with primary hydroxyls is preferential and, therefore, the structure can be defined as linear with variable branching depending on the amount of esterified secondary hydroxyls. The occurrence side oxidative reactions like the diol cleavage are responsible for chain cross-linking. Films are thermally stable up to 200-250°C though this limit can be extended up to 300°C in the absence of ester bonds involving secondary hydroxyls. By analogy with natural occurring fatty polyesters (i.e. cutin in higher plants these polymers are proposed as biodegradable and non-toxic barrier films or coatings to be used, for instance, in food packing

  16. Managing Naturally Occurring Radioactive Materials In the Petroleum Industry in Egypt

    International Nuclear Information System (INIS)

    Bahsat, H.; Korany, Y.

    1999-01-01

    Naturally Occurring Radioactive Materials (NORM) have been known to be present in varying concentrations in hydrocarbon reservoirs. These NORM under certain reservoir conditions can reach hazardous contamination levels.the recognition of NORM as a potential source of contamination to oil and gas facilities has become widely spread and gained increased momentum from the industry. Some contamination levels may be sufficiently severe that maintenance and other personnel may be sufficiently severe that maintenance and other personnel may be exposed to hazardous concentrations. Health and environmental concerns regarding NORM have become an important safety issue in upstream petroleum industry in Egypt since the early 1990's when NORM have been detected in different gas and oil production facilities. In these facilities, radiation protection measures were taken to realize safe handling and disposal of NORM according to the applicable international standards. This paper describes the extent of the NORM contamination problem in Egypt and presents guidelines for dealing with NORM based on the latest scientific techniques and international experiences

  17. Study of 222Rn emanation levels present in naturally occurring radioactive materials - NORM

    International Nuclear Information System (INIS)

    Miranda, Marcia Valeria F.E. Sa; Crispim, Verginia Reis; Lima, Clara Teresa S.

    2009-01-01

    The presence of Naturally Occurring Radioactive Material (NORM), contaminating oil and gas installations, is usual in the petroleum industry, and can be severe enough to expose the workers to elevated levels of radiation. The segregation of contaminated residues although necessary, is still a problem without a satisfactory solution. Currently, the most practical and economic option for discarding this material is to stock it in areas of the installation with controlled access. Certain equipment used in the petroleum industry has scale and sludge that could be associated to important levels of radioactivity. Typically, the scales are mixtures of carbonate and sulphate minerals, such as barite (BaSO 4 ), that easily incorporate 226 Ra and 228 Ra in their structures. The objective of this work was to measure the emanations of the radon present in NORM samples, via diffusion chambers containing a nuclear track detector (CR-39). The images of α particle tracks emanated by 222 Rn registered on CR-39 were observed with a Nikon E400 optic microscope and captured by a Nikon Coolpix digital camera and then stored in a database, to later count the tracks using the computational program, Image Pro plus. Since the number of those tracks resulted proportional to the emanation rate of 222 Rn this methodology allowed the comparison of contamination levels in analyzed samples. (author)

  18. Actinonin, a naturally occurring antibacterial agent, is a potent deformylase inhibitor.

    Science.gov (United States)

    Chen, D Z; Patel, D V; Hackbarth, C J; Wang, W; Dreyer, G; Young, D C; Margolis, P S; Wu, C; Ni, Z J; Trias, J; White, R J; Yuan, Z

    2000-02-15

    Peptide deformylase (PDF) is essential in prokaryotes and absent in mammalian cells, thus making it an attractive target for the discovery of novel antibiotics. We have identified actinonin, a naturally occurring antibacterial agent, as a potent PDF inhibitor. The dissociation constant for this compound was 0.3 x 10(-)(9) M against Ni-PDF from Escherichia coli; the PDF from Staphylococcus aureus gave a similar value. Microbiological evaluation revealed that actinonin is a bacteriostatic agent with activity against Gram-positive and fastidious Gram-negative microorganisms. The PDF gene, def, was placed under control of P(BAD) in E. coli tolC, permitting regulation of PDF expression levels in the cell by varying the external arabinose concentration. The susceptibility of this strain to actinonin increases with decreased levels of PDF expression, indicating that actinonin inhibits bacterial growth by targeting this enzyme. Actinonin provides an excellent starting point from which to derive a more potent PDF inhibitor that has a broader spectrum of antibacterial activity.

  19. Theoretical simulations on the antioxidant mechanism of naturally occurring flavonoid: A DFT approach

    Energy Technology Data Exchange (ETDEWEB)

    Praveena, R. [Department of Chemistry, Bannari Amman Institute of Technology, Sathyamangalam, Erode, Tamil Nadu (India); Sadasivam, K. [Department of Physics, Bannari Amman Institute of Technology, Sathyamangalam, Erode, Tamil Nadu (India)

    2016-05-06

    Synthetic antioxidants such as butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT) are found to be toxic, hence non-carcinogenic naturally occurring radical scavengers especially flavonoids have gained considerable importance in the past two decades. In the present investigation, the radical scavenging activity of C-glycosyl flavonoids is evaluated using theoretical approach which could broaden its scope in therapeutic applications. Gas and solvent phase studies of structural and molecular characteristics of C-glycosyl flavonoid, isovitexin is investigated through hydrogen atom transfer mechanism (HAT), Electron transfer-proton transfer (ET–PT) and Sequential proton loss electron transfer (SPLET) by Density functional theory (DFT) using hybrid parameters. The computed values of the adiabatic ionization potential, electron affinity, hardness, softness, electronegativity and electrophilic index indicate that isovitexin possess good radical scavenging activity. The behavior of different –OH groups in polyphenolic compounds is assessed by considering electronic effects of the neighbouring groups and the overall geometry of molecule which in turn helps in analyzing the antioxidant capacity of the polyphenolic molecule. The studies indicate that the H–atom abstraction from 4’–OH site is preferred during the radical scavenging process. From Mulliken spin density analysis and FMOs, B–ring is found to be more delocalized center and capable of electron donation. Comparison of antioxidant activity of vitexin and isovitexin leads to the conclusion that isovitexin acts as a better radical scavenger. This is an evidence for the importance of position of glucose unit in the flavonoid.

  20. Single Agent Polysaccharopeptide Delays Metastases and Improves Survival in Naturally Occurring Hemangiosarcoma

    Directory of Open Access Journals (Sweden)

    Dorothy Cimino Brown

    2012-01-01

    Full Text Available The 2008 World Health Organization World Cancer Report describes global cancer incidence soaring with many patients living in countries that lack resources for cancer control. Alternative treatment strategies that can reduce the global disease burden at manageable costs must be developed. Polysaccharopeptide (PSP is the bioactive agent from the mushroom Coriolus versicolor. Studies indicate PSP has in vitro antitumor activities and inhibits the growth of induced tumors in animal models. Clear evidence of clinically relevant benefits of PSP in cancer patients, however, is lacking. The investment of resources required to complete large-scale, randomized controlled trials of PSP in cancer patients is more easily justified if antitumor and survival benefits are documented in a complex animal model of a naturally occurring cancer that parallels human disease. Because of its high metastatic rate and vascular origin, canine hemangiosarcoma is used for investigations in antimetastatic and antiangiogenic therapies. In this double-blind randomized multidose pilot study, high-dose PSP significantly delayed the progression of metastases and afforded the longest survival times reported in canine hemangiosarcoma. These data suggest that, for those cancer patients for whom advanced treatments are not accessible, PSP as a single agent might offer significant improvements in morbidity and mortality.

  1. Naturally occurring 32Si and low-background silicon dark matter detectors

    Science.gov (United States)

    Orrell, John L.; Arnquist, Isaac J.; Bliss, Mary; Bunker, Raymond; Finch, Zachary S.

    2018-05-01

    The naturally occurring radioisotope 32Si represents a potentially limiting background in future dark matter direct-detection experiments. We investigate sources of 32Si and the vectors by which it comes to reside in silicon crystals used for fabrication of radiation detectors. We infer that the 32Si concentration in commercial single-crystal silicon is likely variable, dependent upon the specific geologic and hydrologic history of the source (or sources) of silicon "ore" and the details of the silicon-refinement process. The silicon production industry is large, highly segmented by refining step, and multifaceted in terms of final product type, from which we conclude that production of 32Si-mitigated crystals requires both targeted silicon material selection and a dedicated refinement-through-crystal-production process. We review options for source material selection, including quartz from an underground source and silicon isotopically reduced in 32Si. To quantitatively evaluate the 32Si content in silicon metal and precursor materials, we propose analytic methods employing chemical processing and radiometric measurements. Ultimately, it appears feasible to produce silicon detectors with low levels of 32Si, though significant assay method development is required to validate this claim and thereby enable a quality assurance program during an actual controlled silicon-detector production cycle.

  2. Microbial utilization of naturally occurring hydrocarbons at the Guaymas Basin hydrothermal vent site

    International Nuclear Information System (INIS)

    Bazylinski, D.A.; Wirsen, C.O.; Jannasch, H.W.

    1989-01-01

    The Guaymas Basin (Gulf of California; depth, 2,000 m) is a site of hydrothermal activity in which petroliferous materials is formed by thermal alteration of deposited planktonic and terrestrial organic matter. We investigated certain components of these naturally occurring hydrocarbons as potential carbon sources for a specific microflora at these deep-sea vent sites. Respiratory conversion of [1- 14 C]hexadecane and [1(4,5,8)- 14 C]naphthalene to 14 CO 2 was observed at 4 degree C and 25 degree C, and some was observed at 55 degree C, but none was observed at 80 degree C. Bacterial isolates were capable of growing on both substrates as the sole carbon source. All isolates were aerobic and mesophilic with respect to growth on hydrocarbons but also grew at low temperatures (4 to 5 degree C). These results correlate well with previous geochemical analyses, indicating microbial hydrocarbon degradation, and show that at least some of the thermally produced hydrocarbons at Guaymas Basin are significant carbon sources to vent microbiota

  3. Industries processing naturally occurring radioactive materials: twenty years of emission data in the Netherlands

    International Nuclear Information System (INIS)

    Tanzi, C.P.

    2008-01-01

    This paper provides a review of the dose assessment of discharges to air of two industries processing NORM (Naturally Occurring Radioactive Materials) in the Netherlands. An industrial plant producing elemental phosphorus (thermal process, unique within Europe) reports since 1987 its emission data to the Dutch Ministry of the Environment (VROM: Ministry of Housing, Spatial Planning and the Environment). This plant accounts for the highest release of Po-210 to air in the Netherlands, with a yearly average of approximately 500 GBq. Other significant NORM discharges to air arise from an industrial plant with blast-furnaces for steel production. Yearly discharges fall under permit, and are reported, since 1993. RIVM, the National Institute for Public Health and the Environment, is tasked by the Ministry to assess the dose to the general public arising from these discharges to air. Air transport modelling is used to determine both air concentration (for inhalation exposure) and deposition rate of the radionuclides. A (conservative) committed ingestion dose is determined by modelling the uptake of radionuclides from contaminated farmland, and assuming a food basket to be fairly representative for the population of the Netherlands. Discharges to water in the Netherlands have decreased in the past twenty years, due both to the closure of two phosphoric acid plants a decade ago and the improved treatment of waste fluids by other NORM industries. The collective dose assessed from discharges to air since 1987 is presented here. (author)

  4. Histological evaluation of the pulp in teeth from dogs with naturally occurring periodontal disease.

    Science.gov (United States)

    Nemec, Ana; Pavlica, Zlatko; Stiblar-Martincic, Draga; Petelin, Milan; Erzen, Damjan; Crossley, David

    2007-12-01

    The purpose of this investigation was to evaluate the pulp of dog teeth affected by advanced periodontal disease. Histological examination was done on demineralized teeth extracted during clinical treatment of mature, client owned small and medium-size breed dogs with either good periodontal health or with advanced naturally occurring periodontal disease. Routinely stained sections from 5 clinically normal teeth and 22 teeth with advanced periodontitis from dogs between 5 and 12-years of age were examined using light microscopy. The pulp cavities of most teeth were narrow with low cellularity and some fibrosis of the pulp. Findings specific to periodontally affected teeth included acute and chronic pulpitis, vascular congestion, and pulp necrosis. A glomus body was identified in the pulp of one tooth and areas of poorly mineralized cementum were seen in both normal and diseased teeth. Age related changes in dog teeth appear similar to those reported for man and the rat. In addition to age related changes, the pulp of dog teeth with advanced periodontal disease were frequently inflamed or necrotic. This may reflect the advanced periodontitis affecting these teeth or a mechanical effect related to excessive tooth mobility. Further study is required to determine the etiology and significance of these findings and to investigate pulp status in less severely diseased teeth.

  5. HAEMATOLOGICAL IMPACT OF NATURALLY OCCURING TICK BORNE HAEMOPARASITIC INFECTIONS IN CATTLE OF WEST BENGAL, INDIA

    Directory of Open Access Journals (Sweden)

    Apurba Debbarma

    2017-12-01

    Full Text Available Haemoparasites reduces productivity and may lead to high mortality among animals. The present study was carried out to evaluate the heamotological change in cattle of different districts in West Bengal, India affected with naturally occurring tick- borne haemoparasitic diseases (TBHD. A total of 310 cattle blood samples were screened for the presence of haemoparasites from July, 2015 to June, 2016. The blood samples were examined for haemoparasites by making thin blood smear and staining with Giemsa’s stain. The result showed that108 (34.84% cattle were found positive with TBHD, out of which 22.9% were Theileria sp, 5.8% were Babesia sp., 11.93% Anaplasma sp., and 5.8% were having mixed infection, respectively. The positive samples were subjected to estimations of haematological parameters i. e. Haemoglobin concentration (Hb, packed cell volume (PCV, total erythrocyte count (TEC and Total leucocytes count (TLC using standard protocol. The haematological analysis showed statistically a significant (p<0.01 decreased levels of Hb, PCV, TEC and TLC in infected groups of cattle compared to infection free group cattle. This is probably the first systematic report in West Bengal, India. The result showed the haemoparasites have a negative impact on haematological parameters. This study may be useful in disease epidemiological map preparation, parasitic control policy preparation of the study areas.

  6. A naturally occurring contrast agent for OCT imaging of smokers' lung

    International Nuclear Information System (INIS)

    Yang Ying; Bagnaninchi, Pierre O; Whiteman, Suzanne C; Pittius, Daniel Gey van; Haj, Alicia J El; Spiteri, Monica A; Wang, Ruikang K

    2005-01-01

    Optical coherence tomography (OCT) offers great potential for clinical applications in terms of its cost, safety and real-time imaging capability. Improvement of its resolution for revealing sub-layers or sub-cellular components within a tissue will further widen its application. In this study we report that carbon pigment, which is frequently present in the lungs of smokers, could be used as a contrast agent to improve the OCT imaging of lung tissue. Carbon produced an intense bright OCT image at a relatively deep location. The parallel histopathological section analysis confirmed the presence of carbon pigment in such tissues. The underlying mechanism of the OCT image formation has been discussed based on a model system in which carbon particles were dispersed in agar gel. Calculations and in-depth intensity profiles of OCT revealed that higher refractive index particles with a size close to or smaller than the wavelength would greatly increase backscattering and generate a sharp contrast, while a particle size several times larger than the wavelength would absorb or obstruct the light path. The naturally occurring contrast agent could provide a diagnostic biomarker of lung tissue in smokers. Furthermore, carbon under such circumstances, can be used as an effective exogenous contrast agent, with which specific components or tissues exhibiting early tumour formation can be optically labelled to delineate the location and boundary, providing potential for early cancer detection and its treatment

  7. Study of the emanation levels of 222Rn present in Naturally Occurring Radioactive Materials - NORM

    International Nuclear Information System (INIS)

    Miranda, Marcia Valeria de Fatima da Encarnacao Sa

    2009-01-01

    The presence of Naturally Occurring Radioactive Material (NORM), contaminating oil and gas facilities, is a common fact in the petroleum industry, and can be severe enough to expose the workers to elevated levels of radiation. Thus, contaminated residues need to be segregated but, this is still a problem without a satisfactory solution. Currently, the most practical and economic option for discarding this material is to stock it in areas of the facility whose access is controlled. Certain equipment used in the petroleum industry has scale and sludge that could be associated to important levels of radioactivity. Typically, the scale is a mixture of carbonate and sulphate minerals, such as barite (BaSO 4 ), that easily incorporates 226 Ra and 228 Ra in its structures. The objective of this work was to measure the emanations of the radon present in these NORM samples, via diffusion chambers containing a nuclear track detector (CR-39). The images of particle alpha tracks emanated by 222 Rn registered on CR-39 were observed with a Nikon E400 optic microscope and captured by a Nikon Coolpix digital camera and then stored in a database, to later count the tracks using the computational program, Image Pro plus. Being that the emanation rate of 222 Rn was proportional to the number of these tracks the methodology permitted the comparison of contamination levels of the analyzed samples. (author)

  8. Naturally occurring glucagon-like peptide-2 (GLP-2) receptors in human intestinal cell lines.

    Science.gov (United States)

    Sams, Anette; Hastrup, Sven; Andersen, Marie; Thim, Lars

    2006-02-17

    Although clinical trials with GLP-2 receptor agonists are currently ongoing, the mechanisms behind GLP-2-induced intestinal epithelial growth remain to be understood. To approach the GLP-2 mechanism of action this study aimed to identify intestinal cell lines endogenously expressing the GLP-2 receptor. Here we report the first identification of a cell line endogenously expressing functional GLP-2 receptors. The human intestinal epithelial cell line, FHC, expressed GLP-2 receptor encoding mRNA (RT-PCR) and GLP-2 receptor protein (Western blot). In cultured FHC cells, GLP-2 induced concentration dependent cAMP accumulation (pEC(50)=9.7+/-0.04 (mean+/-S.E.M., n=4)). In addition, a naturally occurring human intestinal fibroblast cell line, 18Co, endogenously expressing GLP-2 receptor encoding mRNA (RT-PCR) and protein (Western blot) was identified. No receptor functionality (binding or G-protein signalling) could be demonstrated in 18Co cells. The identified gut-relevant cell lines provide tools for future clarification of the mechanisms underlying GLP-2-induced epithelial growth.

  9. Natural Course of Co-Occurring PTSD and Alcohol Use Disorder Among Recent Combat Veterans.

    Science.gov (United States)

    Possemato, Kyle; Maisto, Stephen A; Wade, Michael; Barrie, Kimberly; Johnson, Emily M; Ouimette, Paige C

    2017-06-01

    Posttraumatic stress disorder (PTSD) and alcohol use disorder (AUD) commonly co-occur in veterans, yet little is known about the longitudinal course of PTSD and drinking in comorbid populations. This study assessed the natural course of daily alcohol consumption and weekly changes in PTSD symptoms in 112 recent combat veterans over the course of 11 months. Latent class growth mixture modeling was used to classify individuals into distinct classes with similar PTSD symptom and alcohol use growth trajectories. We then investigated theorized predictors of class membership including sociodemographics; pre-, peri-, and postdeployment factors; coping; symptom severity; and number of mental health/substance use appointments attended. Results revealed that most participants had severe and nonremitting PTSD. Trajectories for alcohol use included gradual and drastic declines, and chronic low-level drinking. The use of behavioral health services (odds ratio = 2.47) and fewer current stressors (odds ratio = 0.42) predicted AUD remission. Because little variation was observed in the PTSD course, our study did not observe coordinated fluctuations of PTSD symptoms and heavy drinking. Our findings suggest that treatment impacts the course of AUD and that recent combat veterans who do not seek PTSD treatment may have chronic and severe PTSD symptoms. Copyright © 2017 International Society for Traumatic Stress Studies.

  10. Amplification of HER2 is a marker for global genomic instability

    International Nuclear Information System (INIS)

    Ellsworth, Rachel E; Ellsworth, Darrell L; Patney, Heather L; Deyarmin, Brenda; Love, Brad; Hooke, Jeffrey A; Shriver, Craig D

    2008-01-01

    Genomic alterations of the proto-oncogene c-erbB-2 (HER-2/neu) are associated with aggressive behavior and poor prognosis in patients with breast cancer. The variable clinical outcomes seen in patients with similar HER2 status, given similar treatments, suggests that the effects of amplification of HER2 can be influenced by other genetic changes. To assess the broader genomic implications of structural changes at the HER2 locus, we investigated relationships between genomic instability and HER2 status in patients with invasive breast cancer. HER2 status was determined using the PathVysion ® assay. DNA was extracted after laser microdissection from the 181 paraffin-embedded HER2 amplified (n = 39) or HER2 negative (n = 142) tumor specimens with sufficient tumor available to perform molecular analysis. Allelic imbalance (AI) was assessed using a panel of microsatellite markers representing 26 chromosomal regions commonly altered in breast cancer. Student t-tests and partial correlations were used to investigate relationships between genomic instability and HER2 status. The frequency of AI was significantly higher (P < 0.005) in HER2 amplified (27%) compared to HER2 negative tumors (19%). Samples with HER2 amplification showed significantly higher levels of AI (P < 0.05) at chromosomes 11q23, 16q22-q24 and 18q21. Partial correlations including ER status and tumor grade supported associations between HER2 status and alterations at 11q13.1, 16q22-q24 and 18q21. The poor prognosis associated with HER2 amplification may be attributed to global genomic instability as cells with high frequencies of chromosomal alterations have been associated with increased cellular proliferation and aggressive behavior. In addition, high levels of DNA damage may render tumor cells refractory to treatment. In addition, specific alterations at chromosomes 11q13, 16q22-q24, and 18q21, all of which have been associated with aggressive tumor behavior, may serve as genetic modifiers to HER2

  11. Immunohistochemical expression of HER-2/neu in patients with lung carcinoma and its prognostic significance

    International Nuclear Information System (INIS)

    Petrusevska, G.; Banev, S.; Ilievska-Poposka, B.; Smickova, S.; Spirovski, Z.

    2004-01-01

    Background. The HER-2 protein or p185her2 is a membrane receptor with tyrosine kinase activity encoded by HER-2/neu gene. Overexpression of HER-2/neu has been observed in many human cancers, including lung cancer. In the study, the expression of HER-2 protein is determined in the spectrum of lung cancer (adenocarcinoma, squamous cell carcinoma and small cell carcinoma). Patients and methods. The study population consisted of two groups: 19 patients that had undergone surgical treatment and 10 patients that had undergone fiber-optic bronchoscopy and biopsy for primary diagnosis only. Tissue specimens were neutral formaldehyde-fixed and paraffin-embedded. Standard histochemical and immunohistochemical staining were used for diagnosis. Expression of HER-2/neu protein was determined by immunohistochemical staining with Hercep Test (DAKO). The results were graded 0-1 as negative and 2-3 as positive. Results. Overall incidence of HER-2/neu overexpression was 34.4% (10 of 29). Higher incidence was found in the patients with adenocarcinoma 45.4% (5 of 11). In squamous cell carcinoma and small cell carcinoma, the overexpression incidence was 30.7% (4 of 13) and 20% (1 of 5), respectively. No statistically significant difference was seen given the age and gender. HER-2/neu overexpression was more pronounced in the patients with advanced tumour: all patients with squamous cell carcinoma and HER-2/neu overexpression had stage IIIB and stage IV disease, while 80 % of adenocarcinoma patients with HER-2/neu overexpression had stage IIIA and IIIB disease. Conclusions. These results are satisfactory and encourage us to continue this work in the follow-up study to evaluate HER-2/neu role as predictive and prognostic factor for the patients with lung cancer. (author)

  12. Amplification of HER2 is a marker for global genomic instability

    Directory of Open Access Journals (Sweden)

    Love Brad

    2008-10-01

    Full Text Available Abstract Background Genomic alterations of the proto-oncogene c-erbB-2 (HER-2/neu are associated with aggressive behavior and poor prognosis in patients with breast cancer. The variable clinical outcomes seen in patients with similar HER2 status, given similar treatments, suggests that the effects of amplification of HER2 can be influenced by other genetic changes. To assess the broader genomic implications of structural changes at the HER2 locus, we investigated relationships between genomic instability and HER2 status in patients with invasive breast cancer. Methods HER2 status was determined using the PathVysion® assay. DNA was extracted after laser microdissection from the 181 paraffin-embedded HER2 amplified (n = 39 or HER2 negative (n = 142 tumor specimens with sufficient tumor available to perform molecular analysis. Allelic imbalance (AI was assessed using a panel of microsatellite markers representing 26 chromosomal regions commonly altered in breast cancer. Student t-tests and partial correlations were used to investigate relationships between genomic instability and HER2 status. Results The frequency of AI was significantly higher (P P Conclusion The poor prognosis associated with HER2 amplification may be attributed to global genomic instability as cells with high frequencies of chromosomal alterations have been associated with increased cellular proliferation and aggressive behavior. In addition, high levels of DNA damage may render tumor cells refractory to treatment. In addition, specific alterations at chromosomes 11q13, 16q22-q24, and 18q21, all of which have been associated with aggressive tumor behavior, may serve as genetic modifiers to HER2 amplification. These data not only improve our understanding of HER in breast pathogenesis but may allow more accurate risk profiles and better treatment options to be developed.

  13. Neratinib shows efficacy in the treatment of HER2 amplified carcinosarcoma in vitro and in vivo.

    Science.gov (United States)

    Schwab, Carlton L; English, Diana P; Black, Jonathan; Bellone, Stefania; Lopez, Salvatore; Cocco, Emiliano; Bonazzoli, Elena; Bussi, Beatrice; Predolini, Federica; Ferrari, Francesca; Ratner, Elena; Silasi, Dan-Arin; Azodi, Masoud; Rutherford, Thomas; Schwartz, Peter E; Santin, Alessandro D

    2015-10-01

    Carcinosarcoma is a deadly gynecologic malignancy with few effective treatment options. The study of new therapies is difficult because of its rarity. The objective of this study was to determine the efficacy of neratinib in the treatment of HER2 amplified carcinosarcoma. The efficacy of neratinib in the treatment of HER2 amplified carcinosarcoma was determined in vitro using seven primary carcinosarcoma cell lines with differential expression of HER2/neu. Data regarding IC50, cell cycle distribution, and cell signaling changes were assessed by flow cytometry. The efficacy of neratinib was determined in treating mice harboring HER2 amplified carcinosarcoma xenografts. Two of seven (28.5%) carcinosarcoma cell lines were HER2/neu amplified. HER2/neu amplified cell lines SARARK6 and SARARK9 were significantly more sensitive to neratinib than the five non-HER2/neu amplified carcinosarcoma cell lines (mean±SEM IC50:0.014μM±0.004vs.0.164μM±0.019 p=0.0003). Neratinib treatment caused a significant build up in G0/G1 phase of the cell cycle, arrest auto phosphorylation of HER2/neu and activation of S6. Neratinib inhibited tumor growth (p=0.012) and prolonged survival in mice harboring HER2 amplified carcinosarcoma xenografts (p=0.0039). Neratinib inhibits HER2 amplified carcinosarcoma proliferation, signaling, cell cycle progression and tumor growth in vitro. Neratinib inhibits HER2/neu amplified xenograft growth and improves overall survival. Clinical trials are warranted. Copyright © 2015 Elsevier Inc. All rights reserved.

  14. Correlation between apparent diffusion coefficients and HER2 status in gastric cancers: pilot study

    International Nuclear Information System (INIS)

    He, Jian; Shi, Hua; Zhou, Zhuping; Chen, Jun; Guan, Wenxian; Wang, Hao; Yu, Haiping; Liu, Song; Zhou, Zhengyang; Yang, Xiaofeng; Liu, Tian

    2015-01-01

    To evaluate whether apparent diffusion coefficient (ADC) value of gastric cancer obtained from diffusion weighted imaging (DWI) correlates with the HER2 status. Forty-five patients, who had been diagnosed with gastric cancer through biopsy, were enrolled in this IRB-approved study. Each patient underwent a DWI (b values: 0 and 1,000 sec/mm 2 ) prior to surgery (curative gastrectomy or palliative resection). Postoperative microscopic findings, HER2 status by immunohistochemical analysis and fluorescence in situ hybridization (FISH) were obtained. HER2 status was compared among gastric cancers with various histopathological features using the chi square test. The ADC values of gastric cancers with positive and negative HER2 were compared using the student t test. A weak yet significant correlation was observed between the mean ADC values and HER2 status (r = 0.312, P = 0.037) and scores (r = 0.419, P = 0.004). The mean ADC value of HER2-positive gastric cancers was significantly higher than those of HER2-negative tumors (1.211 vs. 0.984 mm 2 /s, P = 0.020). The minimal ADC value of HER2-positive gastric cancers was significantly higher than those of HER2-negative tumors (1.105 vs. 0.905 × 10 −3 mm 2 /s, P = 0.036). In this pilot study, we have demonstrated that the ADC values of gastric cancer correlate with the HER2 status. Future research is warranted to see if DWI can predict HER2 status and help in tailoring therapy for gastric cancer

  15. Trace elements and naturally occurring radioactive materials in 'Non-traditional fertilizers' used in Ghana

    International Nuclear Information System (INIS)

    Assibey, E. O.

    2013-07-01

    Fertilizers have been implicated for being contaminated with toxic trace elements and naturally occurring radioactive materials (NORMs) even though they are an indispensable component of our agriculture. This phenomenon of contamination has been investigated and established world-wide in various forms of fertilizers (i.e., granular or 'traditional' type and liquid/powder or 'non-traditional type'). In Ghana, the crop sub-sector has seen a gradual rise in the importation and use of 'non-traditional fertilizers' which are applied to both the foliar parts and roots of plants. This notwithstanding, research on fertilizers has been largely skewed towards the 'traditional' types, focusing principally on the subjects of yield, effects of application and their quality. This study was, therefore, undertaken to bridge the knowledge gap by investigating the levels of trace elements and NORMs found in the 'non-traditional' fertilizers used in Ghana. The principal objective of the study was to investigate the suitability of the 'non-traditional fertilizers' for agricultural purposes with respect to trace elements and NORMs contamination. Atomic Absorption Spectrometry and instrumental Neutron Activation Analysis were employed to determine the trace elements (Cu, Zn, Fe, Na, Al, Br, Ni, Cd, As, Hg, Co, Pb, La, Mn, Si, Ca, Cl, S, K, Ba and V) and NORMs ( 238 U, 232 Th and 40 K) concentrations in thirty-nine (39) fertilizer samples taken from two major agro-input hubs in the country (Kumasi-Kejetia and Accra). Multivariate statistical analyses (cluster analysis, principal component analysis and pearson's correlation) were applied to the data obtained in order to identify possible sources of contamination, investigate sample/ parameter affinities and groupings and for fingerprinting. The toxic trace element concentrations determined in all samples were found to be in the order Fe>Cu>Co>Cd>Cr >Ni>Pb>As>Hg. The study found most of the trace elements determined to be within limits set

  16. Immunization with a novel chimeric peptide representing B and T cell epitopes from HER2 extracellular domain (HER2 ECD) for breast cancer.

    Science.gov (United States)

    Mahdavi, Manijeh; Keyhanfar, Mehrnaz; Jafarian, Abbas; Mohabatkar, Hassan; Rabbani, Mohammad

    2014-12-01

    Because of direct stimulating immune system against disease, vaccination or active immunotherapy is preferable compared to passive immunotherapy. For this purpose, a newly designed chimeric peptide containing epitopes for both B and T cells from HER2 ECD subdomain III was proposed. To evaluate the effects of the active immunization, a discontinuous B cell epitope peptide was selected based on average antigenicity by bioinformatics analysis. The selected peptide was collinearly synthesized as a chimera with a T helper epitope from the protein sequence of measles virus fusion (208-302) using the GPSL linker. Three mice were immunized with the chimeric peptide. Reactive antibodies with HER2 protein in ELISA and immunofluorescence assays with no cross-reactivity were generated. The 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT) assay indicated that the anti-peptide sera had inhibitory effects on proliferation of SK-BR-3 cells. Hence, the newly designed, discontinuous chimeric peptide representing B and T cell epitopes from subdomain III of HER2-ECD can form the basis for future vaccines design, where these data can be applied for monoclonal antibody production targeting the distinct epitope of HER2 receptor compared to the two broadly used anti-HER2 monoclonal antibodies, Herceptin and pertuzumab.

  17. (64)Cu-DOTA-trastuzumab PET imaging and HER2 specificity of brain metastases in HER2-positive breast cancer patients.

    Science.gov (United States)

    Kurihara, Hiroaki; Hamada, Akinobu; Yoshida, Masayuki; Shimma, Schuichi; Hashimoto, Jun; Yonemori, Kan; Tani, Hitomi; Miyakita, Yasuji; Kanayama, Yousuke; Wada, Yasuhiro; Kodaira, Makoto; Yunokawa, Mayu; Yamamoto, Harukaze; Shimizu, Chikako; Takahashi, Kazuhiro; Watanabe, Yasuyoshi; Fujiwara, Yasuhiro; Tamura, Kenji

    2015-01-01

    The purpose of this study was to determine whether brain metastases from HER2-positive breast cancer could be detected noninvasively using positron emission tomography (PET) with (64)Cu-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-trastuzumab. PET was performed on five patients with brain metastases from HER2-positive breast cancer, at 24 or 48 h after the injection of approximately 130 MBq of the probe (64)Cu-DOTA-trastuzumab. Radioactivity in metastatic brain tumors was evaluated based on PET images in five patients. Autoradiography, immunohistochemistry (IHC), and liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis were performed in one surgical case to confirm HER2 specificity of (64)Cu-DOTA-trastuzumab. Metastatic brain lesions could be visualized by (64)Cu-DOTA-trastuzumab PET in all of five cases, which might indicated that trastuzumab passes through the blood-brain barrier (BBB). The HER2 specificity of (64)Cu-DOTA-trastuzumab was demonstrated in one patient by autoradiography, immunohistochemistry, and LC-MS/MS. Cu-DOTA-trastuzumab PET could be a potential noninvasive procedure for serial identification of metastatic brain lesions in patients with HER2-positive breast cancer. UMIN000004170.

  18. Naturally occurring clay nanoparticles in Latosols of Brazil central region: detection and characterization

    Science.gov (United States)

    Dominika Dybowska, Agnieszka; Luciene Maltoni, Katia; Piella, Jordi; Najorka, Jens; Puntes, Victor; Valsami-Jones, Eugenia

    2015-04-01

    hematite and goethite) was only possible with XRD, which revealed also subtle differences in mineralogical composition of the clay fraction (<2µm) and nanofraction (<100nm). The kaolinite's crystallite size (calculated from XRD data) was found to range 14-17nm in the nanofraction and 26-50nm in the clay fraction. For hematite, it was 13nm in the nanofraction and ranged from 21-30nm in the clay fraction. Such small particles can be expected to play an important role in soil sorption processes with implications on nutrient and contaminant cycling. Identification and understanding of the properties of naturally occurring nanoparticles in soils can therefore help soil scientists to better understand retention/mobilization of nutrients and pollutants in soils.

  19. Aldosterone breakthrough in dogs with naturally occurring myxomatous mitral valve disease.

    Science.gov (United States)

    Ames, M K; Atkins, C E; Eriksson, A; Hess, A M

    2017-06-01

    Aldosterone breakthrough (ABT) is the condition in which angiotensin converting enzyme inhibitors (ACEIs) and/or angiotensin receptor blockers fail to effectively suppress the activity of the renin angiotensin aldosterone system. The objective of this study was to determine if ABT occurs in dogs with naturally occurring myxomatous mitral valve disease receiving an ACEI, using the urine aldosterone to creatinine ratio (UAldo:C) as a measure of renin angiotensin aldosterone system activation. This study includes 39 dogs with myxomatous mitral valve disease. A UAldo:C cut-off definition (derived from a normal population of healthy, adult, and client-owned dogs) was used to determine the prevalence of ABT in this population. Spearman analysis and univariate logistic regression were used to evaluate the relationship between UAldo:C and ABT (yes/no) and eight variables (age, serum K + concentration, serum creatinine concentration, ACEI therapy duration and ACEI dosage, furosemide therapy duration and furosemide dosage, and urine sample storage time). Finally, the UAldo:C in dogs receiving spironolactone, as part congestive heart failure (CHF) therapy, was compared to dogs with CHF that were not receiving spironolactone. The prevalence of ABT was 32% in dogs with CHF and 30% in dogs without CHF. There was no relationship between either the UAldo:C or the likelihood of ABT and the eight variables. Therapy with spironolactone lead to a significant elevation of the UAldo:C. Using the UAldo:C and a relatively stringent definition of ABT, it appears that incomplete RAAS blockade is common in dogs with MMVD receiving an ACEI. The prevalence of ABT in this canine population mirrors that reported in humans. While the mechanism of ABT is likely multifactorial and still poorly understood, the proven existence of ABT in dogs offers the potential to improve the prognosis for MMVD with the addition of a mineralocorticoid receptor blocker to current therapeutic regimens

  20. Quantification and imaging of HER2 protein using nanocrystals conjugated with single-domain antibodies

    International Nuclear Information System (INIS)

    Glukhov, S; Berestovoy, M; Nabiev, I; Sukhanova, A; Chames, P; Baty, D

    2017-01-01

    This study dealt with quantification and imaging of human epidermal growth factor receptor 2 (HER2), an important prognostic marker for cancer diagnosis and treatment, using specific quantum-dot-based conjugates. Fluorescent inorganic nanocrystals or quantum dots (QDs) are extremely highly resistant to photobleaching and have a high emission quantum yield and a continuous range of emission spectra, from the ultraviolet to the infrared regions. Ultrasmall nanoprobes consisting of highly affine anti-HER2 single-domain antibodies (sdAbs or 'nanobodies') conjugated with QDs in a strictly oriented manner have been designed. QDs with a fluorescence peak maxima at wavelengths of 562 nm, 569 nm, 570 nm or in the near-infrared region were used. Here, we present our results of ISA quantification of HER2 protein, in situ imaging of HER2 protein on the surface of HER2-positive SK-BR-3 cells in immunohistochemical experiments, and counting of stained with anti-HER2 conjugates HER2-positive SK-BR-3 cells in their mixture with unstained cells of the same culture in flow cytometry experiments. The data demonstrate that the anti-HER2 QD–sdAb conjugates obtained are highly specific and sensitive and could be used in numerous applications for advanced integrated diagnosis. (paper)

  1. Modeling ductal carcinoma in situ: a HER2-Notch3 collaboration enables luminal filling.

    LENUS (Irish Health Repository)

    Pradeep, C-R

    2012-02-16

    A large fraction of ductal carcinoma in situ (DCIS), a non-invasive precursor lesion of invasive breast cancer, overexpresses the HER2\\/neu oncogene. The ducts of DCIS are abnormally filled with cells that evade apoptosis, but the underlying mechanisms remain incompletely understood. We overexpressed HER2 in mammary epithelial cells and observed growth factor-independent proliferation. When grown in extracellular matrix as three-dimensional spheroids, control cells developed a hollow lumen, but HER2-overexpressing cells populated the lumen by evading apoptosis. We demonstrate that HER2 overexpression in this cellular model of DCIS drives transcriptional upregulation of multiple components of the Notch survival pathway. Importantly, luminal filling required upregulation of a signaling pathway comprising Notch3, its cleaved intracellular domain and the transcriptional regulator HES1, resulting in elevated levels of c-MYC and cyclin D1. In line with HER2-Notch3 collaboration, drugs intercepting either arm reverted the DCIS-like phenotype. In addition, we report upregulation of Notch3 in hyperplastic lesions of HER2 transgenic animals, as well as an association between HER2 levels and expression levels of components of the Notch pathway in tumor specimens of breast cancer patients. Therefore, it is conceivable that the integration of the Notch and HER2 signaling pathways contributes to the pathophysiology of DCIS.

  2. Development of an Anti-HER2 Monoclonal Antibody H2Mab-139 Against Colon Cancer.

    Science.gov (United States)

    Kaneko, Mika K; Yamada, Shinji; Itai, Shunsuke; Kato, Yukinari

    2018-02-01

    Human epidermal growth factor receptor 2 (HER2) expression has been reported in several cancers, such as breast, gastric, lung, pancreatic, and colorectal cancers. HER2 is overexpressed in those cancers and is associated with poor clinical outcomes. Trastuzumab, a humanized anti-HER2 antibody, provides significant survival benefits for patients with HER2-overexpressing breast cancers and gastric cancers. In this study, we developed a novel anti-HER2 monoclonal antibody (mAb), H 2 Mab-139 (IgG 1 , kappa) and investigated it against colon cancers using flow cytometry, western blot, and immunohistochemical analyses. Flow cytometry analysis revealed that H 2 Mab-139 reacted with colon cancer cell lines, such as Caco-2, HCT-116, HCT-15, HT-29, LS 174T, COLO 201, COLO 205, HCT-8, SW1116, and DLD-1. Although H 2 Mab-139 strongly reacted with LN229/HER2 cells on the western blot, we did not observe a specific signal for HER2 in colon cancer cell lines. Immunohistochemical analyses revealed sensitive and specific reactions of H 2 Mab-139 against colon cancers, indicating that H 2 Mab-139 is useful in detecting HER2 overexpression in colon cancers using flow cytometry and immunohistochemical analyses.

  3. Over-expression of HER-2 is associated with the stage in ...

    African Journals Online (AJOL)

    Background: The frequency of over-expression of human epidermal growth factor receptor-2 (HER-2) in bladder cancer is one of the highest among all human malignancies. This over-expression is thought to play a role in aberrant proliferation of cancer cells. Studies on HER-2 expression in bladder carcinoma have shown ...

  4. Quantification and imaging of HER2 protein using nanocrystals conjugated with single-domain antibodies

    Science.gov (United States)

    Glukhov, S.; Berestovoy, M.; Chames, P.; Baty, D.; Nabiev, I.; Sukhanova, A.

    2017-01-01

    This study dealt with quantification and imaging of human epidermal growth factor receptor 2 (HER2), an important prognostic marker for cancer diagnosis and treatment, using specific quantum-dot-based conjugates. Fluorescent inorganic nanocrystals or quantum dots (QDs) are extremely highly resistant to photobleaching and have a high emission quantum yield and a continuous range of emission spectra, from the ultraviolet to the infrared regions. Ultrasmall nanoprobes consisting of highly affine anti-HER2 single-domain antibodies (sdAbs or "nanobodies") conjugated with QDs in a strictly oriented manner have been designed. QDs with a fluorescence peak maxima at wavelengths of 562 nm, 569 nm, 570 nm or in the near-infrared region were used. Here, we present our results of ISA quantification of HER2 protein, in situ imaging of HER2 protein on the surface of HER2-positive SK-BR-3 cells in immunohistochemical experiments, and counting of stained with anti-HER2 conjugates HER2-positive SK-BR-3 cells in their mixture with unstained cells of the same culture in flow cytometry experiments. The data demonstrate that the anti-HER2 QD-sdAb conjugates obtained are highly specific and sensitive and could be used in numerous applications for advanced integrated diagnosis.

  5. ADAM10 mediates trastuzumab resistance and is correlated with survival in HER2 positive breast cancer

    Science.gov (United States)

    Feldinger, Katharina; Generali, Daniele; Kramer-Marek, Gabriela; Gijsen, Merel; Ng, Tzi Bun; Wong, Jack Ho; Strina, Carla; Cappelletti, Mariarosa; Andreis, Daniele; Li, Ji-Liang; Bridges, Esther; Turley, Helen; Leek, Russell; Roxanis, Ioannis; Capala, Jacek; Murphy, Gillian; Harris, Adrian L.; Kong, Anthony

    2014-01-01

    Trastuzumab prolongs survival in HER2 positive breast cancer patients. However, resistance remains a challenge. We have previously shown that ADAM17 plays a key role in maintaining HER2 phosphorylation during trastuzumab treatment. Beside ADAM17, ADAM10 is the other well characterized ADAM protease responsible for HER ligand shedding. Therefore, we studied the role of ADAM10 in relation to trastuzumab treatment and resistance in HER2 positive breast cancer. ADAM10 expression was assessed in HER2 positive breast cancer cell lines and xenograft mice treated with trastuzumab. Trastuzumab treatment increased ADAM10 levels in HER2 positive breast cancer cells (p≤0.001 in BT474; p≤0.01 in SKBR3) and in vivo (p≤0.0001) compared to control, correlating with a decrease in PKB phosphorylation. ADAM10 inhibition or knockdown enhanced trastuzumab response in naïve and trastuzumab resistant breast cancer cells. Trastuzumab monotherapy upregulated ADAM10 (p≤0.05); and higher pre-treatment ADAM10 levels correlated with decreased clinical response (p≤0.05) at day 21 in HER2 positive breast cancer patients undergoing a trastuzumab treatment window study. Higher ADAM10 levels correlated with poorer relapse-free survival (p≤0.01) in a cohort of HER2 positive breast cancer patients. Our studies implicate a role of ADAM10 in acquired resistance to trastuzumab and establish ADAM10 as a therapeutic target and a potential biomarker for HER2 positive breast cancer patients. PMID:24952873

  6. Combination therapies for the treatment of HER2-positive breast cancer: current and future prospects.

    Science.gov (United States)

    Brandão, Mariana; Pondé, Noam F; Poggio, Francesca; Kotecki, Nuria; Salis, Mauren; Lambertini, Matteo; de Azambuja, Evandro

    2018-05-24

    HER2-positive disease is an aggressive subtype of breast cancer that has been revolutionized by anti-HER2 directed therapies. Multiple drugs have been developed and are currently in clinical use, including trastuzumab, lapatinib, pertuzumab, T-DM1, and neratinib, alone or combined in 'dual HER2-blockade' regimens. Areas covered: A comprehensive literature review was performed regarding the current state and the future of combination regimens containing anti-HER2 agents, focusing on their efficacy, toxicity, and cost-effectiveness. Expert commentary: The combination of trastuzumab/pertuzumab is approved in all disease settings, while trastuzumab/neratinib is approved in the adjuvant setting and trastuzumab/lapatinib in metastatic disease. Meanwhile, as breast cancer biology and resistance mechanisms become clearer, combinations with drugs like PI3K/Akt/mTOR inhibitors, CDK4/6 inhibitors, anti-PD(L)1 antibodies, endocrine therapy, and new anti-HER2 agents (panHER and HER2 tyrosine kinase inhibitors, bispecific antibodies, anti-HER3 antibodies, and antibody-drug conjugates) are being extensively tested in clinical trials. More specific strategies for the 'triple-positive' (estrogen receptor-positive/HER2-positive) disease are also being explored. However, there is an urgent need for the development of predictive biomarkers for a better tailoring of anti-HER2 directed therapy. This is the only way to further improve clinical outcomes and quality of life and to decrease costs and toxicities of unnecessary treatments.

  7. Quantification of Cell-Free HER-2 DNA in Plasma from Breast Cancer Patients

    DEFF Research Database (Denmark)

    Sørensen, Patricia Diana; Andersen, Rikke Fredslund; Pallisgaard, Niels

    2015-01-01

    The purpose of this study was to quantify the free-circulating plasma HER-2 DNA (cfHER-2 DNA) and to assess the ability of analysis to discriminate between patients with primary breast cancer and healthy controls in order to detect metastatic recurrence in comparison with serum HER-2 protein...... and also HER-2 gene amplification. The study population consisted of 100 patients with primary breast cancer and 50 healthy female donors. An additional 22 patients with metastases were subsequently included. cfHER-2 DNA was quantified with a quantitative PCR method together with a reference gene. RESULTS......: Using a cut-off of 2.5 for the ratio of the cfHER-2 DNA/reference gene, three (of 15) tissue HER-2-positive patients had a ratio >2.5 prior to the detection of metastatic disease. In the post-metastatic/pre-chemotherapy setting, 11 (of 23) tissue HER-2-positive patients with metastases had a ratio >2...

  8. HER2-Targeted Polyinosine/Polycytosine Therapy Inhibits Tumor Growth and Modulates the Tumor Immune Microenvironment.

    Science.gov (United States)

    Zigler, Maya; Shir, Alexei; Joubran, Salim; Sagalov, Anna; Klein, Shoshana; Edinger, Nufar; Lau, Jeffrey; Yu, Shang-Fan; Mizraji, Gabriel; Globerson Levin, Anat; Sliwkowski, Mark X; Levitzki, Alexander

    2016-08-01

    The development of targeted therapies that affect multiple signaling pathways and stimulate antitumor immunity is greatly needed. About 20% of patients with breast cancer overexpress HER2. Small molecules and antibodies targeting HER2 convey some survival benefits; however, patients with advanced disease succumb to the disease under these treatment regimens, possibly because HER2 is not completely necessary for the survival of the targeted cancer cells. In the present study, we show that a polyinosine/polycytosine (pIC) HER2-homing chemical vector induced the demise of HER2-overexpressing breast cancer cells, including trastuzumab-resistant cells. Targeting pIC to the tumor evoked a number of cell-killing mechanisms, as well as strong bystander effects. These bystander mechanisms included type I IFN induction, immune cell recruitment, and activation. The HER2-targeted pIC strongly inhibited the growth of HER2-overexpressing tumors in immunocompetent mice. The data presented here could open additional avenues in the treatment of HER2-positive breast cancer. Cancer Immunol Res; 4(8); 688-97. ©2016 AACR. ©2016 American Association for Cancer Research.

  9. Standardization of HER2 testing: results of an international proficiency-testing ring study

    NARCIS (Netherlands)

    Dowsett, Mitch; Hanna, Wedad M.; Kockx, Mark; Penault-Llorca, Frederique; Rüschoff, Josef; Gutjahr, Thorsten; Habben, Kai; van de Vijver, Marc J.

    2007-01-01

    Human epidermal growth factor receptor 2 (HER2) positivity in breast cancer is a prognostic factor regarding tumor aggressiveness and a predictive factor for response to trastuzumab (Herceptin). Early and accurate HER2 testing of all breast cancer patients at primary diagnosis is essential for

  10. The clinical significance of HER-2 and NF-KB expression in gastric cancer.

    Science.gov (United States)

    Li, Xiaogai; Tu, Jiancheng; Zhang, Di; Xu, Zhigao; Yang, Guifang; Gong, Lingling; Yu, Mingxia

    2013-09-01

    To investigate the expression of human epidermal growth factor 2 (HER-2) and Nuclear factor-Kb (NF-KB) in gastric cancer, and the relation of these two parameters with stage, grade and metastasis of gastric cancer. The serum level of HER-2 in 75 gastric cancer patients and control participants were determined by enzyme-linked immunosorbent assay (ELISA) kits. Expression of HER-2 and NF-KB protein were detected by immunohistochemical staining (SP method) of paraffin-embedded tissues in 75 tumors (observed group) and 22 normal gastric specimens. The clinical pathological data was statistically analyzed. Serum HER-2 level were significantly increased in study group compared with those in the control group (pKB in the observed group was 24.00% (18/75) and 62.67% (47/75) respectively. The expression of HER-2 and NF-KB were not correlated with age and gender, but with stage, grade and metastasis (pKB was correlated with tumor size (pKB had a positive rate of 94.44% (17/18), but a positive rate of 52.63% (30/57) when HER-2 was negative. Expression of NF-KB in gastric cancer tissue was correlated with HER-2 expression (X2 = 8.514, pKB in gastric cancer tissue is correlated with HER-2 expression, and they may play a very important role in the progress of gastric cancer.

  11. Quantitative Determination of Noa (Naturally Occurring Asbestos) in Rocks : Comparison Between Pcom and SEM Analysis

    Science.gov (United States)

    Baietto, Oliviero; Amodeo, Francesco; Giorgis, Ilaria; Vitaliti, Martina

    2017-04-01

    The quantification of NOA (Naturally Occurring Asbestos) in a rock or soil matrix is complex and subject to numerous errors. The purpose of this study is to compare two fundamental methodologies used for the analysis: the first one uses Phase Contrast Optical Microscope (PCOM) while the second one uses Scanning Electron Microscope (SEM). The two methods, although they provide the same result, which is the asbestos mass to total mass ratio, have completely different characteristics and both present pros and cons. The current legislation in Italy involves the use of SEM, DRX, FTIR, PCOM (DM 6/9/94) for the quantification of asbestos in bulk materials and soils and the threshold beyond which the material is considered as hazardous waste is a concentration of asbestos fiber of 1000 mg/kg.(DM 161/2012). The most used technology is the SEM which is the one among these with the better analytical sensitivity.(120mg/Kg DM 6 /9/94) The fundamental differences among the analyses are mainly: - Amount of analyzed sample portion - Representativeness of the sample - Resolution - Analytical precision - Uncertainty of the methodology - Operator errors Due to the problem of quantification of DRX and FTIR (1% DM 6/9/94) our Asbestos Laboratory (DIATI POLITO) since more than twenty years apply the PCOM methodology and in the last years the SEM methodology for quantification of asbestos content. The aim of our research is to compare the results obtained from a PCOM analysis with the results provided by SEM analysis on the base of more than 100 natural samples both from cores (tunnel-boring or explorative-drilling) and from tunnelling excavation . The results obtained show, in most cases, a good correlation between the two techniques. Of particular relevance is the fact that both techniques are reliable for very low quantities of asbestos, even lower than the analytical sensitivity. This work highlights the comparison between the two techniques emphasizing strengths and weaknesses of

  12. Natural occurring radionuclide 210Po in the components of the Black Sea ecosystem

    International Nuclear Information System (INIS)

    Lazorenko, G. G.; Polikarpov, G. G.

    2006-01-01

    The interest to study of the behavior of naturally occurring radionuclide 2 10Po in marine ecosystem was caused by its main contribution to the doses of irradiation to hydrobionts. This work presents own data of 2 10Po concentrations determined in water, bottom sediments and hydrobionts of the Black Sea in 1998-2004. 2 10Po concentrations in water varied from 0.58 to 1.02 Bqxm - 3. Their range in bottom sediments from shelf zone and open part of the Black Sea was 11.5-496.5 Bqxkg - 1 dry weight with maximum in the North-West region. The range of 2 10Po concentrations in bottom sediments from the Eastern part of the Black Sea was 4.5-220 Bqxkg-1 dry weight. Concentration factors (CF) of 2 10Po in bottom sediments reached 10 4 -10 5 . 2 10Po concentrations in the Black Sea hydrobionts are reported and compared with published data in the same taxa. The range of 2 10Po concentrations in the Black Sea mesozooplankton was 1.7-3.5 Bqxkg - 1 wet weight. It was 1.9-2.9 Bqxkg - 1 wet weight in the representative species of macro plankton community, namely the ctenophore Beroe ovata. 2 10Po concentrations in the Black Sea fishes depend on their belonging to different ecological groups and decrease from pelagic species to demersal and bottom ones. 2 10Po concentrations in the Black Sea mollusks excluding small species Nana nerithea were on the highest levels determined in hydrobionts inhabiting in this region. Concentration factors of this radionuclide, estimated on a wet weight basis, reached values of 1.5x10 3 for macrophytes, 4x10 3 for total zooplankton, 10 3 -10 4 for the entire fishes, depending on their ecological groups affiliation and (3.0-6.7) x10 4 for mollusks. So, the ability of the Black Sea hydrobionts to accumulate natural radionuclide 2 10Po is comparable with that of similar species from others marine and oceanic areas

  13. Cell-specific regulation of proliferation by Ano1/TMEM16A in breast cancer with different ER, PR, and HER2 status.

    Science.gov (United States)

    Wu, Huizhe; Wang, Hui; Guan, Shu; Zhang, Jing; Chen, Qiuchen; Wang, Xiaodong; Ma, Ke; Zhao, Pengfei; Zhao, Haishan; Yao, Weifan; Jin, Feng; Xiao, Qinghuan; Wei, Minjie

    2017-10-17

    The calcium-activated chloride channel Ano1 (TMEM16A) is overexpressed in many tumors. However, conflicting data exist regarding the role of Ano1 in cell proliferation. Here, we performed immunohistochemistry to investigate the expression of Ano1 and Ki67 in 403 patients with breast cancer, and analyzed the association between the expression of Ano1 and Ki67 in breast cancer subtypes categorized according to estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). Ano1 expression was negatively correlated with Ki67 expression. Ano1 overexpression more frequently occurred in ER-positive or HER2-negative patients with the low expression of Ki67. Ano1 overexpression was associated with longer overall survival (OS) in breast cancer with the low expression of Ki67, especially in ER-positive, PR-positive, and HER2-negative breast cancer. Multivariate Cox regression analysis showed that Ano1 overexpression was a prognostic factor for longer overall survival in ER-positive, PR-positive, or HER2-negative patients with the low expression of Ki67. Furthermore, Ano1 promoted cell proliferation in ER-positive, PR-positive, and HER2-negative MCF7 cells, but inhibited cell proliferation in ER-negative, PR-negative, and HER2-negative MDA-MB-435S cells. Our findings suggest that Ano1 may differentially regulate cell proliferation in a subtype of breast cancer defined by ER, PR, and HER2. Combined expression of Ano1 and Ki67 may be used for predicting clinical outcomes of breast cancer patients with different subtypes of ER, PR, and HER2.

  14. The extracellular domain of Her2 in serum as a biomarker of breast cancer.

    Science.gov (United States)

    Perrier, Alexandre; Gligorov, Joseph; Lefèvre, Guillaume; Boissan, Mathieu

    2018-02-28

    Breast cancer is a major health problem worldwide. In ~15% of breast cancers, the epidermal growth factor receptor HER2, a transmembrane protein, is overexpressed. This HER2 overexpression is associated with an aggressive form of the disease and a poor clinical prognosis. The extracellular domain (ECD) of HER2 is released into the blood by a proteolytic mechanism known as "ECD shedding". This proteolytic shedding leaves a constitutively active truncated receptor in the membrane that is 10-100-fold more oncogenic than the full-length receptor and promotes the growth and survival of cancer cells. Shedding of the HER2 ECD is increased during metastasis: whereas 15% of primary breast cancer patients have elevated levels of serum HER2 ECD (sHER2 ECD), the levels reach 45% in patients with metastatic disease. Thus, sHER2 ECD has been proposed as a promising biomarker for cancer recurrence and for monitoring the disease status of patients overexpressing HER2. Nevertheless, in 2016, the American Society of Clinical Oncology advises clinicians not to use soluble HER2 levels to guide their choice of adjuvant therapy for patients with HER2-positive breast cancer, because the evidence was considered not strong enough. Currently, biomarkers such as carcinoembryonic antigen and cancer antigen 15-3 are widely used to monitor metastatic breast cancer disease even if the level of evidence of clinical impact of this monitoring is poor. In this article, we review the evidence that sHER2 ECD might be used in some situations as a biomarker for breast cancer. Although this serum biomarker will not replace the direct measurement of tumor HER2 status for diagnosis of early-stage tumors; it might be especially useful in metastatic disease for prognosis, as an indicator of cancer progression and of therapy response, particularly to anti-HER2 therapies. Owing to these data, sHER2 ECD should be considered as a promising biomarker to detect cancer recurrence and metastasis.

  15. C-Cbl reverses HER2-mediated tamoxifen resistance in human breast cancer cells.

    Science.gov (United States)

    Li, Wei; Xu, Ling; Che, Xiaofang; Li, Haizhou; Zhang, Ye; Song, Na; Wen, Ti; Hou, Kezuo; Yang, Yi; Zhou, Lu; Xin, Xing; Xu, Lu; Zeng, Xue; Shi, Sha; Liu, Yunpeng; Qu, Xiujuan; Teng, Yuee

    2018-05-02

    Tamoxifen is a frontline therapy for estrogen receptor (ER)-positive breast cancer in premenopausal women. However, many patients develop resistance to tamoxifen, and the mechanism underlying tamoxifen resistance is not well understood. Here we examined whether ER-c-Src-HER2 complex formation is involved in tamoxifen resistance. MTT and colony formation assays were used to measure cell viability and proliferation. Western blot was used to detect protein expression and protein complex formations were detected by immunoprecipitation and immunofluorescence. SiRNA was used to examine the function of HER2 in of BT474 cells. An in vivo xenograft animal model was established to examine the role of c-Cbl in tumor growth. MTT and colony formation assay showed that BT474 cells are resistant to tamoxifen and T47D cells are sensitive to tamoxifen. Immunoprecipitation experiments revealed ER-c-Src-HER2 complex formation in BT474 cells but not in T47D cells. However, ER-c-Src-HER2 complex formation was detected after overexpressing HER2 in T47D cells and these cells were more resistant to tamoxifen. HER2 knockdown by siRNA in BT474 cells reduced ER-c-Src-HER2 complex formation and reversed tamoxifen resistance. ER-c-Src-HER2 complex formation was also disrupted and tamoxifen resistance was reversed in BT474 cells by the c-Src inhibitor PP2 and HER2 antibody trastuzumab. Nystatin, a lipid raft inhibitor, reduced ER-c-Src-HER2 complex formation and partially reversed tamoxifen resistance. ER-c-Src-HER2 complex formation was disrupted by overexpression of c-Cbl but not by the c-Cbl ubiquitin ligase mutant. In addition, c-Cbl could reverse tamoxifen resistance in BT474 cells, but the ubiquitin ligase mutant had no effect. The effect of c-Cbl was validated in BT474 tumor-bearing nude mice in vivo. Immunofluorescence also revealed ER-c-Src-HER2 complex formation was reduced in tumor tissues of nude mice with c-Cbl overexpression. Our results suggested that c-Cbl can reverse tamoxifen

  16. Short communication: Change of naturally occurring benzoic acid during skim milk fermentation by commercial cheese starters.

    Science.gov (United States)

    Han, Noori; Park, Sun-Young; Kim, Sun-Young; Yoo, Mi-Young; Paik, Hyun-Dong; Lim, Sang-Dong

    2016-11-01

    This study sought to investigate the change of naturally occurring benzoic acid (BA) during skim milk fermentation by 4 kinds of commercial cheese starters used in domestic cheese. The culture was incubated at 3-h intervals for 24h at 30, 35, and 40°C. The BA content during fermentation by Streptococcus thermophilus STB-01 was detected after 12h at all temperatures, sharply increasing at 30°C. In Lactobacillus paracasei LC431, BA was detected after 9h at all temperatures, sharply increasing until 18h and decreasing after 18h at 30 and 35°C. In the case of R707 (consisting of Lactococcus lactis ssp. lactis and Lactococcus lactis ssp. cremoris), BA increased from 6h to 15h and decreased after 15h at 40°C. The BA during STB-01 and CHN-11 (1:1; mixture of S. thermophilus, Lc. lactis ssp. lactis, Lc. lactis ssp. cremoris, Lc. lactis ssp. diacetylactis, Leuconostoc mesenteroides ssp. cremoris) fermentation was detected after 3h at 35 and 40°C, sharply increasing up to 12h and decreasing after 15h at 35°C, and after 6h, increasing up to 9h at 30°C. After 3h, it steadily decreased at 40°C. The highest amount of BA was found during the fermentation by R707 at 30°C; 15h with 12.46mg/kg. Copyright © 2016 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

  17. Functional analysis of four naturally occurring variants of human constitutive androstane receptor.

    Science.gov (United States)

    Ikeda, Shinobu; Kurose, Kouichi; Jinno, Hideto; Sai, Kimie; Ozawa, Shogo; Hasegawa, Ryuichi; Komamura, Kazuo; Kotake, Takeshi; Morishita, Hideki; Kamakura, Shiro; Kitakaze, Masafumi; Tomoike, Hitonobu; Tamura, Tomohide; Yamamoto, Noboru; Kunitoh, Hideo; Yamada, Yasuhide; Ohe, Yuichiro; Shimada, Yasuhiro; Shirao, Kuniaki; Kubota, Kaoru; Minami, Hironobu; Ohtsu, Atsushi; Yoshida, Teruhiko; Saijo, Nagahiro; Saito, Yoshiro; Sawada, Jun-ichi

    2005-01-01

    The human constitutive androstane receptor (CAR, NR1I3) is a member of the orphan nuclear receptor superfamily that plays an important role in the control of drug metabolism and disposition. In this study, we sequenced all the coding exons of the NR1I3 gene for 334 Japanese subjects. We identified three novel single nucleotide polymorphisms (SNPs) that induce non-synonymous alterations of amino acids (His246Arg, Leu308Pro, and Asn323Ser) residing in the ligand-binding domain of CAR, in addition to the Val133Gly variant, which was another CAR variant identified in our previous study. We performed functional analysis of these four naturally occurring CAR variants in COS-7 cells using a CYP3A4 promoter/enhancer reporter gene that includes the CAR responsive elements. The His246Arg variant caused marked reductions in both transactivation of the reporter gene and in the response to 6-(4-chlorophenyl)imidazo[2,1-b][1,3]thiazole-5-carbaldehyde O-(3,4-dichlorobenzyl)oxime (CITCO), which is a human CAR-specific agonist. The transactivation ability of the Leu308Pro variant was also significantly decreased, but its responsiveness to CITCO was not abrogated. The transactivation ability and CITCO response of the Val133Gly and Asn323Ser variants did not change as compared to the wild-type CAR. These data suggest that the His246Arg and Leu308Pro variants, especially His246Arg, may influence the expression of drug-metabolizing enzymes and transporters that are transactivated by CAR.

  18. Occurrence, clinical manifestation and the epidemiological implications of naturally occurring canine trypanosomosis in western Kenya

    Directory of Open Access Journals (Sweden)

    G.O. Matete

    2003-11-01

    Full Text Available Domestic dogs were screened for Trypanosoma brucei infection using the haematocrit centrifugation technique as part of routine active surveillance exercises in the Busia and Teso districts of Kenya. The purpose was to assess the role of dogs as sentinels for the occurrence of human sleeping sickness. Out of 200 dogs screened, five were found to be infected at the various test sites. These five succumbed to the disease within four weeks, and exhibited a distinct and pronounced corneal opacity before death. Blood from two naturally infected dogs were tested for the presence of the serum resistance associated (SRA gene and one tested positive, confirming it as human infective (T. brucei rhodesiense prevalence (0.5 %. It is considered that the occurrence of this clinical sign could be used as an early warning prediction of future outbreaks. This type of prediction could form an integral part of an indigenous technical knowledge set in areas lying at the edges of the tsetse (Glossina belts where T. brucei is the main trypanosome species that affects dogs. The occurrence of corneal opacity in dogs could indicate a rise in the levels of T. brucei a proportion of which could be human infective T. b. rhodesiense circulating in the population early enough before disease outbreak occurs. It is thought that during sleeping sickness epidemics the domestic dog will be the first casualty rapidly succumbing to disease long before it is noticed in man. Prompt prediction of disease outbreaks would thus enable early interventions that would reduce the morbidity, mortality and the general economic losses associated with sleeping sickness to be instituted.

  19. Clinical, laboratory, and hemostatic findings in cats with naturally occurring sepsis.

    Science.gov (United States)

    Klainbart, Sigal; Agi, Limor; Bdolah-Abram, Tali; Kelmer, Efrat; Aroch, Itamar

    2017-11-01

    OBJECTIVE To characterize clinical and laboratory findings in cats with naturally occurring sepsis, emphasizing hemostasis-related findings, and evaluate these variables for associations with patient outcomes. DESIGN Prospective, observational, clinical study. ANIMALS 31 cats with sepsis and 33 healthy control cats. PROCEDURES Data collected included history; clinical signs; results of hematologic, serum biochemical, and hemostatic tests; diagnosis; and outcome (survival vs death during hospitalization or ≤ 30 days after hospital discharge). Differences between cats with and without sepsis and associations between variables of interest and death were analyzed statistically. RESULTS The sepsis group included cats with pyothorax (n = 10), septic peritonitis (7), panleukopenia virus infection (5), bite wounds (5), abscesses and diffuse cellulitis (3), and pyometra (1). Common clinical abnormalities included dehydration (21 cats), lethargy (21), anorexia (18), pale mucous membranes (15), and dullness (15). Numerous clinicopathologic abnormalities were identified in cats with sepsis; novel findings included metarubricytosis, hypertriglyceridemia, and high circulating muscle enzyme activities. Median activated partial thromboplastin time and plasma D-dimer concentrations were significantly higher, and total protein C and antithrombin activities were significantly lower, in the sepsis group than in healthy control cats. Disseminated intravascular coagulopathy was uncommon (4/22 [18%] cats with sepsis). None of the clinicopathologic abnormalities were significantly associated with death on multivariate analysis. CONCLUSIONS AND CLINICAL RELEVANCE Cats with sepsis had multiple hematologic, biochemical, and hemostatic abnormalities on hospital admission, including several findings suggestive of hemostatic derangement. Additional research including larger numbers of cats is needed to further investigate these findings and explore associations with outcome.

  20. Antioxidant effect of naturally occurring xanthines on the oxidative damage of DNA bases

    Science.gov (United States)

    Vieira, A. J. S. C.; Telo, J. P.; Pereira, H. F.; Patrocínio, P. F.; Dias, R. M. B.

    1999-01-01

    The repair of the oxidised radicals of adenine and guanosine by several naturally occurring xanthines was studied. Each pair of DNA purine/xanthine was made to react with the sulphate radical and the decrease of the concentration of both compounds was measured by HPLC as a function of irradiation time. The results show that xanthine efficiently prevents the oxidation of the two DNA purines. Theophyline and paraxanthine repair the oxidised radical of adenine but not the one from guanosine. Theobromine and caffeine do not show any protecting effect. An order of the oxidation potentials of all the purines studied is proposed. La réparation des radicaux oxydés de l'adénine et de la guanosine par des xanthines naturelles a été étudiée en soumettant chaque paire base de l'ADN/xanthine à l'oxydation par le radical sulfate et en mesurant par HPLC la disparition des deux composés en fonction du temps d'irradiation. Les résultats montrent que la xanthine joue un rôle protecteur efficace contre l'oxydation des deux purines de l'ADN. La théophyline et la paraxanthine réparent le radical oxydé de l'adénine mais pas celui de la guanosine. La théobromine et la cafeíne n'ont pas d'effet protecteur. Un ordre de potentiels d'oxydation des purines étudiées est proposé.

  1. Novel environment friendly corrosion inhibitor pigments based on naturally occurring clay minerals

    Energy Technology Data Exchange (ETDEWEB)

    Bohm, S.; McMurray, H.N.; Worsley, D.A. [University of Wales, Swansea (United Kingdom). Dept. of Materials Engineering; Powell, S.M. [University of Wales, Swansea (United Kingdom). Engineering Doktorate Centre

    2001-12-01

    Novel, ceramic, corrosion inhibitor pigments consisting of cerium (III) and calcium (II) cation exchanged bentonites have been shown to provide effective cut-edge corrosion resistance in organic coated galvanised steel. The bentonite pigments were prepared from a naturally occurring (Wyoming) bentonite with a cation-exchange-capacity of 0.7 milli-equivalents per gram. Cation exchange was carried out by repeated washing with aqueous solutions of cerium (III) chloride and calcium (II) chloride to produce bentonites containing 31500 ppm exchangeable cerium (III) and 13500 ppm exchangeable calcium (II) respectively. The resulting bentonite pigments were dispersed in a polyester-resin based primer paint system to give a pigment volume concentration of 19%. For comparison, two similar primer systems were prepared containing a commercial calcium (II) exchanged silica pigment Shieldex: 60 000 ppm calcium (II) and a strontium chromate dispersion, both with a 19% pigment volume concentration. All three primer systems were applied (5 {mu}m) to the zinc surface of galvanised 0.7 mm gauge sheet steel and overcoated with an architectural polyester topcoat (18 {mu}m). The performance of the inhibitor pigments was compared by measuring the rate of corrosion-driven organic coating delamination from the cut edge of samples during 1000 h of salt-spray testing. The calcium (II) bentonite pigment exhibited an anti-delamination performance similar to that of strontium chromate but superior to that of Shieldex. However, the cerium (III) bentonite pigment was superior in performance to both strontium chromate and Shieldex. Thus, the bentonite pigments represent promising, environmentally friendly, ion-exchange corrosion inhibitors which exhibit good anti-delamination performance by comparison with current commercial systems. (orig.)

  2. Naturally occurring secondary nutritional hyperparathyroidism in cattle egrets (Bubulcus ibis) from central Texas.

    Science.gov (United States)

    Phalen, David N; Drew, Mark L; Contreras, Cindy; Roset, Kimberly; Mora, Miguel

    2005-04-01

    Naturally occurring secondary nutritional hyperparathyroidism is described in the nestlings of two colonies of cattle egrets (Bubulcus ibis) from Central Texas (Bryan and San Antonio, Texas, USA). Nestlings from a third colony (Waco, Texas, USA) were collected in a subsequent year for comparison. Birds from the first two colonies consistently had severe osteopenia and associated curving deformities and folding fractures of their long bones. These birds also had reduced bone ash, increased osteoclasia, a marked decrease in osteoblast activity, variable lengthening and shortening of the hypertrophic zone of the epiphyseal cartilage, decreased and disorganized formation of new bone, and a marked hypertrophy and hyperplasia of the parathyroid glands as compared to birds collected from the third colony. Fibrous osteodystrophy was found in all of the birds from San Antonio and Bryan. Evidence of moderate to severe calcium deficiency was also identified in 33% of the cattle egrets collected from Waco. Gut contents of affected chicks contained predominately grasshoppers and crickets; vertebrate prey items were absent from the Bryan birds. Grasshoppers and crickets collected from fields frequented by the adult egrets in 1994 had 0.12-0.28% calcium and 0.76-0.81% phosphorus. Pooled grasshoppers and crickets collected during a subsequent wet early spring averaged 0.24% calcium and 0.65% phosphorus. Although the phosphorus content of the insect prey was adequate for growth, calcium was approximately one-third the minimum calcium requirement needed for growth for other species of birds. It was postulated that cattle egrets breeding in Central Texas have expanded their range into habitat that contains less vertebrate prey, and as a result, many nestling egrets are being fed diets that contain suboptimal calcium. Therefore, in years where vertebrate prey is scarce and forage for insect prey is reduced in calcium, nestling egrets are at risk for developing secondary nutritional

  3. Naturally occurring secondary nutritional hyperparathyroidism in cattle egrets (Bubulcus ibis) from Central Texas

    Science.gov (United States)

    Phalen, D.N.; Drew, M.L.; Contreras, C.; Roset, K.; Mora, M.

    2005-01-01

    Naturally occurring secondary nutritional hyperparathyroidism is described in the nestlings of two colonies of cattle egrets (Bubulcus ibis) from Central Texas (Bryan and San Antonio, Texas, USA). Nestlings from a third colony (Waco, Texas, USA) were collected in a subsequent year for comparison. Birds from the first two colonies consistently had severe osteopenia and associated curving deformities and folding fractures of their long bones. These birds also had reduced bone ash, increased osteoclasia, a marked decrease in osteoblast activity, variable lengthening and shortening of the hypertrophic zone of the epiphyseal cartilage, decreased and disorganized formation of new bone, and a marked hypertrophy and hyperplasia of the parathyroid glands as compared to birds collected from the third colony. Fibrous osteodystrophy was found in all of the birds from San Antonio and Bryan. Evidence of moderate to severe calcium deficiency was also identified in 33% of the cattle egrets collected from Waco. Gut contents of affected chicks contained predominately grasshoppers and crickets; vertebrate prey items were absent from the Bryan birds. Grasshoppers and crickets collected from fields frequented by the adult egrets in 1994 had 0.12-0.28% calcium and 0.76-0.81% phosphorus. Pooled grasshoppers and crickets collected during a subsequent wet early spring averaged 0.24% calcium and 0.65% phosphorus. Although the phosphorus content of the insect prey was adequate for growth, calcium was approximately one-third the minimum calcium requirement needed for growth for other species of birds. It was postulated that cattle egrets breeding in Central Texas have expanded their range into habitat that contains less vertebrate prey, and as a result, many nestling egrets are being fed diets that contain suboptimal calcium. Therefore, in years where vertebrate prey is scarce and forage for insect prey is reduced in calcium, nestling egrets are at risk for developing secondary nutritional

  4. Impact modelling of naturally occurring radioactive materials (NORM) in the environment

    International Nuclear Information System (INIS)

    Olyslaegers, G.

    2009-01-01

    Remediation of sites contaminated by Naturally Occurring Radioactive Materials (NORM) is a current issue in many countries world wide. These materials could arise from many types of industries such as mining and milling of uranium, thorium and other metals, phosphate industry, coal mining and combustion, oil and gas industry, abandoned radium and thorium extraction facilities. Waste products originating from these industries need to be managed in a proper way. In recent years, new radiation protection legislation, growing awareness of radiation risks at some sites and public perception have created the necessity to develop remediation strategies for those sites. These strategies can be based on the exploration of hypothetical scenarios, where different exposure pathways are screened. The Belgian Nuclear Research Centre SCK-CEN has been involved in an international comparison exercise under the IAEA EMRAS programme where the radiological impact of a hypothetical NORM waste dump site and the effect of corrective actions had to be assessed. The outcome of different radiological assessment models was compared. The waste dump (surface 1 km 2 , 10 m deep, containing 1 Bq g -1 of 238 U in secular equilibrium with her daughters) is located above an aquifer which can be contaminated by the waste due to percolation of rain water. The waste dump is either uncovered or covered by a 2 m thick layer, with an erosion rate of 0.1 mm y -1 and an effective porosity of 0.2. The dose, resulting from living on top and at 200 m distance from the border of the waste dump was to be calculated

  5. Sarcosine induces increase in HER2/neu expression in androgen-dependent prostate cancer cells

    DEFF Research Database (Denmark)

    Dahl, Malin; Bouchelouche, Pierre; Kramer-Marek, Gabriela

    2011-01-01

    Increasing evidence suggests that Human epidermal growth factor receptor 2 (HER2/neu) is involved in progression of prostate cancer. Recently, sarcosine was reported to be highly increased during prostate cancer progression, and exogenous sarcosine induces an invasive phenotype in benign prostate...... epithelial cells. The aim of this work was to investigate the effect of sarcosine on HER2/neu expression in prostate cancer cell lines LNCaP (androgen dependent), PC-3 and DU145 (both androgen independent). Relative amounts of HER2/neu and androgen receptor (AR) transcripts were determined using RT...... that sarcosine is involved in the regulation of the oncoprotein HER2/neu. Thus, sarcosine may induce prostate cancer progression by increased HER2/neu expression. However, detailed information on cellular mechanisms remains to be elucidated....

  6. A naturally-occurring new lead-based halocuprate(I)

    Energy Technology Data Exchange (ETDEWEB)

    Welch, Mark D.; Rumsey, Michael S. [Department of Earth Sciences, Natural History Museum, London SW7 5BD (United Kingdom); Kleppe, Annette K. [Diamond Light Source, Harwell Science and Innovation Campus, Didcot, Oxfordshire OX11 0DE (United Kingdom)

    2016-06-15

    natural halocuprate(I) Pb{sub 2}Cu(OH){sub 2}I{sub 3} showing the chequerboard alternation of cubane-like [Pb{sub 4}(OH){sub 4}]{sup 4+} and non-polymerised [Cu{sub 2}I{sub 6}]{sup 4−} groups. Pb atoms are black spheres, oxygen atoms are red spheres, iodine atoms are mauve spheres and Cu{sub 2}I{sub 6} groups are shown as paired edge-sharing blue tetrahedra. Display Omitted - Highlights: • A naturally-occurring new inorganic halocuprate(I). • The first natural halocuprate(I). • New structure topology based upon [Pb{sub 4}(OH){sub 4}]{sup 4+} and [Cu{sub 2}I{sub 6}]{sup 4−} groups. • Comparison with synthetic halocuprates suggests tailoring of topology via halogen composition.

  7. Inhibitor of Apoptosis (IAP) survivin is indispensable for survival of HER2 gene-amplified breast cancer cells with primary resistance to HER1/2-targeted therapies

    International Nuclear Information System (INIS)

    Oliveras-Ferraros, Cristina; Vazquez-Martin, Alejandro; Cufi, Silvia; Torres-Garcia, Violeta Zenobia; Sauri-Nadal, Tamara; Barco, Sonia Del; Lopez-Bonet, Eugeni; Brunet, Joan; Martin-Castillo, Begona; Menendez, Javier A.

    2011-01-01

    Highlights: → Intrinsic trastuzumab resistance occurs in ∼70% of metastatic HER2 + breast carcinomas (BC). → Approximately 15% of early HER2 + BC relapse in spite of treatment with trastuzumab-based therapies. → HER2-independent downstream pro-survival pathways might underlie trastuzumab refractoriness. → Survivin is indispensable for proliferation and survival of HER2 + BC unresponsive to HER2-targeted therapies ab initio. → Survivin antagonists may clinically circumvent the occurrence of de novo resistance to HER2-directed drugs. -- Abstract: Primary resistance of HER2 gene-amplified breast carcinomas (BC) to HER-targeted therapies can be explained in terms of overactive HER2-independent downstream pro-survival pathways. We here confirm that constitutive overexpression of Inhibitor of Apoptosis (IAP) survivin is indispensable for survival of HER2-positive BC cells with intrinsic cross-resistance to multiple HER1/2 inhibitors. The IC 50 values for the HER1/2 Tyrosine Kinase Inhibitors (TKIs) gefitinib, erlotinib and lapatinib were up to 40-fold higher in trastuzumab-unresponsive JIMT-1 cells than in trastuzumab-naive SKBR3 cells. ELISA-based and immunoblotting assays demonstrated that trastuzumab-refractory JIMT-1 cells constitutively expressed ∼4 times more survivin protein than trastuzumab-responsive SKBR3 cells. In response to trastuzumab, JIMT-1 cells accumulated ∼10 times more survivin than SKBR3 cells. HER1/2 TKIs failed to down-regulate survivin expression in JIMT-1 cells whereas equimolar doses of HER1/HER2 TKIs drastically depleted survivin protein in SKBR3 cells. ELISA-based detection of histone-associated DNA fragments confirmed that trastuzumab-refractory JIMT-1 cells were intrinsically protected against the apoptotic effects of HER1/2 TKIs. Of note, when we knocked-down survivin expression using siRNA and then added trastuzumab, cell proliferation and colony formation were completely suppressed in JIMT-1 cells. Our current findings may

  8. Inhibitor of Apoptosis (IAP) survivin is indispensable for survival of HER2 gene-amplified breast cancer cells with primary resistance to HER1/2-targeted therapies

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    Oliveras-Ferraros, Cristina; Vazquez-Martin, Alejandro; Cufi, Silvia; Torres-Garcia, Violeta Zenobia [Unit of Translational Research, Catalan Institute of Oncology-Girona, Avenida de Francia S/N, E-17007 Girona, Catalonia (Spain); Girona Biomedical Research Institute, Avenida de Francia S/N, E-17007 Girona, Catalonia (Spain); Sauri-Nadal,