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Sample records for le erbe medicinali

  1. Falsificazione di medicinali, criminalità organizzata e cooperazione internazionale

    Directory of Open Access Journals (Sweden)

    Anna G. Micara

    2016-07-01

    Full Text Available La contraffazione dei medicinali rappresenta una minaccia per tutti i Paesi della Comunità internazionale ed è strettamente legata alla criminalità organizzata. Il carattere transnazionale di tale fenomeno rende evidente l’importanza della cooperazione internazionale in materia che, tuttavia, non è ancora adeguatamente sviluppata. Nonostante i progressi relativi alla nozione di medicinale falsificato, non vi è ancora una definizione comune negli strumenti internazionali analizzati. Inoltre, la Convenzione MEDICRIME, appena entrata in vigore, rappresenta un notevole passo avanti per il rafforzamento del quadro sanzionatorio a livello internazionale ma non vi sono adeguatamente disciplinati gli aspetti legati alla criminalità organizzata. Vengono perciò in rilievo l’applicabilità della Convenzione UNCTOC alla falsificazione dei medicinali, il modello di legislazione UNODC sulle medicine fraudolente e le ipotesi di elaborazione di uno strumento internazionale di più ampio respiro.   Counterfeiting of medicines is a threat to the whole international community and is deeply related to organised crime. The transnational dimension of this multifaceted phenomenon makes necessary to develop international instruments to tackle it. However, and notwithstanding the advancements on the notion of falsified medicines, there is not a common definition in the international legal instruments analyzed. Furthermore, the MEDICRIME Convention, although representing a remarkable step forward concerning criminal sanctions, has been ratified by few States and does not adequately take into account aspects related to the organized crime involvement. In this regard, the applicability of the UN Convention against Transnational Organized Crime to the falsification of medicines and the draft model law of UNODC on fraudulent medicines become relevant. Finally, the proposals to elaborate a broader international instrument within the WHO or the UNODC do not seem

  2. First Isolation of a Giant Virus from Wild Hirudo medicinalis Leech: Mimiviridae isolation in Hirudo medicinalis

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    Mondher Boughalmi

    2013-11-01

    Full Text Available Giant viruses and amoebae are common in freshwater, where they can coexist with other living multicellular organisms. We screened leeches from the species Hirudo medicinalis for giant viruses. We analyzed five H. medicinalis obtained from Tunisia (3 and France (2. The leeches were decontaminated and then dissected to remove internal parts for co-culture with Acanthamoeba polyphaga. The genomes of isolated viruses were sequenced on a 454 Roche instrument, and a comparative genomics analysis was performed. One Mimivirus was isolated and the strain was named Hirudovirus. The genome assembly generated two scaffolds, which were 1,155,382 and 25,660 base pairs in length. Functional annotations were identified for 47% of the genes, which corresponds to 466 proteins. The presence of Mimividae in the same ecological niche as wild Hirudo may explain the presence of the mimivirus in the digestive tract of the leech, and several studies have already shown that viruses can persist in the digestive tracts of leeches fed contaminated blood. As leeches can be used medically and Mimiviruses have the potential to be an infectious agent in humans, patients treated with leeches should be surveyed to investigate a possible connection.

  3. Voelt de medicinale bloedzuiger Hirudo medicinalis zich wel zo lekker in Nederland (Hirudinea)?

    NARCIS (Netherlands)

    Felix, R.P.W.H.; Velde, van der G.

    2000-01-01

    Does the medicinal leech Hirudo medicinalis feel well in the Netherlands (Hirudinea)? This paper provides information on the medicinal leech Hirudo medicinalis Linnaeus, 1758 particularly in The Netherlands. Although this species was common in The Netherlands in the 18th century, nowadays it is very

  4. Naragh Suburb, Center of Iran; A Natural Habitat of Hirudo medicinalis

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    Dehghani R.1 PhD,

    2014-08-01

    Full Text Available Aims A very common species of leeches has been named as Hirudo medicinalis. Regarding to the application of leeches in medicine and their fast extinction, this study was performed in aquatic habitats of Kashan aimed to determine the distribution of leeches and to provide information about their regional and habitat characteristics. Materials & Methods This descriptive study was conducted during 2008 to 2010 in three periods and 90 samples from 30 sites were collected, totally. 30 lentic and lotic aquatic habitats located in different regions of Naragh were recognized and selected. Leeches were collected initially in 10% ethanol followed by washing and removing mucus and then maintained in 70% ethanol. The identification keys were used for recognizing the species of leeches. Findings According to the identification key of the leech species, 15 samples from the total samples of 30 locations were Hirudo medicinalis. Total Hirudo medicinalis samples were collected just from Naragh River. These species of leeches were relatively large with 7-10cm and their colors were olive green, brown and greenish brown with a red stripe on the sides. Conclusion Naragh River is one of the habitats of Hirudo medicinalis.

  5. ERBE bidirectional model consistency check

    Science.gov (United States)

    Baldwin, D. G.; Coakley, J. A., Jr.

    1986-01-01

    A short analysis is presented of Earth Radiation Budget Experiment (ERBE) errors inherent in the directional models used for data interpretation. The models were all developed on the basis of experience with the Nimbus-7 ERB experiment, which had a spatial resolution one-third that of ERBE instrumentation. A pseudo-directional model is defined to simulate the ERBE scanner data, using the assumptions that the average radiant exitance for any particular scene is independent of the viewing geometry, geographic location and time the data is collected. The directionality of the view angle and solar zenith angle is accounted for by a method of bins.

  6. ACETYL-L-CARNITINE AFFECTS THE ELECTRICAL ACTIVITY OF MECHANOSENSORY NEURONS IN HIRUDO MEDICINALIS GANGLIA

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    Giovanna Traina

    2017-04-01

    Full Text Available Was previously discovered that in the leech Hirudo medicinalis, acetyl-l-carnitine (ALC affects forms of non-associative learning, such as sensitization and dishabituation, due to nociceptive stimulation of the dorsal skin in the swim induction behavioural paradigm, likely through modulating the activity of the mechanosensory tactile (T neurons, which initiate swimming. Since was found that ALC impaired sensitization and dishabituation, both of which are mediated by the neurotransmitter serotonin, the present study analyzed how ALC may interfere with the sensitizing response. Was already found that ALC reduced the activity of nociceptive (N neurons, which modulate T cell activity through serotonergic mediation.

  7. ERBE_S4G_WFOV_NF_N10

    Data.gov (United States)

    National Aeronautics and Space Administration — Earth Radiation Budget Experiment (ERBE) S-4G Nonscanner, Wide Field of View (WFOV) Numerical Filter (NF) 5 degree nested to 10.0 degree Regional Averages in...

  8. ERBE_S4G_MFOV_NF_N10

    Data.gov (United States)

    National Aeronautics and Space Administration — Earth Radiation Budget Experiment (ERBE) S-4G Nonscanner, Medium Field of View (MFOV) Numerical Filter (NF) 5 degree nested to 10 degree Regional Averages in...

  9. ERBE_S4GN_WFV_NF_N10

    Data.gov (United States)

    National Aeronautics and Space Administration — Earth Radiation Budget Experiment (ERBE) S-4GN (Nonscanner-only) Wide Field of View Numerical Filter (NF) 5.0 degrees nested to 10.0 degrees Regional Averages in...

  10. ERBE_S10N_WFOV_SF_Edition2

    Data.gov (United States)

    National Aeronautics and Space Administration — Earth Radiation Budget Experiment (ERBE) S-10N (Nonscanner-only) Wide Field of View (WFOV) Shape Factor (SF) Radiant Flux and Albedo Edition 2 in Native Format

  11. Digitalisierung des Kulturellen Erbes (Europas)

    NARCIS (Netherlands)

    Gruber, Marion

    2011-01-01

    Gruber, M. R. (2011, 13 December). Digitalisierung des Kulturellen Erbes (Europas). Guest lecture at the IPMZ - Institute of Mass Communication and Media Research, Devision Media Change & Innovation, University of Zurich, Switzerland.

  12. Small bite, large impact-saliva and salivary molecules in the medicinal leech, Hirudo medicinalis

    Science.gov (United States)

    Hildebrandt, Jan-Peter; Lemke, Sarah

    2011-12-01

    Blood-sucking leeches have been used for medical purposes in humans for hundreds of years. Accordingly, one of the most prominent species has been named Hirudo medicinalis by Carl Linne in 1758. Feeding on vertebrate blood poses some serious problems to blood-sucking ectoparasites, as they have to penetrate the body surface of the host and to suppress the normal reactions of the host to such injuries (swelling, pain, inflammation) to remain undetected during the feeding period. Furthermore, the parasites have to take measures to inhibit the normal reactions in host tissues to blood vessel damage, namely hemostasis and blood coagulation (platelet aggregation and activation, activation of thrombin and formation of fibrin clots). During evolution, leeches have acquired the ability to control these processes in their hosts by transferring various bioactive substances to the host. These substances are supposedly produced in unicellular salivary gland cells and injected into the wound at the feeding site through tiny salivary ductule openings in the jaws that the leech uses to slice open the host body surface and to cut blood vessels in the depth of the wound. This review summarizes current knowledge about the salivary gland cells and the biological effects of individual saliva components as well as hints to the potential usefulness of some of these compounds for medical purposes.

  13. Intracellular recording, sensory field mapping, and culturing identified neurons in the leech, Hirudo medicinalis.

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    Titlow, Josh; Majeed, Zana R; Nicholls, John G; Cooper, Robin L

    2013-11-04

    The freshwater leech, Hirudo medicinalis, is a versatile model organism that has been used to address scientific questions in the fields of neurophysiology, neuroethology, and developmental biology. The goal of this report is to consolidate experimental techniques from the leech system into a single article that will be of use to physiologists with expertise in other nervous system preparations, or to biology students with little or no electrophysiology experience. We demonstrate how to dissect the leech for recording intracellularly from identified neural circuits in the ganglion. Next we show how individual cells of known function can be removed from the ganglion to be cultured in a Petri dish, and how to record from those neurons in culture. Then we demonstrate how to prepare a patch of innervated skin to be used for mapping sensory or motor fields. These leech preparations are still widely used to address basic electrical properties of neural networks, behavior, synaptogenesis, and development. They are also an appropriate training module for neuroscience or physiology teaching laboratories.

  14. Differentially expressed genes in Hirudo medicinalis ganglia after acetyl-L-carnitine treatment.

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    Giuseppe Federighi

    Full Text Available Acetyl-L-carnitine (ALC is a naturally occurring substance that, when administered at supra-physiological concentration, is neuroprotective. It is involved in membrane stabilization and in enhancement of mitochondrial functions. It is a molecule of considerable interest for its clinical application in various neural disorders, including Alzheimer's disease and painful neuropathies. ALC is known to improve the cognitive capability of aged animals chronically treated with the drug and, recently, it has been reported that it impairs forms of non-associative learning in the leech. In the present study the effects of ALC on gene expression have been analyzed in the leech Hirudo medicinalis. The suppression subtractive hybridisation methodology was used for the generation of subtracted cDNA libraries and the subsequent identification of differentially expressed transcripts in the leech nervous system after ALC treatment. The method detects differentially but also little expressed transcripts of genes whose sequence or identity is still unknown. We report that a single administration of ALC is able to modulate positively the expression of genes coding for functions that reveal a lasting effect of ALC on the invertebrate, and confirm the neuroprotective and neuromodulative role of the substance. In addition an important finding is the modulation of genes of vegetal origin. This might be considered an instance of ectosymbiotic mutualism.

  15. Differentially expressed genes in Hirudo medicinalis ganglia after acetyl-L-carnitine treatment.

    Science.gov (United States)

    Federighi, Giuseppe; Macchi, Monica; Bernardi, Rodolfo; Scuri, Rossana; Brunelli, Marcello; Durante, Mauro; Traina, Giovanna

    2013-01-01

    Acetyl-L-carnitine (ALC) is a naturally occurring substance that, when administered at supra-physiological concentration, is neuroprotective. It is involved in membrane stabilization and in enhancement of mitochondrial functions. It is a molecule of considerable interest for its clinical application in various neural disorders, including Alzheimer's disease and painful neuropathies. ALC is known to improve the cognitive capability of aged animals chronically treated with the drug and, recently, it has been reported that it impairs forms of non-associative learning in the leech. In the present study the effects of ALC on gene expression have been analyzed in the leech Hirudo medicinalis. The suppression subtractive hybridisation methodology was used for the generation of subtracted cDNA libraries and the subsequent identification of differentially expressed transcripts in the leech nervous system after ALC treatment. The method detects differentially but also little expressed transcripts of genes whose sequence or identity is still unknown. We report that a single administration of ALC is able to modulate positively the expression of genes coding for functions that reveal a lasting effect of ALC on the invertebrate, and confirm the neuroprotective and neuromodulative role of the substance. In addition an important finding is the modulation of genes of vegetal origin. This might be considered an instance of ectosymbiotic mutualism.

  16. Das Erbe der Menschheit.

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    Joana Breidenbach

    2005-09-01

    Full Text Available Le concept d’« héritage » est apparu avec les efforts des États-nations occidentaux modernes émergents, au 19 e siècle, pour apporter une signification nationale à leurs paysages et à leurs environnements construits. Aujourd’hui, cependant, certains des moteurs centraux de ce mouvement de l’héritage sont des acteurs globaux plutôt que nationaux. Le projet le plus prestigieux pour la promotion de l’idée d’« héritage global » est la liste de l’Héritage mondial de l’ Unesco . Que deviennent les sites qui sont promus du statut d’héritage national à celui d’héritage global ? Deviennent-ils effectivement le véhicule d’une conscience globale partagée ? En se basant sur une recherche de terrain menée en Russie et en Chine, deux pays avec un tourisme de masse nouveau et émergent, nous arrivons à la conclusion que « les trésors de l’humanité entière » dans ces deux pays ne sont pas tant les sites d’une conscience planétaire que les véhicules de pédagogies postsocialistes hautement divergentes et qui reflètent les différentes traditions historiques, visions du développement, de la consommation et de la « belle vie », et structurations de l’ordre social opposées des deux pays. The concept of “heritage” arose as from nineteenth-century efforts by emergent modern Western nation-states to endow their landscapes and built environments with national significance. Today, however, some of the central activists of the heritage movement are global rather than national players. The highest-profile effort to promote the idea of a “global heritage” is Unesco ’s World Heritage list. What happens to sites that are promoted from national to global heritage status? Do they indeed become vehicles of a shared global consciousness? Based on fieldwork in Russia and China, two countries with a new and emergent mass tourism, we conclude that “the treasures of all humankind” in both countries

  17. Rev-erb regulation of cholesterologenesis.

    Science.gov (United States)

    Sitaula, Sadichha; Zhang, Jinsong; Ruiz, Fernanda; Burris, Thomas P

    2017-05-01

    REV-ERBα and REV-ERBβ are heme regulated nuclear receptors that are known to regulate metabolic pathways. We previously demonstrated that treatment of mice with synthetic REV-ERB agonists suppressed plasma cholesterol levels and the hepatic levels of the rate limiting enzyme in cholesterol biosynthesis (3-hydroxy-3-methylglutaryl-CoA reductase). Here, we characterize the role of REV-ERB on the cholesterol biosynthetic pathway in greater detail. The REV-ERB agonist SR9009 reduced plasma cholesterol levels in both wild type C57Bl/6 and low density lipoprotein receptor (LDLR) null mice as well as reducing the expression of an array of genes within the cholesterol biosynthetic pathway. Consistent with these data, we observed increased expression of these genes in mice deficient in expression of Rev-erbα. Analysis of global run-on and deep sequencing (GRO-Seq) and chromatin immunoprecipitation deep sequencing (ChIP-Seq) data revealed that Rev-erb directly binds to the majority of genes involved in cholesterol biosynthesis and directly suppresses their expression. This study reveals insight into the complex mechanism by which Rev-erb directly and indirectly (via inhibition of Srebf2 expression) regulates cholesterol biosynthesis and provides information of how cholesterol levels are regulated in a circadian fashion. Additionally, these studies suggest that targeting Rev-erb may be an effective method for suppressing LDL cholesterol levels in the clinic. Copyright © 2017 Elsevier Inc. All rights reserved.

  18. Acute oral toxicity and anti-inflammatory activity of hydroalcoholic extract from Lampaya medicinalis Phil in rats.

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    Morales, Glauco; Paredes, Adrián; Olivares, Alberto; Bravo, Jaime

    2014-03-26

    Algesia and inflammation are related with several pathological conditions. It is known that many drugs available for the treatment of these problems cause unwanted side effects. This study was aimed at evaluating acute toxicity and anti-inflammatory activity of Lampaya medicinalis Phil. (Verbenaceae) widely used in the folk medicine of Northern Chile against rheumatism, arthritis and body joints pain. Oral administration of hydroalcoholic extract (HAE) at the highest dose of 3000 mg/ Kg body weight resulted in no mortalities or evidence of significant behavioral changes. Histological examination revealed normal architecture and no significant adverse effects were observed on the liver, kidney, heart, lung or ovaries and testicles. The results suggest that the oral administration of hydroalcoholic extract (HAE) from Lampaya medicinalis did not produce any toxic effect in rats. Hydroalcoholic extract (HAE) significantly inhibited the carrageenan-induced rat paw edema in dose - response relationship, at test doses of 37.5, 75, 150 and 300 mg/Kg body weight. Maximum inhibition (61.98 ± 2.69%) was noted at 300 mg/Kg after 2 h of drug treatment carrageenan induced paw edema, whereas indomethacin produced 47.90 ± 1.16% of inhibition. The inhibitory values of edema at 3 h postcarrageenan were 31.04 ± 0.75%, 40.51 ± 2.36%, 48.97 ± 1.14% and 56.87 ± 0.41% for 37.5, 75, 150, and 300 mg/kg of extract respectively. Indomethacin (10 mg/Kg) gave a percentage inhibition of 49.44 ± 1.44. HAE (300 and 150 mg/kg) induced an anti-inflammatory effect greater than (or comparable) with the effect of indomethacin from 2nd to 4th hours of the experiment. Our results reveal for first time that compounds contained in the hydroalcoholic extract of Lampaya medicinalis Phil exert anti-inflammatory effect and the oral administration is safe and non toxic up to dose level 3000 mg/kg body weight. The anti-inflammatory activity may be associated with the presence of flavonoids. These

  19. Acute oral toxicity and anti-inflammatory activity of hydroalcoholic extract from Lampaya medicinalis Phil in rats

    Directory of Open Access Journals (Sweden)

    Glauco Morales

    2014-01-01

    Full Text Available BACKGROUND: Algesia and inflammation are related with several pathological conditions. It is known that many drugs available for the treatment of these problems cause unwanted side effects. This study was aimed at evaluating acute toxicity and anti-inflammatory activity of Lampaya medicinalis Phil. (Verbenaceae widely used in the folk medicine of Northern Chile against rheumatism, arthritis and body joints pain. RESULTS: Oral administration of hydroalcoholic extract (HAE at the highest dose of 3000 mg/ Kg body weight resulted in no mortalities or evidence of significant behavioral changes. Histological examination revealed normal architecture and no significant adverse effects were observed on the liver, kidney, heart, lung or ovaries and testicles. The results suggest that the oral administration of hydroalcoholic extract (HAE from Lampaya medicinalis did not produce any toxic effect in rats. Hydroalcoholic extract (HAE significantly inhibited the carrageenan-induced rat paw edema in dose - response relationship, at test doses of 37.5, 75, 150 and 300 mg/Kg body weight. Maximum inhibition (61.98 ± 2.69% was noted at 300 mg/Kg after 2 h of drug treatment carrageenan induced paw edema, whereas indomethacin produced 47.90 ± 1.16% of inhibition. The inhibitory values of edema at 3 h postcarrageenan were 31.04±0.75%, 40.51 ± 2.36%, 48.97 ± 1.14% and 56.87 ± 0.41% for 37.5, 75, 150, and 300 mg/kg of extract respectively. Indomethacin (10 mg/Kg gave a percentage inhibition of 49.44 ± 1.44. HAE (300 and 150 mg/kg induced an anti-inflammatory effect greater than (or comparable with the effect of indomethacin from 2nd to 4th hours of the experiment. CONCLUSIONS: Our results reveal for first time that compounds contained in the hydroalcoholic extract ofLampaya medicinalis Phil exert anti-inflammatory effect and the oral administration is safe and non toxic up to dose level 3000 mg/kg body weight. The anti

  20. Characterization of an Experimental Referee Broadened Specification (ERBS) aviation turbine fuel and ERBS fuel blends

    Science.gov (United States)

    Seng, G. T.

    1982-01-01

    Characterization data and comparisons of these data are presented for three individual lots of a research test fuel designated as an Experimental Referee Broadened Specification (ERBS) aviation turbine fuel. This research fuel, which is a blend of kerosene and hydrotreated catalytic gas oil, is a representation of a kerojet fuel with broadened properties. To lower the hydrogen content of the ERBS fuel, a blending stock, composed of xylene bottoms and hydrotreated catalytic gas oil, was developed and employed to produce two different ERBS fuel blends. The ERBS fuel blends and the blending stock were also characterized and the results for the blends are compared to those of the original ERBS fuel. The characterization results indicate that with the exception of the freezing point for ERBS lot 2, which was slightly high, the three lots, produced over a 2 year period, met all general fuel requirements. However, although the properties of the fuels were found to be fairly consistent, there were differences in composition. Similarly, all major requirements for the ERBS fuel blends were met or closely approached, and the properties of the blended fuels were found to generally reflect those expected for the proportions of ERBS fuel and blending stock used in their production.

  1. v-erbA overexpression is required to extinguish c-erbA function in erythroid cell differentiation and regulation of the erbA target gene CAII

    DEFF Research Database (Denmark)

    Disela, C; Glineur, C; Bugge, T

    1991-01-01

    The v-erbA oncoprotein represents a retrovirus-transduced oncogenic version of the thyroid hormone (T3/T4) receptor c-erbA (type alpha). It contributes to virus-induced erythroleukemia by efficiently arresting differentiation of red cell progenitors and by suppressing transcription of erythrocyte...... of this CAII reporter construct could only be suppressed by very high amounts of v-erbA. Our results suggest that overexpression of v-erbA is required for its function as an oncoprotein....

  2. ErbB2, but not ErbB1, reinitiates proliferation and induces luminal repopulation in epithelial acini

    Energy Technology Data Exchange (ETDEWEB)

    Muthuswamy, Senthil K; Li, Dongmei; Lelievre, Sophie; Bissell, Mina J; Brugge, Joan S

    2001-08-08

    Both ErbB1 and ErbB2 are overexpressed or amplified in breast tumors. To examine the effects of activating ErbB receptors in a context that mimics polarized epithelial cells in vivo, we activated ErbB1 and ErbB2 homodimers in preformed, growth-arrested mammary acini cultured in three-dimensional basement membrane gels. Activation of ErbB2, but not that of ErbB1, led to a reinitiation of cell proliferation and altered the properties of mammary acinar structures. These altered structures share several properties with early-stage tumors, including a loss of proliferative suppression, an absence of lumen, retention of the basement membrane and a lack of invasive properties. ErbB2 activation also disrupted tight junctions and the cell polarity of polarized epithelia, whereas ErbB1 activation did not have any effect. Our results indicate that ErbB receptors differ in their ability to induce early stages of mammary carcinogenesis in vitro and this three-dimensional model system can reveal biological activities of oncogenes that cannot be examined in vitro in standard transformation assays.

  3. Bispecific antibody to ErbB2 overcomes trastuzumab resistance through comprehensive blockade of ErbB2 heterodimerization.

    Science.gov (United States)

    Li, Bohua; Meng, Yanchun; Zheng, Lei; Zhang, Xunmin; Tong, Qing; Tan, Wenlong; Hu, Shi; Li, Hui; Chen, Yang; Song, Jinjing; Zhang, Ge; Zhao, Lei; Zhang, Dapeng; Hou, Sheng; Qian, Weizhu; Guo, Yajun

    2013-11-01

    The anti-ErbB2 antibody trastuzumab has shown significant clinical benefits in metastatic breast cancer. However, resistance to trastuzumab is common. Heterodimerization between ErbB2 and other ErbBs may redundantly trigger cell proliferation signals and confer trastuzumab resistance. Here, we developed a bispecific anti-ErbB2 antibody using trastuzumab and pertuzumab, another ErbB2-specific humanized antibody that binds to a distinct epitope from trastuzumab. This bispecific antibody, denoted as TPL, retained the full binding activities of both parental antibodies and exhibited pharmacokinetic properties similar to those of a conventional immunoglobulin G molecule. Unexpectedly, TPL showed superior ErbB2 heterodimerization-blocking activity over the combination of both parental monoclonal antibodies, possibly through steric hindrance and/or inducing ErbB2 conformational change. Further data indicated that TPL potently abrogated ErbB2 signaling in trastuzumab-resistant breast cancer cell lines. In addition, we showed that TPL was far more effective than trastuzumab plus pertuzumab in inhibiting the growth of trastuzumab-resistant breast cancer cell lines, both in vitro and in vivo. Importantly, TPL treatment eradicated established trastuzumab-resistant tumors in tumor-bearing nude mice. Our results suggest that trastuzumab-resistant breast tumors remain dependent on ErbB2 signaling and that comprehensive blockade of ErbB2 heterodimerization may be an effective therapeutic avenue. The unique potential of TPL to overcome trastuzumab resistance warrants its consideration as a promising treatment in the clinic.

  4. Suppression of atherosclerosis by synthetic REV-ERB agonist

    International Nuclear Information System (INIS)

    Sitaula, Sadichha; Billon, Cyrielle; Kamenecka, Theodore M.; Solt, Laura A.; Burris, Thomas P.

    2015-01-01

    The nuclear receptors for heme, REV-ERBα and REV-ERBβ, play important roles in the regulation of metabolism and inflammation. Recently it was demonstrated that reduced REV-ERBα expression in hematopoetic cells in LDL receptor null mice led to increased atherosclerosis. We sought to determine if synthetic REV-ERB agonists that we have developed might have the ability to suppress atherosclerosis in this model. A previously characterized synthetic REV-ERB agonist, SR9009, was used to determine if activation of REV-ERB activity would affect atherosclerosis in LDL receptor deficient mice. Atherosclerotic plaque size was significantly reduced (p < 0.05) in mice administered SR9009 (100 mg/kg) for seven weeks compared to control mice (n = 10 per group). SR9009 treatment of bone marrow-derived mouse macrophages (BMDM) reduced the polarization of BMDMs to proinflammatory M1 macrophage while increasing the polarization of BMDMs to anti-inflammatory M2 macrophages. Our results suggest that pharmacological targeting of REV-ERBs may be a viable therapeutic option for treatment of atherosclerosis. - Highlights: • Synthetic REV-ERB agonist treatment reduced atherosclerosis in a mouse model. • Pharmacological activation of REV-ERB decreased M1 macrophage polarization. • Pharmacological activation of REV-ERB increased M2 macrophage polarization

  5. Suppression of atherosclerosis by synthetic REV-ERB agonist

    Energy Technology Data Exchange (ETDEWEB)

    Sitaula, Sadichha [Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, FL 33458 (United States); Billon, Cyrielle [Department of Pharmacological & Physiological Science, Saint Louis University School of Medicine, St. Louis, MO 63104 (United States); Kamenecka, Theodore M.; Solt, Laura A. [Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, FL 33458 (United States); Burris, Thomas P., E-mail: burristp@slu.edu [Department of Pharmacological & Physiological Science, Saint Louis University School of Medicine, St. Louis, MO 63104 (United States)

    2015-05-08

    The nuclear receptors for heme, REV-ERBα and REV-ERBβ, play important roles in the regulation of metabolism and inflammation. Recently it was demonstrated that reduced REV-ERBα expression in hematopoetic cells in LDL receptor null mice led to increased atherosclerosis. We sought to determine if synthetic REV-ERB agonists that we have developed might have the ability to suppress atherosclerosis in this model. A previously characterized synthetic REV-ERB agonist, SR9009, was used to determine if activation of REV-ERB activity would affect atherosclerosis in LDL receptor deficient mice. Atherosclerotic plaque size was significantly reduced (p < 0.05) in mice administered SR9009 (100 mg/kg) for seven weeks compared to control mice (n = 10 per group). SR9009 treatment of bone marrow-derived mouse macrophages (BMDM) reduced the polarization of BMDMs to proinflammatory M1 macrophage while increasing the polarization of BMDMs to anti-inflammatory M2 macrophages. Our results suggest that pharmacological targeting of REV-ERBs may be a viable therapeutic option for treatment of atherosclerosis. - Highlights: • Synthetic REV-ERB agonist treatment reduced atherosclerosis in a mouse model. • Pharmacological activation of REV-ERB decreased M1 macrophage polarization. • Pharmacological activation of REV-ERB increased M2 macrophage polarization.

  6. A peptide antagonist of ErbB receptors, Inherbin3, induces neurite outgrowth from rat cerebellar granule neurons through ErbB1 inhibition

    DEFF Research Database (Denmark)

    Xu, Ruodan; Pankratova, Stanislava; Christiansen, Søren Hofman

    2013-01-01

    ErbB receptors not only function in cancer, but are also key developmental regulators in the nervous system. We previously identified an ErbB1 peptide antagonist, Inherbin3, that is capable of inhibiting tumor growth in vitro and in vivo. In this study, we found that inhibition of ErbB1 kinase...

  7. Le caratteristiche linguistiche del foglietto illustrativo

    Directory of Open Access Journals (Sweden)

    Silvia Giumelli

    2013-07-01

    Full Text Available Nell’articolo si affronta il problema della comprensibilità del foglietti illustrativi (i bugiardini” allegati ai medicinali, di cui indicano posologia, modalità d’uso ed effetti indesiderati (FI nel testo. Linguisticamente il testo dei FI si pone nel più ampio contesto dei linguaggi specialistici, ma si distingue per alcune particolarità (il destinatario e la funzione che ricopre. Attraverso l’analisi del FI presente in un comune antipiretico, Tachipirina 1000 ®, si mettono in evidenza le strategie comunicative messe in atto dall’estensore e il grado di comprensione da parte del presunto destinatario. L’analisi mette inoltre in luce le caratteristiche comuni di questo tipo di testi altamente specialistici con il linguaggio settoriale della medicina.  Language features of medicine packaging leaflets This article addresses the problem of the comprehensibility of the leaflets in medicine packaging which indicate dosage, method of use and side effects (FI in the text. Linguistically, the text of the FI is placed in the broader context of specialist languages, but it is characterized by some peculiarities (the recipient and the role it plays. By analyzing the FI of a common antipyretic, paracetamol 1000 ®, we highlight the communicative strategies put in place by the author and the degree of understanding on the part of the intended recipient. The analysis also highlights the common features of this type of highly specialized text with the technical language of medicine.

  8. Development of an ErbB4 monoclonal antibody that blocks neuregulin-1-induced ErbB4 activation in cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Okazaki, Shogo [Division of Gene Regulation, Institute for Advanced Medical Research, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582 (Japan); Nakatani, Fumi [Cell Biology Laboratory, Department of Pharmaceutical Sciences, Faculty of Pharmacy, Kinki University, Higashiosaka, Osaka 577-8502 Japan (Japan); Masuko, Kazue; Tsuchihashi, Kenji [Division of Gene Regulation, Institute for Advanced Medical Research, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582 (Japan); Ueda, Shiho; Masuko, Takashi [Cell Biology Laboratory, Department of Pharmaceutical Sciences, Faculty of Pharmacy, Kinki University, Higashiosaka, Osaka 577-8502 Japan (Japan); Saya, Hideyuki [Division of Gene Regulation, Institute for Advanced Medical Research, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582 (Japan); Nagano, Osamu, E-mail: osmna@sb3.so-net.ne.jp [Division of Gene Regulation, Institute for Advanced Medical Research, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582 (Japan)

    2016-01-29

    The use of monoclonal antibodies (mAbs) for cancer therapy is one of the most important strategies for current cancer treatment. The epidermal growth factor receptor (EGFR) family of receptor tyrosine kinases, which regulates cancer cell proliferation, survival, and migration, is a major molecular target for antibody-based therapy. ErbB4/HER4, which contains a ligand-binding extracellular region, is activated by several ligands, including neuregulins (NRGs), heparin-binding EGF-like growth factor, betacellulin and epiregulin. Although there are clinically approved antibodies for ErbB1 and ErbB2, there are no available therapeutic mAbs for ErbB4, and it is not known whether ErbB4 is a useful target for antibody-based cancer therapy. In this study, we developed an anti-ErbB4 mAb (clone P6-1) that suppresses NRG-dependent activation of ErbB4 and examined its effect on breast cancer cell proliferation in the extracellular matrix. - Highlights: • We newly generated four clones of human ErbB4 specific mAb. • ErbB4 mAb clone P6-1 blocks ErbB4 phosphorylation induced by NRG-1. • ErbB4 mAb clone P6-1 suppresses NRG-1-promoted breast cancer cells proliferation on three dimensional culture condition.

  9. Role of the erbB3 Gene Product in Breast Cancer Cell Proliferation

    National Research Council Canada - National Science Library

    Koland, John

    1998-01-01

    The role of the ErbB3 protein in breast cancer cell proliferation was examined. In the first year of funding, it was demonstrated that the ErbB3 protein, although possessing a protein tyrosine kinase (PTK...

  10. Role of the erbB3 Gene Product in Breast Cancer Cell Proliferation

    National Research Council Canada - National Science Library

    Koland, John

    1997-01-01

    The role of the ErbB3 protein in breast cancer cell proliferation was examined. In the first year of funding, it was demonstrated that the ErbB3 protein, although possessing a protein tyrosine kinase (PTK...

  11. Structure-Based Design of erbB-2 Selective Small Molecule Kinase Inhibitors

    National Research Council Canada - National Science Library

    Wang, Shaomeng

    2003-01-01

    .... Among these initial lead compounds, B-17 has excellent activity in inhibition of erbB-2 auto-phosphorylation and inhibition of cell proliferation using MDA-453 human breast cancer cells with erbB-2 overexpression...

  12. Role of Erbin in ErbB2-dependent breast tumor growth

    Science.gov (United States)

    Tao, Yanmei; Shen, Chengyong; Luo, Shiwen; Traoré, Wilfried; Marchetto, Sylvie; Santoni, Marie-Josée; Xu, Linlin; Wu, Biao; Shi, Chao; Mei, Jinghong; Bates, Ryan; Liu, Xihui; Zhao, Kai; Xiong, Wen-Cheng; Borg, Jean-Paul; Mei, Lin

    2014-01-01

    ErbB2 (v-erb-b2 avian erythroblastic leukemia viral oncogene homolog 2), a receptor tyrosine kinase of the ErbB family, is overexpressed in around 25% of breast cancers. In addition to forming a heterodimer with other ErbB receptors in response to ligand stimulation, ErbB2 can be activated in a ligand-independent manner. We report here that Erbin, an ErbB2-interacting protein that was thought to act as an antitumor factor, is specifically expressed in mammary luminal epithelial cells and facilitates ErbB2-dependent proliferation of breast cancer cells and tumorigenesis in MMTV-neu transgenic mice. Disruption of their interaction decreases ErbB2-dependent proliferation, and deletion of the PDZ domain in Erbin hinders ErbB2-dependent tumor development in MMTV-neu mice. Mechanistically, Erbin forms a complex with ErbB2, promotes its interaction with the chaperon protein HSP90, and thus prevents its degradation. Finally, ErbB2 and Erbin expression correlates in human breast tumor tissues. Together, these observations establish Erbin as an ErbB2 regulator for breast tumor formation and progression. PMID:25288731

  13. ErbB polymorphisms: Insights and implications for response to targeted cancer therapeutics

    Directory of Open Access Journals (Sweden)

    Moulay A Alaoui-Jamali

    2015-02-01

    Full Text Available Advances in high-throughput genomic-scanning have expanded the repertory of genetic variations in DNA sequences encoding ErbB tyrosine kinase receptors in humans, including single nucleotide polymorphisms (SNPs, polymorphic repetitive elements, microsatellite variations, small-scale insertions and deletions. The ErbB family members: EGFR, ErbB2, ErbB3 and ErbB4 receptors are established as drivers of many aspects of tumor initiation and progression to metastasis. This knowledge has provided rationales for the development of an arsenal of anti-ErbB therapeutics, ranging from small molecule kinase inhibitors to monoclonal antibodies. Anti-ErbB agents are becoming the cornerstone therapeutics for the management of cancers that overexpress hyperactive variants of ErbB receptors, in particular ErbB2-positive breast cancer and non-small cell lung carcinomas. However, their clinical benefit has been limited to a subset of patients due to a wide heterogeneity in drug response despite the expression of the ErbB targets, attributed to intrinsic (primary and to acquired (secondary resistance. Somatic mutations in ErbB tyrosine kinase domains have been extensively investigated in preclinical and clinical setting as determinants for either high sensitivity or resistance to anti-ErbB therapeutics. In contrast, only scant information is available on the impact of SNPs, which are widespread in genes encoding ErbB receptors, on receptor structure and activity, and their predictive values for drug susceptibility. This review aims to briefly update polymorphic variations in genes encoding ErbB receptors based on recent advances in deep sequencing technologies, and to address challenging issues for a better understanding of the functional impact of single versus combined SNPs in ErbB genes to receptor topology, receptor-drug interaction, and drug susceptibility. The potential of exploiting SNPs in the era of stratified targeted therapeutics is discussed.

  14. ErbB3 drives mammary epithelial survival and differentiation during pregnancy and lactation.

    Science.gov (United States)

    Williams, Michelle M; Vaught, David B; Joly, Meghan Morrison; Hicks, Donna J; Sanchez, Violeta; Owens, Philip; Rahman, Bushra; Elion, David L; Balko, Justin M; Cook, Rebecca S

    2017-09-08

    During pregnancy, as the mammary gland prepares for synthesis and delivery of milk to newborns, a luminal mammary epithelial cell (MEC) subpopulation proliferates rapidly in response to systemic hormonal cues that activate STAT5A. While the receptor tyrosine kinase ErbB4 is required for STAT5A activation in MECs during pregnancy, it is unclear how ErbB3, a heterodimeric partner of ErbB4 and activator of phosphatidyl inositol-3 kinase (PI3K) signaling, contributes to lactogenic expansion of the mammary gland. We assessed mRNA expression levels by expression microarray of mouse mammary glands harvested throughout pregnancy and lactation. To study the role of ErbB3 in mammary gland lactogenesis, we used transgenic mice expressing WAP-driven Cre recombinase to generate a mouse model in which conditional ErbB3 ablation occurred specifically in alveolar mammary epithelial cells (aMECs). Profiling of RNA from mouse MECs isolated throughout pregnancy revealed robust Erbb3 induction during mid-to-late pregnancy, a time point when aMECs proliferate rapidly and undergo differentiation to support milk production. Litters nursed by ErbB3 KO dams weighed significantly less when compared to litters nursed by ErbB3 WT dams. Further analysis revealed substantially reduced epithelial content, decreased aMEC proliferation, and increased aMEC cell death during late pregnancy. Consistent with the potent ability of ErbB3 to activate cell survival through the PI3K/Akt pathway, we found impaired Akt phosphorylation in ErbB3 KO samples, as well as impaired expression of STAT5A, a master regulator of lactogenesis. Constitutively active Akt rescued cell survival in ErbB3-depleted aMECs, but failed to restore STAT5A expression or activity. Interestingly, defects in growth and survival of ErbB3 KO aMECs as well as Akt phosphorylation, STAT5A activity, and expression of milk-encoding genes observed in ErbB3 KO MECs progressively improved between late pregnancy and lactation day 5. We found a

  15. ErbB2 resembles an autoinhibited invertebrate epidermal growth factor receptor

    Energy Technology Data Exchange (ETDEWEB)

    Alvarado, Diego; Klein, Daryl E.; Lemmon, Mark A.; (UPENN-MED)

    2009-09-25

    The orphan receptor tyrosine kinase ErbB2 (also known as HER2 or Neu) transforms cells when overexpressed, and it is an important therapeutic target in human cancer. Structural studies have suggested that the oncogenic (and ligand-independent) signalling properties of ErbB2 result from the absence of a key intramolecular 'tether' in the extracellular region that autoinhibits other human ErbB receptors, including the epidermal growth factor (EGF) receptor. Although ErbB2 is unique among the four human ErbB receptors, here we show that it is the closest structural relative of the single EGF receptor family member in Drosophila melanogaster (dEGFR). Genetic and biochemical data show that dEGFR is tightly regulated by growth factor ligands, yet a crystal structure shows that it, too, lacks the intramolecular tether seen in human EGFR, ErbB3 and ErbB4. Instead, a distinct set of autoinhibitory interdomain interactions hold unliganded dEGFR in an inactive state. All of these interactions are maintained (and even extended) in ErbB2, arguing against the suggestion that ErbB2 lacks autoinhibition. We therefore suggest that normal and pathogenic ErbB2 signalling may be regulated by ligands in the same way as dEGFR. Our findings have important implications for ErbB2 regulation in human cancer, and for developing therapeutic approaches that target novel aspects of this orphan receptor.

  16. v-erbA oncogene activation entails the loss of hormone-dependent regulator activity of c-erbA

    DEFF Research Database (Denmark)

    Zenke, M; Muñoz, A; Sap, J

    1990-01-01

    and erythrocyte-specific gene expression in a T3-dependent fashion, when introduced into erythroid cells via a retrovirus. In contrast, the endogenous thyroid hormone receptor does not detectably affect erythroid differentiation. The analysis of a series of chimeric v-/c-erbA proteins suggests that the v...

  17. Rev-erbα and Rev-erbβ coordinately protect the circadian clock and normal metabolic function

    DEFF Research Database (Denmark)

    Bugge, Anne Skovsø; Feng, Dan; Everett, Logan J

    2012-01-01

    to relatively subtle changes upon loss of either subtype alone. These findings establish the two Rev-erbs as major regulators of both clock function and metabolism, displaying a level of subtype collaboration that is unusual among nuclear receptors but common among core clock proteins, protecting the organism...

  18. The Nuclear Receptor Rev-erbα Controls Circadian Thermogenic Plasticity

    Science.gov (United States)

    Gerhart-Hines, Zachary; Everett, Logan J.; Loro, Emanuele; Briggs, Erika R.; Bugge, Anne; Hou, Catherine; Ferrara, Christine; Seale, Patrick; Pryma, Daniel A.; Khurana, Tejvir S.; Lazar, Mitchell A.

    2013-01-01

    Circadian oscillation of body temperature is a basic, evolutionary-conserved feature of mammalian biology1. Additionally, homeostatic pathways allow organisms to protect their core temperatures in response to cold exposure2. However, the mechanism responsible for coordinating daily body temperature rhythm and adaptability to environmental challenges is unknown. Here we show that the nuclear receptor Rev-erbα, a powerful transcriptional repressor, links circadian and thermogenic networks through the regulation of brown adipose tissue (BAT) function. Mice exposed to cold fare dramatically better at 5 AM (Zeitgeber time 22) when Rev-erbα is barely expressed than at 5 PM (ZT10) when Rev-erbα is abundant. Deletion of Rev-erbα markedly improves cold tolerance at 5 PM, indicating that overcoming Rev-erbα-dependent repression is a fundamental feature of the thermogenic response to cold. Physiological induction of uncoupling protein 1 (UCP1) by cold temperatures is preceded by rapid down-regulation of Rev-erbα in BAT. Rev-erbα represses UCP1 in a brown adipose cell-autonomous manner and BAT UCP1 levels are high in Rev-erbα-null mice even at thermoneutrality. Genetic loss of Rev-erbα also abolishes normal rhythms of body temperature and BAT activity. Thus, Rev-erbα acts as a thermogenic focal point required for establishing and maintaining body temperature rhythm in a manner that is adaptable to environmental demands. PMID:24162845

  19. The nuclear receptor Rev-erbα controls circadian thermogenic plasticity.

    Science.gov (United States)

    Gerhart-Hines, Zachary; Feng, Dan; Emmett, Matthew J; Everett, Logan J; Loro, Emanuele; Briggs, Erika R; Bugge, Anne; Hou, Catherine; Ferrara, Christine; Seale, Patrick; Pryma, Daniel A; Khurana, Tejvir S; Lazar, Mitchell A

    2013-11-21

    Circadian oscillation of body temperature is a basic, evolutionarily conserved feature of mammalian biology. In addition, homeostatic pathways allow organisms to protect their core temperatures in response to cold exposure. However, the mechanism responsible for coordinating daily body temperature rhythm and adaptability to environmental challenges is unknown. Here we show that the nuclear receptor Rev-erbα (also known as Nr1d1), a powerful transcriptional repressor, links circadian and thermogenic networks through the regulation of brown adipose tissue (BAT) function. Mice exposed to cold fare considerably better at 05:00 (Zeitgeber time 22) when Rev-erbα is barely expressed than at 17:00 (Zeitgeber time 10) when Rev-erbα is abundant. Deletion of Rev-erbα markedly improves cold tolerance at 17:00, indicating that overcoming Rev-erbα-dependent repression is a fundamental feature of the thermogenic response to cold. Physiological induction of uncoupling protein 1 (Ucp1) by cold temperatures is preceded by rapid downregulation of Rev-erbα in BAT. Rev-erbα represses Ucp1 in a brown-adipose-cell-autonomous manner and BAT Ucp1 levels are high in Rev-erbα-null mice, even at thermoneutrality. Genetic loss of Rev-erbα also abolishes normal rhythms of body temperature and BAT activity. Thus, Rev-erbα acts as a thermogenic focal point required for establishing and maintaining body temperature rhythm in a manner that is adaptable to environmental demands.

  20. Large-scale analysis by SAGE reveals new mechanisms of v-erbA oncogene action

    Directory of Open Access Journals (Sweden)

    Faure Claudine

    2007-10-01

    Full Text Available Abstract Background: The v-erbA oncogene, carried by the Avian Erythroblastosis Virus, derives from the c-erbAα proto-oncogene that encodes the nuclear receptor for triiodothyronine (T3R. v-ErbA transforms erythroid progenitors in vitro by blocking their differentiation, supposedly by interference with T3R and RAR (Retinoic Acid Receptor. However, v-ErbA target genes involved in its transforming activity still remain to be identified. Results: By using Serial Analysis of Gene Expression (SAGE, we identified 110 genes deregulated by v-ErbA and potentially implicated in the transformation process. Bioinformatic analysis of promoter sequence and transcriptional assays point out a potential role of c-Myb in the v-ErbA effect. Furthermore, grouping of newly identified target genes by function revealed both expected (chromatin/transcription and unexpected (protein metabolism functions potentially deregulated by v-ErbA. We then focused our study on 15 of the new v-ErbA target genes and demonstrated by real time PCR that in majority their expression was activated neither by T3, nor RA, nor during differentiation. This was unexpected based upon the previously known role of v-ErbA. Conclusion: This paper suggests the involvement of a wealth of new unanticipated mechanisms of v-ErbA action.

  1. Interaction with epsin 1 regulates the constitutive clathrin-dependent internalization of ErbB3.

    Science.gov (United States)

    Szymanska, Monika; Fosdahl, Anne Marthe; Raiborg, Camilla; Dietrich, Markus; Liestøl, Knut; Stang, Espen; Bertelsen, Vibeke

    2016-06-01

    In contrast to other members of the EGF receptor family, ErbB3 is constitutively internalized in a clathrin-dependent manner. Previous studies have shown that ErbB3 does not interact with the coated pit localized adaptor complex 2 (AP-2), and that ErbB3 lacks two AP-2 interacting internalization signals identified in the EGF receptor. Several other clathrin-associated sorting proteins which may recruit cargo into coated pits have, however, been identified, and the study was performed to identify adaptors needed for constitutive internalization of ErbB3. A high-throughput siRNA screen was used to identify adaptor proteins needed for internalization of ErbB3. Upon knock-down of candidate proteins internalization of ErbB3 was identified using an antibody-based internalization assay combined with automatic fluorescence microscopy. Among 29 candidates only knock-down of epsin 1 turned out to inhibit ErbB3. Epsin 1 has ubiquitin interacting motifs (UIMs) and we show that ErbB3 interacts with an epsin 1 deletion mutant containing these UIMs. In support of an ErbB3-epsin 1 UIM dependent interaction, we show that ErbB3 is constitutively ubiquitinated, but that both ubiquitination and the ErbB3-epsin 1 interaction increase upon ligand binding. Altogether the results are consistent with a model whereby both constitutive and ligand-induced internalization of ErbB3 are regulated through interaction with epsin 1. Internalization is an important regulator of growth factor receptor mediated signaling and the current study identify mechanisms regulating plasma membrane turnover of ErbB3. Copyright © 2016 Elsevier B.V. All rights reserved.

  2. Truncated ErbB2 receptor enhances ErbB1 signaling and induces reversible, ERK-independent loss of epithelial morphology

    DEFF Research Database (Denmark)

    Egeblad, M; Mortensen, Ole Hartvig; Jäättelä, M

    2001-01-01

    Shedding of the extracellular domain of the ErbB2 tyrosine kinase receptor and expression of the remaining NH(2)-terminally truncated ErbB2 correlates with lymph node metastases and adverse outcome in human breast cancer. To study the possible signaling from such a truncated receptor, MCF-7 human...... breast cancer cells expressing NH(2)-terminally truncated ErbB2 (DeltaNErbB2) were compared with cells overexpressing wild-type ErbB2. Expression of DeltaNErbB2 in MCF-7 cells resulted in sustained activation of extracellular signal-regulated kinases (ERK) 1/2, extensive loss of the epithelial morphology......, appearance of vesicles and long protrusions as well as pronounced scattering of the cells. Similar alterations were observed upon ErbB2 overexpression but at much lower levels. Employing cell clones with inducible expression of DeltaNErbB2, it was revealed that the morphological changes were fully reversible...

  3. Preubiquitinated chimeric ErbB2 is constitutively endocytosed and subsequently degraded in lysosomes

    International Nuclear Information System (INIS)

    Vuong, Tram Thu; Berger, Christian; Bertelsen, Vibeke; Rødland, Marianne Skeie; Stang, Espen; Madshus, Inger Helene

    2013-01-01

    The oncoprotein ErbB2 is endocytosis-deficient, probably due to its interaction with Heat shock protein 90. We previously demonstrated that clathrin-dependent endocytosis of ErbB2 is induced upon incubation of cells with Ansamycin derivatives, such as geldanamycin and its derivative 17-AAG. Furthermore, we have previously demonstrated that a preubiquitinated chimeric EGFR (EGFR-Ub 4 ) is constitutively endocytosed in a clathrin-dependent manner. We now demonstrate that also an ErbB2-Ub 4 chimera is endocytosed constitutively and clathrin-dependently. Upon expression, the ErbB2-Ub 4 was further ubiquitinated, and by Western blotting, we demonstrated the formation of both Lys48-linked and Lys63-linked polyubiquitin chains. ErbB2-Ub 4 was constitutively internalized and eventually sorted to late endosomes and lysosomes where the fusion protein was degraded. ErbB2-Ub 4 was not cleaved prior to internalization. Interestingly, over-expression of Ubiquitin Interaction Motif-containing dominant negative fragments of the clathrin adaptor proteins epsin1 and Eps15 negatively affected endocytosis of ErbB2. Altogether, this argues that ubiquitination is sufficient to induce clathrin-mediated endocytosis and lysosomal degradation of the otherwise plasma membrane localized ErbB2. Also, it appears that C-terminal cleavage is not required for endocytosis. -- Highlights: ► A chimera containing ErbB2 and a tetra-Ubiquitin chain internalizes constitutively. ► Receptor fragmentation is not required for endocytosis of ErbB2. ► Ubiquitination is sufficient to induce endocytosis and degradation of ErbB2. ► ErbB2-Ub4 is internalized clathrin-dependently.

  4. REV-ERB and ROR nuclear receptors as drug targets

    Science.gov (United States)

    Kojetin, Douglas J.; Burris, Thomas P.

    2016-01-01

    The nuclear receptors REV-ERB (consisting of REV-ERBα and REV-ERBβ) and retinoic acid receptor-related orphan receptors (RORs; consisting of RORα, RORβ and RORγ) are involved in many physiological processes, including regulation of metabolism, development and immunity as well as the circadian rhythm. The recent characterization of endogenous ligands for these former orphan nuclear receptors has stimulated the development of synthetic ligands and opened up the possibility of targeting these receptors to treat several diseases, including diabetes, atherosclerosis, autoimmunity and cancer. This Review focuses on the latest developments in ROR and REV-ERB pharmacology indicating that these nuclear receptors are druggable targets and that ligands targeting these receptors may be useful in the treatment of several disorders. PMID:24577401

  5. NOAA-9 Earth Radiation Budget Experiment (ERBE) scanner offsets determination

    Science.gov (United States)

    Avis, Lee M.; Paden, Jack; Lee, Robert B., III; Pandey, Dhirendra K.; Stassi, Joseph C.; Wilson, Robert S.; Tolson, Carol J.; Bolden, William C.

    1994-01-01

    The Earth Radiation Budget Experiment (ERBE) instruments are designed to measure the components of the radiative exchange between the Sun, Earth and space. ERBE is comprised of three spacecraft, each carrying a nearly identical set of radiometers: a three-channel narrow-field-of-view scanner, a two-channel wide-field-of-view (limb-to-limb) non-scanning radiometer, a two-channel medium field-of view (1000 km) non-scanning radiometer, and a solar monitor. Ground testing showed the scanners to be susceptible to self-generated and externally generated electromagnetic noise. This paper describes the pre-launch corrective measures taken and the post-launch corrections to the NOAA-9 scanner data. The NOAA-9 scanner has met the mission objectives in accuracy and precision, in part because of the pre-launch reductions of and post-launch data corrections for the electromagnetic noise.

  6. Transcriptional profiling of ErbB signalling in mammary luminal epithelial cells - interplay of ErbB and IGF1 signalling through IGFBP3 regulation

    Directory of Open Access Journals (Sweden)

    Worthington Jenny

    2010-09-01

    Full Text Available Abstract Background Members of the ErbB family of growth factor receptors are intricately linked with epithelial cell biology, development and tumourigenesis; however, the mechanisms involved in their downstream signalling are poorly understood. Indeed, it is unclear how signal specificity is achieved and the relative contribution each receptor has to specific gene expression. Methods Gene expression profiling of a human mammary luminal epithelial cell model of ErbB2-overexpression was carried out using cDNA microarrays with a common RNA reference approach to examine long-term overlapping and differential responses to EGF and heregulin beta1 treatment in the context of ErbB2 overexpression. Altered gene expression was validated using quantitative real time PCR and/or immunoblotting. One gene of interest was targeted for further characterisation, where the effects of siRNA-mediated silencing on IGF1-dependent signalling and cellular phenotype were examined and compared to the effects of loss of ErbB2 expression. Results 775 genes were differentially expressed and clustered in terms of their growth factor responsiveness. As well as identifying uncharacterized genes as novel targets of ErbB2-dependent signalling, ErbB2 overexpression augmented the induction of multiple genes involved in proliferation (e.g. MYC, MAP2K1, MAP2K3, autocrine growth factor signalling (VEGF, PDGF and adhesion/cytoskeletal regulation (ZYX, THBS1, VCL, CNN3, ITGA2, ITGA3, NEDD9, TAGLN, linking them to the hyper-poliferative and altered adhesive phenotype of the ErbB2-overexpressing cells. We also report ErbB2-dependent down-regulation of multiple interferon-stimulated genes that may permit ErbB2-overexpressing cells to resist the anti-proliferative action of interferons. Finally, IGFBP3 was unique in its pattern of regulation and we further investigated a possible role for IGFBP3 down-regulation in ErbB2-dependent transformation through suppressed IGF1 signalling. We show

  7. Transcriptional profiling of ErbB signalling in mammary luminal epithelial cells - interplay of ErbB and IGF1 signalling through IGFBP3 regulation

    International Nuclear Information System (INIS)

    Worthington, Jenny; Bertani, Mariana; Chan, Hong-Lin; Gerrits, Bertran; Timms, John F

    2010-01-01

    Members of the ErbB family of growth factor receptors are intricately linked with epithelial cell biology, development and tumourigenesis; however, the mechanisms involved in their downstream signalling are poorly understood. Indeed, it is unclear how signal specificity is achieved and the relative contribution each receptor has to specific gene expression. Gene expression profiling of a human mammary luminal epithelial cell model of ErbB2-overexpression was carried out using cDNA microarrays with a common RNA reference approach to examine long-term overlapping and differential responses to EGF and heregulin beta1 treatment in the context of ErbB2 overexpression. Altered gene expression was validated using quantitative real time PCR and/or immunoblotting. One gene of interest was targeted for further characterisation, where the effects of siRNA-mediated silencing on IGF1-dependent signalling and cellular phenotype were examined and compared to the effects of loss of ErbB2 expression. 775 genes were differentially expressed and clustered in terms of their growth factor responsiveness. As well as identifying uncharacterized genes as novel targets of ErbB2-dependent signalling, ErbB2 overexpression augmented the induction of multiple genes involved in proliferation (e.g. MYC, MAP2K1, MAP2K3), autocrine growth factor signalling (VEGF, PDGF) and adhesion/cytoskeletal regulation (ZYX, THBS1, VCL, CNN3, ITGA2, ITGA3, NEDD9, TAGLN), linking them to the hyper-poliferative and altered adhesive phenotype of the ErbB2-overexpressing cells. We also report ErbB2-dependent down-regulation of multiple interferon-stimulated genes that may permit ErbB2-overexpressing cells to resist the anti-proliferative action of interferons. Finally, IGFBP3 was unique in its pattern of regulation and we further investigated a possible role for IGFBP3 down-regulation in ErbB2-dependent transformation through suppressed IGF1 signalling. We show that IGF1-dependent signalling and proliferation were

  8. REV-ERB and ROR: therapeutic targets for treating myopathies

    Science.gov (United States)

    Welch, Ryan D.; Flaveny, Colin A.

    2017-08-01

    Muscle is primarily known for its mechanical roles in locomotion, maintenance of posture, and regulation of cardiac and respiratory function. There are numerous medical conditions that adversely affect muscle, myopathies that disrupt muscle development, regeneration and protein turnover to detrimental effect. Skeletal muscle is also a vital secretory organ that regulates thermogenesis, inflammatory signaling and directs context specific global metabolic changes in energy substrate preference on a daily basis. Myopathies differ in the causative factors that drive them but share common features including severe reduction in quality of life and significantly increased mortality all due irrefutably to the loss of muscle mass. Thus far clinically viable approaches for preserving muscle proteins and stimulating new muscle growth without unwanted side effects or limited efficacy has been elusive. Over the last few decades, evidence has emerged through in vitro and in vivo studies that suggest the nuclear receptors REV-ERB and ROR might modulate pathways involved in myogenesis and mitochondrial biogenesis. Hinting that REV-ERB and ROR might be targeted to treat myopathies. However there is still a need for substantial investigation into the roles of these nuclear receptors in in vivo rodent models of degenerative muscle diseases and acute injury. Although exciting, REV-ERB and ROR have somewhat confounding roles in muscle physiology and therefore more studies utilizing in vivo models of skeletal muscle myopathies are needed. In this review we highlight the molecular forces driving some of the major degenerative muscular diseases and showcase two promising molecular targets that may have the potential to treat myopathies: ROR and REV-ERB.

  9. ErbB2 regulates NHEJ repair pathway by affecting erbB1-triggered IR-induced Akt activity

    International Nuclear Information System (INIS)

    Toulany, Mahmoud; Peter Rodemann, H.

    2009-01-01

    We have already reported that erbBl-PI3K-AKT signaling is an important pathway in regulating radiation sensitivity and DNA double strand break repair of human tumor cells. In the present study using small interfering RNA and pharmacological inhibitors in non-small cell lung cancer cell lines we investigated the role of Aktl on radiation-induced DNA-PKcs activity and DNA-double strand break (DNA-DSB) repair. Likewise, the function of erbB2 as hetrodimerization partner of erbBl in radiation-induced Akt activity and regulation of DNA-dsb repair through DNA-PKcs was evaluated. In A549 and H460 transfected with AKTl-siRNA radiation-induced phosphorylation of DNA-PKcs the key enzyme regulating NHEJ repair pathway was markedly inhibited. In both cell lines downregulation of Aktl led to a significant enhancement of residual DNA-DSB, i.e. impaired DNA-DSB repair. Interestingly, in cells transfected with DNA-PKcs-siRNA a lack of effect of AKTl-siRNA on enhancement of residual DNA-DSBs was observed. This results indicate that Aktl regulates NHEJ repair in a DNA-PKcs dependent manner

  10. Rev-Erb co-regulates muscle regeneration via tethered interaction with the NF-Y cistrome

    Directory of Open Access Journals (Sweden)

    Ryan D. Welch

    2017-07-01

    Conclusions: Disrupting Rev-Erb activity in injured muscle accelerates regenerative muscle repair/differentiation through transcriptional de-repression of myogenic programs. Rev-Erb, therefore, may be a potent therapeutic target for a myriad of muscular disorders.

  11. EGF receptor inhibitors increase ErbB3 mRNA and protein levels in breast cancer cells

    DEFF Research Database (Denmark)

    Grøvdal, Lene Melsæther; Kim, Jiyoung; Holst, Mikkel Roland

    2012-01-01

    The potential benefits of drugs directly targeting the ErbB receptors for cancer therapy have led to an extensive development within this field. However, the clinical effects of ErbB receptor-targeting drugs in cancer treatment are limited due to a high frequency of resistance. It has been reported...... that, when inhibiting the epidermal growth factor receptor (EGFR) with the tyrosine kinase inhibitor gefitinib, increased activation of ErbB3 via MET, or by re-localization of ErbB3 mediates cell survival. Here we show further evidence that members of the ErbB receptor family facilitate resistance...... to EGFR inhibitor treatment in ErbB2 overexpressing breast cancer cells. We found that gefitinib treatment increased ErbB3 expression, both at protein and mRNA levels. ErbB3 expression was upregulated not only by gefitinib but also by a panel of different EGFR inhibitors, suggesting that inhibition...

  12. Development of a Novel Test System for Screening Antagonists of ErbB Receptors in Breast Cancer

    National Research Council Canada - National Science Library

    Blau, Helen

    2004-01-01

    The focus of this project was to design a system for screening chemical compounds that would inhibit the dimerization of the EGFR family members ErbB2 and ErbB3 using beta-galactosidase complementation...

  13. Development of a Novel Test System for Screening for Antagonists of ErbB5 Receptors in Breast Cancer

    National Research Council Canada - National Science Library

    Blau, Helen

    2003-01-01

    The focus of this project was to design a system for screening chemical compounds that would inhibit the dimerization of the EGFR family members ErbB2 and ErbB3 using beta-galactosidase complementation...

  14. Quantitative PCR Detection of c-erbB-2 Gene Amplification.

    Science.gov (United States)

    Dobianer, K; Medl, M; Spona, J

    2001-01-01

    The association of c-erbB-2 oncogene amplification and prognostic factors was intensively studied in human gynecological carcinomas, especially in mammary carcinoma (1). Positive lymph nodes, estrogen and progesterone receptor negative tumors, and short survival time correlate with c-erbB-2 amplification.

  15. Flotillins as regulators of ErbB2 levels in breast cancer

    DEFF Research Database (Denmark)

    Pust, S; Klokk, T I; Musa, N

    2013-01-01

    -induced mechanisms. Here we show that flotillins are involved in the stabilization of ErbB2 at the plasma membrane. In SKBR3 breast cancer cells and breast cancer tissue, a positive correlation between flotillin and ErbB2 expression levels could be demonstrated. Moreover, the tissue microarray analyses of biopsies...

  16. The c-erb-A protein is a high-affinity receptor for thyroid hormone

    DEFF Research Database (Denmark)

    Sap, J; Muñoz, A; Damm, K

    1987-01-01

    Hormone binding and localization of the c-erb-A protein suggest that it is a receptor for thyroid hormone, a nuclear protein that binds to DNA and activates transcription. In contrast, the product of the viral oncogene v-erb-A is defective in binding the hormone but is still located in the nucleus....

  17. Gastric Cancer Cell Glycosylation as a Modulator of the ErbB2 Oncogenic Receptor

    Directory of Open Access Journals (Sweden)

    Henrique O. Duarte

    2017-10-01

    Full Text Available Aberrant expression and hyperactivation of the human epidermal growth factor receptor 2 (ErbB2 constitute crucial molecular events underpinning gastric neoplastic transformation. Despite ErbB2 extracellular domain being a well-known target for glycosylation, its glycosylation profile and the molecular mechanisms through which it actively tunes tumorigenesis in gastric cancer (GC cells remain elusive. We aimed at disclosing relevant ErbB2 glycan signatures and their functional impact on receptor’s biology in GC cells. The transcriptomic profile of cancer-relevant glycosylation enzymes, and the expression and activation of the ErbB receptors were characterized in four GC cell lines. Cellular- and receptor-specific glycan profiling of ErbB2-overexpressing NCI-N87 cells unveiled a heterogeneous glycosylation pattern harboring the tumor-associated sialyl Lewis a (SLea antigen. The expression of SLea and key enzymes integrating its biosynthetic pathway were strongly upregulated in this GC cell line. An association between the expression of ERBB2 and FUT3, a central gene in SLea biosynthesis, was disclosed in GC patients, further highlighting the crosstalk between ErbB2 and SLea expression. Moreover, cellular deglycosylation and CA 19.9 antibody-mediated blocking of SLea drastically altered ErbB2 expression and activation in NCI-N87 cells. Altogether, NCI-N87 cell line constitutes an appealing in vitro model to address glycan-mediated regulation of ErbB2 in GC.

  18. The v-ErbA oncoprotein quenches the activity of an erythroid-specific enhancer.

    NARCIS (Netherlands)

    Braliou, G.G.; Ciana, P; Klaassen, W.; Gandrillon, O.; Stunnenberg, H.G.

    2001-01-01

    v-ErbA is a mutated variant of thyroid hormone receptor (TRalpha/NR1A1) borne by the Avian Erythroblastosis virus causing erythroleukemia. TRalpha is known to activate transcription of specific genes in the presence of its cognate ligand, T3 hormone, while in its absence it represses it. v-ErbA is

  19. Altered Sleep Homeostasis in Rev-erbα Knockout Mice.

    Science.gov (United States)

    Mang, Géraldine M; La Spada, Francesco; Emmenegger, Yann; Chappuis, Sylvie; Ripperger, Jürgen A; Albrecht, Urs; Franken, Paul

    2016-03-01

    The nuclear receptor REV-ERBα is a potent, constitutive transcriptional repressor critical for the regulation of key circadian and metabolic genes. Recently, REV-ERBα's involvement in learning, neurogenesis, mood, and dopamine turnover was demonstrated suggesting a specific role in central nervous system functioning. We have previously shown that the brain expression of several core clock genes, including Rev-erbα, is modulated by sleep loss. We here test the consequences of a loss of REV-ERBα on the homeostatic regulation of sleep. EEG/EMG signals were recorded in Rev-erbα knockout (KO) mice and their wild type (WT) littermates during baseline, sleep deprivation, and recovery. Cortical gene expression measurements after sleep deprivation were contrasted to baseline. Although baseline sleep/wake duration was remarkably similar, KO mice showed an advance of the sleep/wake distribution relative to the light-dark cycle. After sleep onset in baseline and after sleep deprivation, both EEG delta power (1-4 Hz) and sleep consolidation were reduced in KO mice indicating a slower increase of homeostatic sleep need during wakefulness. This slower increase might relate to the smaller increase in theta and gamma power observed in the waking EEG prior to sleep onset under both conditions. Indeed, the increased theta activity during wakefulness predicted delta power in subsequent NREM sleep. Lack of Rev-erbα increased Bmal1, Npas2, Clock, and Fabp7 expression, confirming the direct regulation of these genes by REV-ERBα also in the brain. Our results add further proof to the notion that clock genes are involved in sleep homeostasis. Because accumulating evidence directly links REV-ERBα to dopamine signaling the altered homeostatic regulation of sleep reported here are discussed in that context. © 2016 Associated Professional Sleep Societies, LLC.

  20. Role of ErbB receptors in cancer cell migration and invasion

    Directory of Open Access Journals (Sweden)

    Aline eAppert-Collin

    2015-11-01

    Full Text Available Growth factors mediate their diverse biologic responses (regulation of cellular proliferation, differentiation, migration and survival by binding to and activating cell-surface receptors with intrinsic protein kinase activity named Receptor Tyrosine Kinases (RTKs. About 60 RTKs have been identified and can be classified into more than 16 different receptor families. Their activity is normally tightly controlled and regulated. Overexpression of RTK proteins or functional alterations caused by mutations in the corresponding genes or abnormal stimulation by autocrine growth factor loops contribute to constitutive RTK signaling, resulting in alterations in the physiological activities of cells. The ErbB receptor family of RTKs comprises four distinct receptors: the EGFR (also known as ErbB1/HER1, ErbB2 (neu, HER2, ErbB3 (HER3 and ErbB4 (HER4. ErbB family members are often overexpressed, amplified, or mutated in many forms of cancer, making them important therapeutic targets. EGFR has been found to be amplified in gliomas and non-small-cell lung carcinoma while ErbB2 amplifications are seen in breast, ovarian, bladder, non-small-cell lung carcinoma, as well as several other tumor types. Several data have shown that ErbB receptor family and its downstream pathway regulate epithelial-mesenchymal transition, migration, and tumor invasion by modulating extracellular matrix components. Recent findings indicate that extracellular matrix components such as matrikines bind specifically to EGF receptor and promote cell invasion. In this review, we will present an in-depth overview of the structure, mechanisms, cell signaling, and functions of ErbB family receptors in cell adhesion and migration. Furthermore, we will describe in a last part the new strategies developed in anti-cancer therapy to inhibit ErbB family receptor activation.

  1. Altered Sleep Homeostasis in Rev-erbα Knockout Mice

    Science.gov (United States)

    Mang, Géraldine M.; La Spada, Francesco; Emmenegger, Yann; Chappuis, Sylvie; Ripperger, Jürgen A.; Albrecht, Urs; Franken, Paul

    2016-01-01

    Study Objectives: The nuclear receptor REV-ERBα is a potent, constitutive transcriptional repressor critical for the regulation of key circadian and metabolic genes. Recently, REV-ERBα's involvement in learning, neurogenesis, mood, and dopamine turnover was demonstrated suggesting a specific role in central nervous system functioning. We have previously shown that the brain expression of several core clock genes, including Rev-erbα, is modulated by sleep loss. We here test the consequences of a loss of REV-ERBα on the homeostatic regulation of sleep. Methods: EEG/EMG signals were recorded in Rev-erbα knockout (KO) mice and their wild type (WT) littermates during baseline, sleep deprivation, and recovery. Cortical gene expression measurements after sleep deprivation were contrasted to baseline. Results: Although baseline sleep/wake duration was remarkably similar, KO mice showed an advance of the sleep/wake distribution relative to the light-dark cycle. After sleep onset in baseline and after sleep deprivation, both EEG delta power (1–4 Hz) and sleep consolidation were reduced in KO mice indicating a slower increase of homeostatic sleep need during wakefulness. This slower increase might relate to the smaller increase in theta and gamma power observed in the waking EEG prior to sleep onset under both conditions. Indeed, the increased theta activity during wakefulness predicted delta power in subsequent NREM sleep. Lack of Rev-erbα increased Bmal1, Npas2, Clock, and Fabp7 expression, confirming the direct regulation of these genes by REV-ERBα also in the brain. Conclusions: Our results add further proof to the notion that clock genes are involved in sleep homeostasis. Because accumulating evidence directly links REV-ERBα to dopamine signaling the altered homeostatic regulation of sleep reported here are discussed in that context. Citation: Mang GM, La Spada F, Emmenegger Y, Chappuis S, Ripperger JA, Albrecht U, Franken P. Altered sleep homeostasis in Rev-erb

  2. A combination of Trastuzumab and 17-AAG induces enhanced ubiquitinylation and lysosomal pathway-dependent ErbB2 degradation and cytotoxicity in ErbB2-overexpressing breast cancer cells.

    Science.gov (United States)

    Raja, Srikumar M; Clubb, Robert J; Bhattacharyya, Mitra; Dimri, Manjari; Cheng, Hao; Pan, Wei; Ortega-Cava, Cesar; Lakku-Reddi, Alagarsamy; Naramura, Mayumi; Band, Vimla; Band, Hamid

    2008-10-01

    ErbB2 (or Her2/Neu) overexpression in breast cancer signifies poorer prognosis, yet it has provided an avenue for targeted therapy as demonstrated by the success of the humanized monoclonal antibody Trastuzumab (Herceptin). Resistance to Trastuzumab and eventual failure in most cases, however, necessitate alternate ErbB2-targeted therapies. HSP90 inhibitors such as 17-allylaminodemethoxygeldanamycin (17-AAG), potently downregulate the cell surface ErbB2. While the precise mechanisms of Trastuzumab or 17-AAG action remain unclear, ubiquitinylation-dependent proteasomal or lysosomal degradation of ErbB2 appears to play a substantial role. As Trastuzumab and 17-AAG induce the recruitment of distinct E3 ubiquitin ligases, Cbl and CHIP respectively, to ErbB2, we hypothesized that 17-AAG and Trastuzumab combination could induce a higher level of ubiquitinylation and downregulation of ErbB2 as compared to single drug treatments. We present biochemical and cell biological evidence that combined 17-AAG and Trastuzumab treatment of ErbB2-overexpressing breast cancer cell lines leads to enhanced ubiquitinylation, downregulation from the cell surface and lysosomal degradation of ErbB2. Importantly, combined 17-AAG and Trastuzumab treatment induced synergistic growth arrest and cell death specifically in ErbB2-overexpressing but not in ErbB2-low breast cancer cells. Our results suggest the 17-AAG and Trastuzumab combination as a mechanism-based combinatorial targeted therapy for ErbB2-overexpressing breast cancer patients.

  3. Mek activity is required for ErbB2 expression in breast cancer cells detached from the extracellular matrix.

    Science.gov (United States)

    Khan, Iman A; Yoo, Byong H; Rak, Janusz; Rosen, Kirill V

    2017-12-01

    Detachment of non-malignant epithelial cells from the extracellullar matrix (ECM) triggers their growth arrest and apoptosis. Conversely, carcinoma cells can grow without adhesion to the ECM. This capacity for anchorage-independent growth is thought to be critical for tumor progression. ErbB2/Her2 oncoprotein is overproduced by a significant fraction of breast cancers and promotes anchorage-independent tumor cell growth by poorly understood mechanisms. In an effort to understand them we found that in order to produce ErbB2, detached breast cancer cells require the activity of an ErbB2 effector protein kinase Mek and that Mek-driven ErbB2 expression is neccesary for anchorage-independent growth of such cells. We observed that Mek inhibition does not alter ErbB2 mRNA levels in detached cancer cells and that ErbB2 protein loss induced by this inhibition can be blocked by a lysosomal inhibitor. We also noticed that an increase of the density of cancer cells detached from the ECM downregulates a Mek effector protein kinase Erk and causes ErbB2 loss. Those cells that survive after ErbB2 loss display resistance to trastuzumab, an anti-ErbB2 antibody used for ErbB2-positive breast cancer treatment. Thus, Mek-induced ErbB2 stabilization in detached breast cancer cells is critical for their ability to grow anchorage-independently and their trastuzumab sensitivity.

  4. Co-conserved features associated with cis regulation of ErbB tyrosine kinases.

    Directory of Open Access Journals (Sweden)

    Amar Mirza

    Full Text Available BACKGROUND: The epidermal growth factor receptor kinases, or ErbB kinases, belong to a large sub-group of receptor tyrosine kinases (RTKs, which share a conserved catalytic core. The catalytic core of ErbB kinases have functionally diverged from other RTKs in that they are activated by a unique allosteric mechanism that involves specific interactions between the kinase core and the flanking Juxtamembrane (JM and COOH-terminal tail (C-terminal tail. Although extensive studies on ErbB and related tyrosine kinases have provided important insights into the structural basis for ErbB kinase functional divergence, the sequence features that contribute to the unique regulation of ErbB kinases have not been systematically explored. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we use a Bayesian approach to identify the selective sequence constraints that most distinguish ErbB kinases from other receptor tyrosine kinases. We find that strong ErbB kinase-specific constraints are imposed on residues that tether the JM and C-terminal tail to key functional regions of the kinase core. A conserved RIxKExE motif in the JM-kinase linker region and a glutamine in the inter-lobe linker are identified as two of the most distinguishing features of the ErbB family. While the RIxKExE motif tethers the C-terminal tail to the N-lobe of the kinase domain, the glutamine tethers the C-terminal tail to hinge regions critical for inter-lobe movement. Comparison of the active and inactive crystal structures of ErbB kinases indicates that the identified residues are conformationally malleable and can potentially contribute to the cis regulation of the kinase core by the JM and C-terminal tail. ErbB3, and EGFR orthologs in sponges and parasitic worms, diverge from some of the canonical ErbB features, providing insights into sub-family and lineage-specific functional specialization. CONCLUSION/SIGNIFICANCE: Our analysis pinpoints key residues for mutational analysis, and

  5. FASN, ErbB2-mediated glycolysis is required for breast cancer cell migration.

    Science.gov (United States)

    Zhou, Lan; Jiang, Sufang; Fu, Qiang; Smith, Kelly; Tu, Kailing; Li, Hua; Zhao, Yuhua

    2016-05-01

    Both fatty acid synthase (FASN) and ErbB2 have been shown to promote breast cancer cell migration. However, the underlying molecular mechanism remains poorly understood and there is no reported evidence that directly links glycolysis to breast cancer cell migration. In this study, we investigated the role of FASN, ErbB2-mediated glycolysis in breast cancer cell migration. First, we compared lactate dehydrogenase A (LDHA) protein levels, glycolysis and cell migration between FASN, ErbB2-overexpressing SK-BR-3 cells and FASN, ErbB2-low-expressing MCF7 cells. Then, SK-BR-3 cells were treated with cerulenin (Cer), an inhibitor of FASN, and ErbB2, LDHA protein levels, glycolysis, and cell migration were detected. Next, we transiently transfected ErbB2 plasmid into MCF7 cells and detected FASN, LDHA protein levels, glycolysis and cell migration. Heregulin-β1 (HRG-β1) is an activator of ErbB2 and 2-deoxyglucose (2-DG) and oxamate (OX) are inhibitors of glycolysis. MCF7 cells were treated with HRG-β1 alone, HRG-β1 plus 2-DG, OX or cerulenin and glycolysis, and cell migration were measured. We found that FASN, ErbB2-high-expressing SK-BR-3 cells displayed higher levels of glycolysis and migration than FASN, ErbB2-low-expressing MCF7 cells. Inhibition of FASN by cerulenin impaired glycolysis and migration in SK-BR-3 cells. Transient overexpression of ErbB2 in MCF7 cells promotes glycolysis and migration. Moreover, 2-deoxyglucose (2-DG), oxamate (OX), or cerulenin partially reverses heregulin-β1 (HRG-β1)-induced glycolysis and migration in MCF7 cells. In conclusion, this study demonstrates that FASN, ErbB2-mediated glycolysis is required for breast cancer cell migration. These novel findings indicate that targeting FASN, ErbB2-mediated glycolysis may be a new approach to reverse breast cancer cell migration.

  6. Overexpression of ErbB2 induces invasion of MCF10A human breast epithelial cells via MMP-9.

    Science.gov (United States)

    Kim, In-Young; Yong, Hae-Young; Kang, Keon Wook; Moon, Aree

    2009-03-18

    Metastasis is the principal cause of death from breast cancer. ErbB2 (HER-2/neu) has been identified as an important regulator of metastatic potential of breast cancer. The present study investigated the molecular mechanism underlying the role of ErbB2 in malignant phenotypic conversion of MCF10A human breast epithelial cells which originally have 'normal' cell character. Here we report that ErbB2 induces invasion and migration of MCF10A cells though up-regulation of matrix metalloproteinase (MMP)-9. We also observed a marked reduction of an epithelial cell marker, E-cadherin, and an induction of vimentin in ErbB2-MCF10A cells, suggesting that epithelial-mesenchymal transition may play a role in the ErbB2-induced invasion and migration of MCF10A cells. Overexpression of ErbB2 significantly activated p38 MAPK and Akt, while Raf-1/MEK/ERK pathway was not activated by ErbB2. Using pharmacological inhibitors, we further show that p38 MAPK and Akt signaling pathways are crucial for the ErbB2-induced MMP-9 up-regulation, invasion and migration of MCF10A cells. Given that ErbB2 is one of the most important oncogenes in human breast cancer and thus is an attractive therapeutic target, our findings may provide a molecular basis for the promoting role of ErbB2 in breast cancer progression.

  7. Antipsychotic potential of quinazoline ErbB1 inhibitors in a schizophrenia model established with neonatal hippocampal lesioning.

    Science.gov (United States)

    Mizuno, Makoto; Iwakura, Yuriko; Shibuya, Masako; Zheng, Yingjun; Eda, Takeyoshi; Kato, Taisuke; Takasu, Yohei; Nawa, Hiroyuki

    2010-01-01

    Hyper-signaling of the epidermal growth factor receptor family (ErbB) is implicated in the pathophysiology of schizophrenia. Various quinazoline inhibitors targeting ErbB1 or ErbB2 - 4 have been developed as anti-cancer agents and might be useful for antipsychotic treatment. In the present study, we used an animal model of schizophrenia established by neonatal hippocampal lesioning and evaluated the neurobehavioral consequences of ErbB1-inhibitor treatment. Subchronic administration of the ErbB1 inhibitor ZD1839 to the cerebroventricle of rats receiving neonatal hippocampal lesioning ameliorated deficits in prepulse inhibition as well as those in the latent inhibition of tone-dependent fear learning. There were no apparent adverse effects on basal learning scores or locomotor activity, however. The administration of other ErbB1 inhibitors, PD153035 and OSI-774, similarly attenuated the prepulse inhibition impairment of this animal model. In parallel, there were decreases in ErbB1 phosphorylation in animals treated with ErbB1 inhibitors. These results indicate an antipsychotic potential of quinazoline ErbB1 inhibitors. ErbB receptor tyrosine kinases may be novel therapeutic targets for schizophrenia or its related psychotic symptoms.

  8. ISLSCP II Earth Radiation Budget Experiment (ERBE) Monthly Albedo, 1986-1990

    Data.gov (United States)

    National Aeronautics and Space Administration — The goals of the Earth Radiation Budget Experiment (ERBE) are (1) to understand the radiation balance between the Sun, Earth, atmosphere, and space and (2) to...

  9. ErbB2 Regulation of c-src Activity in Breast Cancer

    National Research Council Canada - National Science Library

    Sheffield, Lewis

    1999-01-01

    ErbB2 transformation of mammary epithelial cells activated c-src. C-src activation was associated with decreased phosphorylation of tyrosine 527, but not by a decrease in C-terminal-src-kinase (CSK) activity...

  10. CERES ERBE-like Gridded Instantaneous TOA Fluxes Aqua Crosstrack Edition4

    Data.gov (United States)

    National Aeronautics and Space Administration — The ERBE-like Monthly Regional Averages (ES-9) product contains a month of space and time averaged Clouds and the Earth's Radiant Energy System (CERES) data for a...

  11. CERES ERBE-like Time-Interpolated TOA Fluxes Terra Crosstrack Edition4

    Data.gov (United States)

    National Aeronautics and Space Administration — The ERBE-like Monthly Geographical Averages (ES-4) product contains a month of space and time averaged Clouds and the Earth's Radiant Energy System (CERES) data for...

  12. CERES ERBE-like Time-Interpolated TOA Fluxes Aqua Crosstrack Edition4

    Data.gov (United States)

    National Aeronautics and Space Administration — The ERBE-like Monthly Geographical Averages (ES-4) product contains a month of space and time averaged Clouds and the Earth's Radiant Energy System (CERES) data for...

  13. CERES ERBE-like Time-Interpolated TOA Fluxes NPP FM5 Edition1

    Data.gov (United States)

    National Aeronautics and Space Administration — The ERBE-like Monthly Geographical Averages (ES-4) product contains a month of space and time averaged Clouds and the Earth's Radiant Energy System (CERES) data for...

  14. CERES ERBE-like Gridded Instantaneous TOA Fluxes Terra and Aqua Crosstrack Edition4

    Data.gov (United States)

    National Aeronautics and Space Administration — The ERBE-like Monthly Regional Averages (ES-9) product contains a month of space and time averaged Clouds and the Earth's Radiant Energy System (CERES) data for both...

  15. CERES ERBE-like Gridded Instantaneous TOA Fluxes NPP CERES FM-5 Edition1

    Data.gov (United States)

    National Aeronautics and Space Administration — The ERBE-like Monthly Regional Averages (ES-9) product contains a month of space and time averaged Clouds and the Earth's Radiant Energy System (CERES) data for a...

  16. CERES ERBE-like Gridded Instantaneous TOA Fluxes Terra Crosstrack Edition4

    Data.gov (United States)

    National Aeronautics and Space Administration — The ERBE-like Monthly Regional Averages (ES-9) product contains a month of space and time averaged Clouds and the Earth's Radiant Energy System (CERES) data for a...

  17. CERES ERBE-like Time-Interpolated TOA Fluxes Terra and Aqua Crosstrack Edition4

    Data.gov (United States)

    National Aeronautics and Space Administration — The ERBE-like Monthly Geographical Averages (ES-4) product contains a month of space and time averaged Clouds and the Earth's Radiant Energy System (CERES) data for...

  18. EGF Regulation of VEGF: Role in Progression of ErbB2 Overexpressing Mammary Tumors

    National Research Council Canada - National Science Library

    Loureiro, Robyn

    2004-01-01

    .... ErbB2, an epidermal growth factor receptor family member whose overexpression in mammary tumors is correlated with poor patient prognosis, has been previously implicated as a positive modulator of VEGF expression...

  19. Novel Peptide/Protein Delivery System Targeting erbB2-Overexpressing Breast Cancer Cells

    National Research Council Canada - National Science Library

    Yu, Dihua

    2002-01-01

    .... During this funding year, we focused on the delivery of erbB2 signal-blocking ESP peptides (objective 2) . Because of the complexity of biotin-penetratin-AHNP-ESP, the synthesis was unsuccessful...

  20. Integrin-Associated CD151 Drives ErbB2-Evoked Mammary Tumor Onset and Metastasis

    Directory of Open Access Journals (Sweden)

    Xinyu Deng

    2012-08-01

    Full Text Available ErbB2+ human breast cancer is a major clinical problem. Prior results have suggested that tetraspanin CD151 might contribute to ErbB2-driven breast cancer growth, survival, and metastasis. In other cancer types, CD151 sometimes supports tumor growth and metastasis. However, a definitive test of CD151 effects on de novo breast cancer initiation, growth, and metastasis has not previously been done. We used CD151 gene-deleted mice expressing the MMTV-ErbB2 transgene to show that CD151 strongly supports ErbB2+ mammary tumor initiation and metastasis. Delayed tumor onset (by 70–100 days in the absence of CD151 was accompanied by reduced survival of mammary epithelial cells and impaired activation of FAK- and MAPK-dependent pathways. Both primary tumors and metastatic nodules showed smooth, regular borders, consistent with a less invasive phenotype. Furthermore, consistent with impaired oncogenesis and decreased metastasis, CD151-targeted MCF-10A/ErbB2 cells showed substantial decreases in three-dimensional colony formation, EGF-stimulated tumor cell motility, invasion, and transendothelial migration. These CD151-dependent functions were largely mediated through α6β4 integrin. Moreover, CD151 ablation substantially prevented PKC- and EGFR/ERK-dependent α6β4 integrin phosphorylation, consistent with retention of epithelial cell polarity and intermediate filament cytoskeletal connections, which helps to explain diminished metastasis. Finally, clinical data analyses revealed a strong correlation between CD151 and ErbB2 expression and metastasis-free survival of breast cancer patients. In conclusion, we provide strong evidence that CD151 collaborates with LB integrins (particularly α6β4 and ErbB2 (and EGFR receptors to regulate multiple signaling pathways, thereby driving mammary tumor onset, survival, and metastasis. Consequently, CD151 is a useful therapeutic target in malignant ErbB2+ breast cancer.

  1. Chimeric DNA Vaccines against ErbB2{sup +} Carcinomas: From Mice to Humans

    Energy Technology Data Exchange (ETDEWEB)

    Quaglino, Elena; Riccardo, Federica; Macagno, Marco; Bandini, Silvio; Cojoca, Rodica; Ercole, Elisabetta [Molecular Biotechnology Center, Department of Clinical and Biological Sciences, University of Turin, 10126 Turin (Italy); Amici, Augusto [Department of Molecular Cellular and Animal Biology, University of Camerino, 62032 Camerino (Italy); Cavallo, Federica, E-mail: federica.cavallo@unito.it [2 Department of Molecular Cellular and Animal Biology, University of Camerino, 62032 Camerino (Italy)

    2011-08-10

    DNA vaccination exploits a relatively simple and flexible technique to generate an immune response against microbial and tumor-associated antigens (TAAs). Its effectiveness is enhanced by the application of an electrical shock in the area of plasmid injection (electroporation). In our studies we exploited a sophisticated electroporation device approved for clinical use (Cliniporator, IGEA, Carpi, Italy). As the target antigen is an additional factor that dramatically modulates the efficacy of a vaccine, we selected ErbB2 receptor as a target since it is an ideal oncoantigen. It is overexpressed on the cell membrane by several carcinomas for which it plays an essential role in driving their progression. Most oncoantigens are self-tolerated molecules. To circumvent immune tolerance we generated two plasmids (RHuT and HuRT) coding for chimeric rat/human ErbB2 proteins. Their immunogenicity was compared in wild type mice naturally tolerant for mouse ErbB2, and in transgenic mice that are also tolerant for rat or human ErbB2. In several of these mice, RHuT and HuRT elicited a stronger anti-tumor response than plasmids coding for fully human or fully rat ErbB2. The ability of heterologous moiety to blunt immune tolerance could be exploited to elicit a significant immune response in patients. A clinical trial to delay the recurrence of ErbB2{sup +} carcinomas of the oral cavity, oropharynx and hypopharynx is awaiting the approval of the Italian authorities.

  2. Repression of transcription mediated at a thyroid hormone response element by the v-erb-A oncogene product

    DEFF Research Database (Denmark)

    Sap, J; Muñoz, A; Schmitt, J

    1989-01-01

    Several recent observations, such as the identification of the cellular homologue of the v-erb-A oncogene as a thyroid-hormone receptor, have strongly implicated nuclear oncogenes in transcriptional control mechanisms. The v-erb-A oncogene blocks the differentiation of erythroid cells, and change......-erb-A protein negatively interferes with normal transcriptional-control mechanisms, and that amino-acid substitutions have altered its DNA-binding properties....

  3. Decreased internalisation of erbB1 mutants in lung cancer is linked with a mechanism conferring sensitivity to gefitinib.

    Science.gov (United States)

    Hendriks, B S; Griffiths, G J; Benson, R; Kenyon, D; Lazzara, M; Swinton, J; Beck, S; Hickinson, M; Beusmans, J M; Lauffenburger, D; de Graaf, D

    2006-11-01

    A majority of gefitinib (IRESSA)-responsive tumours in non-small cell lung cancer have been found to carry mutations in ErbB1. Previously, it has been observed that internalisation-deficient ErbB1 receptors are strong drivers of oncogenesis. Using a computational model of ErbB1 trafficking and signalling, it is found that a deficiency in ErbB1 internalisation is sufficient to explain the observed signalling phenotype of these gefitinib-responsive ErbB1 mutants in lung cancer cell lines. Experimental tests confirm that gefitinib-sensitive cell lines with and without ErbB1 mutations exhibit markedly slower internalisation rates than gefitinib-insensitive cell lines. Moreover, the computational model demonstrates that reduced ErbB1 internalisation rates are mechanistically linked to upregulated AKT signalling. Experimentally it is confirmed that impaired internalisation of ErbB1 is associated with increased AKT activity, which can be blocked by gefitinib. On the basis of these experimental and computational results, it is surmised that gefitinib sensitivity is a marker of a reliance on AKT signalling for cell survival that may be brought about by impaired ErbB1 internalisation.

  4. Expression of Eag1 K+ channel and ErbBs in human pituitary adenomas: cytoskeleton arrangement patterns in cultured cells.

    Science.gov (United States)

    del Pliego, Margarita González; Aguirre-Benítez, Elsa; Paisano-Cerón, Karina; Valdovinos-Ramírez, Irene; Rangel-Morales, Carlos; Rodríguez-Mata, Verónica; Solano-Agama, Carmen; Martín-Tapia, Dolores; de la Vega, María Teresa; Saldoval-Balanzario, Miguel; Camacho, Javier; Mendoza-Garrido, María Eugenia

    2013-01-01

    Pituitary adenomas can invade surrounded tissue, but the mechanism remains elusive. Ether à go-go-1 (Eag1) potassium channel and epidermal growth factor receptors (ErbB1 and ErbB2) have been associated to invasive phenotypes or poor prognosis in cancer patients. However, cells arrange their cytoskeleton in order to acquire a successful migration pattern. We have studied ErbBs and Eag1 expression, and cytoskeleton arrangements in 11 human pituitary adenomas. Eag1, ErbB1 and ErbB2 expression were studied by immunochemistry in tissue and cultured cells. The cytoskeleton arrangement was analyzed in cultured cells by immunofluorescence. Normal pituitary tissue showed ErbB2 expression and Eag1 only in few cells. However, Eag1 and ErbB2 were expressed in all the tumors analyzed. ErbB1 expression was observed variable and did not show specificity for a tumor characteristic. Cultured cells from micro- and macro-adenomas clinically functional organize their cytoskeleton suggesting a mesenchymal pattern, and a round leucocyte/amoeboid pattern from invasive clinically silent adenoma. Pituitary tumors over-express EGF receptors and the ErbB2 repeated expression suggests is a characteristic of adenomas. Eag 1 was express, in different extent, and could be a therapeutic target. The cytoskeleton arrangements observed suggest that pituitary tumor cells acquire different patterns: mesenchymal, and leucocyte/amoeboid, the last observed in the invasive adenomas. Amoeboid migration pattern has been associated with high invasion capacity.

  5. Peripheral Transcription of NRG-ErbB Pathway Genes Are Upregulated in Treatment-Resistant Schizophrenia

    Directory of Open Access Journals (Sweden)

    Md Shaki Mostaid

    2017-11-01

    Full Text Available Investigation of peripheral gene expression patterns of transcripts within the NRG–ErbB signaling pathway, other than neuregulin-1 (NRG1, among patients with schizophrenia and more specifically treatment-resistant schizophrenia (TRS is limited. The present study built on our previous work demonstrating elevated levels of NRG1 EGFα, EGFβ, and type I(Ig2 containing transcripts in TRS by investigating 11 NRG–ErbB signaling pathway mRNA transcripts (NRG2, ErbB1, ErbB2, ErbB3, ErbB4, PIK3CD, PIK3R3, AKT1, mTOR, P70S6K, eIF4EBP1 in whole blood of TRS patients (N = 71 and healthy controls (N = 57. We also examined the effect of clozapine exposure on transcript levels using cultured peripheral blood mononuclear cells (PBMCs from 15 healthy individuals. Five transcripts (ErbB3, PIK3CD, AKT1, P70S6K, eIF4EBP1 were significantly elevated in TRS patients compared to healthy controls but only expression of P70S6K (Pcorrected = 0.018, a protein kinase linked to protein synthesis, cell growth, and cell proliferation, survived correction for multiple testing using the Benjamini–Hochberg method. Investigation of clinical factors revealed that ErbB2, PIK3CD, PIK3R3, AKT1, mTOR, and P70S6K expression were negatively correlated with duration of illness. However, no transcript was associated with chlorpromazine equivalent dose or clozapine plasma levels, the latter supported by our in vitro PBMC clozapine exposure experiment. Taken together with previously published NRG1 results, our findings suggest an overall upregulation of transcripts within the NRG–ErbB signaling pathway among individuals with schizophrenia some of which attenuate over duration of illness. Follow-up studies are needed to determine if the observed peripheral upregulation of transcripts within the NRG–ErbB signaling pathway are specific to TRS or are a general blood-based marker of schizophrenia.

  6. Continuous requirement of ErbB2 kinase activity for loss of cell polarity and lumen formation in a novel ErbB2/Neu-driven murine cell line model of metastatic breast cancer

    Directory of Open Access Journals (Sweden)

    Cesar F Ortega-Cava

    2011-01-01

    Full Text Available Background: Well over a quarter of human breast cancers are ErbB2-driven and constitute a distinct subtype with substantially poorer prognosis. Yet, there are substantial gaps in our understanding of how ErbB2 tyrosine kinase activity unleashes a coordinated program of cellular and extracellular alterations that culminate in aggressive breast cancers. Cellular models that exhibit ErbB2 kinase dependency and can induce metastatic breast cancer in immune competent hosts are likely to help bridge this gap. Materials and Methods: Here, we derived and characterized a cell line model obtained from a transgenic ErbB2/Neu-driven mouse mammary adenocarcinoma. Results: The MPPS1 cell line produces metastatic breast cancers when implanted in the mammary fat pads of immune-compromised as well as syngeneic immune-competent hosts. MPPS1 cells maintain high ErbB2 overexpression when propagated in DFCI-1 or related media, and their growth is ErbB2-dependent, as demonstrated by concentration-dependent inhibition of proliferation with the ErbB kinase inhibitor Lapatinib. When grown in 3-dimensional (3-D culture on Matrigel, MPPS1 cells predominantly form large irregular cystic and solid structures. Remarkably, low concentrations of Lapatinib led to a switch to regular acinar growth on Matrigel. Immunofluorescence staining of control vs. Lapatinib-treated acini for markers of epithelial polarity revealed that inhibition of ErbB2 signaling led to rapid resumption of normal mammary epithelium-like cell polarity. Conclusions: The strict dependence of the MPPS1 cell system on ErbB2 signals for proliferation and alterations in cell polarity should allow its use to dissect ErbB2 kinase-dependent signaling pathways that promote loss of cell polarity, a key component of the epithelial mesenchymal transition and aggressiveness of ErbB2-driven breast cancers.

  7. ErbB2 Activation Upregulates Glutaminase 1 Expression Which Promotes Breast Cancer Cell Proliferation

    Science.gov (United States)

    Qie, Shuo; Chu, Clarissa; Li, Weihua; Wang, Chenguang; Sang, Nianli

    2015-01-01

    Active glutamine utilization is critical for tumor cell proliferation. Glutaminolysis represents the first and rate-limiting step of glutamine utilization and is catalyzed by glutaminase (GLS). Activation of ErbB2 is one of the major causes of breast cancers, the second most common cause of death for women in many countries. However, it remains unclear whether ErbB2 signaling affects glutaminase expression in breast cancer cells. In this study, we show that MCF10A-NeuT cell line has higher GLS1 expression at both mRNA and protein levels than its parental line MCF10A, and knockdown of ErbB2 decreases GLS1 expression in MCF10A-NeuT cells. We further show that in these cells, ErbB2-mediated upregulation of GLS1 is not correlated to c-Myc expression. Moreover, activation of neither PI3K-Akt nor MAPK pathway is sufficient to upregulate GLS1 expression. Interestingly, inhibition of NF-κB blocks ErbB2-stimulated GLS1 expression, whereas stimulation of NF-κB is sufficient to enhance GLS1 levels in MCF10A cells, suggesting a PI3K-Akt-independent activation of NF-κB upregulates GLS1 in ErbB2-positive breast cancer cells. Finally, knockdown or inhibition of GLS1 significantly decreased the proliferation of breast cancer cells with high GLS1 levels. Taken together, our data indicate that ErbB2 activation promotes GLS1 expression via a PI3K-Akt-independent NF-κB pathway in breast cancer cells, identifying another oncogenic signaling pathway which stimulates GLS1 expression, and thus promoting glutamine utilization in cancer cells. These findings, if validated by in vivo model, may facilitate the identification of novel biochemical targets for cancer prevention and therapy. PMID:24122876

  8. Le Sanskrit

    CERN Document Server

    Balbir, Nalini

    2013-01-01

    Cet ouvrage est destiné à tous ceux qui souhaitent se mettre ou se remettre à l'étude du sanskrit et ne peuvent y consacrer que quelques minutes par jour. En suivant le principe de la méthode quotidienne Assimil, vous acquerrez progressivement le vocabulaire et la grammaire de base qui sont nécessaires à la lecture des textes de la littérature sanskrite classique. Vous trouverez dans cette méthode une approche vivante de la langue et de la culture sanskrite classique à travers des textes d'abord adaptés pour le débutant puis authentiques. En quelques mois, vous manierez la langue sans efforts ni hésitation, de manière très naturelle. Les enregistrements reprennent l'intégralité des textes en sanskrit des leçons et des exercices de traduction du livre. Ils sont interprétés, à un rythme progressif, par des locuteurs natifs professionnels.

  9. ErbB4 localization to cardiac myocyte nuclei, and its role in myocyte DNA damage response

    Energy Technology Data Exchange (ETDEWEB)

    Icli, Basak [Department of Medicine, Cardiovascular Division, Brigham and Women' s Hospital, Harvard Medical School, Boston, MA 02115 (United States); Bharti, Ajit [Center of Molecular Stress Response Whitaker Cardiovascular Institute, Department of Medicine, Boston University Medical Center, Boston, MA 02118 (United States); Pentassuglia, Laura; Peng, Xuyang [Department of Medicine, Vanderbilt University Medical Center, Nashville, TN (United States); Sawyer, Douglas B., E-mail: douglas.b.sawyer@vanderbilt.edu [Department of Medicine, Vanderbilt University Medical Center, Nashville, TN (United States)

    2012-02-03

    Highlights: Black-Right-Pointing-Pointer ErbB4 localizes to cardiac myocyte nuclei as a full-length receptor. Black-Right-Pointing-Pointer Cardiac myocytes express predominantly JM-a/CYT-1 ErbB4. Black-Right-Pointing-Pointer Myocyte p53 activation in response to doxorubicin requires ErbB4 activity. -- Abstract: The intracellular domain of ErbB4 receptor tyrosine kinase is known to translocate to the nucleus of cells where it can regulate p53 transcriptional activity. The purpose of this study was to examine whether ErbB4 can localize to the nucleus of adult rat ventricular myocytes (ARVM), and regulate p53 in these cells. We demonstrate that ErbB4 does locate to the nucleus of cardiac myocytes as a full-length protein, although nuclear location occurs as a full-length protein that does not require Protein Kinase C or {gamma}-secretase activity. Consistent with this we found that only the non-cleavable JM-b isoform of ErbB4 is expressed in ARVM. Doxorubicin was used to examine ErbB4 role in regulation of a DNA damage response in ARVM. Doxorubicin induced p53 and p21 was suppressed by treatment with AG1478, an EGFR and ErbB4 kinase inhibitor, or suppression of ErbB4 expression with small interfering RNA. Thus ErbB4 localizes to the nucleus as a full-length protein, and plays a role in the DNA damage response induced by doxorubicin in cardiac myocytes.

  10. A holistic approach to the management of Erb's palsy

    Science.gov (United States)

    Srilakshmi, Dasari; Chaganti, Sreelakshmi

    2013-01-01

    A 4.5-month-old female baby, presenting with complete paralysis of right upper limb with typical waiter's tip deformity, diagnosed as Erb's palsy was brought to Sri Ganapati Sachchidananda Hospital. Patient was treated with an integrated approach of physiotherapy and Ayurvedic treatment with an intention of aiding faster recovery of the patient to lead a near normal life. As per Ayurvedic classics, this condition can be correlated to Ekangavata (Vata effecting any one part of the body), which is Apatarpana in nature (diseases with deprived growth of body tissue). Hence, the choice of treatment is Santarpana Chikitsa (nourishing treatment). Santarpana Bahyopakramas (nourishing external treatment modalities) such as Ashwagandhabalalakshadi Taila (Ayurvedic medicated oil) Abhyanga (oleation therapy) and Shastikashali Anna Lepa (application of processed rice paste) were administered along with electrical stimulation (physiotherapy modality), both galvanic and faradic current in three sessions. Appreciable results were observed in the form of reduction of disparity in length and mid-arm circumference of right upper limb compared to unaffected left upper limb and the muscle power too improved from zero to four, facilitating patient to near normal movement. PMID:24459391

  11. Heather M. Erb, The Path of Spiritual Happiness

    Directory of Open Access Journals (Sweden)

    Steven J. Brust

    2017-03-01

    Full Text Available One of the most famous political documents, The Declaration of Independence, claims that our Creator has created everyone with the right to the pursuit of happiness. When asked about what they think the happiness actually is that one has a right to pursue, many students respond in a relativist manner, claiming that it is different for everyone, or rather, it is what each determines it to be. It can be difficult to get students to entertain the possibility that there might be an objective understanding of happiness that everyone is called to achieve. That is why I am glad Professor Heather Erb has written this excellent book. In the introduction we discover that her motivation for this book is the unfortunate state of affairs where there appears to be an emphasis on the pursuit of ephemeral desires and too little desire for truth and wonderment about reality. One is reminded of the infamous Rolling Stones, who tell us we can’t get our satisfaction no matter how hard we try. The author makes the case that only in the two sources of reason and revelation, as transmitted by Christian philosophy and theology, is a reflective and authentic spiritual happiness to be found.

  12. Activation of protein kinase C or cAMP-dependent protein kinase increases phosphorylation of the c-erbA-encoded thyroid hormone receptor and of the v-erbA-encoded protein

    DEFF Research Database (Denmark)

    Goldberg, Y; Glineur, C; Gesquière, J C

    1988-01-01

    The c-erbA proto-oncogene encodes a nuclear receptor for thyroid hormone (T3), which is believed to stimulate transcription from specific target promoters upon binding to cis-acting DNA sequence elements. The v-erbA oncogene of avian erythroblastosis virus (AEV) encodes a ligand-independent version...

  13. Pharmacological and Genetic Modulation of REV-ERB Activity and Expression Affects Orexigenic Gene Expression.

    Directory of Open Access Journals (Sweden)

    Ariadna Amador

    Full Text Available The nuclear receptors REV-ERBα and REV-ERBβ are transcription factors that play pivotal roles in the regulation of the circadian rhythm and various metabolic processes. The circadian rhythm is an endogenous mechanism, which generates entrainable biological changes that follow a 24-hour period. It regulates a number of physiological processes, including sleep/wakeful cycles and feeding behaviors. We recently demonstrated that REV-ERB-specific small molecules affect sleep and anxiety. The orexinergic system also plays a significant role in mammalian physiology and behavior, including the regulation of sleep and food intake. Importantly, orexin genes are expressed in a circadian manner. Given these overlaps in function and circadian expression, we wanted to determine whether the REV-ERBs might regulate orexin. We found that acute in vivo modulation of REV-ERB activity, with the REV-ERB-specific synthetic ligand SR9009, affects the circadian expression of orexinergic genes in mice. Long term dosing with SR9009 also suppresses orexinergic gene expression in mice. Finally, REV-ERBβ-deficient mice present with increased orexinergic transcripts. These data suggest that the REV-ERBs may be involved in the repression of orexinergic gene expression.

  14. The relationship between c-erbB-2 oncogene expression and clinicopathological factors in gastric cancer.

    Science.gov (United States)

    Gürel, S; Dolar, E; Yerci, O; Samli, B; Oztürk, H; Nak, S G; Gülten, M; Memik, F

    1999-01-01

    Gastric carcinoma is one of the most common carcinomas and a leading cause of death from cancer in Turkey. The relationship between clinicopathological features of the disease and oncogenes is under investigation. In this retrospective study we investigated the relationships between expression of c-erbB-2 oncoprotein and grade, stage and pathological characteristics of the tumour, and prognosis. Formalin-fixed, paraffin-embedded tissue sections were prepared from gastrectomy specimens from 55 patients with gastric carcinoma. The tissue sections were stained immunohistochemically to reveal c-erbB-2 protein. Six (10%) of the tumours stained positively for c-erbB-2 protein. There was no statistically significant association (P > 0.5) between c-erbB-2 staining and tumour grade, stage or pathological characteristics (necrosis, lymph-node infiltration), or between staining and prognosis. The results suggest that overexpression of c-erb-B-2 protein is not related to the pathological characteristics of the tumour in gastric carcinoma and is not an important prognostic indicator.

  15. Dysregulation of ErbB Receptor Trafficking and Signaling in Demyelinating Charcot-Marie-Tooth Disease.

    Science.gov (United States)

    Lee, Samuel M; Chin, Lih-Shen; Li, Lian

    2017-01-01

    Charcot-Marie-Tooth (CMT) disease is the most common inherited peripheral neuropathy with the majority of cases involving demyelination of peripheral nerves. The pathogenic mechanisms of demyelinating CMT remain unclear, and no effective therapy currently exists for this disease. The discovery that mutations in different genes can cause a similar phenotype of demyelinating peripheral neuropathy raises the possibility that there may be convergent mechanisms leading to demyelinating CMT pathogenesis. Increasing evidence indicates that ErbB receptor-mediated signaling plays a major role in the control of Schwann cell-axon communication and myelination in the peripheral nervous system. Recent studies reveal that several demyelinating CMT-linked proteins are novel regulators of endocytic trafficking and/or phosphoinositide metabolism that may affect ErbB receptor signaling. Emerging data have begun to suggest that dysregulation of ErbB receptor trafficking and signaling in Schwann cells may represent a common pathogenic mechanism in multiple subtypes of demyelinating CMT. In this review, we focus on the roles of ErbB receptor trafficking and signaling in regulation of peripheral nerve myelination and discuss the emerging evidence supporting the potential involvement of altered ErbB receptor trafficking and signaling in demyelinating CMT pathogenesis and the possibility of modulating these trafficking and signaling processes for treating demyelinating peripheral neuropathy.

  16. Dicty_cDB: Contig-U11786-1 [Dicty_cDB

    Lifescience Database Archive (English)

    Full Text Available spleen cDNA, RIKEN full-le... 52 0.057 1 ( EY502489 ) CBBP6397.rev CBBP Hirudo medicinalis hermaphrodit... ...52 0.057 1 ( EY501142 ) CBBP5660.rev CBBP Hirudo medicinalis hermaphrodit... 52 0.057 1 ( EY498689 ) CBBP4264.fwd CBBP Hirudo medicin...alis hermaphrodit... 52 0.057 1 ( EY496087 ) CBBP2702.rev CBBP Hirudo medicina...lis hermaphrodit... 52 0.057 1 ( EY495298 ) CBBP2215.fwd CBBP Hirudo medicinalis herma...phrodit... 52 0.057 1 ( EY486742 ) CBBP15371.rev CBBP Hirudo medicinalis hermaphrodi... 52 0.057 1 ( EY30352

  17. The sorting protein PACS-2 promotes ErbB signalling by regulating recycling of the metalloproteinase ADAM17

    DEFF Research Database (Denmark)

    Dombernowsky, Sarah Louise; Samsøe-Petersen, Jacob; Petersen, Camilla Hansson

    2015-01-01

    are poorly understood. Here, through a functional genome-wide siRNA screen, we identify the sorting protein PACS-2 as a regulator of ADAM17 trafficking and ErbB signalling. PACS-2 loss reduces ADAM17 cell-surface levels and ADAM17-dependent ErbB ligand shedding, without apparent effects on related proteases...

  18. Identification of a novel antagonist of the ErbB1 receptor capable of inhibiting migration of human glioblastoma cells

    DEFF Research Database (Denmark)

    Staberg, Mikkel; Riemer, Christian; Xu, Ruodan

    2013-01-01

    BACKGROUND: Receptors of the ErbB family are involved in the development of various cancers, and the inhibition of these receptors represents an attractive therapeutic concept. Upon ligand binding, ErbB receptors become activated as homo- or heterodimers, leading to the activation of downstream...... signaling cascades that result in the facilitation of cell proliferation and migration. A region of the extracellular part of the receptor, termed the 'dimerization arm', is important for the formation of receptor dimers and represents an attractive target for the design of ErbB inhibitors. METHODS: An Erb......B1 targeting peptide, termed Herfin-1, was designed based on a model of the tertiary structure of the EGF-EGFR ternary complex. The binding kinetics of this peptide were determined employing surface plasmon resonance analyses. ErbB1-4 expression and phosphorylation in human glioblastoma cell lines U...

  19. ERBS fuel addendum: Pollution reduction technology program small jet aircraft engines, phase 3

    Science.gov (United States)

    Bruce, T. W.; Davis, F. G.; Kuhn, T. E.; Mongia, H. C.

    1982-01-01

    A Model TFE731-2 engine with a low emission, variable geometry combustion system was tested to compare the effects of operating the engine on Commercial Jet-A aviation turbine fuel and experimental referee broad specification (ERBS) fuels. Low power emission levels were essentially identical while the high power NOx emission indexes were approximately 15% lower with the EBRS fuel. The exhaust smoke number was approximately 50% higher with ERBS at the takeoff thrust setting; however, both values were still below the EPA limit of 40 for the Model TFE731 engine. Primary zone liner wall temperature ran an average of 25 K higher with ERBS fuel than with Jet-A. The possible adoption of broadened proprties fuels for gas turbine applications is suggested.

  20. ErbB4 in laminated brain structures: a neurodevelopmental approach to schizophrenia

    Directory of Open Access Journals (Sweden)

    Carlos Gustavo Perez-Garcia

    2015-12-01

    Full Text Available The susceptibility genes for schizophrenia Neuregulin-1 (NRG1 and ErbB4 have critical functions during brain development and in the adult. Alterations in the ErbB4 signaling pathway cause a variety of neurodevelopmental defects including deficiencies in neuronal migration, synaptic plasticity and myelination. I have used the ErbB4-/- HER4heart KO mice to study the neurodevelopmental insults associated to deficiencies in the NRG1-ErbB4 signaling pathway and their potential implication with brain disorders such as schizophrenia, a chronic psychiatric disease affecting 1% of the population worldwide. ErbB4 deletion results in an array of neurodevelopmental deficits that are consistent with a schizophrenic model. First, similar defects appear in multiple brain structures, from the cortex to the cerebellum. Second, these defects affect multiple aspects of brain development, from deficits in neuronal migration to impairments in excitatory/inhibitory systems, including reductions in brain volume, cortical and cerebellar heteropias, alterations in number and distribution of specific subpopulations of interneurons, deficiencies in the astrocytic and oligodendrocytic lineages, and additional insults in major brain structures. This suggests that alterations in specific neurodevelopmental genes that play similar functions in multiple neuroanatomical structures might account for some of the symptomatology observed in schizophrenic patients, such as defects in cognition. ErbB4 mutation uncovers flaws in brain development that are compatible with a neurodevelopmental model of schizophrenia, and it establishes a comprehensive model to study the basis of the disorder before symptoms are detected in the adult.

  1. Down-Regulation of Neuregulin1/ErbB4 Signaling in the Hippocampus Is Critical for Learning and Memory.

    Science.gov (United States)

    Tian, Jia; Geng, Fei; Gao, Feng; Chen, Yi-Hua; Liu, Ji-Hong; Wu, Jian-Lin; Lan, Yu-Jie; Zeng, Yuan-Ning; Li, Xiao-Wen; Yang, Jian-Ming; Gao, Tian-Ming

    2017-08-01

    Hippocampal function is important for learning and memory, and dysfunction of the hippocampus has been linked to the pathophysiology of neuropsychiatric diseases such as schizophrenia. Neuregulin1 (NRG1) and ErbB4, two susceptibility genes for schizophrenia, reportedly modulate long-term potentiation (LTP) at hippocampal Schaffer collateral (SC)-CA1 synapses. However, little is known regarding the contribution of hippocampal NRG1/ErbB4 signaling to learning and memory function. Here, quantitative real-time PCR and Western blotting were used to assess the mRNA and protein levels of NRG1 and ErbB4. Pharmacological and genetic approaches were used to manipulate NRG1/ErbB4 signaling, following which learning and memory behaviors were evaluated using the Morris water maze, Y-maze test, and the novel object recognition test. Spatial learning was found to reduce hippocampal NRG1 and ErbB4 expression. The blockade of NRG1/ErbB4 signaling in hippocampal CA1, either by neutralizing endogenous NRG1 or inhibiting/ablating ErbB4 receptor activity, enhanced hippocampus-dependent spatial learning, spatial working memory, and novel object recognition memory. Accordingly, administration of exogenous NRG1 impaired those functions. More importantly, the specific ablation of ErbB4 in parvalbumin interneurons also improved learning and memory performance. The manipulation of NRG1/ErbB4 signaling in the present study revealed that NRG1/ErbB4 activity in the hippocampus is critical for learning and memory. These findings might provide novel insights on the pathophysiological mechanisms of schizophrenia and a new target for the treatment of Alzheimer's disease, which is characterized by a progressive decline in cognitive function.

  2. Le barde et le bouffon

    OpenAIRE

    Fasquel, Samuel

    2013-01-01

    La Gatomaquia de Lope de Vega, La Moschea de Villaviciosa et le Poema heroico de las necedades y locuras de Orlando el enamorado de Quevedo constituent un corpus poétique qui réunit les meilleurs fruits produits par la geste burlesque dans l’Espagne du Siècle d’or. Cet article analyse les profondes différences esthétiques qui caractérisent ces œuvres dans le but de montrer que, malgré ces différences et en dépit de l’importance des éléments carnavalesques et grotesques, ces trois poèmes ne pr...

  3. Rev-erbα and the circadian transcriptional regulation of metabolism

    DEFF Research Database (Denmark)

    Gerhart-Hines, Z.; Lazar, M. A.

    2015-01-01

    The circadian clock orchestrates the coordinated rhythmicity of numerous metabolic pathways to anticipate daily and seasonal changes in energy demand. This vital physiol. function is controlled by a set of individual clock components that are present in each cell of the body, and regulate each...... other as well as clock output genes. A key factor is the nuclear receptor, Rev-erbα, a transcriptional repressor which functions not only as a clock component but also as a modulator of metabolic programming in an array of tissues. This review explores the role of Rev-erbα in mediating this crosstalk...

  4. Using spatial coherence to retrieve cloud properties - ERBE experience and CERES applications

    Science.gov (United States)

    Coakley, James A., Jr.

    1990-01-01

    Cloud properties for individual ERBE scanner fields of view are obtained from simultaneous, collocated imagery data. The cloud properties are used to assess the performance of the ERBE maximum likelihood estimate of cloud conditions which ultimately influences estimates of the radiative fluxes at the top of the atmosphere. During EOS the analysis of MODIS observations within the fields of view of the CERES instruments promises to yield, in addition, estimates of surface radiative fluxes as well as the vertical distribution of radiative heating within the atmosphere.

  5. Nuc-ErbB3 regulates H3K27me3 levels and HMT activity to establish epigenetic repression during peripheral myelination.

    Science.gov (United States)

    Ness, Jennifer K; Skiles, Amanda A; Yap, Eng-Hui; Fajardo, Eduardo J; Fiser, Andras; Tapinos, Nikos

    2016-06-01

    Nuc-ErbB3 an alternative transcript from the ErbB3 locus binds to a specific DNA motif and associates with Schwann cell chromatin. Here we generated a nuc-ErbB3 knockin mouse that lacks nuc-ErbB3 expression in the nucleus without affecting the neuregulin-ErbB3 receptor signaling. Nuc-ErbB3 knockin mice exhibit hypermyelination and aberrant myelination at the paranodal region. This phenotype is attributed to de-repression of myelination associated gene transcription following loss of nuc-ErbB3 and histone H3K27me3 promoter occupancy. Nuc-ErbB3 knockin mice exhibit reduced association of H3K27me3 with myelination-associated gene promoters and increased RNA Pol-II rate of transcription of these genes. In addition, nuc-ErbB3 directly regulates levels of H3K27me3 in Schwann cells. Nuc-ErbB3 knockin mice exhibit significant decrease of histone H3K27me3 methyltransferase (HMT) activity and reduced levels of H3K27me3. Collectively, nuc-ErbB3 is a master transcriptional repressor, which regulates HMT activity to establish a repressive chromatin landscape on promoters of genes during peripheral myelination. © 2016 The Authors. Glia Published by Wiley Periodicals, Inc.

  6. Pertuzumab Increases 17-AAG-Induced Degradation of ErbB2, and This Effect Is Further Increased by Combining Pertuzumab with Trastuzumab

    Science.gov (United States)

    Hughes, Juliana Bentes; Rødland, Marianne Skeie; Hasmann, Max; Madshus, Inger Helene; Stang, Espen

    2012-01-01

    ErbB2 is an important oncogenic protein involved in carcinogenesis of, among others, breast, gastric, and ovarian carcinoma. Over-expression of ErbB2 is found in almost 20% of breast cancers, and this results in proliferative and anti-apoptotic signalling. ErbB2 is therefore an important treatment target. Antibodies recognizing full-length ErbB2 are clinically established, and drugs targeting the ErbB2 stabilizing heat shock protein 90 (Hsp90) are under clinical evaluation. We have investigated effects of the ErbB2-binding antibodies trastuzumab and pertuzumab alone and in combination, as well as the effect of the antibodies in combination with the Hsp90 inhibitor 17-AAG. Our results confirm the notion that combination of different ErbB2-binding antibodies more efficiently down-regulates ErbB2 than does one antibody in isolation. Additionally, our data demonstrate that ErbB2 is most efficiently down-regulated upon incubation with anti-ErbB2 antibodies in combination with Hsp90 inhibitors. The combination of anti-ErbB2 antibodies, and especially the combination of antibodies with 17-AAG, did also increase the inhibition of Akt activation of either agent, which could suggest an anti-proliferative effect. In such case, combining these agents could be beneficial in treatment of tumors not responding to trastuzumab only. PMID:24281706

  7. Pertuzumab Increases 17-AAG-Induced Degradation of ErbB2, and This Effect Is Further Increased by Combining Pertuzumab with Trastuzumab

    Directory of Open Access Journals (Sweden)

    Juliana Bentes Hughes

    2012-06-01

    Full Text Available ErbB2 is an important oncogenic protein involved in carcinogenesis of, among others, breast, gastric, and ovarian carcinoma. Over-expression of ErbB2 is found in almost 20% of breast cancers, and this results in proliferative and anti-apoptotic signalling. ErbB2 is therefore an important treatment target. Antibodies recognizing full-length ErbB2 are clinically established, and drugs targeting the ErbB2 stabilizing heat shock protein 90 (Hsp90 are under clinical evaluation. We have investigated effects of the ErbB2-binding antibodies trastuzumab and pertuzumab alone and in combination, as well as the effect of the antibodies in combination with the Hsp90 inhibitor 17-AAG. Our results confirm the notion that combination of different ErbB2-binding antibodies more efficiently down-regulates ErbB2 than does one antibody in isolation. Additionally, our data demonstrate that ErbB2 is most efficiently down-regulated upon incubation with anti-ErbB2 antibodies in combination with Hsp90 inhibitors. The combination of anti-ErbB2 antibodies, and especially the combination of antibodies with 17-AAG, did also increase the inhibition of Akt activation of either agent, which could suggest an anti-proliferative effect. In such case, combining these agents could be beneficial in treatment of tumors not responding to trastuzumab only.

  8. The potential for collocated AGLP and ERBE data for fire, smoke, and radiation budget studies

    International Nuclear Information System (INIS)

    Christopher, S.A.; Chou, J.

    1997-01-01

    One month of the Advanced Very High Resolution Radiometer (AVHRR) Global Area Coverage (GAC) Land Pathfinder (AGLP) data from September 1985 are used to examine the spatial and temporal distribution of fires over four major ecosystems in South America. The Earth Radiation Budget Experiment (ERBE) scanner data are used to examine the top of atmosphere (TOA) shortwave and longwave fluxes over smoke generated from biomass burn- ing. The relationship between the AGLP-derived Normalized Difference Vegetation Index (NDVI) and the ERBE-estimated clear sky albedos are also examined as a function of the four ecosystems. This study shows that the grassland areas in South America have the highest number of fires for September 1985, and their corresponding NDVI values are smaller than the tropical rainforest region where the number of fires were comparatively small. Clear sky statistics accumulated during the days when smoke was not present show that clear sky albedos derived from ERBE are higher for grassland areas when compared to the tropical rainforest. The results show that the AGLP can be used to determine the spatial and temporal distribution of fires along with vegetation characteristics, while ERBE data can provide necessary information on broadband albedos and regional top of atmosphere radiative impacts of biomass burning aerosols. Since the AGLP data are available from 1981 to the present day, several climate-related issues can be addressed

  9. Comparison of ERBS orbit determination accuracy using batch least-squares and sequential methods

    Science.gov (United States)

    Oza, D. H.; Jones, T. L.; Fabien, S. M.; Mistretta, G. D.; Hart, R. C.; Doll, C. E.

    1991-01-01

    The Flight Dynamics Div. (FDD) at NASA-Goddard commissioned a study to develop the Real Time Orbit Determination/Enhanced (RTOD/E) system as a prototype system for sequential orbit determination of spacecraft on a DOS based personal computer (PC). An overview is presented of RTOD/E capabilities and the results are presented of a study to compare the orbit determination accuracy for a Tracking and Data Relay Satellite System (TDRSS) user spacecraft obtained using RTOS/E on a PC with the accuracy of an established batch least squares system, the Goddard Trajectory Determination System (GTDS), operating on a mainframe computer. RTOD/E was used to perform sequential orbit determination for the Earth Radiation Budget Satellite (ERBS), and the Goddard Trajectory Determination System (GTDS) was used to perform the batch least squares orbit determination. The estimated ERBS ephemerides were obtained for the Aug. 16 to 22, 1989, timeframe, during which intensive TDRSS tracking data for ERBS were available. Independent assessments were made to examine the consistencies of results obtained by the batch and sequential methods. Comparisons were made between the forward filtered RTOD/E orbit solutions and definitive GTDS orbit solutions for ERBS; the solution differences were less than 40 meters after the filter had reached steady state.

  10. ERalpha and ErbB-2 Cross-talk in Mammary Tumorigenesis and Metastasis

    National Research Council Canada - National Science Library

    Muller, William J

    2006-01-01

    .... The results of these analyses did not show any influence of the expression of an activated form of ER on ErbB-2 induced mammary tumor formation. No evidence of c- Src or Akt-1 acting synergistically with ER to accelerate mammary tumor progression has been observed either.

  11. Detection of erbB2 copy number variations in plasma of patients with esophageal carcinoma

    International Nuclear Information System (INIS)

    Andolfo, Immacolata; Orditura, Michele; Ciardiello, Fortunato; De Vita, Fernando; Zollo, Massimo; Petrosino, Giuseppe; Vecchione, Loredana; De Antonellis, Pasqualino; Capasso, Mario; Montanaro, Donatella; Gemei, Marica; Troncone, Giancarlo; Iolascon, Achille

    2011-01-01

    Mortality is high in patients with esophageal carcinoma as tumors are rarely detected before the disease has progressed to an advanced stage. Here, we sought to isolate cell-free DNA released into the plasma of patients with esophageal carcinoma, to analyze copy number variations of marker genes in the search for early detection of tumor progression. Plasma of 41 patients with esophageal carcinoma was prospectively collected before tumor resection and chemotherapy. Our dataset resulted heterogeneous for clinical data, resembling the characteristics of the tumor. DNA from the plasma was extracted to analyze copy number variations of the erbB2 gene using real-time PCR assays. The real-time PCR assays for erbB2 gene showed significant (P = 0.001) copy number variations in the plasma of patients with esophageal carcinoma, as compared to healthy controls with high sensitivity (80%) and specificity (95%). These variations in erbB2 were negatively correlated to the progression free survival of these patients (P = 0.03), and revealed a further risk category stratification of patients with low VEGF expression levels. The copy number variation of erbB2 gene from plasma can be used as prognostic marker for early detection of patients at risk of worse clinical outcome in esophageal cancer

  12. No evidence for c-erbB-2 overexpression in gastric carcinogenesis

    NARCIS (Netherlands)

    Blok, P.; Craanen, M. E.; Dekker, W.; Offerhaus, G. J.; Tytgat, G. N.

    1998-01-01

    Conflicting data on c-erbB-2 overexpression in gastric carcinomas can be found in the literature with regard to overall prevalence, prognostic significance and the histological type according to Lauren. The majority of these studies have focused on advanced gastric carcinomas whereas data on

  13. In silico prediction of ErbB signal activation from receptor expression ...

    Indian Academy of Sciences (India)

    85

    Annals of biomedical engineering 35 1012-1025. Machado D, Costa RS, Rocha M, Ferreira EC, Tidor B, Rocha I 2011 Modeling formalisms in Systems Biology. AMB Express 1 45. McCabe Pryor M, et al. 2015 Orchestration of ErbB3 signaling through heterointeractions and homointeractions. Mol Biol Cell 26 4109-4123.

  14. Alterations of c-Myc and c-erbB-2 genes in ovarian tumours

    Directory of Open Access Journals (Sweden)

    Pastor Tibor

    2009-01-01

    Full Text Available Introduction. According to clinical and epidemiological studies, ovarian cancer ranks fifth in cancer deaths among women. The causes of ovarian cancer remain largely unknown but various factors may increase the risk of developing it, such as age, family history of cancer, childbearing status etc. This cancer results from a succession of genetic alterations involving oncogenes and tumour suppressor genes, which have a critical role in normal cell growth regulation. Mutations and/or overexpression of three oncogenes, c-erbB-2, c-Myc and K-ras, and of the tumour suppressor gene p53, have been frequently observed in a sporadic ovarian cancer. Objective. The aim of the present study was to analyze c-Myc and c-erbB-2 oncogene alterations, specifically amplification, as one of main mechanisms of their activation in ovarian cancers and to establish a possible association with the pathogenic process. Methods. DNA was isolated from 15 samples of malignant and 5 benign ovarian tumours, using proteinase K digestion, followed by phenol-chloroform isoamyl extraction and ethanol precipitation. C-Myc and c-erbB-2 amplification were detected by differential PCR. The level of gene copy increase was measured using the Scion image software. Results. The amplification of both c-Myc and c-erbB-2 was detected in 26.7% of ovarian epithelial carcinoma specimens. Only one tumour specimen concomitantly showed increased gene copy number for both studied genes. Interestingly, besides amplification, gene deletion was also detected (26.7% for c-erbB-2. Most of the ovarian carcinomas with alterations in c-Myc and c-erbB-2 belonged to advanced FIGO stages. Conclusion. The amplification of c-Myc and c-erbB-2 oncogenes in ovarian epithelial carcinomas is most probably a late event in the pathogenesis conferring these tumours a more aggressive biological behaviour. Similarly, gene deletions point to genomic instability in epithelial carcinomas in higher clinical stages as the

  15. [Alterations of c-Myc and c-erbB-2 genes in ovarian tumours].

    Science.gov (United States)

    Pastor, Tibor; Popović, Branka; Gvozdenović, Ana; Boro, Aleksandar; Petrović, Bojana; Novaković, Ivana; Puzović, Dragana; Luković, Ljiljana; Milasin, Jelena

    2009-01-01

    According to clinical and epidemiological studies, ovarian cancer ranks fifth in cancer deaths among women. The causes of ovarian cancer remain largely unknown but various factors may increase the risk of developing it, such as age, family history of cancer, childbearing status etc. This cancer results from a succession of genetic alterations involving oncogenes and tumour suppressor genes, which have a critical role in normal cell growth regulation. Mutations and/or overexpression of three oncogenes, c-erbB-2, c-Myc and K-ras, and of the tumour suppressor gene p53, have been frequently observed in a sporadic ovarian cancer. The aim of the present study was to analyse c-Myc and c-erbB-2 oncogene alterations, specifically amplification, as one of main mechanisms of their activation in ovarian cancers and to establish a possible association with the pathogenic process. DNA was isolated from 15 samples of malignant and 5 benign ovarian tumours, using proteinase K digestion, followed by phenol-chloroform isoamyl extraction and ethanol precipitation. C-Myc and c-erbB-2 amplification were detected by differential PCR. The level of gene copy increase was measured using the Scion image software. The amplification of both c-Myc and c-erbB-2 was detected in 26.7% of ovarian epithelial carcinoma specimens. Only one tumour specimen concomitantly showed increased gene copy number for both studied genes. Interestingly, besides amplification, gene deletion was also detected (26.7% for c-erbB-2). Most of the ovarian carcinomas with alterations in c-Myc and c-erbB-2 belonged to advanced FIGO stages. The amplification of c-Myc and c-erbB-2 oncogenes in ovarian epithelial carcinomas is most probably a late event in the pathogenesis conferring these tumours a more aggressive biological behaviour. Similarly, gene deletions point to genomic instability in epithelial carcinomas in higher clinical stages as the result of clonal evolution and selection.

  16. c-erbB-2 expression and nuclear pleomorphism in canine mammary tumors

    Directory of Open Access Journals (Sweden)

    Dutra A.P.

    2004-01-01

    Full Text Available The objective of the present investigation was to study the expression of c-erbB-2 and MIB-1 and try to associate them with morphological features of the cell such as nuclear pleomorphism, mitotic count and histological grade in a series of 70 canine mammary gland tumors, 22 of them benign and 48 malignant. Tumors were collected at the Veterinary Hospital of UFMG (Brazil and the Veterinary Faculty of Porto University (Portugal. c-erbB-2 expression was determined according to the guidelines provided by the manufacturer of the HercepTest system and nuclear pleomorphism, mitotic count and histological grade according the Elston and Ellis grading system. The HercepTest is the FDA-approved in vitro diagnostic test marketed by Dako. It is a semi-quantitative immunohistochemical assay used to determine overexpression of HER2 protein (human epidermal growth factor receptor in breast cancer tissue. MIB-1 expression was also evaluated in 28 malignant tumors. Seventeen (35.4% of the malignant tumors were positive for c-erbB-2 expression, which was positively associated with nuclear pleomorphism (P < 0.0001, histological grade (P = 0.0017 and mitotic count (P < 0.05. Nuclear pleomorphism also showed a positive association with MIB-1 index (P < 0.0001. These results suggest that some of the biological and morphological characteristics of the tumor are associated in canine mammary gland tumors, as also reported for human breast cancer. It was also possible to show that the immunoexpression of c-erbB-2 can be a factor in mammary carcinogenesis. This fact opens the possibility of using anti-c-erbB-2 antibodies in the treatment of canine mammary tumors.

  17. Inhibition of eIF2α dephosphorylation inhibits ErbB2-induced deregulation of mammary acinar morphogenesis

    Directory of Open Access Journals (Sweden)

    Avivar-Valderas Alvaro

    2009-09-01

    Full Text Available Abstract Background The ErbB2/Her2/Neu receptor tyrosine kinase is amplified in ~30% of human breast cancers. Phosphorylation of the translation initiation factor, eIF2α inhibits global protein synthesis and activates a stress signaling and growth suppressive program. We have shown that forced phosphorylation of eIF2α can suppress head and neck, colorectal carcinoma and multiple myeloma tumor growth and/or survival. Here we explore whether ErbB2 modulates eIF2α phosphorylation and whether forced phosphorylation of the latter can antagonize ErbB2 deregulation of mammary acinar morphogenesis. Results We tested whether ErbB2 signaling influenced eIF2α signaling and whether enhanced phosphorylation of the latter affected ErbB2-deregulated mammary acinar development. We obtained stable MCF10A cells overexpressing wild-type (Wt Neu/ErbB2 or a constitutively active (CA variant via retroviral delivery or mammary tumor cells from MMTV-Neu tumors. Western blotting, RT-PCR and confocal microscopy were used to analyze the effects of ErbB2 activation on eIF2α signaling and the effect of the GADD34-PP1C inhibitor salubrinal. Wt- and MMTV-Neu cells formed aberrant acini structures resembling DCIS, while CA-ErbB2 overexpression induced invasive lesions. In these structures we found that CA-ErbB2 but not the Wt variant significantly down-regulated the pro-apoptotic gene CHOP. This occurred without apparent modulation of basal phosphorylation of PERK and eIF2α or induction of its downstream target ATF4. However, inhibition of eIF2α dephosphorylation with salubrinal was sufficient to inhibit Wt- and CA-ErbB2- as well as MMTV-Neu-induced deregulation of acinar growth. This was linked to enhanced CHOP expression, inhibition of proliferation, induction of apoptosis and luminal clearing in Wt-ErbB2 and to inhibition of cyclin D1 levels and subsequent proliferation in CA-ErbB2 cells. Conclusion Depending on the strength of ErbB2 signaling there is a differential

  18. AKT Rescue in Cardiomyocytes but not Breast Cancer Cells after Doxorubicin and Anti-erbB2 Treatment

    National Research Council Canada - National Science Library

    Gabrielson, Kathleen

    2007-01-01

    Study Design: The proposed study will first evaluate the role of Akt, in protection against doxorubicin and anti-erbB2-cardiomyocyte toxicity, using adenoviral expression of active Akt pharmacological inhibitors...

  19. ErbB receptors and cell polarity: New pathways and paradigms for understanding cell migration and invasion

    International Nuclear Information System (INIS)

    Feigin, Michael E.; Muthuswamy, Senthil K.

    2009-01-01

    The ErbB family of receptor tyrosine kinases is involved in initiation and progression of a number of human cancers, and receptor activation or overexpression correlates with poor patient survival. Research over the past two decades has elucidated the molecular mechanisms underlying ErbB-induced tumorigenesis, which has resulted in the development of effective targeted therapies. ErbB-induced signal transduction cascades regulate a wide variety of cell processes, including cell proliferation, apoptosis, cell polarity, migration and invasion. Within tumors, disruption of these core processes, through cooperative oncogenic lesions, results in aggressive, metastatic disease. This review will focus on the ErbB signaling networks that regulate migration and invasion and identify a potential role for cell polarity pathways during cancer progression

  20. Involvement of the clock gene Rev-erb alpha in the regulation of glucagon secretion in pancreatic alpha-cells.

    Directory of Open Access Journals (Sweden)

    Elaine Vieira

    Full Text Available Disruption of pancreatic clock genes impairs pancreatic beta-cell function, leading to the onset of diabetes. Despite the importance of pancreatic alpha-cells in the regulation of glucose homeostasis and in diabetes pathophysiology, nothing is known about the role of clock genes in these cells. Here, we identify the clock gene Rev-erb alpha as a new intracellular regulator of glucagon secretion. Rev-erb alpha down-regulation by siRNA (60-70% inhibition in alphaTC1-9 cells inhibited low-glucose induced glucagon secretion (p<0.05 and led to a decrease in key genes of the exocytotic machinery. The Rev-erb alpha agonist GSK4112 increased glucagon secretion (1.6 fold and intracellular calcium signals in alphaTC1-9 cells and mouse primary alpha-cells, whereas the Rev-erb alpha antagonist SR8278 produced the opposite effect. At 0.5 mM glucose, alphaTC1-9 cells exhibited intrinsic circadian Rev-erb alpha expression oscillations that were inhibited by 11 mM glucose. In mouse primary alpha-cells, glucose induced similar effects (p<0.001. High glucose inhibited key genes controlled by AMPK such as Nampt, Sirt1 and PGC-1 alpha in alphaTC1-9 cells (p<0.05. AMPK activation by metformin completely reversed the inhibitory effect of glucose on Nampt-Sirt1-PGC-1 alpha and Rev-erb alpha. Nampt inhibition decreased Sirt1, PGC-1 alpha and Rev-erb alpha mRNA expression (p<0.01 and glucagon release (p<0.05. These findings identify Rev-erb alpha as a new intracellular regulator of glucagon secretion via AMPK/Nampt/Sirt1 pathway.

  1. Hepatitis C Virus Activates a Neuregulin-Driven Circuit to Modify Surface Expression of Growth Factor Receptors of the ErbB Family.

    Directory of Open Access Journals (Sweden)

    Sabine Stindt

    Full Text Available Recently, the epidermal growth factor (EGF receptor (EGFR, a member of the ErbB receptor family, and its down-stream signalling have been identified as co-factors for HCV entry and replication. Since EGFR also functions as a heterodimer with other ErbB receptor family members, the subject of the present study was to investigate a possible viral interference with these cellular components. By using genotype 1b replicon cells as well as an infection-based system we found that while transcript and protein levels of EGFR and ErbB2 were up-regulated or unaffected, respectively, HCV induced a substantial reduction of ErbB3 and ErbB4 expression. Down-regulation of ErbB3 expression by HCV involves specificity protein (Sp1-mediated induction of Neuregulin (NRG1 expression as well as activation of Akt. Consistently, at transcript level disruption of ErbB3 expression by HCV can be prevented by knockdown of NRG1 or Sp1 expression, whereas reconstitution of ErbB3 protein levels requires inhibition of HCV-induced NRG1 expression and of Akt activity. Interestingly, the NRG1-mediated suppression of ErbB3 expression by HCV results in an enhanced expression of EGFR and ErbB2 on the cell surface, which can be mimicked by siRNA-mediated knockdown of ErbB3 expression. These data delineate a novel mechanism enabling HCV to sway the composition of the ErbB family members on the surface of its host cell by an NRG1-driven circuit and unravels a yet unknown cross-regulation between ErbB3 and the two other family members ErbB2 and EGFR. The shift of the receptor surface expression of the ErbB family towards enhanced expression of ErbB2 and EGFR triggered by HCV was found to promote viral RNA replication and infectivity. This suggests that HCV rearranges expression of ErbB family members to adapt the cellular environment to its requirements.

  2. Estradiol rapidly activates Akt via the ErbB2 signaling pathway.

    Science.gov (United States)

    Stoica, Gerald E; Franke, Thomas F; Wellstein, Anton; Czubayko, Frank; List, Heinz-Joachim; Reiter, Ronald; Morgan, Elisha; Martin, Mary Beth; Stoica, Adriana

    2003-05-01

    Previously, we have demonstrated that the two mitogenic growth factors epidermal growth factor and IGF-I can activate Akt and estrogen receptor-alpha (ERalpha) in the hormone-dependent breast cancer cell line, MCF-7. In this report we now show that estradiol can also rapidly activate phosphatidylinositol 3-kinase (PI 3-K)/Akt and that this effect is mediated by the ErbB2 signaling pathway. Treatment of cells with estradiol resulted in phosphorylation of Akt and a 9-fold increase in Akt activity in 10 min. Akt activation was blocked by wortmannin and LY 294,002, two inhibitors of PI 3-K; by genistein, a protein tyrosine kinase inhibitor and an ER agonist; by AG825, a selective ErbB2 inhibitor; and by the antiestrogens ICI 182,780 and 4-hydroxy-tamoxifen; but not by rapamycin, an inhibitor of the ribosomal protein kinase p70S6K; nor by AG30, a selective epidermal growth factor receptor inhibitor. Akt activation by estradiol was abrogated by an arginine-to-cysteine mutation in the pleckstrin homology domain of Akt (R25C). Growth factors also activated Akt in the ER-negative variant of MCF-7, MCF-7/ADR, but estradiol did not induce Akt activity in these cells. Transient transfection of ERalpha into these cells restored Akt activation by estradiol, suggesting that estradiol activation of Akt requires the ERalpha. Estradiol did not activate Akt in MCF-7 cells stably transfected with an anti-ErbB2-targeted ribozyme, further confirming a role for ErbB2. In vitro kinase assays using immunoprecipitation and anti-Akt1, -Akt2, and -Akt3-specific antibodies demonstrated that Akt1 is activated by estradiol in MCF-7 cells whereas Akt3 is the activated isoform in ER-negative MDA-MB231 cells, implying that selective activation of Akt subtypes plays a role in the actions of estradiol. Taken together, our data suggest that estradiol, bound to membrane ERalpha, interacts with and activates an ErbB dimer containing ErbB2, inducing activation of PI 3-K/Akt.

  3. Le CRDI au Cambodge

    International Development Research Centre (IDRC) Digital Library (Canada)

    Le CRDI a été l'un des premiers bailleurs de fonds à établir des relations avec le Cambodge au début des années 1990, alors que le pays progres- sait vers la paix. Depuis, le Centre aide à reconstruire le Cambodge, qui se remet du régime inhumain des Khmers rouges et de décennies de conflits régionaux. Un État ...

  4. 1910 - Le mouchoir

    NARCIS (Netherlands)

    Winkler, M.F.; Cohen, Nadja; Reverseau, Anne

    2015-01-01

    Une histoire littéraire buissonnière. Ainsi pourrait-on qualifier le parcours original auquel nous convie cet ouvrage, qui propose une lecture insolente et insolite de cinquante années de littérature – de 1900 à 1950 – par le prisme des objets. Objets de tous les jours comme le tabac, le vélo ou le

  5. Small tyrosine kinase inhibitors interrupt EGFR signaling by interacting with erbB3 and erbB4 in glioblastoma cell lines

    Energy Technology Data Exchange (ETDEWEB)

    Carrasco-Garcia, Estefania; Saceda, Miguel [Instituto de Biologia Molecular y Celular, Universidad Miguel Hernandez, 03202 Elche (Alicante) (Spain); Unidad de Investigacion, Hospital General Universitario de Elche, 03203 Elche (Alicante) (Spain); Grasso, Silvina; Rocamora-Reverte, Lourdes; Conde, Mariano; Gomez-Martinez, Angeles [Instituto de Biologia Molecular y Celular, Universidad Miguel Hernandez, 03202 Elche (Alicante) (Spain); Garcia-Morales, Pilar [Instituto de Biologia Molecular y Celular, Universidad Miguel Hernandez, 03202 Elche (Alicante) (Spain); Unidad de Investigacion, Hospital General Universitario de Elche, 03203 Elche (Alicante) (Spain); Ferragut, Jose A. [Instituto de Biologia Molecular y Celular, Universidad Miguel Hernandez, 03202 Elche (Alicante) (Spain); Martinez-Lacaci, Isabel, E-mail: imlacaci@umh.es [Instituto de Biologia Molecular y Celular, Universidad Miguel Hernandez, 03202 Elche (Alicante) (Spain); Unidad AECC de Investigacion Traslacional en Cancer, Hospital Universitario Virgen de la Arrixaca, 30120 Murcia (Spain)

    2011-06-10

    Signaling through the epidermal growth factor receptor (EGFR) is relevant in glioblastoma. We have determined the effects of the EGFR inhibitor AG1478 in glioblastoma cell lines and found that U87 and LN-229 cells were very sensitive to this drug, since their proliferation diminished and underwent a marked G{sub 1} arrest. T98 cells were a little more refractory to growth inhibition and A172 cells did not undergo a G{sub 1} arrest. This G{sub 1} arrest was associated with up-regulation of p27{sup kip1}, whose protein turnover was stabilized. EGFR autophosphorylation was blocked with AG1478 to the same extent in all the cell lines. Other small-molecule EGFR tyrosine kinase inhibitors employed in the clinic, such as gefitinib, erlotinib and lapatinib, were able to abrogate proliferation of glioblastoma cell lines, which underwent a G{sub 1} arrest. However, the EGFR monoclonal antibody, cetuximab had no effect on cell proliferation and consistently, had no effect on cell cycle either. Similarly, cetuximab did not inhibit proliferation of U87 {Delta}EGFR cells or primary glioblastoma cell cultures, whereas small-molecule EGFR inhibitors did. Activity of downstream signaling molecules of EGFR such as Akt and especially ERK1/2 was interrupted with EGFR tyrosine kinase inhibitors, whereas cetuximab treatment could not sustain this blockade over time. Small-molecule EGFR inhibitors were able to prevent phosphorylation of erbB3 and erbB4, whereas cetuximab only hindered EGFR phosphorylation, suggesting that EGFR tyrosine kinase inhibitors may mediate their anti-proliferative effects through other erbB family members. We can conclude that small-molecule EGFR inhibitors may be a therapeutic approach for the treatment of glioblastoma patients.

  6. A moderate elevation of circulating levels of IGF-I does not alter ErbB2 induced mammary tumorigenesis

    Directory of Open Access Journals (Sweden)

    Brown Powel H

    2011-08-01

    Full Text Available Abstract Background Epidemiological evidence suggests that moderately elevated levels of circulating insulin-like growth factor-I (IGF-I are associated with increased risk of breast cancer in women. How circulating IGF-I may promote breast cancer incidence is unknown, however, increased IGF-I signaling is linked to trastuzumab resistance in ErbB2 positive breast cancer. Few models have directly examined the effect of moderately high levels of circulating IGF-I on breast cancer initiation and progression. The purpose of this study was to assess the ability of circulating IGF-I to independently initiate mammary tumorigenesis and/or accelerate the progression of ErbB2 mediated mammary tumor growth. Methods We crossed heterozygous TTR-IGF-I mice with heterozygous MMTV-ErbB2 mice to generate 4 different genotypes: TTR-IGF-I/MMTV-ErbB2 (bigenic, TTR-IGF-I only, MMTV-ErbB2 only, and wild type (wt. Virgin females were palpated twice a week and harvested when tumors reached 1000 mm3. For study of normal development, blood and tissue were harvested at 4, 6 and 9 weeks of age in TTR-IGF-I and wt mice. Results TTR-IGF-I and TTR-IGF-I/ErbB2 bigenic mice showed a moderate 35% increase in circulating total IGF-I compared to ErbB2 and wt control mice. Elevation of circulating IGF-I had no effect upon pubertal mammary gland development. The transgenic increase in IGF-I alone wasn't sufficient to initiate mammary tumorigenesis. Elevated circulating IGF-I had no effect upon ErbB2-induced mammary tumorigenesis or metastasis, with median time to tumor formation being 30 wks and 33 wks in TTR-IGF-I/ErbB2 bigenic and ErbB2 mice respectively (p = 0.65. Levels of IGF-I in lysates from ErbB2/TTR-IGF-I tumors compared to ErbB2 was elevated in a similar manner to the circulating IGF-I, however, there was no effect on the rate of tumor growth (p = 0.23. There were no morphological differences in tumor type (solid adenocarcinomas between bigenic and ErbB2 mammary glands

  7. A novel mouse monoclonal antibody targeting ErbB2 suppresses breast cancer growth

    Energy Technology Data Exchange (ETDEWEB)

    Kawa, Seiji [Division of Oncology, Institute of Medical Science, University of Tokyo, Shirokanedai 4-6-1, Minato-ku, Tokyo 108-8639 (Japan); Matsushita, Hirohisa; Ohbayashi, Hirokazu [Department of Research and Development, Nichirei Biosciences Inc., Tokyo 104-8402 (Japan); Semba, Kentaro [Department of Life Science and Medical Bio-Science, School of Science and Engineering, Waseda University, Tokyo 169-8555 (Japan); Yamamoto, Tadashi, E-mail: tyamamot@ims.u-tokyo.ac.jp [Division of Oncology, Institute of Medical Science, University of Tokyo, Shirokanedai 4-6-1, Minato-ku, Tokyo 108-8639 (Japan)

    2009-07-03

    Overexpression of ErbB2 in breast cancer is associated with increased recurrence and worse prognosis. Accumulating evidences suggest that molecular targeted therapy is a promising anticancer strategy. In this study, we produced a novel anti-ErbB2 monoclonal antibody, 6G10, that recognized an epitope distinct from the trastuzumab binding site. 6G10 induced aggregation of BT474 breast cancer cells and inhibited proliferation of various breast cancer cell lines including BT474. A growth inhibition assay showed that 6G10 had EC{sub 50} values comparable to trastuzumab, indicating that the drugs have a similar level of potency. Furthermore, intraperitoneal administration of 6G10 completely inhibited the growth of xenografted tumors derived from BT474 and SK-BR-3 cells. These data suggested that 6G10 has great therapeutic potential and could be administered to patients alternatively, or synergistically, with trastuzumab.

  8. Weaponization study of canard actuator control systems for an ERB/TIGER II application

    Energy Technology Data Exchange (ETDEWEB)

    Leuenberger, W.R.

    1979-08-01

    The report describes a weaponization study of four types of canard actuator control systems for an ERB/TIGER II application. The systems considered are cold gas, warm gas, hydraulic, and electromechanical. For this application, the cold gas actuator was selected to be the prime candidate, not only because it is the lightest weight but also because its design is least complicated and has minimal risks.

  9. Nuclear ErbB4 signaling through H3K9me3 is antagonized by EGFR-activated c-Src.

    Science.gov (United States)

    Ishibashi, Kenichi; Fukumoto, Yasunori; Hasegawa, Hitomi; Abe, Kohei; Kubota, Shoichi; Aoyama, Kazumasa; Kubota, Sho; Nakayama, Yuji; Yamaguchi, Naoto

    2013-01-15

    The ErbB family of receptor tyrosine kinases comprises four members: epidermal growth factor receptor (EGFR)/ErbB1, HER2/ErbB2, ErbB3 and ErbB4, and plays roles in signal transduction at the plasma membrane upon ligand stimulation. Stimulation with neuregulin-1 (NRG-1) cleaves ErbB4 and releases the ErbB4 intracellular domain (4ICD) that translocates into the nucleus to control gene expression. However, little is known about the regulation of 4ICD nuclear signaling through tyrosine phosphorylation. We show here that 4ICD nuclear signaling is antagonized by EGF-induced c-Src activation through EGFR. Generation of 4ICD by NRG-1 leads to increased levels of trimethylated histone H3 on lysine 9 (H3K9me3) in a manner dependent on the nuclear accumulation of 4ICD and its tyrosine kinase activity. Once EGF activates c-Src downstream of EGFR concomitantly with NRG-1-induced ErbB4 activation, c-Src associates with phospho-Tyr950 and phospho-Tyr1056 on 4ICD, thereby decreasing nuclear accumulation of 4ICD and inhibiting an increase of H3K9me3 levels. Moreover, 4ICD-induced transcriptional repression of the human telomerase reverse transcriptase (hTERT) is inhibited by EGF-EGFR-Src signaling. Thus, our findings reveal c-Src-mediated inhibitory regulation of ErbB4 nuclear signaling upon EGFR activation.

  10. Disruption of laminin-integrin-CD151-focal adhesion kinase axis sensitizes breast cancer cells to ErbB2 antagonists.

    Science.gov (United States)

    Yang, Xiuwei H; Flores, Ludmila M; Li, Qinglin; Zhou, Pengcheng; Xu, Fenghui; Krop, Ian E; Hemler, Martin E

    2010-03-15

    Resistance to anti-ErbB2 agents is a significant problem in the treatment of human ErbB2+ breast cancers. We show here that adhesion of human ErbB2+ breast cancer cells to basement membrane laminin-5 provides substantial resistance to trastuzumab and lapatinib, agents that respectively target the extracellular and kinase domains of ErbB2. Knockdown of laminin-binding integrins (alpha6beta4, alpha3beta1) or associated tetraspanin protein CD151 reversed laminin-5 resistance and sensitized ErbB2+ cells to trastuzumab and lapatinib. CD151 knockdown, together with trastuzumab treatment, inhibited ErbB2 activation and downstream signaling through Akt, Erk1/2, and focal adhesion kinase (FAK). Hence, ErbB2 function in mammary tumor cells is promoted by integrin-mediated adhesion to laminin-5, with strong support by CD151, leading to signaling through FAK. Consequently, removal or inhibition of any of these components (laminin-5, integrin, CD151, FAK) markedly sensitizes cells to anti-ErbB2 agents. These new insights should be useful when devising strategies for overcoming drug resistance in ErbB2+ cancers.

  11. Le vieillard et le chevalier

    Directory of Open Access Journals (Sweden)

    Mélanie JECKER

    2010-05-01

    Full Text Available La fin du Moyen Âge fascine. Deux facteurs principaux expliquent l’attraction qu’exerce cette période : elle apparaît d’une part comme un moment historique riche car double, phase de transition entre le Moyen Âge et la Renaissance, où se mêlent des cadres de représentation anciens et nouveaux. L’insinuation d’une pensée humaniste balbutiante s’y traduirait notamment par l’émergence de la notion d’individu, qui constitue l’un des objets de ce travail. Il faut invoquer, d’autre part, l’image macabre d’un bas Moyen Âge hanté par l’idée de la maladie et de la mort depuis l’épidémie de peste noire de 1348, obsédé par la brièveté de la vie humaine. Ces deux facettes de « l’automne du Moyen Âge » tel que l’évoque avec poésie Joan Huizinga sont-elles autre chose qu’une plaisante image d’Epinal? Cette étude cherche précisément à déterminer le degré de validité de ces deux topiques, à travers l’analyse de la représentation des âges de la vie dans un corpus bien défini, celui de la biographie chevaleresque castillane du XVe siècle. L’intérêt porté à l’individu, la conscience de la singularité impliquent en effet celle du caractère mouvant de la personne, or quel thème mieux que celui des âges permet de confirmer ou d’infirmer l’hypothèse du surgissement d’une nouvelle manière de concevoir l’homme, proprement « renaissante », en ce siècle de transition , La nature même du corpus retenu – des récits biographiques – suggère en effet une mutation dans l’appréhension de la personne, une attention prêtée à sa progressive transformation. L’étude de la représentation de la vieillesse, en particulier, révèle non seulement à quel point était alors réelle cette prétendue obsession de la déchéance physique et de la mortalité, mais aussi dans quelle mesure étaient soulignés et valorisés les changements individuels parallèles à l

  12. Earth Radiation Budget Experiment (ERBE) Data Sets for Global Environment and Climate Change Studies

    Science.gov (United States)

    Bess, T. Dale; Carlson, Ann B.; Denn, Fredrick M.

    1997-01-01

    For a number of years there has been considerable interest in the earth's radiation budget (ERB) or energy balance, and entails making the best measurements possible of absorbed solar radiation, reflected shortwave radiation (RSW), thermal outgoing longwave radiation (OLR), and net radiation. ERB data are fundamental to the development of realistic climate models and studying natural and anthropogenic perturbations of the climate. Much of the interest and investigations in the earth's energy balance predated the age of earth-orbiting satellites (Hunt et al., 1986). Beginning in the mid 1960's earth-orbiting satellites began to play an important role in making measurements of the earth's radiation flux although much effort had gone into measuring ERB parameters prior to 1960 (House et al., 1986). Beginning in 1974 and extending until the present time, three different satellite experiments (not all operating at the same time) have been making radiation budget measurements almost continually in time. Two of the experiments were totally dedicated to making radiation budget measurements of the earth, and the other experiment flown on NOAA sun-synchronous AVHRR weather satellites produced radiation budget parameters as a by-product. The heat budget data from the AVHRR satellites began collecting data in June 1974 and have operated almost continuously for 23 years producing valuable data for long term climate monitoring.

  13. Le gouvernement Mansard

    OpenAIRE

    Curton, Émile de

    2013-01-01

    Le fait même de sa nomination au poste de Gouverneur allait donner au conflit qui opposait Mansard au docteur Alain toute sa dimension. Le Médecin-chef et ses complices avaient manqué leur premier objectif : remettre en cause le ralliement de la colonie avant le départ du Gouverneur de Géry. Toutefois, ils jugeaient toujours possible de saper l’autorité encore fragile du nouveau gouverneur en la contestant. Dans ce but, le chef du service de santé prenait, dès le 15 septembre, une double init...

  14. Le beau et le vrai

    Directory of Open Access Journals (Sweden)

    Létitia Mouze

    2006-05-01

    Full Text Available La vie des abeilles de Maeterlinck est un ouvrage à la fois scientifique et littéraire, non pas parce qu’il appartiendrait à la science par son exactitude et à la littérature par son style, mais en ce qu’il invite à penser l’unité des deux domaines. Les aspects littéraires de l’ouvrage (beauté de l’écriture, usage des images, de l’analogie, etc. ne sont pas des accessoires, mais des outils indispensables à l’élaboration d’un authentique savoir sur les abeilles, c’est-à-dire un savoir qui reconnaît la part d’inconnu et le mystère qui subsistent en dépit de toutes les explications physiques et mécaniques que l’on peut par ailleurs donner des phénomènes observés. Etre scientifique, dans cette perspective, c’est-à-dire donner à connaître, c’est donc être littéraire. Cette conception de la science repose en dernière instance sur une conception philosophique de l’univers comme un tout où toutes choses sont reliées, unies, par des relations d’analogies, ce qui fonde et justifie l’emploi d’un style symboliste.The life of bees, one of Maeterlinck’s works, is together a scientific and literary book, not because of it scientific exactness and its literary style, but for the reason it suggests the unity of both these domains. Literay’s aspects of this work (writing’s beauty, use of images, analogy, etc. are not secondary but necessary to elaborate an authentic knowledge about bees, that means a knowledge which admit the unknown part and the mistery that subsist despite all the physical and mechanical explanations we can give moreover about the observed phenomenons. Be a scientist, in this sense, that is give something to know, therefore means be literary. Finally, this conception of science consist in a philosophiacl conception of Universe as a whole where everything links together, and is united by analogical relations, that base and justify the use of a symbolist style.

  15. REV-ERBs agonism suppresses osteoclastogenesis and prevents ovariectomy-induced bone loss partially via FABP4 upregulation.

    Science.gov (United States)

    Song, Chao; Tan, Peng; Zhang, Zheng; Wu, Wei; Dong, Yonghui; Zhao, Liming; Liu, Huiyong; Guan, Hanfeng; Li, Feng

    2018-01-22

    REV-ERBs (REV-ERBα and REV-ERBβ) are transcription repressors and circadian regulators. Previous investigations have shown that REV-ERBs repress the expression of target genes, including MMP9 and CX3CR1, in macrophages. Because MMP9 and CX3CR1 reportedly participate in receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclastogenesis, we inferred that REV-ERBs might play a role in osteoclastogenesis. In the present study, we found that the REV-ERBα level decreased significantly during RANKL-induced osteoclast differentiation from primary bone marrow-derived macrophages (BMMs). REV-ERBα knockdown by small interfering RNA in BMMs resulted in the enhanced formation of osteoclasts, whereas REV-ERBβ knockdown showed no effect on osteoclast differentiation. Moreover, the REV-ERB agonist SR9009 inhibited osteoclast differentiation and bone resorption. Intraperitoneal SR9009 administration prevented ovariectomy-induced bone loss; this effect was accompanied by decreased serum RANKL and C-terminal telopeptide of type I collagen levels and increased osteoprotegerin levels. Further investigation revealed that NF-κB and MAPK activation and nuclear factor of activated T cells, cytoplasmic 1, and c-fos expression were suppressed by SR9009. The level of reactive oxygen species was also decreased by SR9009, with NADPH oxidase subunits also being down-regulated. In addition, an expression microarray showed that FABP4, an intracellular lipid-binding protein, was up-regulated by REV-ERB agonism. BMS309403, an inhibitor of FABP4, partially prevented the suppression of osteoclastogenesis by SR9009 through stabilizing phosphorylation of p65. To summarize, our results proved that the REV-ERB agonism inhibited osteoclastogenesis partially via FABP4 up-regulation.-Song, C., Tan, P., Zhang, Z., Wu, W., Dong, Y., Zhao, L., Liu, H., Guan, H., Li, F. REV-ERBs agonism suppresses osteoclastogenesis and prevents ovariectomy-induced bone loss partially via FABP4 upregulation.

  16. Integrin α3β1-CD151 complex regulates dimerization of ErbB2 via RhoA.

    Science.gov (United States)

    Novitskaya, V; Romanska, H; Kordek, R; Potemski, P; Kusińska, R; Parsons, M; Odintsova, E; Berditchevski, F

    2014-05-22

    Integrin α3β1 regulates adhesive interactions of cells with laminins and have a critical role in adhesion-dependent cellular responses. Here, we examined the role of α3β1-integrin in ErbB2-dependent proliferation of breast cancer cells in three-dimensional laminin-rich extracellular matrix (3D lr-ECM). Depletion of α3β1 in ErbB2-overexpressing breast cancer cells suppressed growth and restore cell polarity in 3D lr-ECM. The phenotype of α3β1-depleted cells was reproduced upon depletion of tetraspanin CD151 and mirrored that of the cells treated with Herceptin, an established ErbB2 antagonist. Breast cancer cells expressing the α3β1-CD151 complex have higher steady-state phosphorylation of ErbB2 and show enhanced dimerization of the protein when compared with α3β1-/CD151-depleted cells. Furthermore, Herceptin-dependent dephosphorylation of ErbB2 was only observed in α3β1-CD151-expressing cells. Importantly, the inhibitory activity of Herceptin was more pronounced when cells expressed both α3β1 and CD151. We also found that the level of active RhoA was increased in α3β1- and CD151-depleted cells and that Rho controls dimerization of ErbB2. Expression of α3β1 alone did not have significant prognostic value in patients with invasive ductal carcinoma of the breast. However, expression of α3β1 in combination with CD151 represented a more stringent indicator of poor survival than CD151 alone. Taken together, these results demonstrate that the α3β1-CD151 complex has a critical regulatory role in ErbB2-dependent signalling and thereby may be involved in breast cancer progression.

  17. Preliminary study of p53 and c-erbB-2 expression in gallbladder cancer in Indian patients

    Directory of Open Access Journals (Sweden)

    Singh Usha

    2006-05-01

    Full Text Available Abstract Background The inactivation of the tumour suppressor gene and activation of the proto-oncogene are the key steps in the development of the human cancer. The p53 and c-erbB-2 are the best examples of it. In the present study, our aim was to determine the role of these genes in the carcinogenesis of gallbladder by immunohistochemistry. Methods In all 78 consecutive patients of gall bladder diseases were studied for p53 and c-erbB-2 expression immunohistochemically and their expression was correlated with the age, grades and stages of the disease and presence of stone. An informed consent was obtained in each case. Chi square and z test were applied to see the association of p53 and c-erbB-2 over expression with other clinicopathological factors. Results Eight (20% patients of gall bladder cancer were positive for p53 expression and 10 (25% patients for c-erbB-2. The p53 positivity increased with increasing grade while cerbB-2 positivity decreased with increasing grade of gall bladder cancer. Mean age in cerbB-2 positive cases were lesser as compared to negative cases while p53 did not show such association with age. Conclusion Only one case of gall bladder cancer co-expressed the p53 and c-erbB-2, thereby suggesting that p53 and c-erbB-2 may have independent role in carcinogenesis of gall bladder cancer. c-erbB-2 over expression in adenoma and younger age group indicates its role as an early event in carcinogenesis of gallbladder. However study of larger sample is required to further validate the results.

  18. Expressão imuno-histoquímica de c-erb-B2 e p53 em carcinomas gástricos Imunohistochemical expression of c-erb-B2 and p53 in gastric carcinomas

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    Maria Dirlei F. S. Begnami

    2005-08-01

    Full Text Available INTRODUÇÃO: Em nosso meio, os carcinomas gástricos ainda são neoplasias bastante freqüentes e responsáveis por altas taxas de mortalidade. Recentemente, têm-se demonstrado a expressão de p53 e a amplificação do gene c-erb-B2 nos carcinomas gástricos. A relevância e o significado biológico destas alterações ainda não foram totalmente estabelecidos. OBJETIVO: Estudar as expressões imuno-histoquímicas de p53 e c-erb-B2 em 482 casos de carcinomas gástricos. MATERIAL E MÉTODOS: Foram construídos três blocos de tissue microarray (TMA utilizando-se duplicatas de 482 casos de carcinomas gástricos. Os cortes foram corados por hematoxilina e eosina (HE, tendo sido feita pesquisa para p53 e c-erb-B2. Foram considerados positivos para p53 os casos com marcação nuclear em mais de 10% das células tumorais. Para o c-erb-B2 foram considerados positivos os casos com marcação de membrana completa em mais de 10% das células tumorais. RESULTADOS: A expressão de p53 e c-erb-B2 foi observada em 30% e 12% dos casos, respectivamente. Em relação aos tipos histológicos observou-se correlação entre os carcinomas do tipo intestinal e a expressão de c-erb-B2 (p INTRODUCTION: Gastric cancer is one of the commonest cancers in our country being responsible for a high mortality rate. Recently, the expression of p53 and amplification of c-erb-B2 gene have been described in gastric carcinoma. The relevance and biological significance of these findings are not established yet. OBJECTIVE: The authors investigated p53, c-erb-B2 immunohistochemical expression in 482 cases of gastric carcinomas. MATERIAL AND METHODS: Tissue microarray (TMA blocks were designed using replicate samples of paraffin-embedded tissue from 482 gastric carcinomas. Sections were stained with HE, and antibodies to p53 and c-erb-B2. Cases were considered p53 positive if nuclear staining was detected in > 10% of the tumor cells. Cases were assessed c-erb-B2 positive if the

  19. Hsp90 inhibitor 17-AAG reduces ErbB2 levels and inhibits proliferation of the trastuzumab resistant breast tumor cell line JIMT-1.

    Science.gov (United States)

    Zsebik, Barbara; Citri, Ami; Isola, Jorma; Yarden, Yosef; Szöllosi, János; Vereb, György

    2006-04-15

    ErbB2, a member of the EGF receptor family of tyrosine kinases is overexpressed on many tumor cells of epithelial origin and is the molecular target of trastuzumab (Herceptin), the first humanized antibody used in the therapy of solid tumors. Trastuzumab, which is thought to act, at least in part, by downregulating ErbB2 expression is only effective in approximately 30-40% of ErbB2 positive breast tumors. Geldanamycin and its derivative 17-AAG are potential antitumor agents capable of downregulating client proteins of Hsp90, including ErbB2. To investigate the ability of 17-AAG to downregulate ErbB2 in trastuzumab resistant breast cancer cells and the possibility of 17-AAG and trastuzumab potentiating each other's effect, the recently established trastuzumab resistant breast cancer cell line, JIMT-1 was compared to the known trastuzumab sensitive SKBR-3 line. Baseline and stimulus-evoked dimerization and activation levels of ErbB2, and the effects of trastuzumab and 17-AAG alone and in combination on cell proliferation and apoptosis, as well as on ErbB2 expression and phosphorylation have been measured. Baseline activation and amenability to activation and downregulation by trastuzumab was much lower in the resistant line. However, 17-AAG enhanced ErbB2 homodimerization after 5-10 min of treatment in both cell lines, and decreased proliferation with an IC50 of 70 nM for SKBR-3 and 10nM for JIMT-1. Thus, 17-AAG may be a useful drug in trastuzumab resistant ErbB2 overexpressing tumors. The antiproliferative effect of 17-AAG was positively correlated with phosphorylation and downregulation of ErbB2 and was dominated by apoptosis, although, especially at higher doses, necrosis was also present. Interestingly, IC50 values for ErbB2 downregulation and phosphorylation, in the 30-40 nM range, were not significantly different for the two cell lines. This observation and the negative correlation between resting ErbB2 levels and the antiproliferative effect of 17-AAG may

  20. Neuregulin repellent signaling via ErbB4 restricts GABAergic interneurons to migratory paths from ganglionic eminence to cortical destinations

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    Li Hao

    2012-02-01

    Full Text Available Abstract Background Cortical GABAergic interneurons (INs are generated in the medial ganglionic eminence (MGE and migrate tangentially into cortex. Because most, if not all, migrating MGE-derived INs express the neuregulin (NRG receptor, ErbB4, we investigated influences of Nrg1 isoforms and Nrg3 on IN migration through ventral telencephalon (vTel and within cortex. Results During IN migration, NRG expression domains and distributions of ErbB4-expressing, MGE-derived INs are complementary with minimal overlap, both in vTel and cortex. In wild-type mice, within fields of NRG expression, these INs are focused at positions of low or absent NRG expression. However, in ErbB4-/- HER4heart mutant mice in which INs lack ErbB4, these complementary patterns are degraded with considerable overlap evident between IN distribution and NRG expression domains. These findings suggest that NRGs are repellents for migrating ErbB4-expressing INs, a function supported by in vitro and in vivo experiments. First, in collagen co-cultures, MGE-derived cells preferentially migrate away from a source of secreted NRGs. Second, cells migrating from wild-type MGE explants on living forebrain slices from wild-type embryonic mice tend to avoid endogenous NRG expression domains, whereas this avoidance behavior is not exhibited by ErbB4-deficient cells migrating from MGE explants and instead they have a radial pattern with a more uniform distribution. Third, ectopic NRG expression in the IN migration pathway produced by in utero electroporation blocks IN migration and results in cortex distal to the blockade being largely devoid of INs. Finally, fewer INs reach cortex in ErbB4 mutants, indicating that NRG-ErbB4 signaling is required for directing IN migration from the MGE to cortex. Conclusions Our results show that NRGs act as repellents for migrating ErbB4-expressing, MGE-derived GABAergic INs and that the patterned expression of NRGs funnels INs as they migrate from the MGE

  1. Expression of the neuregulin receptor ErbB4 in the brain of the rhesus monkey (Macaca mulatta.

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    Jörg Neddens

    Full Text Available We demonstrated recently that frontal cortical expression of the Neuregulin (NRG receptor ErbB4 is restricted to interneurons in rodents, macaques, and humans. However, little is known about protein expression patterns in other areas of the brain. In situ hybridization studies have shown high ErbB4 mRNA levels in various subcortical areas, suggesting that ErbB4 is also expressed in cell types other than cortical interneurons. Here, using highly-specific monoclonal antibodies, we provide the first extensive report of ErbB4 protein expression throughout the cerebrum of primates. We show that ErbB4 immunoreactivity is high in association cortices, intermediate in sensory cortices, and relatively low in motor cortices. The overall immunoreactivity in the hippocampal formation is intermediate, but is high in a subset of interneurons. We detected the highest overall immunoreactivity in distinct locations of the ventral hypothalamus, medial habenula, intercalated nuclei of the amygdala and structures of the ventral forebrain, such as the islands of Calleja, olfactory tubercle and ventral pallidum, and medium expression in the reticular thalamic nucleus. While this pattern is generally consistent with ErbB4 mRNA expression data, further investigations are needed to identify the exact cellular and subcellular sources of mRNA and protein expression in these areas. In contrast to in situ hybridization in rodents, we detected only low levels of ErbB4-immunoreactivity in mesencephalic dopaminergic nuclei but a diffuse pattern of immunofluorescence that was medium in the dorsal striatum and high in the ventral forebrain, suggesting that most ErbB4 protein in dopaminergic neurons could be transported to axons. We conclude that the NRG-ErbB4 signaling pathway can potentially influence many functional systems throughout the brain of primates, and suggest that major sites of action are areas of the "corticolimbic" network. This interpretation is functionally

  2. Assessment of staging, prognosis and mortality of colorectal cancer by tumor markers: receptor erbB-2 and cadherins

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    Jesus Eliane C.

    2005-01-01

    Full Text Available PURPOSE: To evaluate the prognostic significance and correlation with staging and degree of cell differentiation of the tumoral expression of the proteins c-erbB-2 and E-cadherin, in patients with colorectal adenocarcinoma. METHODS: The study included 117 patients with an average age of 63.1 years and an average follow-up duration of 28.1 months. The disease-free interval, survival, incidence of recurrence and specific mortality were evaluated. c-erbB-2 anti-oncoprotein antibodies (Dako were utilized via the streptavidin-biotin technique. Samples were considered to be positive for c-erbB-2 if 10% or more of the tumor cell membranes were stained.The anti-E-cadherin antibodies (Dako, evaluated this protein and is considered positive, if 50% or more of the cell membranes were stained. Statistical analysis was performed using Pearson's chi-squared test, Fisher's exact test, Kaplan-Meier's estimator, the log-rank test and Wilcoxon's test (Breslow version, setting the level of statistical significance at 5% (p<0.05. RESULTS: 52 of 108 patients studied for c-erbB-2 were positive (48,1%, 47 of 93 patients studied for E-cadherin were negative (50,5%. These data do not express any correlation with TNM (tumor, node and metastasis staging and the degree of cell differentiation or with the tumor recurrence rate. The disease-free interval among patients who were positive for c-erbB-2 and negative for E-cadherin was 68.0 months and did not differ from those with c-erbB-2 negative and E-cadherin positive ( 55.0 months - p = 0.5510. The average survival among patients positive for c-erbB-2 and negative for E-cadherin was 75 months without statistical significance difference with the other group ( 61 months - p = 0.5256. Specific mortality occurred in 20.0% of the cases and did not correlate with the expression of c-erbB-2 (p=0,446, E-cadherin (p=0,883. CONCLUSION: The tumoral expression of c-erbB-2 and E-cadherin did not demonstrate a correlation with the

  3. Small molecule ErbB inhibitors decrease proliferative signaling and promote apoptosis in philadelphia chromosome-positive acute lymphoblastic leukemia.

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    Mary E Irwin

    Full Text Available The presence of the Philadelphia chromosome in patients with acute lymphoblastic leukemia (Ph(+ALL is a negative prognostic indicator. Tyrosine kinase inhibitors (TKI that target BCR/ABL, such as imatinib, have improved treatment of Ph(+ALL and are generally incorporated into induction regimens. This approach has improved clinical responses, but molecular remissions are seen in less than 50% of patients leaving few treatment options in the event of relapse. Thus, identification of additional targets for therapeutic intervention has potential to improve outcomes for Ph+ALL. The human epidermal growth factor receptor 2 (ErbB2 is expressed in ~30% of B-ALLs, and numerous small molecule inhibitors are available to prevent its activation. We analyzed a cohort of 129 ALL patient samples using reverse phase protein array (RPPA with ErbB2 and phospho-ErbB2 antibodies and found that activity of ErbB2 was elevated in 56% of Ph(+ALL as compared to just 4.8% of Ph(-ALL. In two human Ph+ALL cell lines, inhibition of ErbB kinase activity with canertinib resulted in a dose-dependent decrease in the phosphorylation of an ErbB kinase signaling target p70S6-kinase T389 (by 60% in Z119 and 39% in Z181 cells at 3 µM. Downstream, phosphorylation of S6-kinase was also diminished in both cell lines in a dose-dependent manner (by 91% in both cell lines at 3 µM. Canertinib treatment increased expression of the pro-apoptotic protein Bim by as much as 144% in Z119 cells and 49% in Z181 cells, and further produced caspase-3 activation and consequent apoptotic cell death. Both canertinib and the FDA-approved ErbB1/2-directed TKI lapatinib abrogated proliferation and increased sensitivity to BCR/ABL-directed TKIs at clinically relevant doses. Our results suggest that ErbB signaling is an additional molecular target in Ph(+ALL and encourage the development of clinical strategies combining ErbB and BCR/ABL kinase inhibitors for this subset of ALL patients.

  4. Transactivation of ErbB receptors by leptin in the cardiovascular system: mechanisms, consequences and target for therapy.

    Science.gov (United States)

    Bełtowski, Jerzy; Jazmroz-Wiśniewska, Anna

    2014-01-01

    Many experimental and clinical studies have demonstrated that elevated leptin concentration in patients with obesity/metabolic syndrome contributes to the pathogenesis of cardiovascular disorders including arterial hypertension, atherosclerosis, restenosis after coronary angioplasty and myocardial hypertrophy. Receptor tyrosine kinases belonging to the ErbB family, especially ErbB1 (epidermal growth factor receptor) and ErbB2 are abundantly expressed in the blood vessels and the heart. EGFR is activated not only by its multiple peptide ligands but also by many other factors including angiotensin II, endothelin-1, norepinephrine, thrombin and prorenin; the phenomenon referred to as "transactivation". Augmented EGFR signaling contributes to abnormalities of vascular tone and renal sodium handling as well as vascular remodeling and myocardial hypertrophy through various intracellular mechanisms, in particular extracellular signal-regulated kinases (ERK) and phosphoinositide 3-kinase (PI3K). Recent experimental studies indicate that chronically elevated leptin transactivates the EGFR through the mechanisms requiring reactive oxygen species and cytosolic tyrosine kinase, c-Src. In addition, hyperleptinemia increases ErbB2 activity in the arterial wall. Stimulation of EGFR and ErbB2 downstream signaling pathways such as ERK and PI3K in the vascular wall and the kidney may contribute to the increase in vascular tone, enhanced tubular sodium reabsorption as well as vascular and renal lesions in hyperleptinemic obese subjects.

  5. Characterization of the hormone-binding domain of the chicken c-erbA/thyroid hormone receptor protein

    DEFF Research Database (Denmark)

    Muñoz, A; Zenke, M; Gehring, U

    1988-01-01

    To identify and characterize the hormone-binding domain of the thyroid hormone receptor, we analyzed the ligand-binding capacities of proteins representing chimeras between the normal receptor and P75gag-v-erbA, the retrovirus-encoded form deficient in binding ligand. Our results show that several...... mutations present in the carboxy-terminal half of P75gag-v-erbA co-operate in abolishing hormone binding, and that the ligand-binding domain resides in a position analogous to that of steroid receptors. Furthermore, a point mutation that is located between the putative DNA and ligand-binding domains of P75......gag-v-erbA and that renders it biologically inactive fails to affect hormone binding by the c-erbA protein. These results suggest that the mutation changed the ability of P75gag-v-erbA to affect transcription since it also had no effect on DNA binding. Our data also suggest that hormone...

  6. Transcriptome analysis of basal and luminal tumor-initiating cells in ErbB2-driven breast cancer

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    Nicholas Borcherding

    2015-06-01

    Full Text Available Breast cancer is the leading cause of cancer-related mortality for females worldwide [1]. Improving early screening strategies and understanding the events that lead to tumor initiation have led to demonstrable improvements in clinical outcome. Our previous work revealed a variance in the tumorigenic capacity between different mammary epithelial cell populations in an MMTV-ErbB2 mouse model. In order to greater understand how different mammary epithelial cells influence the tumorigenic capacity in ErbB2-induced breast cancer, we transplanted different cell populations from pre-neoplastic MMTV-ErbB2 female mice into recipient mice for tumorigenic study. We found that different mammary epithelial cells bear different tumorigenic potentials even when induced by the same ErbB2 proto-oncogene. To understand the difference in tumors formed from different epithelial cells, we performed gene expression profiling using these tumors (GSE64487. Several genes were further validated using real-time reverse transcription polymerase chain reaction (RT-PCR. Here we provide further details on the experimental methods and microarray analysis. This data provides a resource to further understanding how different mammary cell populations can initiate ErbB2-driven tumors and the role of these cell populations as putative tumor-initiating cells (TICs.

  7. Neuregulin 1-ErbB4 signaling in the bed nucleus of the stria terminalis regulates anxiety-like behavior.

    Science.gov (United States)

    Geng, Fei; Zhang, Jie; Wu, Jian-Lin; Zou, Wen-Jun; Liang, Zhi-Ping; Bi, Lin-Lin; Liu, Ji-Hong; Kong, Ying; Huang, Chu-Qiang; Li, Xiao-Wen; Yang, Jian-Ming; Gao, Tian-Ming

    2016-08-04

    The bed nucleus of the stria terminalis (BNST), a nucleus defined as part of the extended amygdala, is involved in the expression of anxiety disorders. However, the regulatory mechanisms of BNST inhibitory activity that is involved in anxiety are unknown. Here, we showed that blocking neuregulin 1 (NRG1)-ErbB4 signaling in the BNST of mice, by either neutralizing endogenous NRG1 with ecto-Erbb4 or antagonizing the ErbB4 receptor with its specific inhibitor, produced anxiogenic responses. Interestingly, application of exogenous NRG1 into the BNST induced no anxiolytic effects, suggesting saturating activity of endogenous NRG1. While infusion of the GABAA receptor antagonist bicuculline into the BNST also led to anxiety-related behaviors, it did not worsen the anxiogenic effects produced by blocking NRG1-ErbB4 signaling, suggesting possible involvement of GABAergic neurotransmission. Further, in vitro electrophysiological recordings showed that BNST NRG1-ErbB4 signaling regulated the presynaptic GABA release. Together, these results suggest that NRG1-ErbB4 signaling in the BNST may play an important role in regulating anxiety-like behaviors. Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.

  8. Mechanisms of Trastuzumab resistance in ErbB2-driven breast cancer and newer opportunities to overcome therapy resistance

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    Tameka A Bailey

    2011-01-01

    Full Text Available The Human Epidermal Growth Factor Receptor 2 (Her2, ErbB2 or Neu is overexpressed in about 20 - 25% of breast cancers and is causally linked to oncogenesis, providing opportunities for targeted therapy. Trastuzumab (Herceptin™, Genentech Inc, San Francisco, CA, a humanized monoclonal antibody against ErbB2, is a successful example of this concept and has vastly improved the response to treatment and overall survival in a majority of ErbB2+ breast cancer patients. However, lack of response in some patients as well as relapse during the course of therapy in others, continue to challenge researchers and clinicians alike towards a better understanding of the fundamental mechanisms of Trastuzumab action and resistance to treatment. The exact in vivo mechanism of action of Trastuzumab remains enigmatic, given its direct effects on the ErbB2 signaling pathway as well as indirect contributions from the immune system, by virtue of the ability of Trastuzumab to elicit Antibody-Dependent Cellular Cytotoxicity. Consequently, multiple mechanisms of resistance have been proposed. We present here a comprehensive review of our current understanding of the mechanisms, both of Trastuzumab action and clinical resistance to Trastuzumab-based therapies. We also review newer strategies (based on ErbB2 receptor biology that are being explored to overcome resistance to Trastuzumab therapy.

  9. Intracavitary 'T4 immunotherapy' of malignant mesothelioma using pan-ErbB re-targeted CAR T-cells.

    Science.gov (United States)

    Klampatsa, Astero; Achkova, Daniela Y; Davies, David M; Parente-Pereira, Ana C; Woodman, Natalie; Rosekilly, James; Osborne, Georgina; Thayaparan, Thivyan; Bille, Andrea; Sheaf, Michael; Spicer, James F; King, Juliet; Maher, John

    2017-05-01

    Malignant mesothelioma remains an incurable cancer. We demonstrated that mesotheliomas expressed EGFR (79.2%), ErbB4 (49.0%) and HER2 (6.3%), but lacked ErbB3. At least one ErbB family member was expressed in 88% of tumors. To exploit ErbB dysregulation in this disease, patient T-cells were engineered by retroviral transduction to express a panErbB-targeted chimeric antigen receptor (CAR), co-expressed with a chimeric cytokine receptor that allows interleukin (IL)-4 mediated CAR T-cell proliferation. This combination is referred to as T4 immunotherapy. T-cells from mesothelioma patients were uniformly amenable to T4 genetic modification and expansion/enrichment thereafter using IL-4. Patient-derived T4 + T-cells were activated upon contact with a panel of four mesothelioma cell lines, leading to cytotoxicity and cytokine release in all cases. Adoptive transfer of T4 immunotherapy to SCID Beige mice with an established bioluminescent LO68 mesothelioma xenograft was followed by regression or eradication of disease in all animals. Despite the established ability of T4 immunotherapy to elicit cytokine release syndrome in SCID Beige mice, therapy was very well tolerated. These findings provide a strong rationale for the clinical evaluation of intracavitary T4 immunotherapy to treat mesothelioma. Copyright © 2017 Elsevier B.V. All rights reserved.

  10. Hyaluronan-induced masking of ErbB2 and CD44-enhanced trastuzumab internalisation in trastuzumab resistant breast cancer.

    Science.gov (United States)

    Pályi-Krekk, Zsuzsanna; Barok, Márk; Isola, Jorma; Tammi, Markku; Szöllosi, János; Nagy, Peter

    2007-11-01

    Although trastuzumab, a recombinant humanised anti-ErbB2 antibody, is widely used in the treatment of breast cancer, neither its mechanism of action, nor the factors leading to resistance are fully understood. We have previously shown that antibody-dependent cellular cytotoxicity is pivotal in the in vivo effect of trastuzumab against JIMT-1, a cell line showing in vitro resistance to the antibody, and suggested that masking of the trastuzumab-binding epitope by MUC-4, a cell surface mucin, took place. Here, we further explored the role of masking of ErbB2 in connection with CD44 expression and synthesis of its ligand, hyaluronan. We show that high expression of CD44 observed in JIMT-1 cells correlates with ErbB2 downregulation in vivo, while siRNA-mediated inhibition of CD44 expression leads to decreased rate of trastuzumab internalisation and low cell proliferation in vitro. An inhibitor of hyaluronan synthesis, 4-methylumbelliferon (4-MU) significantly reduced the hyaluronan level of JIMT-1 cells both in vivo and in vitro leading to enhanced binding of trastuzumab to ErbB2 and increased ErbB2 down-regulation. Furthermore, the inhibitory effect of trastuzumab on the growth of JIMT-1 xenografts was significantly increased by 4-MU treatment. Our results point to the importance of the CD44-hyaluronan pathway in the escape of tumour cells from receptor-oriented therapy.

  11. ErbB2-Driven Breast Cancer Cell Invasion Depends on a Complex Signaling Network Activating Myeloid Zinc Finger-1-Dependent Cathepsin B Expression

    DEFF Research Database (Denmark)

    Rafn, Bo; Nielsen, Christian Thomas Friberg; Andersen, Sofie Hagel

    2012-01-01

    signaling network activates the transcription of cathepsin B gene (CTSB) via myeloid zinc finger-1 transcription factor that binds to an ErbB2-responsive enhancer element in the first intron of CTSB. This work provides a model system for ErbB2-induced breast cancer cell invasiveness, reveals a signaling...

  12. A single amino acid substitution is sufficient to modify the mitogenic properties of the epidermal growth factor receptor to resemble that of gp185erbB-2

    DEFF Research Database (Denmark)

    Di Fiore, P P; Helin, K; Kraus, M H

    1992-01-01

    The epidermal growth factor (EGF) receptor (EGFR) and the erbB-2 gene product, gp185erbB-2, exhibit distinct abilities to stimulate mitogenesis in different target cells. By using chimeric molecules between these two receptors, we have previously shown that their intracellular juxtamembrane regio...

  13. Leukemic transformation by the v-ErbA oncoprotein entails constitutive binding to and repression of an erythroid enhancer in vivo

    NARCIS (Netherlands)

    Ciana, P.; Braliou, G. G.; Demay, F. G.; von Lindern, M.; Barettino, D.; Beug, H.; Stunnenberg, H. G.

    1998-01-01

    v-ErbA, a mutated thyroid hormone receptor alpha (TRalpha), is thought to contribute to avian erythroblastosis virus (AEV)-induced leukemic transformation by constitutively repressing transcription of target genes. However, the binding of v-ErbA or any unliganded nuclear receptor to a

  14. Inhibition of ErbB2 by receptor tyrosine kinase inhibitors causes myofibrillar structural damage without cell death in adult rat cardiomyocytes

    International Nuclear Information System (INIS)

    Pentassuglia, Laura; Graf, Michael; Lane, Heidi; Kuramochi, Yukio; Cote, Gregory; Timolati, Francesco; Sawyer, Douglas B.; Zuppinger, Christian; Suter, Thomas M.

    2009-01-01

    Inhibition of ErbB2 (HER2) with monoclonal antibodies, an effective therapy in some forms of breast cancer, is associated with cardiotoxicity, the pathophysiology of which is poorly understood. Recent data suggest, that dual inhibition of ErbB1 (EGFR) and ErbB2 signaling is more efficient in cancer therapy, however, cardiac safety of this therapeutic approach is unknown. We therefore tested an ErbB1-(CGP059326) and an ErbB1/ErbB2-(PKI166) tyrosine kinase inhibitor in an in-vitro system of adult rat ventricular cardiomyocytes and assessed their effects on 1. cell viability, 2. myofibrillar structure, 3. contractile function, and 4. MAPK- and Akt-signaling alone or in combination with Doxorubicin. Neither CGP nor PKI induced cardiomyocyte necrosis or apoptosis. PKI but not CGP caused myofibrillar structural damage that was additive to that induced by Doxorubicin at clinically relevant doses. These changes were associated with an inhibition of excitation-contraction coupling. PKI but not CGP decreased p-Erk1/2, suggesting a role for this MAP-kinase signaling pathway in the maintenance of myofibrils. These data indicate that the ErbB2 signaling pathway is critical for the maintenance of myofibrillar structure and function. Clinical studies using ErbB2-targeted inhibitors for the treatment of cancer should be designed to include careful monitoring for cardiac dysfunction.

  15. Chronic morphine treatment attenuates cell growth of human BT474 breast cancer cells by rearrangement of the ErbB signalling network.

    Directory of Open Access Journals (Sweden)

    Inka Regine Weingaertner

    Full Text Available There is increasing evidence that opioid analgesics may interfere with tumour growth. It is currently thought that these effects are mediated by transactivation of receptor tyrosine kinase (RTK-controlled ERK1/2 and Akt signalling. The growth of many breast cancer cells is dependent on hyperactive ErbB receptor networks and one of the most successful approaches in antineoplastic therapy during the last decade was the development of ErbB-targeted therapies. However, the response rates of single therapies are often poor and resistance mechanisms evolve rapidly. To date there is no information about the ability of opioid analgesics to interfere with the growth of ErbB-driven cancers.Here we demonstrate that ErbB2 overexpressing BT474 human breast cancer cells carry fully functional endogenous µ-opioid receptors. Most interestingly, the acute opioid effects on basal and Heregulin-stimulated ERK1/2 and Akt phosphorylation changed considerably during chronic Morphine treatment. Investigation of the underlying mechanism by the use of protein kinase inhibitors and co-immunoprecipitation studies revealed that chronic Morphine treatment results in rearrangement of the ErbB signalling network leading to dissociation of ERK1/2 from Akt signalling and a switch from ErbB1/ErbB3 to ErbB1/ErbB2-dependent cell growth. In chronically Morphine-treated cells Heregulin-stimulated ERK1/2 signalling is redirected via a newly established PI3K- and metalloproteinase-dependent feedback loop. Together, these alterations result in apoptosis of BT474 cells. A similar switch in Heregulin-stimulated ERK1/2 signalling from an ErbB2-independent to an ErbB2-, PI3K- and metalloproteinase-dependent mechanism was also observed in κ-opioid receptor expressing SKBR3 human mammary adenocarcinoma cells.The present data demonstrate that the ErbB receptor network of human breast cancer cells represents a target for chronic Morphine treatment. Rearrangement of ErbB signalling by chronic

  16. A peptide antagonist of the ErbB1 receptor inhibits receptor activation, tumor cell growth and migration in vitro and xenograft tumor growth in vivo

    DEFF Research Database (Denmark)

    Xu, Ruodan; Povlsen, Gro Klitgaard; Soroka, Vladislav

    2010-01-01

    The epidermal growth factor family of receptor tyrosine kinases (ErbBs) plays essential roles in tumorigenesis and cancer disease progression, and therefore has become an attractive target for structure-based drug design. ErbB receptors are activated by ligand-induced homo- and heterodimerization......B1 phosphorylation, cell growth, and migration in two human tumor cell lines, A549 and HN5, expressing moderate and high ErbB1 levels, respectively. Furthermore, we show that Inherbin3 inhibits tumor growth in vivo and induces apoptosis in a tumor xenograft model employing the human non-small cell...... lung cancer cell line A549. The Inherbin3 peptide may be a useful tool for investigating the mechanisms of ErbB receptor homo- and heterodimerization. Moreover, the here described biological effects of Inherbin3 suggest that peptide-based targeting of ErbB receptor dimerization is a promising anti...

  17. Evaluation of the Earth Radiation Budget Experiment (ERBE) shortwave channel's stability using in-flight calibration sources

    Science.gov (United States)

    Gibson, Michael A.; Lee, Robert B., III; Thomas, Susan

    1992-01-01

    The Earth Radiation Budget Experiment (ERBE) radiometers were designed to make absolute measurements of the incoming solar, earth-reflected solar, and earth-emitted fluxes for investigations of the earth's climate system. Thermistor bolometers were the sensors used for the ERBE scanning radiometric package. Each thermistor bolometer package consisted of three narrow field of view broadband radiometric channels measuring shortwave, longwave, and total (0.2 micron to 50 microns) radiation. The in-flight calibration facilities include Mirror Attenuator Mosaics, shortwave internal calibration source, and internal blackbody sources to monitor the long-term responsivity of the radiometers. This paper describes the in-flight calibration facilities, the calibration data reduction techniques, and the results from the in-flight shortwave channel calibrations. The results indicate that the ERBE shortwave detectors were stable to within +/- 1 percent for up to five years of flight operation.

  18. [Role of nerve stimulation at Erb point in early diagnosis of Guillain-Barré syndrome in children].

    Science.gov (United States)

    Sun, Rui-Di; Fu, Bin; Li, Cheng; Kuang, Guang-Tao; Luo, Xiao-Qing; Jiang, Jun

    2015-07-01

    To study the role of proximal nerve stimulation at Erb point in the early diagnosis of Guillain-Barré syndrome (GBS) in children. Thirty-two children who were diagnosed with GBS between October 2013 and December 2014 received neurophysiological examination. Thirty healthy children were used as controls. Compound muscle action potentials and distal motor latency of the median and ulnar nerves were determined and analyzed after nerve stimulation at the wrist, elbow, and Erb point in the two groups. Moreover, F-wave latency of the median nerve and H-reflex latency of the tibial nerve were measured and analyzed in the two groups. The F-wave and H-reflex latencies were significantly longer in the patient group than in the control group (P0.05). The nerve stimulation at Erb point holds promise as a routine examination for the early diagnosis of GBS.

  19. A pathological study on overexpression of c-erbB-2, EGFR proteins in human radiation skin ulcer

    International Nuclear Information System (INIS)

    Zhao Po; Yang Zhixiang; Wang Dewen; Li Guomin; Gao Yabin

    1996-01-01

    We performed an immunohistochemical study in 25 cases of human radiation skin ulcer by using c-erbB-2, Epidermal growth factor receptor (EGFR), protein antibodies and repairing method of antigen with microwave oven. The results show that the positive rate for overexpression of c-erbB-2 oncoprotein was 92.0% (23/25), and EGFR was 73.7%(14/19). The positive position for overexpression of c-crbB-2 was mainly observed on cell membrane of squamous epithelial cells and cell plasma of fibroblasts, endotheliocytes, and leiomyocytes in media and fibrocytes in adventitia of the arterioles in mesenchyme. It is suggested that the overexpression of c-erbB-2 and EGFR proteins might be related to cancer transformation and poor healing in radiation skin ulcers

  20. Marked enhancement of lysosomal targeting and efficacy of ErbB2-targeted drug delivery by HSP90 inhibition.

    Science.gov (United States)

    Raja, Srikumar M; Desale, Swapnil S; Mohapatra, Bhopal; Luan, Haitao; Soni, Kruti; Zhang, Jinjin; Storck, Matthew A; Feng, Dan; Bielecki, Timothy A; Band, Vimla; Cohen, Samuel M; Bronich, Tatiana K; Band, Hamid

    2016-03-01

    Targeted delivery of anticancer drugs to tumor cells using monoclonal antibodies against oncogenic cell surface receptors is an emerging therapeutic strategy. These strategies include drugs directly conjugated to monoclonal antibodies through chemical linkers (Antibody-Drug Conjugates, ADCs) or those encapsulated within nanoparticles that in turn are conjugated to targeting antibodies (Antibody-Nanoparticle Conjugates, ANPs). The recent FDA approval of the ADC Trastuzumab-TDM1 (Kadcyla; Genentech; San Francisco) for the treatment of ErbB2-overexpressing metastatic breast cancer patients has validated the strong potential of these strategies. Even though the activity of ANPs and ADCs is dependent on lysosomal traffic, the roles of the endocytic route traversed by the targeted receptor and of cancer cell-specific alterations in receptor dynamics on the efficiency of drug delivery have not been considered in these new targeted therapies. For example, constitutive association with the molecular chaperone HSP90 is thought to either retard ErbB2 endocytosis or to promote its recycling, traits undesirable for targeted therapy with ANPs and ADCs. HSP90 inhibitors are known to promote ErbB2 ubiquitination, targeting to lysosome and degradation. We therefore hypothesized that ErbB2-targeted drug delivery using Trastuzumab-conjugated nanoparticles could be significantly improved by HSP90 inhibitor-promoted lysosomal traffic of ErbB2. Studies reported here validate this hypothesis and demonstrate, both in vitro and in vivo, that HSP90 inhibition facilitates the intracellular delivery of Trastuzumab-conjugated ANPs carrying a model chemotherapeutic agent, Doxorubicin, specifically into ErbB2-overexpressing breast cancer cells, resulting in improved antitumor activity. These novel findings highlight the need to consider oncogene-specific alterations in receptor traffic in the design of targeted drug delivery strategies. We suggest that combination of agents that enhance receptor

  1. p53 and erbB-2 Are Not Associated in Matched Cases of Primary and Metastatic Ovarian Carcinomas

    Directory of Open Access Journals (Sweden)

    Cristina Rodríguez-Burford

    2003-01-01

    Full Text Available Ovarian cancer has a high mortality rate largely due to the limited number of ovarian carcinomas detected at an early stage. Understanding the molecular changes occurring during the progression of ovarian carcinoma would aid in the development of therapies that may inhibit or target metastasis. Primary and metastatic lesions from 54 and 40 patients with advanced ovarian carcinoma, respectively (including matched primary and metastatic lesions from 30 patients were evaluated for nuclear accumulation of p53 (clone BP53-12-1 and cytoplasmic and membranous immunostaining of p185 erbB-2 (clone 3B5 by immunohistochemistry. No differences in the immunostaining of p53 and p185erbB-2 (cytoplasm or membrane were observed between primary and metastatic lesions of the matched cases. Similarly, no differences in the proportion of positive cases of p53 between primary and metastatic lesions of the matched cases was observed. Thus, novel therapies that target p53 or p185erbB-2 can utilize specimens from either primary or metastatic lesions to characterize these targets prior to therapy. Spearman correlations between p53 and p185erbB-2 (cytoplasm or membrane immunohistochemistry scores were insignificant for the matched cases, all primary lesions, and all metastatic lesions. Also, no significant associations occurred between nuclear accumulation of p53 (positive versus negative and phenotypic expression of p185erbB-2 (cytoplasm or membrane immunostaining scores for the matched cases, all primary lesions, and all metastatic lesions. Thus, the nuclear accumulation of p53 and immunostaining of p185erbB-2 in the cytoplasm or on the cellular membranes are independent.

  2. Overexpression of c-erbB-2 and loss of p16 have molecular diagnostic relevance but no prognostic value in lung cancer.

    Science.gov (United States)

    Feng, Xiao-li; Li, Ling; Gao, Yan-ning; Zhang, Jian-jun; Xiao, Ting; Ying, Jian-ming; Gao, Ji-dong; Sun, Yun-tian; Cheng, Shu-jun

    2011-03-01

    This study was designed to evaluate the expression of C-erbB-2 and p16 in lung cancers using tissue microarray technology and to determine their clinical and pathological significance. Immunohistochemical C-erbB-2 and p16 expressions and their associations with clinical and pathological features were analyzed in two tissue microarrays. The membranous and cytoplasmic expression rates of C-erbB-2 were 40.5 and 66.5% in non-small cell lung cancers (NSCLCs), and 0 and 9.5% in small cell lung cancers (SCLCs), respectively. The nuclear and cytoplasmic expression rates of p16 were 11.5 and 32.2% in NSCLs, and 45 and 80% in SCLCs, respectively. The cytoplasmic expression of both C-erbB-2 and p16 was more frequent than the membranous expression of C-erbB-2 and the nuclear expression of p16. The rates of overexpression of C-erbB-2 and loss of p16 expression were significantly higher in NSCLCs than in SCLCs (P < 0.05). Neither C-erbB-2 nor p16 expression was significantly associated with age, tumor grade or stage, presence of lymph node metastasis or survival duration. The abnormal expressions of p16 and C-erbB-2 may play a role in the progression of lung cancers. The variations in the expression patterns of C-erbB-2 and p16 between NSCLCs and SCLCs may aid the molecular classification of lung cancer. The abnormal expression of p16 may be involved in the development of NSCLCs, and the overexpression of C-erbB-2 in NSCLCs indicates that it can be a candidate target for gene therapy.

  3. Prognostic impact of p53, c-erbB-2 and epidermal growth factor receptor on head and neck carcinoma

    Directory of Open Access Journals (Sweden)

    Orlando Parise Junior

    Full Text Available CONTEXT: p53, c-erbB-2 and epidermal growth factor receptor (EGFR are cancer-related proteins that are usually expressed in head and neck squamous cell carcinoma (SCC. Their prognostic value remains controversial. OBJECTIVE: To evaluate the prognostic impact of p53, c-erbB-2 and EGFR expression in head and neck SCC. TYPE OF STUDY: Prospective. SETTING: Head and Neck Surgery Department, Hospital AC Camargo, São Paulo. METHODS: Fifty-four patients were studied for p53, c-erbB-2 and EGFR expression in head and neck SCC and adjacent mucosa, via immunohistochemistry. These data were correlated with histoclinical data and survival. RESULTS: There was a direct association of p53 expression in SCC and mucosa (p = 0.001; loss of c-erbB-2 expression (- from normal mucosa to SCC (p = 0.04; lower frequency of association of c-erbB-2 (+ with EGFR (- in SCC (p = 0.02; and a direct association of EGFR (+ expression in SCC and mitotic index (p = 0.03. The 60-month actuarial survival rates for patients presenting lymph node metastasis were higher when there was no capsule rupture by SCC (48.3%; p = 0.02, no more than one positive lymph node (52.3%; p = 0.004 or clear surgical margins (47.0%; p = 0.01, in comparison with patients presenting capsule rupture (20.2%, two or more positive lymph nodes (18.7% or compromised surgical margins (0.0%, respectively. Patients presenting SCC p53 (+ and EGFR (- demonstrated greater survival (75.0%; p = 0.03 than for the remaining group (33.1%. Multivariate analysis confirmed the positive impact of p53 (+ and EGFR (- on survival (p = 0.02. DISCUSSION: Associations were found for p53, c-erbB-2 and EGFR expression with histoclinical data and prognosis. Interestingly, these results suggest that loss of mucosal c-erbB-2 expression could be involved in SCC carcinogenesis; EGFR expression in SCC is related to tumor mitotic index; and presence of p53 with absence of EGFR expression in head and neck SCC may be a prognostic factor for

  4. Le CRDI au Vietnam

    International Development Research Centre (IDRC) Digital Library (Canada)

    des agriculteurs trouvent des solutions de rechange à la culture du tabac. □ des responsables de politiques agissent pour réduire la pauvreté. Soutien accordé par le CRDI depuis 1991. 111 activités d'une valeur de 30 millions cad. CRDI. Le CRDI au Vietnam centre de recherches pour le développement international ...

  5. ErbB-2 signaling plays a critical role in regulating androgen-sensitive and castration-resistant androgen receptor-positive prostate cancer cells.

    Science.gov (United States)

    Muniyan, Sakthivel; Chen, Siu-Ju; Lin, Fen-Fen; Wang, Zhengzhong; Mehta, Parmender P; Batra, Surinder K; Lin, Ming-Fong

    2015-11-01

    While androgen deprivation therapy (ADT) reduces tumor burden, autocrine growth factor loops such as human epidermal growth factor receptor 2 (HER2/ErbB-2/neu) have been proposed to contribute to prostate cancer (PCa) survival and relapse. However, the role of ErbB-2 in regulating androgen-sensitive (AS) and castration-resistant (CR) cell proliferation remains unclear. Here, we determined the role of ErbB-2 in PCa progression and survival under steroid-reduced conditions using two independent PCa cell progression models. In AR-positive androgen-independent (AI) PCa cells that exhibit the CR phenotype, ErbB-2 was constitutively activated, compared to corresponding AS PCa cells. In AS LNCaP C-33 cells, androgen-induced ErbB-2 activation through ERK1/2 mediates PCa cell proliferation. Further, the ErbB-2-specific but not EGFR-specific inhibitor suppresses basal and androgen-stimulated cell proliferation and also blocks ERK1/2 activation. ErbB-2 ectopic expression and cPAcP siRNA transfection of LNCaP C-33 cells each increases ErbB-2 tyrosine phosphorylation, correlating with increased AI PSA secretion and cell proliferation. Conversely, trapping ErbB-2 by transfected endoplasmic reticulum-targeting ScFv5R expression vector abolished DHT-induced LNCaP C-33 cell growth. Moreover, inhibition of ErbB-2 but not EGFR in AI LNCaP C-81 and MDA PCa2b-AI PCa cells significantly abolished AI cell growth. In contrast to androgens via ErbB-2/ERK1/2 signaling in AS PCa cells, the inhibition of ErbB-2 abrogated AI cell proliferation by inhibiting the cell survival protein Akt in those AI cells. These results suggest that ErbB-2 is a prominent player in mediating the ligand-dependent and -independent activation of AR in AS and AI/CR PCa cells respectively for PCa progression and survival. Copyright © 2015 Elsevier Inc. All rights reserved.

  6. The nonsteroidal anti-inflammatory drug tolfenamic acid inhibits BT474 and SKBR3 breast cancer cell and tumor growth by repressing erbB2 expression.

    Science.gov (United States)

    Liu, Xinyi; Abdelrahim, Maen; Abudayyeh, Ala; Lei, Ping; Safe, Stephen

    2009-05-01

    Tolfenamic acid (TA) is a nonsteroidal anti-inflammatory drug that inhibits pancreatic cancer cell and tumor growth through decreasing expression of specificity protein (Sp) transcription factors. TA also inhibits growth of erbB2-overexpressing BT474 and SKBR3 breast cancer cells; however, in contrast to pancreatic cancer cells, TA induced down-regulation of erbB2 but not Sp proteins. TA-induced erbB2 down-regulation was accompanied by decreased erbB2-dependent kinase activities, induction of p27, and decreased expression of cyclin D1. TA also decreased erbB2 mRNA expression and promoter activity, and this was due to decreased mRNA stability in BT474 cells and, in both cell lines, TA decreased expression of the YY1 and AP-2 transcription factors required for basal erbB2 expression. In addition, TA also inhibited tumor growth in athymic nude mice in which BT474 cells were injected into the mammary fat pad. TA represents a novel and promising new anticancer drug that targets erbB2 by decreasing transcription of this oncogene.

  7. Clinical Significance of ErbB Receptor Family in Urothelial Carcinoma of the Bladder: A Systematic Review and Meta-Analysis

    Directory of Open Access Journals (Sweden)

    Yuh-Shyan Tsai

    2012-01-01

    Full Text Available The prognostic importance of examining ErbB receptor family expression in human bladder cancer remains uncertain. Using published evidence, we examined the clinical value and the updated results of clinical trials targeting ErbB receptor family members. Twenty-seven articles from 65 references related to ErbB receptor expression assessment in bladder cancer were reviewed. The estimates included the association significance, hazard ratios, and 95% confidence intervals (CIs from actuarial curves and survival analyses. A meta-analysis was done on those reports using univariate log-rank tests or a Cox-regression model. The methods of analysis and study subjects chosen varied widely among studies. The overall risks of disease progression for patients with EGFR or ErbB2 overexpression were 4.5 (95% CI: 2.5–8.4 and 1.1 (95% CI: 0.6–1.9, and the risks of mortality were 3.0 (95% CI: 1.6–5.9 and 1.1 (95% CI: 1.0–1.2, respectively. However, the significance of coexpression patterns of the ErbB receptor family remains controversial. None of six clinical trials yielded convincing results for blockading ErbB receptor signaling in urothelial carcinoma. The results of this analysis suggest that assessing co-expression patterns of the ErbB family may provide better prognostic information for bladder cancer patients.

  8. Schwann cell-specific deletion of the endosomal PI 3-kinase Vps34 leads to delayed radial sorting of axons, arrested myelination, and abnormal ErbB2-ErbB3 tyrosine kinase signaling.

    Science.gov (United States)

    Logan, Anne M; Mammel, Anna E; Robinson, Danielle C; Chin, Andrea L; Condon, Alec F; Robinson, Fred L

    2017-09-01

    The PI 3-kinase Vps34 (Pik3c3) synthesizes phosphatidylinositol 3-phosphate (PI3P), a lipid critical for both endosomal membrane traffic and macroautophagy. Human genetics have implicated PI3P dysregulation, and endosomal trafficking in general, as a recurring cause of demyelinating Charcot-Marie-Tooth (CMT) peripheral neuropathy. Here, we investigated the role of Vps34, and PI3P, in mouse Schwann cells by selectively deleting Vps34 in this cell type. Vps34-Schwann cell knockout (Vps34 SCKO ) mice show severe hypomyelination in peripheral nerves. Vps34 -/- Schwann cells interact abnormally with axons, and there is a delay in radial sorting, a process by which large axons are selected for myelination. Upon reaching the promyelinating stage, Vps34 -/- Schwann cells are significantly impaired in the elaboration of myelin. Nerves from Vps34 SCKO mice contain elevated levels of the LC3 and p62 proteins, indicating impaired autophagy. However, in the light of recent demonstrations that autophagy is dispensable for myelination, it is unlikely that hypomyelination in Vps34 SCKO mice is caused by impaired autophagy. Endosomal trafficking is also disturbed in Vps34 -/- Schwann cells. We investigated the activation of the ErbB2/3 receptor tyrosine kinases in Vps34 SCKO nerves, as these proteins, which play essential roles in Schwann cell myelination, are known to traffic through endosomes. In Vps34 SCKO nerves, ErbB3 was hyperphosphorylated on a tyrosine known to be phosphorylated in response to neuregulin 1 exposure. ErbB2 protein levels were also decreased during myelination. Our findings suggest that the loss of Vps34 alters the trafficking of ErbB2/3 through endosomes. Abnormal ErbB2/3 signaling to downstream targets may contribute to the hypomyelination observed in Vps34 SCKO mice. © 2017 Wiley Periodicals, Inc.

  9. Electrocardiographic Characterization of Cardiac Hypertrophy in Mice that Overexpress the ErbB2 Receptor Tyrosine Kinase

    DEFF Research Database (Denmark)

    Sysa-Shah, Polina; Sørensen, Lars L; Abraham, M Roselle

    2015-01-01

    Electrocardiography is an important method for evaluation and risk stratification of patients with cardiac hypertrophy. We hypothesized that the recently developed transgenic mouse model of cardiac hypertrophy (ErbB2(tg)) will display distinct ECG features, enabling WT (wild type) mice...... in other rodent models of cardiac hypertrophy. Furthermore, with appropriate modifications, this method might be translated for use in other species....

  10. [Modulation of biomarkers expression (OR, PR and C-erbB2) in breast cancer following neoadjuvant treatment].

    Science.gov (United States)

    Córdoba, A; Ederra, M; Ariceta, I; Gómez, M L; Arrechea, M A; De Llano, P; Martínez-Peñuela, J M

    2006-01-01

    Pre and post-operative oncological therapy in patients with breast cancer is determined, amongst other factors, by hormone receptor status and by c-erbB2 expression. The aim of this study is to determine the influence of neoadjuvant therapy on the expression of oestrogen receptor (OR), progesterone receptor (PR) and c-erbB2. Fifty-three patients with breast cancer diagnosed by tru-cut biopsy were studied. Patients with locally advanced carcinoma (20) had preoperative treatment. All patients underwent surgical resection. Expression of OR, PR and c-erbB2 in both the tru-cut biopsy and the gross specimen was compared. We found significant differences in OR, PR expression in both biopsy and gross specimen, between the group of patients who underwent neoadjuvant treatment and the group without pre-surgical treatment. Changes in PR, OR and c-erbB2 status were found between the tru-cut biopsy and the gross specimen, in about 10 to 40% of the cases who received neoadjuvant therapy. These changes had no statistical significance.

  11. A peptide conjugate of vitamin E succinate targets breast cancer cells with high erbB2 expression

    Czech Academy of Sciences Publication Activity Database

    Wang, X. F.; Birringer, M.; Dong, L.F.; Vepřek, Pavel; Low, P.; Swettenham, E.; Stantic, M.; Yuan, L. H.; Zobalová, Renata; Wu, K.; Ledvina, Miroslav; Ralph, S.J.; Neužil, Jiří

    2007-01-01

    Roč. 67, č. 7 (2007), s. 3337-3344 ISSN 0008-5472 R&D Projects: GA MZe QF3115 Institutional research plan: CEZ:AV0Z40550506; CEZ:AV0Z50520514 Keywords : vitamin e E * erbB2 * breast cancer Subject RIV: CC - Organic Chemistry Impact factor: 7.672, year: 2007

  12. The heme-regulatory motif of nuclear receptor Rev-erbβ is a key mediator of heme and redox signaling in circadian rhythm maintenance and metabolism.

    Science.gov (United States)

    Carter, Eric L; Ramirez, Yanil; Ragsdale, Stephen W

    2017-07-07

    Rev-erbβ is a heme-responsive transcription factor that regulates genes involved in circadian rhythm maintenance and metabolism, effectively bridging these critical cellular processes. Heme binding to Rev-erbβ indirectly facilitates its interaction with the nuclear receptor co-repressor (NCoR1), resulting in repression of Rev-erbβ target genes. Fe 3+ -heme binds in a 6-coordinate complex with axial His and Cys ligands, the latter provided by a heme-regulatory motif (HRM). Rev-erbβ was thought to be a heme sensor based on a weak K d value for the Rev-erbβ·heme complex of 2 μm determined with isothermal titration calorimetry. However, our group demonstrated with UV-visible difference titrations that the K d value is in the low nanomolar range, and the Fe 3+ -heme off-rate is on the order of 10 -6 s -1 making Rev-erbβ ineffective as a sensor of Fe 3+ -heme. In this study, we dissected the kinetics of heme binding to Rev-erbβ and provided a K d for Fe 3+ -heme of ∼0.1 nm Loss of the HRM axial thiolate via redox processes, including oxidation to a disulfide with a neighboring cysteine or dissociation upon reduction of Fe 3+ - to Fe 2+ -heme, decreased binding affinity by >20-fold. Furthermore, as measured in a co-immunoprecipitation assay, substitution of the His or Cys heme ligands in Rev-erbβ was accompanied by a significant loss of NCoR1 binding. These results demonstrate the importance of the Rev-erbβ HRM in regulating interactions with heme and NCoR1 and advance our understanding of how signaling through HRMs affects the major cellular processes of circadian rhythm maintenance and metabolism. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  13. c-erbB2 and topoisomerase IIα protein expression independently predict poor survival in primary human breast cancer: a retrospective study

    International Nuclear Information System (INIS)

    Fritz, Peter; Cabrera, Cristina M; Dippon, Jürgen; Gerteis, Andreas; Simon, Wolfgang; Aulitzky, Walter E; Kuip, Heiko van der

    2005-01-01

    c-erbB2 (also known as HER-2/neu) and topoisomerase IIα are frequently overexpressed in breast cancer. The aim of the study was to analyze retrospectively whether the expression of c-erbB2 and topoisomerase IIα protein influences the long-term outcome of patients with primary breast cancer. In this study c-erbB2 and topoisomerase IIα protein were evaluated by immunohistochemistry in formalin-fixed paraffin-embedded tissue from 225 samples of primary breast cancer, obtained between 1986 and 1998. The prognostic value of these markers was analyzed. Of 225 primary breast tumor samples, 78 (34.7%) showed overexpression of either c-erbB2 (9.8%) or topoisomerase IIα protein (24.9%), whereas in 21 tumors (9.3%) both proteins were found to be overexpressed. Patients lacking both c-erbB2 and topoisomerase IIα overexpression had the best long-term survival. Overexpression of either c-erbB2 or topoisomerase IIα was associated with shortened survival, whereas patients overexpressing both c-erbB2 and topoisomerase IIα showed the worst disease outcome (P < 0.0001). Treatment with anthracyclines was not capable of reversing the negative prognostic impact of topoisomerase IIα or c-erbB2 overexpression. The results of this exploratory study suggest that protein expression of c-erbB2 and topoisomerase IIα in primary breast cancer tissues are independent prognostic factors and are not exclusively predictive factors for anthracycline response in patients with primary breast cancer

  14. The presence of c-erbB-2 gene product-related protein in culture medium conditioned by breast cancer cell line SK-BR-3

    International Nuclear Information System (INIS)

    Alper, O.; Yamaguchi, K.; Hitomi, J.; Honda, S.; Matsushima, T.; Abe, K.

    1990-01-01

    The Mr 185,000 glycoprotein encoded by human c-erbB-2/neu/HER2 gene, termed c-erbB-2 gene product, shows a close structural similarity with epidermal growth factor receptor and is now regarded to be a growth factor receptor for an as yet unidentified ligand. Abundant c-erbB-2 mRNA was demonstrated by Northern blot studies in the human breast cancer cell line SK-BR-3. Cellular radiolabeling experiments followed by immunoprecipitation with three different anti-c-erbB-2 gene product antibodies, recognizing extracellular domain, kinase domain, and carboxyl-terminal portion, respectively, demonstrated the production of a large amount of c-erbB-2 gene product which had the capacity to be phosphorylated. Immunization of mice with concentrated culture medium conditioned by SK-BR-3 cells always generated antibodies against c-erbB-2 gene product, demonstrating that this culture medium contained substance(s) immunologically indistinguishable from c-erbB-2 gene product. This observation was supported by the successful development of a monoclonal antibody against c-erbB-2 gene product, GFD-OA-p185-1, by immunizing mice with this culture medium. The biochemical nature of the substance(s) present in the culture medium was further characterized. When the culture medium conditioned by [35S]cysteine-labeled SK-BR-3 cells was immunoprecipitated by three different anti-c-erbB-2 gene product antibodies, only the antibody recognizing extracellular domain precipitated the [35S]-labeled protein with a molecular weight of 110,000, namely p110. The newly developed monoclonal antibody also immunoprecipitated this protein

  15. Le Minh Duc

    Indian Academy of Sciences (India)

    Home; Journals; Bulletin of Materials Science. Le Minh Duc. Articles written in Bulletin of Materials Science. Volume 36 Issue 5 October 2013 pp 779-788. Study on photocatalysis of TiO2 nanotubes prepared by methanol-thermal synthesis at low temperature · Chau Thanh Nam Wein-Duo Yang Le Minh Duc · More Details ...

  16. Le Bon, Gustave

    DEFF Research Database (Denmark)

    Borch, Christian

    2017-01-01

    Gustave Le Bon (1841–1931) was a French physician and crowd psychologist who published extensively on themes such as crowds, war, race, revolution, socialism, and war. His work on crowd psychology in particular was highly influential, including beyond scholarly circles. Le Bon argued that crowds ...

  17. Activation of ErbB3, EGFR and Erk is essential for growth of human breast cancer cell lines with acquired resistance to fulvestrant

    DEFF Research Database (Denmark)

    Frogne, Thomas; Benjaminsen, Rikke V; Sonne-Hansen, Katrine

    2008-01-01

    Seven fulvestrant resistant cell lines derived from the estrogen receptor alpha positive MCF-7 human breast cancer cell line were used to investigate the importance of epidermal growth factor receptor (ErbB1-4) signaling. We found an increase in mRNA expression of EGFR and the ErbB3/ErbB4 ligand...... activation was observed only in the parental MCF-7 cells. The downstream kinases pAkt and pErk were increased in five of seven and in all seven resistant cell lines, respectively. Treatment with the EGFR inhibitor gefitinib preferentially inhibited growth and reduced the S phase fraction in the resistant...

  18. Le laboratoire, le temple et le marché

    International Development Research Centre (IDRC) Digital Library (Canada)

    Chapra est conseiller économique auprès de l'Agence monétaire d'Arabie Saoudite. Il a beaucoup écrit sur l'économie et la finance en pays islamique, et son ouvrage le plus important est Towards a Just Monetary System: A Discussion of Money, Banking, and Monetary Policy in the Light of Islamic Teachings (1985).

  19. Lele des chefs traditionnels au Ghana : un modèle inspirant ...

    International Development Research Centre (IDRC) Digital Library (Canada)

    8 févr. 2011 ... Avec ses partenaires du Sud, avec aussi le soutien du Centre de recherches pour le développement international ( CRDI ), organisme canadien, Ray a étudié lele des chefs traditionnels au Ghana dans la lutte contre le VIH et le sida. Les collectivités politiques antérieures au colonialisme sont une ...

  20. Global shortwave energy budget at the earth's surface from ERBE observations

    Science.gov (United States)

    Breon, Francois-Marie; Frouin, Robert

    1994-01-01

    A method is proposed to compute the net solar (shortwave) irradiance at the earth's surface from Earth Radiation Budget Experiment (ERBE) data in the S4 format. The S4 data are monthly averaged broadband planetary albedo collected at selected times during the day. Net surface shortwave irradiance is obtained from the shortwave irradiance incident at the top of the atmosphere (known) by subtracting both the shortwave energy flux reflected by the earth-atmosphere system (measured) and the energy flux absorbed by the atmosphere (modeled). Precalculated atmospheric- and surface-dependent functions that characterize scattering and absorption in the atmosphere are used, which makes the method easily applicable and computationally efficient. Four surface types are distinguished, namely, ocean, vegetation, desert, and snow/ice. Over the tropical Pacific Ocean, the estimates based on ERBE data compare well with those obtained from International Satellite Cloud Climatology Project (ISCCP) B3 data. For the 9 months analyzed the linear correlation coefficient and the standard difference between the two datasets are 0.95 and 14 W/sq m (about 6% of the average shortwave irradiance), respectively, and the bias is 15 W/sq m (higher ERBE values). The bias, a strong function of ISCCP satellite viewing zenith angle, is mostly in the ISCCP-based estimates. Over snow/ice, vegetation, and desert no comparison is made with other satellite-based estimates, but theoretical calculations using the discrete ordinate method suggest that over highly reflective surfaces (snow/ice, desert) the model, which accounts crudely for multiple reflection between the surface and clouds, may substantially overestimate the absorbed solar energy flux at the surface, especially when clouds are optically thick. The monthly surface shortwave irradiance fields produced for 1986 exhibit the main features characteristic of the earth's climate. As found in other studies, our values are generally higher than

  1. Le dernier Wittgenstein et le dernier Husserl sur le langage

    Directory of Open Access Journals (Sweden)

    Paul Ricoeur

    2014-07-01

    Full Text Available This article presents an edited version of lectures given by Paul Ricœur at Johns Hopkins University in April 1966. Ricœur offers a comparative analysis of Wittgenstein’s and Husserl’s late works, taking the problem of language as the common ground of investigation for these two central figures of phenomenology and analytic philosophy. Ricœur develops his study in two parts. The first part considers Husserl’s approach to language after the Logical Investigations and concentrates on Formal and Transcendental Logic; leaving a transcendental reflection on language behind it re-examines a phenomenological conception, according to which the sphere of logic is not separable from that of experience. The main focus of the second part is Wittgenstein’s later philosophy as it moved on from the conception of an isomorphic relation between language and the world, as set out in the picture theory in the Tractatus Logico-Philosophicus, to the more pragmatic notion of a language-game in the Philosophical Investigations. In order to get beyond the irrevocable differences between the two philosophies and the unresolved theoretical issues on both sides, Ricœur suggests turning to a semiological paradigm based on the Saussurean distinction between “language” and “speaking.” Keyword: Analytic Philosophy, Husserl, Phenomenology, Semiology, Wittgenstein.  Résumé Cet article est une version éditée de conférences données par Paul Ricœur à la Johns Hopkins University en avril 1966. Ricœur propose une analyse comparée des dernières œuvres de Wittgenstein et Husserl, avec le problème du langage comme sol commun d’investigations pour ces deux figures centrales de la phénoménologie et la philosophie analytique. Cette analyse de Ricœur se joue à travers deux parties. La première partie revient sur l'approche du langage chez Husserl depuis Recherches logiques avec une attention particulière aux développements de Logique formelle et

  2. Vaincre le vampire violet | CRDI - Centre de recherches pour le ...

    International Development Research Centre (IDRC) Digital Library (Canada)

    Est depuis le début des années 1990 lorsque le Centre de recherches pour le développement international, une société d'État canadienne, l'a invité à se pencher sur le problème de la striga en Afrique subsaharienne.

  3. Le paludisme au Mexique

    International Development Research Centre (IDRC) Digital Library (Canada)

    Nancy Minogue

    Le paludisme est depuis longtemps un important problème de santé publique au Mexique, où les conditions qui prévalent ... C'est dans les régions côtières que le problème a persisté le plus longtemps, les mesures ... recherche sur l'écologie des moustiques a permis d'en découvrir les raisons. « Les moustiques ne se ...

  4. Salivary Levels of ErbB2 and CEA in Oral Squamous Cell Carcinoma Patients.

    Science.gov (United States)

    Honarmand, Marieh Honarmand; Farhad-Mollashahi, Leila; Nakhaee, Alireza; Nehi, Masoume

    2016-01-01

    Oral squamous cell carcinoma (OSCC) is one of the ten most common causes of cancer death worldwide. Assessment of molecular changes can help detect and control lesions. The aim of this study was evaluation of salivary levels of ErbB2 and CEA in OSCC patients. In this case-control study, 27 OSCC patients and 26 healthy controls participated. After obtaining consent and filling out a questionnaire, unstimulated saliva samples were collected from people in the morning for measurement of the two markers using ELISA. Data were analyzed using Mann Whitney U test in SPSS 19 software with Ptumor marker in patients with OSCC must still be regarded as controversial and needs further studies to clarify any significance for early detection or screening. In contrast the salivary level of CEA may find application for early detection of patients.

  5. ErbB-targeted CAR T-cell immunotherapy of cancer.

    Science.gov (United States)

    Whilding, Lynsey M; Maher, John

    2015-01-01

    Chimeric antigen receptor (CAR) based immunotherapy has been under development for the last 25 years and is now a promising new treatment modality in the field of cancer immunotherapy. The approach involves genetically engineering T cells to target malignant cells through expression of a bespoke fusion receptor that couples an HLA-independent antigen recognition domain to one or more intracellular T-cell activating modules. Multiple clinical trials are now underway in several centers to investigate CAR T-cell immunotherapy of diverse hematologic and solid tumor types. The most successful results have been achieved in the treatment of patients with B-cell malignancies, in whom several complete and durable responses have been achieved. This review focuses on the preclinical and clinical development of CAR T-cell immunotherapy of solid cancers, targeted against members of the ErbB family.

  6. Tissue damage drives co-localization of NF-κB, Smad3, and Nrf2 to direct Rev-erb sensitive wound repair in mouse macrophages

    Science.gov (United States)

    Eichenfield, Dawn Z; Troutman, Ty Dale; Link, Verena M; Lam, Michael T; Cho, Han; Gosselin, David; Spann, Nathanael J; Lesch, Hanna P; Tao, Jenhan; Muto, Jun; Gallo, Richard L; Evans, Ronald M; Glass, Christopher K

    2016-01-01

    Although macrophages can be polarized to distinct phenotypes in vitro with individual ligands, in vivo they encounter multiple signals that control their varied functions in homeostasis, immunity, and disease. Here, we identify roles of Rev-erb nuclear receptors in regulating responses of mouse macrophages to complex tissue damage signals and wound repair. Rather than reinforcing a specific program of macrophage polarization, Rev-erbs repress subsets of genes that are activated by TLR ligands, IL4, TGFβ, and damage-associated molecular patterns (DAMPS). Unexpectedly, a complex damage signal promotes co-localization of NF-κB, Smad3, and Nrf2 at Rev-erb-sensitive enhancers and drives expression of genes characteristic of multiple polarization states in the same cells. Rev-erb-sensitive enhancers thereby integrate multiple damage-activated signaling pathways to promote a wound repair phenotype. DOI: http://dx.doi.org/10.7554/eLife.13024.001 PMID:27462873

  7. Short-term early exposure to lapatinib confers lifelong protection from mammary tumor development in MMTV-erbB-2 transgenic mice.

    Science.gov (United States)

    Ma, Zhikun; Parris, Amanda B; Xiao, Zhengzheng; Howard, Erin W; Kosanke, Stanley D; Feng, Xiaoshan; Yang, Xiaohe

    2017-01-06

    Although chemopreventative agents targeting the estrogen/estrogen receptor (ER) pathway have been effective for ER + breast cancers, prevention of hormone receptor-negative breast cancers, such as Her2/erbB-2 + breast cancers, remains a significant issue. Previous studies have demonstrated that administration of EGFR/erbB-2-targeting lapatinib to MMTV-erbB-2 transgenic mice inhibited mammary tumor development. The prevention, however, was achieved by prolonged high dose exposure. The tolerance to high dose/long-term drug administration may hinder its potential in clinical settings. Therefore, we aimed to test a novel, short-term chemopreventative strategy using lapatinib during the premalignant risk window in MMTV-erbB-2 mice. We initially treated cultured cells with lapatinib to explore the anti-proliferative effects of lapatinib in vitro. We used a syngeneic tumor graft model to begin exploring the in vivo anti-tumorigenic effects of lapatinib in MMTV-erbB-2 mice. Then, we tested the efficacy of brief exposure to lapatinib (100 mg/kg/day for 8 weeks), beginning at 16 weeks of age, in the prevention of mammary tumor development in MMTV-erbB-2 mice. In the syngeneic tumor transplant model, we determined that lapatinib significantly inhibited tumor cell proliferation. Furthermore, we demonstrated that short-term lapatinib exposure resulted in life-long protective effects, as supported by increased tumor latency in lapatinib-treated mice compared to the control mice. We further established that delayed tumor development in the treated mice was preceded by decreased BrdU nuclear incorporation and inhibited mammary morphogenesis. Molecular analysis indicated that lapatinib inhibited phosphorylation and expression of EGFR, erbB-3, erbB-2, Akt1, and Erk1/2 in premalignant mammary tissues. Also, lapatinib drastically inhibited the phosphorylation and expression of ERα and the transcription of ER target genes in premalignant mammary tissues. We also determined that

  8. Le Jardin de Fleur

    Index Scriptorium Estoniae

    2008-01-01

    Ettevõtja Martin Reinsalu osalusel Marokosse kerkiv kuurortide kompleks Le Jardin de Fleur tunnistati CNBC Araabiamaade kinnisvaraarendusprojektide seas Maroko parimaks arendusprojektiks ning parimaks golfiarenduskeskuseks. Projekt toetub araabia arhitektuurile, mida on kombineeritud kaasaegse maroko disainiga

  9. A Functionally Significant Cross-talk between Androgen Receptor and ErbB2 Pathways in Estrogen Receptor Negative Breast Cancer

    Directory of Open Access Journals (Sweden)

    Ali Naderi

    2008-06-01

    Full Text Available Recent studies have identified novel subgroups in ER-negative breast cancer based on the expression pattern of androgen receptor (AR. One subtype (molecular apocrine has an over-expression of steroid-response genes and ErbB2. Using breast cancer cell lines with molecular apocrine features, we demonstrate a functional cross-talk between AR and ErbB2 pathways. We show that stimulation of AR and ErbB2 pathways leads to the cross-regulation of gene expression for AR, ErbB2, FOXA1, XBP1, TFF3, and KLK3. As opposed to the physiologic transient phosphorylation of extracellular signal–regulated kinase (ERK1/2 observed with the testosterone treatment, we demonstrate that the addition of ErbB2 inhibition leads to a persistent phosphorylation of ERK1/2, which negatively regulates the downstream signaling and cell growth. This suggests a mechanism for the cross-talk involving the ERK pathway. Moreover, testosterone stimulates the proliferation of molecular apocrine breast cell lines, and this effect can be reversed using antiandrogen flutamide and anti-ErbB2 AG825. Conversely, the growth stimulatory effect of heregulin can also be inhibited with flutamide, suggesting a cross-talk between the AR and ErbB2 pathways affecting cell proliferation. Importantly, there is a synergy with the combined use of flutamide and AG825 on cell proliferation and apoptosis, which indicates a therapeutic advantage in the combined blockage of AR and ErbB2 pathways.

  10. The ectodomain of cadherin-11 binds to erbB2 and stimulates Akt phosphorylation to promote cranial neural crest cell migration.

    Directory of Open Access Journals (Sweden)

    Ketan Mathavan

    Full Text Available During development, a multi-potent group of cells known as the cranial neural crest (CNC migrate to form craniofacial structures. Proper migration of these cells requires proteolysis of cell adhesion molecules, such as cadherins. In Xenopus laevis, preventing extracellular cleavage of cadherin-11 impairs CNC migration. However, overexpression of the soluble cleavage product (EC1-3 is capable of rescuing this phenotype. The mechanism by which EC1-3 promotes CNC migration has not been investigated until now. Here we show that EC1-3 stimulates phosphorylation of Akt, a target of PI3K, in X.laevis CNC. Through immunoprecipitation experiments, we determined that EC1-3 interacts with all ErbB receptors, PDGFRα, and FGFR1. Of these receptors, only ErbB2 was able to produce an increase in Akt phosphorylation upon treatment with a recombinant EC1-3. This increase was abrogated by mubritinib, an inhibitor of ErbB2. We were able to recapitulate this decrease in Akt phosphorylation in vivo by knocking down ErbB2 in CNC cells. Knockdown of the receptor also significantly reduced CNC migration in vivo. We confirmed the importance of ErbB2 and ErbB receptor signaling in CNC migration using mubritinib and canertinib, respectively. Mubritinib and the PI3K inhibitor LY294002 significantly decreased cell migration while canertinib nearly prevented it altogether. These data show that ErbB2 and Akt are important for CNC migration and implicate other ErbB receptors and Akt-independent signaling pathways. Our findings provide the first example of a functional interaction between the extracellular domain of a type II classical cadherin and growth factor receptors.

  11. LPP is Required for TGF-Beta Induced Motility and Invasion of Neu/ErbB-2 Expressing Breast Cancer Cells

    Science.gov (United States)

    2012-09-01

    cancer cells . Furthermore, we show that focal adhesion targeting of LPP, through its LIM1 domain, is required for the migratory and invasive...phenotypes of ErbB2 positive breast cancer cells in response to TGF Beta. Using Fluorescence Recovery After Photobleaching (FRAP) techniques, we also...have identified LPP as a novel mediator that integrates TGF Beta and ErbB2 signaling to promote the migration and invasion of breast cancer cells . Thus

  12. Positive expression of p53, c-erbB2 and MRP proteins is correlated with survival rates of NSCLC patients.

    Science.gov (United States)

    Xu, Yujin; Wang, Liancong; Zheng, Xiao; Liu, Guan; Wang, Yuezhen; Lai, Xiaojing; Li, Jianqiang

    2013-05-01

    The incidence of lung cancer is one of the leading causes of mortality. This study aimed to investigate the prognostic and predictive importance of p53, c-erbB2 and multidrug resistance proteins (MRP) expression and its correlation with clinicopathological characteristics of patients with non-small cell lung cancer (NSCLC). Expression of p53, c-erbB2 and MRP proteins in 152 tumor samples from resected primary NSCLCs was detected by immunohistochemical staining. The correlation of proteins, survival and clinicopathological characteristics was investigated in 152 patients undergoing potentially curative surgery. The positive rates of p53, c-erbB2 and MRP expression were 53.9 (82/152), 44.1 (67/152) and 43.4% (66/152), respectively. Overall survival rates of patients were markedly correlated with the overexpression of p53, c-erbB2 and MRP proteins. One, 2- and 3-year survival rates of patients exhibiting a positive expression of these proteins were 72.6, 54.8 and 32.2%, respectively. These rates were lower compared with those of patients with a negative expression of these proteins (92.1, 78.5 and 63.4%) (P=0.02, 0.01 or 0.00, respectively). Results of Cox's regression analysis showed that c-erbB2 expression and cell differentiation were independent prognostic factors in patients with NSCLC. These findings suggest that the positive expression of p53, c-erbB2 and MRP proteins is correlated with the survival rates of NSCLC patients. Detection of positive p53, c-erbB2 and MRP expression may be a useful predictive indicator of prognosis. Positive c-erbB2 expression is an independent prognostic factor, with a potential to be used as a predictive indicator of chemotherapy efficacy in NSCLC patients.

  13. G1 cell cycle arrest due to the inhibition of erbB family receptor tyrosine kinases does not require the retinoblastoma protein

    International Nuclear Information System (INIS)

    Gonzales, Andrea J.; Fry, David W.

    2005-01-01

    The erbB receptor family (EGFr, erbB-2, erbB-3, and erbB-4) consists of transmembrane glycoproteins that transduce extracellular signals to the nucleus when activated. erbB family members are widely expressed in epithelial, mesenchymal, and neuronal cells and contribute to the proliferation, differentiation, migration, and survival of these cell types. The present study evaluates the effects of erbB family signaling on cell cycle progression and the role that pRB plays in regulating this process. ErbB family RTK activity was inhibited by PD 158780 in the breast epithelial cell line MCF10A. PD 158780 (0.5 μM) inhibited EGF-stimulated and heregulin-stimulated autophosphorylation and caused a G1 cell cycle arrest within 24 h, which correlated with hypophosporylation of pRB. MCF10A cells lacking functional pRB retained the ability to arrest in G1 when treated with PD 158780. Both cell lines showed induction of p27 KIP1 protein when treated with PD 158780 and increased association of p27 KIP1 with cyclin E-CDK2. Furthermore, CDK2 kinase activity was dramatically inhibited with drug treatment. Changes in other pRB family members were noted with drug treatment, namely a decrease in p107 and an increase in p130. These findings show that the G1 arrest induced through inhibition of erbB family RTK activity does not require functional pRB

  14. Reversal of Impaired Hippocampal Long-term Potentiation and Contextual Fear Memory Deficits in Angelman Syndrome Model Mice by ErbB Inhibitors

    Science.gov (United States)

    Kaphzan, Hanoch; Hernandez, Pepe; Jung, Joo In; Cowansage, Kiriana K.; Deinhardt, Katrin; Chao, Moses V.; Abel, Ted; Klann, Eric

    2012-01-01

    Background Angelman syndrome (AS) is a human neuropsychiatric disorder associated with autism, mental retardation, motor abnormalities, and epilepsy. In most cases, AS is caused by the deletion of the maternal copy of UBE3A gene, which encodes the enzyme ubiquitin ligase E3A, also termed E6-AP. A mouse model of AS has been generated and these mice exhibit many of the observed neurological alterations in humans. Because of clinical and neuroanatomical similarities between AS and schizophrenia, we examined AS model mice for alterations in the neuregulin-ErbB4 pathway, which has been implicated in the pathophysiology of schizophrenia. We focused our studies on the hippocampus, one of the major brain loci impaired in AS mice. Methods We determined the expression of NRG1 and ErbB4 receptors in AS mice and wild-type littermates (ages 10-16 weeks), and studied the effects of ErbB inhibition on long-term potentiation (LTP) in hippocampal area CA1 and on hippocampus-dependent contextual fear memory. Results We observed enhanced neuregulin-ErbB4 signaling in the hippocampus of AS model mice and found that ErbB inhibitors could reverse deficits in LTP, a cellular substrate for learning and memory. In addition, we found that an ErbB inhibitor enhanced long-term contextual fear memory in AS model mice. Conclusions Our findings suggest that neuregulin-ErbB4 signaling is involved in synaptic plasticity and memory impairments in AS model mice, suggesting that ErbB inhibitors have therapeutic potential for the treatment of AS. PMID:22381732

  15. Le CRDI en Tanzanie

    International Development Research Centre (IDRC) Digital Library (Canada)

    Il y a longtemps que le CRDI appuie la recherche en Tanzanie, une démocratie stable. Depuis la fin des années 1990, le pays jouit d'une croissance économique soutenue, bien qu'il demeure l'un des. États les plus pauvres de la planète. Ses gouvernements successifs ont reconnu que la réduction de la pauvreté passait ...

  16. Le CRDI au Mali

    International Development Research Centre (IDRC) Digital Library (Canada)

    contre le paludisme n les chercheurs contribuent à l'amélioration des services de santé n de jeunes femmes participent à la vie politique. Soutien accordé par le CRDI depuis 1971. 93 activités d'une valeur de 15 millions cad. Les chercheurs ont aidé à offrir l'enseignement primaire dans les langues maternelles. CRDI.

  17. Le CRDI au Maroc

    International Development Research Centre (IDRC) Digital Library (Canada)

    démocratiques. Au Maroc, le Centre d'études et de recherches en sciences sociales analyse ce que pourrait être la réaction du gouverne- ment aux pressions exercées par la population en vue d'un changement sur le plan politique. Rabat. Casablanca. Marrakech. Tan-Tan. Bou Arfa. Zagora. Oujda. Tanger. Fès. ALGÉRIE.

  18. Le CRDI en Afghanistan

    International Development Research Centre (IDRC) Digital Library (Canada)

    Depuis près de 40 ans, le CRDI collabore étroitement avec les chercheurs des pays en développement et les appuie dans leur quête de moyens de créer des sociétés en meilleure santé, plus équitables et plus prospères. Centre de recherches pour le développement international. CP 8500, Ottawa (Ontario) Canada K1G ...

  19. Le CRDI au Bhoutan

    International Development Research Centre (IDRC) Digital Library (Canada)

    Il en résulte des solutions locales, novatrices et durables, qui offrent des choix aux personnes qui en ont le plus besoin et font changer les choses. Centre de recherches pour le développement international. CP 8500, Ottawa (Ontario) Canada K1G 3H9. Pour en savoir plus, consulter la page. Web du Bureau régional de ...

  20. Le CRDI au Kenya

    International Development Research Centre (IDRC) Digital Library (Canada)

    afin d'y favoriser la croissance et le développement. Il en résulte des solutions novatrices et durables qui ont pour but d'améliorer les conditions de vie et les moyens de subsistance. Centre de recherches pour le développement international. CP 8500, Ottawa (Ontario) Canada K1G 3H9. Pour en savoir plus, consulter.

  1. Le CRDI en Jordanie

    International Development Research Centre (IDRC) Digital Library (Canada)

    ... dans les pays en développement afin d'y favoriser la croissance et le développement. Il en résulte des solutions novatrices et durables qui ont pour but d'améliorer les conditions de vie et les moyens de subsistance. Centre de recherches pour le développement international. CP 8500, Ottawa (Ontario) Canada K1G 3H9.

  2. Le CRDI en Bolivie

    International Development Research Centre (IDRC) Digital Library (Canada)

    plus grandes responsabilités aux munici- palités en matière de développement économique. De 2002 à 2007, le CRDI a appuyé la collaboration entre l'Atlantic. Community Economic Development. Institute, de Halifax, en Nouvelle-Écosse, et deux organismes boliviens, le Centro de Servicios Agropecuarios Técnicos, du.

  3. Le faussaire roman

    CERN Document Server

    D'Anna, Gianfranco

    2016-01-01

    À l'aube du XXIe siècle, le monde de la science est sur le point de vivre une révolution. Le jeune physicien allemand Albert Hendrick Thebell, des célèbres laboratoires de recherche B-Labs, à Summit, dans le New Jersey, publie, dans les plus grandes revues scientifiques internationales, une série d'articles dans lesquels il prétend avoir obtenu des résultats extraordinaires qui pourraient révolutionner les bases mêmes de la technologie. Rapidement, la communauté scientifique puis les médias saluent en lui un futur prix Nobel; on compare même son génie à celui d'Albert Einstein. Le progrès scientifique semble avoir franchi une étape décisive, susceptible d'amener un futur meilleur. Mais ces découvertes sont-elles authentiques ? Car pendant ce temps, dans les mêmeslaboratoires, des voix s'élèvent pour contester non seulement les théories de Thebell mais aussi la légitimité même de ses expériences ; certains le soupçonnent d'avoir combiné la plus grande fraude scientifique de tous l...

  4. Direct binding of Copine3 with Jab1 activates downstream ErbB2 signaling and motility in SKBr3 breast cancer cells.

    Science.gov (United States)

    Choi, Hye Young; Park, Nammi; Na, Jae Boem; Ko, Eun Sook; Park, Jae-Yong; Yoo, Jae Cheal

    2016-02-01

    Copine3, a known calcium-dependent membrane binding protein, contains two tandem C2 domains and an A domain. This protein has been shown to interact with receptor tyrosine kinase 2 (ErbB2), but little is known concerning the physiological function of Copine3. To better understand its cellular function, we carried out a yeast two-hybrid screen to find Copine3 binding partners. Among the identified proteins, Jun activation domain-binding protein 1 (Jab1) appears to directly interact with Copine3. This physical interaction between Copine3 and Jab1 as well as the specific binding regions of both proteins were confirmed in vitro and in vivo. Our results also demonstrate that binding of Copine3 to ErbB2 is increased when Jab1 is overexpressed in SKBr3 breast cancer cells. Furthermore, two ErbB2 downstream signaling proteins [phosphatidylinositol 3 (PI3) kinase and protein kinase B (AKT)] were also activated by Jab1 overexpression in these cells. These data suggest that binding of Copine3 and Jab1 regulates, at least to some extent, the ErbB2 signaling pathway. Moreover, overexpression of both Copine3 and Jab1 in SKBr3 cells effectively increased cellular migration. Collectively, our findings indicating that Jab1 enhances the ErbB2 binding ability of Copine3, further activating the ErbB2 signaling pathways involved in breast cancer cell pathogenesis.

  5. ErbB2-enhanced invasiveness of H-Ras MCF10A breast cells requires MMP-13 and uPA upregulation via p38 MAPK signaling.

    Science.gov (United States)

    Yong, Hae-Young; Kim, In-Young; Kim, Jong Suk; Moon, Aree

    2010-02-01

    Overexpression of ErbB2 has been frequently found in mammary carcinoma. We have previously shown that the aberrant activation of H-Ras induces human breast cell invasion and migration. The present study was aimed at investigating the effect of ErbB2 overexpression on H-Ras-induced breast cell invasion and to elucidate the underlying mechanisms. Herein, we show that overexpression of ErbB2 promotes invasive and migratory abilities of H-Ras-activated MCF10A human breast epithelial cells through upregulation of matrix metalloproteinase (MMP)-13 and urokinase-type plasminogen activator (uPA). We also demonstrate that the p38 MAPK is an important signaling molecule in the ErbB2-induced upregulation of MMP-13 and uPA and invasion/migration of H-Ras MCF10A cells overexpressing ErbB2. The present study elucidating the molecular mechanism underlying ErbB2-induced promotion of H-Ras MCF10A cell invasion may provide invaluable information for understanding breast cancer progression and establishing therapeutic interventions for breast cancer.

  6. Clouds and the Earth's Radiant Energy System (CERES) algorithm theoretical basis document. volume 2; Geolocation, calibration, and ERBE-like analyses (subsystems 1-3)

    Science.gov (United States)

    Wielicki, B. A. (Principal Investigator); Barkstrom, B. R. (Principal Investigator); Charlock, T. P.; Baum, B. A.; Green, R. N.; Minnis, P.; Smith, G. L.; Coakley, J. A.; Randall, D. R.; Lee, R. B., III

    1995-01-01

    The theoretical bases for the Release 1 algorithms that will be used to process satellite data for investigation of the Clouds and Earth's Radiant Energy System (CERES) are described. The architecture for software implementation of the methodologies is outlined. Volume 2 details the techniques used to geolocate and calibrate the CERES scanning radiometer measurements of shortwave and longwave radiance to invert the radiances to top-of-the-atmosphere (TOA) and surface fluxes following the Earth Radiation Budget Experiment (ERBE) approach, and to average the fluxes over various time and spatial scales to produce an ERBE-like product. Spacecraft ephemeris and sensor telemetry are used with calibration coefficients to produce a chronologically ordered data product called bidirectional scan (BDS) radiances. A spatially organized instrument Earth scan product is developed for the cloud-processing subsystem. The ERBE-like inversion subsystem converts BDS radiances to unfiltered instantaneous TOA and surface fluxes. The TOA fluxes are determined by using established ERBE techniques. Hourly TOA fluxes are computed from the instantaneous values by using ERBE methods. Hourly surface fluxes are estimated from TOA fluxes by using simple parameterizations based on recent research. The averaging process produces daily, monthly-hourly, and monthly means of TOA and surface fluxes at various scales. This product provides a continuation of the ERBE record.

  7. Heregulin-β1-induced GPR30 upregulation promotes the migration and invasion potential of SkBr3 breast cancer cells via ErbB2/ErbB3-MAPK/ERK pathway.

    Science.gov (United States)

    Ruan, Shu-Qin; Wang, Zhan-Huai; Wang, Shan-Wei; Fu, Zhi-Xuan; Xu, Kan-Lun; Li, Dong-Bo; Zhang, Su-Zhan

    2012-04-06

    Estrogen receptor (ER)-negative breast cancer cells are probably more aggressive with larger metastatic potential than ER-positive cells. Loss of ER in recurrent breast cancer is associated with poor response to endocrine therapy. G protein-coupled receptor 30 (GPR30) is expressed in half of ER-negative breast cancers. Tumor cell-derived heregulin-β1 (HRG-β1) is also found mainly in ER-negative cancer. In SkBr3 breast cancer cells that lack ER but express GPR30, HRG-β1 upregulates mRNA and protein levels of GPR30 by promoting ErbB2-ErbB3 heterodimerization and activating the downstream MAPK-ERK signaling pathway. Moreover, GPR30 boosts HRG-β1-induced migration and invasion of SkBr3 cells after combinative treatment with E2, 4-hydroxy-tamoxifen or the specific GPR30 agonist G-1, which are blocked by the specific GPR30 antagonist G-15 or the transfection with the small interfering RNA for GPR30. The ErbB2 inhibitor AG825 and the MEK1/2 inhibitor U0126 also partly inhibit the enhanced migration and invasion. Therefore, HRG-β1-induced migration and invasion partly depend on the upregulation of GPR30 expression through activation of the ErbB2-ERK pathway in SkBr3 cells. The results of this study indicate that the crosstalk between GPR30 and HRGs signaling is important for endocrine therapy resistance and may provide a new therapeutic way to treat breast cancer. Copyright © 2012 Elsevier Inc. All rights reserved.

  8. An information theory approach for evaluating earth radiation budget (ERB) measurements - Nonuniform sampling of diurnal longwave flux variations

    Science.gov (United States)

    Halyo, Nesim; Direskeneli, Haldun; Barkstrom, Bruce R.

    1991-01-01

    Satellite measurements are subject to a wide range of uncertainties due to their temporal, spatial, and directional sampling characteristics. An information-theory approach is suggested to examine the nonuniform temporal sampling of ERB measurements. The information (i.e., its entropy or uncertainty) before and after the measurements is determined, and information gain (IG) is defined as a reduction in the uncertainties involved. A stochastic model for the diurnal outgoing flux variations that affect the ERB is developed. Using Gaussian distributions for the a priori and measured radiant exitance fields, the IG is obtained by computing the a posteriori covariance. The IG for the monthly outgoing flux measurements is examined for different orbital parameters and orbital tracks, using the Earth Observing System orbital parameters as specific examples. Variations in IG due to changes in the orbit's inclination angle and the initial ascending node local time are investigated.

  9. A carbon-13 and proton nuclear magnetic resonance study of some experimental referee broadened-specification /ERBS/ turbine fuels

    Science.gov (United States)

    Dalling, D. K.; Pugmire, R. J.

    1982-01-01

    Preliminary results of a nuclear magnetic resonance (NMR) spectroscopy study of alternative jet fuels are presented. A referee broadened-specification (ERBS) aviation turbine fuel, a mixture of 65 percent traditional kerosene with 35 percent hydrotreated catalytic gas oil (HCGO) containing 12.8 percent hydrogen, and fuels of lower hydrogen content created by blending the latter with a mixture of HCGO and xylene bottoms were studied. The various samples were examined by carbon-13 and proton NMR at high field strength, and the resulting spectra are shown. In the proton spectrum of the 12.8 percent hydrogen fuel, no prominent single species is seen while for the blending stock, many individual lines are apparent. The ERBS fuels were fractionated by high-performance liquid chromatography and the resulting fractions analyzed by NMR. The species found are identified.

  10. Humeral internal rotation osteotomy for the treatment of Erb-Duchenne-type obstetric palsy: clinical and radiographic results

    OpenAIRE

    Assunção, Jorge Henrique; Ferreira Neto, Arnaldo Amado; Benegas, Eduardo; Bolliger Neto, Raul; Prada, Flávia Santis; Malavolta, Eduardo Angeli; Gracitelli, Mauro Emilio Conforto; Camanho, Gilberto Luis

    2013-01-01

    OBJECTIVE: To evaluate the functional and radiographic results in patients undergoing shoulder anterior soft tissue stretching in association with open reduction and internal rotation osteotomy to centralize the humeral head as a treatment for Erb-Duchenne obstetric palsy sequelae. METHOD: A total of 35 patients underwent this surgical treatment, and the mean follow-up was 4.6 years. The Mallet scale was applied before and after the surgical procedure. A total of 20 patients underwent compute...

  11. Spectral unfiltering of ERBE WFOV nonscanner shortwave observations and revisiting its radiation dataset from 1985 to 1998

    Science.gov (United States)

    Shrestha, A. K.; Kato, S.; Wong, T.; Stackhouse, P. W.; Rose, F.; Miller, W. F.; Bush, K.; Rutan, D. A.; Minnis, P.; Doelling, D.

    2017-02-01

    Wide-field-of-view (WFOV) nonscanner instruments were onboard NASA's Earth Radiation Budget Satellite (ERBS) and the NOAA-9 and NOAA-10 satellites, and provided broadband shortwave (SW) and longwave (LW) irradiances from 1984 to 1999. However, Lee et al. (2002) noted degradation in the WFOV SW dome transmissivity. To account for this degradation, these SW instruments were calibrated with the spectrally flat gray assumption. More recently, Loeb et al. (2012) showed higher degradation in the transmissivity of shorter wavelengths suggesting a need for both temporal and spectral dependent corrections for better calibration. Such an approach may also eliminate an additional adjustment that was applied to irradiances in the existing products to remove the observed trend of day-minus-night longwave irradiances (Wong et al. 2006). We plan to reprocess the ERBE WFOV nonscanner record by characterizing the spectral degradation of the SW dome transmissivity over time. Solar data observed by the WFOV SW nonscanner during calibration days are used to estimate a time and spectral dependent spectral response function (SRF). Coefficients derived from this SRF are then used to improve the irradiance estimate. In addition, since the spectrum of reflected irradiance depends on scene type, ISCCP-derived cloud properties and surface type are used. Preliminary results indicate that taking account of spectral degradation reduces the observed day-minus-night longwave irradiance trends in the tropics (20ON and 20OS) by ˜34%, while almost all of the trend is removed in the region between 60ON and 60OS. This presentation explains the reprocessing approach and compares the existing and reprocessed ERBE dataset. Once ERBS measurements are calibrated against CERES instruments, this work allows for the generation of a long-term radiation datasets consistent with those provided by CERES.

  12. ErbB2 receptor over-expression improves post-traumatic peripheral nerve regeneration in adult mice.

    Science.gov (United States)

    Ronchi, Giulia; Gambarotta, Giovanna; Di Scipio, Federica; Salamone, Paolina; Sprio, Andrea E; Cavallo, Federica; Perroteau, Isabelle; Berta, Giovanni N; Geuna, Stefano

    2013-01-01

    In a transgenic mice (BALB-neuT) over-expressing ErbB2 receptor, we investigated the adult mouse median nerve in physiological and pathological conditions. Results showed that, in physiological conditions, the grip function controlled by the median nerve in BALB-neuT mice was similar to wild-type (BALB/c). Stereological assessment of ErbB2-overexpressing intact nerves revealed no difference in number and size of myelinated fibers compared to wild-type mice. By contrast, after a nerve crush injury, the motor recovery was significantly faster in BALB-neuT compared to BALB/c mice. Moreover, stereological assessment revealed a significant higher number of regenerated myelinated fibers with a thinner axon and fiber diameter and myelin thickness in BALB-neuT mice. At day-2 post-injury, the level of the mRNAs coding for all the ErbB receptors and for the transmembrane (type III) Neuregulin 1 (NRG1) isoforms significantly decreased in both BALB/c and BALB-neuT mice, as shown by quantitative real time PCR. On the other hand, the level of the mRNAs coding for soluble NRG1 isoforms (type I/II, alpha and beta) increased at the same post-traumatic time point though, intriguingly, this response was significantly higher in BALB-neuT mice with respect to BALB/c mice. Altogether, these results suggest that constitutive ErbB2 receptor over-expression does not influence the physiological development of peripheral nerves, while it improves nerve regeneration following traumatic injury, possibly through the up-regulation of soluble NRG1 isoforms.

  13. Rev-erb agonist improves adverse cardiac remodeling and survival in myocardial infarction through an anti-inflammatory mechanism.

    Directory of Open Access Journals (Sweden)

    Endin Nokik Stujanna

    Full Text Available Rev-erb α, known as nuclear receptor 1D1 (NR1D1, regulates circadian rhythm, modulates glucose and lipid metabolism, and inflammatory response. However, little is known about the effect of Rev-erb agonist on the progression of myocardial infarction (MI and heart failure. To investigate it, wild-type male mice underwent sham-operation or permanent ligation of the left anterior descending coronary artery to create MI model. Rev-erb agonist SR9009 (100 mg/kg/day or vehicle was intraperitoneally administered. Echocardiography was performed to evaluate cardiac function 1 week after surgery. The gene and protein expression levels in the left ventricles (LVs were determined with real-time PCR, western blotting, and immunofluorescence. Moreover, immune cell infiltration into the LVs was analyzed by flow cytometry. Survival rate and reduced LV function were significantly improved by the treatment with SR9009 after MI. The expression level and plasma concentration of brain natriuretic peptide were significantly lower in MI mice treated with SR9009 (MI+SR than in MI mice treated with vehicle (MI+V. Moreover, the mRNA expression levels of inflammatory-related molecules such as Il6, Mcp1, Ly6g, Cd11b, matrix metallopeptidase (Mmp9, and the protein expression levels of phosphorylated NF-κB p65, phosphorylated ERK, and phosphorylated p38 were also significantly lower in MI+SR than in MI+V. Immunofluorescence intensity for MMP-9 was enhanced in the LVs, but was less so in MI+SR than in MI+V. Furthermore, infiltrations of neutrophils and proinflammatory macrophages in the LVs were dramatically increased in MI+V and were significantly suppressed in MI+SR. Rev-erb agonist SR9009 treatment inhibited post-MI mortality and improved cardiac function through modulating inflammation and remodeling process.

  14. The anti-erbB3 antibody MM-121/SAR256212 in combination with trastuzumab exerts potent antitumor activity against trastuzumab-resistant breast cancer cells.

    Science.gov (United States)

    Huang, Jingcao; Wang, Shuiliang; Lyu, Hui; Cai, Bo; Yang, XiaoHe; Wang, Jianxiang; Liu, Bolin

    2013-11-11

    Elevated expression of erbB3 receptor has been reported to induce resistance to therapeutic agents, including trastuzumab in erbB2-overexpressing breast cancer. Our recent studies indicate that erbB3 interacts with both erbB2 and IGF-1 receptor to form a heterotrimeric complex in trastuzumab-resistant breast cancer cells. Herein, we investigate the antitumor activity of MM-121/SAR256212, a fully human anti-erbB3 antibody (Ab), against two erbB2-overexpressing breast cancer cell lines resistant to trastuzumab. MTS-based proliferation assays were used to determine cell viability upon treatment of trastuzumab and/or MM-121/SAR256212. Cell cycle progression was examined by flow cytometric analysis. Western blot analyses were performed to determine the expression and activation of proteins. Tumor xenografts were established by inoculation of the trastuzumab-resistant BT474-HR20 cells into nude mice. The tumor-bearing mice were treated with trastuzumab and/or MM-121/SAR256212 via i.p injection to determine the Abs' antitumor activity. Immunohistochemical analyses were carried out to study the Abs' inhibitory effects on tumor cell proliferation and induction of apoptosis in vivo. MM-121 significantly enhanced trastuzumab-induced growth inhibition in two sensitive and two resistant breast cancer cell lines. MM-121 in combination with trastuzumab resulted in a dramatic reduction of phosphorylated erbB3 (P-erbB3) and Akt (P-Akt) in the in vitro studies. MM-121 combined with trastuzumab did not induce apoptosis in the trastuzumab-resistant cell lines under our cell culture condition, rather induced cell cycle G1 arrest mainly associated with the upregulation of p27(kip1). Interestingly, in the tumor xenograft model established from the trastuzumab-resistant cells, MM-121 in combination with trastuzumab as compared to either agent alone dramatically inhibited tumor growth correlated with a significant reduction of Ki67 staining and increase of cleaved caspase-3 in the tumor

  15. The Clock Gene Rev-Erbα Regulates Methamphetamine Actions on Circadian Timekeeping in the Mouse Brain.

    Science.gov (United States)

    Salaberry, Nora L; Mateo, Maria; Mendoza, Jorge

    2017-09-01

    Circadian rhythms are strongly affected by drugs. In rodents, chronic methamphetamine (METH) intake changes circadian activity rhythms, mainly by altering light synchronization that generates the expression of a free-running rhythm with a period longer than 24 h and a second behavioral component that is independent of the main suprachiasmatic (SCN) clock. Although a number of clock genes do not appear to be involved in the effects of METH on circadian behavior, the molecular clockwork controlling these changes is still unclear. Therefore, we investigated the role of the clock gene Rev-Erbα in METH-induced behavioral and molecular responses using knockout mice and their wild-type littermates. Chronic intake of METH alters period circadian behavior of wild-type mice. However, in mice lacking the clock gene Rev-Erbα METH had no effect on their behavioral rhythms. Furthermore, PER2 bioluminescence rhythms in two extra-SCN brain oscillators, the dorsomedial hypothalamus and the habenula, were altered by METH in wild type but not in KO mice. Together, the present results implicate Rev-Erbα in the modulation of the circadian responses to METH and may provide a better comprehension into the mechanisms underlying circadian alterations provoked by drug addiction.

  16. Detection of survivin, carcinoembryonic antigen and ErbB2 level in oral squamous cell carcinoma patients.

    Science.gov (United States)

    Li, Shu-Xia; Yang, Yan-Qi; Jin, Li-Jian; Cai, Zhi-Gang; Sun, Zheng

    2016-01-01

    The aim of this study was to detect the survivin, carcinoembryonic antigen (CEA) and ErbB2 in the saliva, serum and local tumor-exfoliated cells of oral squamous cell carcinoma (OSCC) patients, for providing reliable tumor markers for the early detection of oral malignant cancer. The saliva, serum, and local tumor-exfoliated cell samples of 26 OSCC patients without chemotherapy and 10 non-cancer patients were collected in Department of Oral and Maxillofacial Surgery, School of Stomatology, Peking University. The contents of survivin, CEA and ErbB2 using were detected usingenzyme-linked immunosorbent assay. The survivin and CEA levels in saliva and local tumor-exfoliated cells of OSCC patients were significantly higher than those in the non-cancer patients (P < 0.05), but there was no significant difference in the content of the above factors in the serum sample between two groups. There was no significant difference in the ErbB2 content in the saliva, serum or local tumor-exfoliated cells between two groups. Survivin and CEA levels are significantly increased in the saliva and local tumor-exfoliated cells in OSCC patients, and they can be used as reliable markers for the early detection of oral malignant cancer.

  17. Le modèle basque

    Directory of Open Access Journals (Sweden)

    Juan-Angel PORTUGAL

    1986-12-01

    Full Text Available À l'intérieur du quadrilatère basque se dessine un sous-espace triangulaire dont les sommets sont les capitales provinciales; les côtés délimitent une aire prospère. La localisation de ces trois noyaux résulte d'une décision politico-économique et d'une diffusion de l'industrialisation. Ce triangle est un espace dynamique et attractif, autant dans le domaine de la démographie que du développement économique et industriel.

  18. Le sens du portrait.

    Directory of Open Access Journals (Sweden)

    Christophe Apprill

    2007-01-01

    Full Text Available À l’entrée du vieux port de Marseille, le projet Euroméditerranée prévoit la construction d’un musée, le Musée des Civilisations de l’Europe et de la Méditerranée (M ucem . Il accueillera les anciennes collections du Musée National des Arts et Traditions Populaires (M natp que les badauds en promenade au jardin d’acclimatation croisaient sans le savoir. Un concours d’architecture a été lancé, remporté par un architecte de la région, Rudy Riccioti. Son projet ...

  19. Le stockage inertiel

    OpenAIRE

    KAUV, J; BONAL, J

    2010-01-01

    La fourniture d'une énergie propre et abondante à une population mondiale largement appelée à croître va être un défi considérable pour le XXIe siècle. Aujourd'hui nous dépendons encore considérablement des énergies fossiles, certes très énergétiques et d'utilisation commode, mais épuisables et productrices de CO2 responsable du réchauffement climatique. Le stockage d'énergie électrique et de chaleur est un domaine technique difficile et délicat, mais dont le développement est indispensable p...

  20. Le Nouveau Monde

    Directory of Open Access Journals (Sweden)

    Alain Musset

    2006-04-01

    Full Text Available L’histoire de la conquête du Nouveau Monde par les Européens semble devoir se résumer au destin de deux femmes chargées d’assurer le truchement entre les deux mondes et de jouer lele d’intermédiaire amoureuse ou de grande traîtresse : au Nord, Pocahontas, au Sud, La Malinche. Quand Cortés débarque en 1519 sur les côtes du Tabasco, un cacique désireux de lui plaire lui offre vingt femmes dont une superbe jeune fille, Malintzin (la Malinche, rebaptisée Marina. Celle-ci deviendra sa maîtres...

  1. Imunoexpressão do c-erbB-2 nas lesões epiteliais proliferativas intraductais da mama de mulheres Immunoexpression of c-erbB-2 in intraductal proliferative lesions of the female breast

    Directory of Open Access Journals (Sweden)

    Agliberto Barbosa de Oliveira

    2004-09-01

    Full Text Available OBJETIVOS: Alterações genéticas são relacionadas à gênese e progressão do câncer. Neoplasias de vários órgãos expressam o oncogene c-erbB-2. Nas proliferações intraductais da mama tem sido avaliado como fator de risco para o desenvolvimento de câncer. Foram avaliadas a imunoexpressão do c-erbB-2 em lesões epiteliais proliferativas intraductais e as possíveis correlações com características anatomopatológicas do carcinoma ductal "in situ" (CDIS. MÉTODOS: Foi utilizado material de arquivo, amostras teciduais fixadas em formalina e incluídas em blocos de parafina de 88 mulheres. Destas, 51 com CDIS e 37 com hiperplasia ductal sem atipias (HDT. A idade variou de 35 a 76 anos. Revisados todos os casos, verificou-se: o grau nuclear, a presença de necrose, o subtipo histológico predominante e sua extensão. Obteve-se material suficiente para o estudo imunohistoquímico do c-erbB-2 de 84 sujeitos do estudo. RESULTADOS: Não foi observada a expressão do oncogene nas hiperplasias sem atipias e nos tecidos adjacentes a todas amostras teciduais. A expressão do c-erbB-2 foi verificada em nove (19,1% dos CDIS (p= 0,0001. A imunoexpressão não se relacionou à extensão das lesões. A imunoexpressão do c-erbB-2 no CDIS correlacionou-se com subtipo histológico (p=0,019, com a presença de necrose (p=0,0066, com o grau nuclear (p=0,0084 e com a Classificação de Van Nuys (p=0,039. CONCLUSÕES: A expressão do c-erbB-2 foi estatisticamente significante nas lesões proliferativas de risco (CDIS e correlacionou-se com características histopatológicas: alto grau nuclear, presença de necrose, subtipo comedo. Não houve expressão nas hiperplasias sem atipias e tecidos adjacentes.OBJECTIVES: Genetic modifications are related to genesis and development of cancer. Neoplasias in various organs express the c-erbB-2 oncogene. In intraductal proliferations of the breast it has been assessed as a risk factor for subsequent development of

  2. The erbB3- and IGF-1 receptor-initiated signaling pathways exhibit distinct effects on lapatinib sensitivity against trastuzumab-resistant breast cancer cells.

    Science.gov (United States)

    Lyu, Hui; Yang, Xiao He; Edgerton, Susan M; Thor, Ann D; Wu, Xiaoying; He, Zhimin; Liu, Bolin

    2016-01-19

    Both erbB3 and IGF-1 receptor (IGF-1R) have been shown to play an important role in trastuzumab resistance. However, it remains unclear whether erbB3- and IGF-1R-initiated signaling pathways possess distinct effects on the sensitivity of lapatinib, a dual tyrosine kinase inhibitor against both EGFR and erbB2, in trastuzumab-resistant breast cancer. Here, we show that the trastuzumab-resistant SKBR3-pool2 and BT474-HR20 breast cancer sublines, as compared the parental SKBR3 and BT474 cells, respectively, exhibit refractoriness to lapatinib. Knockdown of erbB3 inhibited Akt in SKBR3-pool2 and BT474-HR20 cells, significantly increased lapatinib efficacy, and dramatically re-sensitized the cells to lapatinib-induced apoptosis. In contrast, specific knockdown of IGF-1R did not alter the cells' responsiveness to lapatinib. While the levels of phosphorylated Src (P-Src) were reduced upon IGF-1R downregulation, the P-Akt levels remained unchanged. Furthermore, a specific inhibitor of Akt, but not Src, significantly enhanced lapatinib-mediated anti-proliferative/anti-survival effects on SKBR3-pool2 and BT474-HR20 cells. These data indicate that erbB3 signaling is critical for both trastuzumab and lapatinib resistances mainly through the PI-3K/Akt pathway, whereas IGF-1R-initiated Src activation results in trastuzumab resistance without affecting lapatinib sensitivity. Our findings may facilitate the development of precision therapeutic regimens for erbB2-positive breast cancer patients who become resistant to erbB2-targeted therapy.

  3. Exercise training and return to a well-balanced diet activate the neuregulin 1/ErbB pathway in skeletal muscle of obese rats

    Science.gov (United States)

    Ennequin, Gaël; Boisseau, Nathalie; Caillaud, Kevin; Chavanelle, Vivien; Gerbaix, Maude; Metz, Lore; Etienne, Monique; Walrand, Stéphane; Masgrau, Aurélie; Guillet, Christelle; Courteix, Daniel; Niu, Airu; Li, Yi-Ping; Capel, Fréderic; Sirvent, Pascal

    2015-01-01

    Some studies suggest that the signalling pathway of neuregulin 1 (NRG1), a protein involved in the regulation of skeletal muscle metabolism, could be altered by nutritional and exercise interventions. We hypothesized that diet-induced obesity could lead to alterations of the NRG1 signalling pathway and that chronic exercise could improve NRG1 signalling in rat skeletal muscle. To test this hypothesis, male Wistar rats received a high fat/high sucrose (HF/HS) diet for 16 weeks. At the end of this period, NRG1 and ErbB expression/activity in skeletal muscle was assessed. The obese rats then continued the HF/HS diet or were switched to a well-balanced diet. Moreover, in both groups, half of the animals also performed low intensity treadmill exercise training. After another 8 weeks, NRG1 and ErbB expression/activity in skeletal muscle were tested again. The 16 week HF/HS diet induced obesity, but did not significantly affect the NRG1/ErbB signalling pathway in rat skeletal muscle. Conversely, after the switch to a well-balanced diet, NRG1 cleavage ratio and ErbB4 amount were increased. Chronic exercise training also promoted NRG1 cleavage, resulting in increased ErbB4 phosphorylation. This result was associated with increased protein expression and phosphorylation ratio of the metalloprotease ADAM17, which is involved in NRG1 shedding. Similarly, in vitro stretch-induced activation of ADAM17 in rat myoblasts induced NRG1 cleavage and ErbB4 activation. These results show that low intensity endurance training and well-balanced diet activate the NRG1-ErbB4 pathway, possibly via the metalloprotease ADAM17, in skeletal muscle of diet-induced obese rats. PMID:25820551

  4. Peripheral blood c-erbB-2 expression by reverse transcriptase-polymerase chain reaction in breast cancer patients receiving chemotherapy.

    Science.gov (United States)

    Fonseca, Fernando L A; Soares, Heloisa P; Manhani, Ana Rita; Bendit, Israel; Novaes, Mafalda; Zatta, Simone M; Arias, Vitor; Pinhal, Maria Aparecida S; Weinschenker, Patrícia; del Giglio, Auro

    2002-08-01

    Minimal residual disease (MRD) evaluation in breast cancer patients is a promising tool to improve current staging procedures. In a previous work employing a CK-19-based reverse transcriptase-polymerase chain reaction (RT-PCR) technique for MRD detection, we identified a group of women who exhibited persistent negativity for this assay and for whom this technique was considered noninformative. In order to improve the yield of MRD detection in these patients, we evaluated the usefulness of RT-PCR detection of c-erbB-2 expression. We were able to detect up to 1 MCF-7 cell (positive for c-erbB-2 expression) in a mixture of 1,000,000 CCRF-CEM cells (negative for c-erbB-2 expression). We evaluated the specificity of this technique in the peripheral-blood mononuclear cells (PBMCs) of 20 healthy women and found that 2 of these women were positive for c-erbB-2 expression. In the PBMCs of a group of 16 women with breast cancer, 25% of the samples were positive for c-erbB-2 expression before chemotherapy. Except for race (P = 0.017), no other significant correlations were found, including c-erbB-2 expression in the primary tumor by immunoperoxidase. Interestingly, in the subgroup of 6 patients for whom this technique was informative, we found that 80% of the samples obtained while on chemotherapy were negative compared to only 10% obtained off treatment (P = 0.017). Additionally, 2 patients for whom CK-19 expression was noninformative had at least 1 c-erbB-2-positive sample. We conclude that this technique might be useful for MRD detection in breast cancer patients, but further studies are necessary to confirm our findings.

  5. Targeting inhibitor of apoptosis proteins in combination with ErbB antagonists in breast cancer.

    Science.gov (United States)

    Foster, Fiona M; Owens, Thomas W; Tanianis-Hughes, Jolanta; Clarke, Robert B; Brennan, Keith; Bundred, Nigel J; Streuli, Charles H

    2009-01-01

    Inhibitor of apoptosis (IAPs) proteins are a family of proteins that can block apoptosis in normal cells and have been suggested to cause resistance to apoptosis in cancer. Overexpression of oncogenic receptor tyrosine kinases is common in breast cancer; in particular 20% of all cases show elevated Her2. Despite clinical success with the use of targeted therapies, such as Trastuzumab, only up to 35% of Her2-positive patients initially respond. We reasoned that IAP-mediated apoptosis resistance might contribute to this insensitivity to receptor tyrosine kinase therapy, in particular ErbB antagonists. Here we examine the levels of IAPs in breast cancer and evaluate whether targeting IAPs can enhance apoptosis in response to growth factor receptor antagonists and TRAIL. IAP levels were examined in a breast cancer cell line panel and in patient samples. IAPs were inhibited using siRNA or cell permeable mimetics of endogenous inhibitors. Cells were then exposed to TRAIL, Trastuzumab, Lapatinib, or Gefitinib for 48 hours. Examining nuclear morphology and staining for cleaved caspase 3 was used to score apoptosis. Proliferation was examined by Ki67 staining. Four members of the IAP family, Survivin, XIAP, cIAP1 and cIAP2, were all expressed to varying extents in breast cancer cell lines or tumours. MDAMB468, BT474 and BT20 cells all expressed XIAP to varying extents. Depleting the cells of XIAP overcame the intrinsic resistance of BT20 and MDAMB468 cells to TRAIL. Moreover, siRNA-based depletion of XIAP or use of a Smac mimetic to target multiple IAPs increased apoptosis in response to the ErbB antagonists, Trastuzumab, Lapatinib or Gefitinib in Her2-overexpressing BT474 cells, or Gefitinib in EGFR-overexpressing MDAMB468 cells. The novel findings of this study are that multiple IAPs are concomitantly expressed in breast cancers, and that, in combination with clinically relevant Her2 treatments, IAP antagonists promote apoptosis and reduce the cell turnover index of

  6. The single N-glycan deletion mutant of soluble ErbB3 protein attenuates heregulin β1-induced tumor progression by blocking of the HIF-1 and Nrf2 pathway

    Energy Technology Data Exchange (ETDEWEB)

    Takamiya, Rina, E-mail: rinataka0429@gmail.com; Takahashi, Motoko; Uehara, Yasuaki; Ariki, Shigeru; Hashimoto, Jiro; Hasegawa, Yoshihiro; Kuroki, Yoshio

    2014-11-21

    Highlights: • The sErbB3 N418Q mutant blocks heregulin β1 induced nuclear accumulation of HIF-1α. • The sErbB3 N418Q mutant attenuates cancer cell migration induced by heregulin β1. • The sErbB3 N418Q mutant blocks heregulin β1 induced nuclear accumulation of Nrf2. • The sErbB3 N418Q mutant may be a potential therapeutic application for tumor. - Abstract: It has been well documented that activation of the ErbB3–PI3K–Akt pathway is implicated in tumor survival and progression. We previously demonstrated that the single N-glycan deletion mutant of soluble ErbB3 protein (sErbB3 N418Q) attenuates heregulin β1-induced ErbB3 signaling. The active PI3K–Akt pathway augments the nuclear accumulation of hypoxia inducible factor (HIF)-1α, which activates the transcription of many target genes and drives cancer progression. In this study, we focused on the effects of sErbB3 N418Q mutant on nuclear accumulation of HIF-1α. Pretreatment with the sErbB3 N418Q mutant suppressed heregulin β1-induced HIF-1α activation in MCF7 cells. Similar results were also obtained in other breast cancer cell lines, T47D and BT474. Interestingly, these suppressive effects were not observed with the sErbB3 wild type. In addition, pretreatment with the sErbB3 N418Q mutant suppressed the cell migration of MCF7 cells induced by heregulin β1. Furthermore, incubation with heregulin β1 also induced the nuclear accumulation of Nrf2, and this effect was also reduced by the sErbB3 N418Q mutant, but not the sErbB3 wild type. These findings indicated that the sErbB3 N418Q mutant suppressed malignant formation of cancer cells by blocking of the HIF-1α and Nrf2 pathways.

  7. Oser le corps

    Directory of Open Access Journals (Sweden)

    Alex Cormanski

    2015-05-01

    Full Text Available Le corps est la voie primordiale dans le processus d’énonciation, mais reste encore (trop souvent corps étranger dans le processus d’enseignement/apprentissage des langues étrangères. Or entrer dans une langue étrangère, se l’approprier physiquement, sonner juste dans une autre langue, précisément pour qu’elle ne soit plus étrangère, implique un travail sur le corps, peut impliquer un transfert de corporéité. Oser les pratiques de corps dans la classe de langue : voie incontournable pour éviter les voix dissonantes. Dare the body voice Abstract: Focusing and working on the body is inescapable in the process of enunciation, but unfortunately not sufficiently put into practice in language learning. Speaking a foreign language, being attuned in that target language, i.e. to sound as close as possible to a native speaker, implies to work on the body physically as well as mentally, which means dealing with representation because of the transfer of identity the user may experience. Dare the body voice for a body change when switching from a language to another is a necessary direction the teacher ought to lead the learners to work on.

  8. Candide et le physicien

    CERN Document Server

    Espagnat, Bernard d'

    2008-01-01

    Les avancées considérables de la physique d'après guerre n'ont - on le sait - été possibles qu'au prix d'une vraie rupture entre elle et la physique dite " classique ". A quels changements cette rupture nous contraint-elle en ce qui concerne des notions essentielles, telles celles d'espace, de temps, d'objet et d'objectivité ? Quelles en sont les incidences quant à la portée de la connaissance, au rôle de la conscience, aux relations entre science et ontologie ? Ce sont là des questions de fond, fort délicates, auxquelles les personnes de tendance quelque peu philosophique sont plus sensibles que ne le sont les physiciens. Malheureusement, les premières ne disposent normalement pas des connaissances de pointe qui seules permettent d'approfondir de tels problèmes sans trop risquer de s'égarer. Etant donné l'impact que, par ses applications, la science a sur nos vies, nombreux sont ceux qui souhaitent se former une idée plus juste de ce qu'elle implique vraiment. Le présent ouvrage prend la for...

  9. Dynamical mechanism of Bmal 1 / Rev- erbα loop in circadian clock

    Science.gov (United States)

    Li, Ying; Liu, Zengrong

    2015-07-01

    In mammals, the circadian clock is driven by multiple integrated transcriptional feedback loops involving three kinds of central clock-controlled elements (CCEs): E-boxes, D-boxes and ROR-elements. With the aid of CCEs, the concentrations of the active proteins are approximated by the delayed concentrations of mRNAs, which simplifies the circadian system drastically. The regulatory loop composed by BMAL1 and REV-ERB- α plays important roles in circadian clock. With delay differential equations, we gave a mathematical model of this loop and investigated its dynamical mechanisms. Specially, we theoretically provided the sufficient conditions for sustained oscillation of the loop with Hopf bifurcation theory. The total of delays determines the emergence of oscillators, which explains the crucial roles of delays in circadian clock revealed by biological experiments. Numerically, we studied the amplitude and period against the variations of delays and the degradation rates. The different sensitivities of amplitude and period on these factors provide ideas to adjust the amplitude or period of circadian oscillators.

  10. Stimulation of nuclear receptor REV-ERBs regulates tumor necrosis factor-induced expression of proinflammatory molecules in C6 astroglial cells

    Energy Technology Data Exchange (ETDEWEB)

    Morioka, Norimitsu, E-mail: mnori@hiroshima-u.ac.jp; Tomori, Mizuki; Zhang, Fang Fang; Saeki, Munenori; Hisaoka-Nakashima, Kazue; Nakata, Yoshihiro

    2016-01-08

    Under physiological conditions, astrocytes maintain homeostasis in the CNS. Following inflammation and injury to the CNS, however, activated astrocytes produce neurotoxic molecules such as cytokines and chemokines, amplifying the initial molecular-cellular events evoked by inflammation and injury. Nuclear receptors REV-ERBα and REV-ERBβ (REV-ERBs) are crucial in the regulation of inflammation- and metabolism-related gene transcription. The current study sought to elucidate a role of REV-ERBs in rat C6 astroglial cells on the expression of inflammatory molecules following stimulation with the neuroinflammatory cytokine tumor necrosis factor (TNF). Stimulation of C6 cells with TNF (10 ng/ml) significantly increased the mRNA expression of CCL2, interleukin-6 (IL-6), inducible nitric oxide synthase (iNOS), and matrix metalloprotease (MMP)-9, but not fibroblast growth factor-2 (FGF-2), cyclooxygenase-2 (COX-2) and MMP-2. Treatment with either REV-ERB agonists GSK4112 or SR9009 significantly blocked TNF-induced upregulation of CCL2 mRNA and MMP-9 mRNA, but not IL-6 mRNA and iNOS mRNA expression. Furthermore, treatment with RGFP966, a selective histone deacetylase 3 (HDAC3) inhibitor, potently reversed the inhibitory effects of GSK4112 on TNF-induced expression of MMP-9 mRNA, but not CCL2 mRNA. Expression of Rev-erbs mRNA in C6 astroglial cells, primary cultured rat cortical and spinal astrocytes was confirmed by reverse transcription polymerase chain reaction. Together, the findings demonstrate an anti-inflammatory effect, downregulating of MMP-9 and CCL2 transcription, of astroglial REV-ERBs activation through HDAC3-dependent and HDAC3-independent mechanisms. - Highlights: • Rev-erbα mRNA and Rev-erbβ mRNA are expressed in C6 astroglial cells. • TNF increases the expression of CCL2, IL-6, MMP-9 and iNOS mRNA. • REV-ERB activation inhibits CCL2 mRNA and MMP-9 mRNA expression. • HDAC3 activity is involved in the inhibitory effect of REV-ERB on MMP-9 induction.

  11. Stimulation of nuclear receptor REV-ERBs regulates tumor necrosis factor-induced expression of proinflammatory molecules in C6 astroglial cells

    International Nuclear Information System (INIS)

    Morioka, Norimitsu; Tomori, Mizuki; Zhang, Fang Fang; Saeki, Munenori; Hisaoka-Nakashima, Kazue; Nakata, Yoshihiro

    2016-01-01

    Under physiological conditions, astrocytes maintain homeostasis in the CNS. Following inflammation and injury to the CNS, however, activated astrocytes produce neurotoxic molecules such as cytokines and chemokines, amplifying the initial molecular-cellular events evoked by inflammation and injury. Nuclear receptors REV-ERBα and REV-ERBβ (REV-ERBs) are crucial in the regulation of inflammation- and metabolism-related gene transcription. The current study sought to elucidate a role of REV-ERBs in rat C6 astroglial cells on the expression of inflammatory molecules following stimulation with the neuroinflammatory cytokine tumor necrosis factor (TNF). Stimulation of C6 cells with TNF (10 ng/ml) significantly increased the mRNA expression of CCL2, interleukin-6 (IL-6), inducible nitric oxide synthase (iNOS), and matrix metalloprotease (MMP)-9, but not fibroblast growth factor-2 (FGF-2), cyclooxygenase-2 (COX-2) and MMP-2. Treatment with either REV-ERB agonists GSK4112 or SR9009 significantly blocked TNF-induced upregulation of CCL2 mRNA and MMP-9 mRNA, but not IL-6 mRNA and iNOS mRNA expression. Furthermore, treatment with RGFP966, a selective histone deacetylase 3 (HDAC3) inhibitor, potently reversed the inhibitory effects of GSK4112 on TNF-induced expression of MMP-9 mRNA, but not CCL2 mRNA. Expression of Rev-erbs mRNA in C6 astroglial cells, primary cultured rat cortical and spinal astrocytes was confirmed by reverse transcription polymerase chain reaction. Together, the findings demonstrate an anti-inflammatory effect, downregulating of MMP-9 and CCL2 transcription, of astroglial REV-ERBs activation through HDAC3-dependent and HDAC3-independent mechanisms. - Highlights: • Rev-erbα mRNA and Rev-erbβ mRNA are expressed in C6 astroglial cells. • TNF increases the expression of CCL2, IL-6, MMP-9 and iNOS mRNA. • REV-ERB activation inhibits CCL2 mRNA and MMP-9 mRNA expression. • HDAC3 activity is involved in the inhibitory effect of REV-ERB on MMP-9 induction.

  12. Em08red, a dual functional antiproliferative emodin analogue, is a downregulator of ErbB2 expression and inducer of intracellular oxidative stress

    Directory of Open Access Journals (Sweden)

    Liang FP

    2015-03-01

    Full Text Available Fong-Pin Liang,1,* Jin-Cherng Lien,1,* Yu-Hua Wu,2 Chien-Shu Chen,2 Shin-Hun Juang1–3 1Graduate Institute of Pharmaceutical Chemistry, 2School of Pharmacy and Department of Pediatrics, Children’s Hospital, 3Department of Medical Research, China Medical University Hospital, Taichung, Taiwan *These authors contributed equally to this work Abstract: Expression of ErbB2 protein is inversely correlated with the prognosis in cancer patients. Consequently, strategies targeting ErbB2 remain an attractive option in treating several types of malignancies, including oral cancer. In addition, many studies have shown that emodin and emodin derivatives are able to inhibit growth of ErbB2-overexpressing tumor cells. In this study, a series of computer modeling-generated emodin analogues were synthesized and tested for their antiproliferative activity against oral cancer cell lines overexpressing ErbB2. Among these analogues, em08red (1,8-dihydroxy-9(10H-anthracenone demonstrated potent antiproliferative activity against all three tested ErbB2-overexpressing cell lines, ie, FaDu, HSC3, and OECM1. Treatment with em08red significantly downregulated activation of ErbB2 as well as the ErbB2 protein expression level in the tested cell lines and induced G2 arrest. Antiapoptosis protein (Bcl-xl and Bcl-2 expression levels were also downregulated, and active caspase-3 and caspase-9 was detected in cells after treatment with em08red. Moreover, treatment with em08red stimulated production of cytotoxic reactive oxygen species in treated cells, and this could be partially reversed by pretreatment with N-acetylcysteine. Overall, we demonstrated inhibition of ErbB2 function and induction of reactive oxygen species in tumor cells by em08red, which prevented proliferation of tumor cells and induced apoptotic cell death. Keywords: ErbB2, emodin, em08red, reactive oxygen species, structure-activity relationship 

  13. Le vase de Pandore

    Directory of Open Access Journals (Sweden)

    Nicola Panichi

    2000-06-01

    Full Text Available Il s’agit ici de suivre les stratégies discursives par lesquelles Érasme situe sa Lingua sous le patronage symbolique de deux mythes des plus opératoires à la Renaissance : le vase de Pandore et la tour de Babel, tous deux verrouillant le texte, l’un en guise d’incipit, l’autre d’explicit, dans un dialogue où chacun use de l’autre pour renforcer les significations et instaurer le régime sémantique du texte, tant linguistique qu’éthique. Ce sont ces jeux complexes entre différents niveaux de discours dont dépend le sens ultime de l’œuvre que cet article s’attache à saisir.Se trata de seguir aquí las estrategias discursivas mediante las cuales Erasmo sitúa su Lingua bajo el dominio simbólico de dos de los mitos más funcionales del Renacimiento: el vaso de Pandora y la torre de Babel, los cuales limitan el texto, uno a modo de íncipit, otro de excipit, en un diálogo en el que se valen el uno del otro para reforzar los significados y establecer el régimen semántico del texto, tanto lingüístico como ético. Son esos juegos complejos entre diferentes niveles de discurso, de los que depende el sentido último de la obra, que este artículo intenta captar.

  14. Anti-metastasis activity of black rice anthocyanins against breast cancer: analyses using an ErbB2 positive breast cancer cell line and tumoral xenograft model.

    Science.gov (United States)

    Luo, Li-Ping; Han, Bin; Yu, Xiao-Ping; Chen, Xiang-Yan; Zhou, Jie; Chen, Wei; Zhu, Yan-Feng; Peng, Xiao-Li; Zou, Qiang; Li, Sui-Yan

    2014-01-01

    Increasing evidence from animal, epidemiological and clinical investigations suggest that dietary anthocyanins have potential to prevent chronic diseases, including cancers. It is also noteworthy that human epidermal growth factor receptor 2 (ErbB2) protein overexpression or ErbB2 gene amplification has been included as an indicator for metastasis and higher risk of recurrence for breast cancer. The present experiments investigated the anti-metastasis effects of black rice anthocyanins (BRACs) on ErbB2 positive breast cancer cells in vivo and in vitro. Oral administration of BRACs (150 mg/kg/day) reduced transplanted tumor growth, inhibited pulmonary metastasis, and decreased lung tumor nodules in BALB/c nude mice bearing ErbB2 positive breast cancer cell MDA-MB-453 xenografts. The capacity for migration, adhesion, motility and invasion was also inhibited by BRACs in MDA-MB-453 cells in a concentration dependent manner, accompanied by decreased activity of a transfer promoting factor, urokinase-type plasminogen activator (u-PA). Together, our results indicated that BRACs possess anti-metastasis potential against ErbB2 positive human breast cancer cells in vivo and in vitro through inhibition of metastasis promoting molecules.

  15. RhNRG-1β Protects the Myocardium against Irradiation-Induced Damage via the ErbB2-ERK-SIRT1 Signaling Pathway.

    Directory of Open Access Journals (Sweden)

    Anxin Gu

    Full Text Available Radiation-induced heart disease (RIHD, which is a serious side effect of the radiotherapy applied for various tumors due to the inevitable irradiation of the heart, cannot be treated effectively using current clinical therapies. Here, we demonstrated that rhNRG-1β, an epidermal growth factor (EGF-like protein, protects myocardium tissue against irradiation-induced damage and preserves cardiac function. rhNRG-1β effectively ameliorated irradiation-induced myocardial nuclear damage in both cultured adult rat-derived cardiomyocytes and rat myocardium tissue via NRG/ErbB2 signaling. By activating ErbB2, rhNRG-1β maintained mitochondrial integrity, ATP production, respiratory chain function and the Krebs cycle status in irradiated cardiomyocytes. Moreover, the protection of irradiated cardiomyocytes and myocardium tissue by rhNRG-1β was at least partly mediated by the activation of the ErbB2-ERK-SIRT1 signaling pathway. Long-term observations further showed that rhNRG-1β administered in the peri-irradiation period exerts continuous protective effects on cardiac pump function, the myocardial energy metabolism, cardiomyocyte volume and interstitial fibrosis in the rats receiving radiation via NRG/ErbB2 signaling. Our findings indicate that rhNRG-1β can protect the myocardium against irradiation-induced damage and preserve cardiac function via the ErbB2-ERK-SIRT1 signaling pathway.

  16. Simultaneous suppression of epidermal growth factor receptor and c-erbB-2 reverses aneuploidy and malignant phenotype of a human ovarian carcinoma cell line.

    Science.gov (United States)

    Pack, Svetlana D; Alper, Ozgül M; Stromberg, Kurt; Augustus, Meena; Ozdemirli, Metin; Miermont, Anne M; Klus, Greg; Rusin, Marek; Slack, Rebecca; Hacker, Neville F; Ried, Thomas; Szallasi, Zoltan; Alper, Ozge

    2004-02-01

    Coexpression of epidermal growth factor receptor (EGFR) and c-erbB-2 in 47-68% of ovarian cancer cells indicate their strong association with tumor formation. We examined the effects of simultaneous antisense- or immunosuppression of EGFR and c-erbB-2 expression on the invasive phenotype, aneuploidy, and genotype of cultured human ovarian carcinoma cells (NIH:OVCAR-8). We report here that suppression of both EGFR and c-erbB-2 results in regression of aneuploidy and genomic imbalances in NIH:OVCAR-8 cells, restores a more normal phenotype, and results in a more normal gene expression profile. Combined with cytogenetic analysis, our data demonstrate that the regression of aneuploidy is due to the selective apoptosis of double antisense transfected cells with highly abnormal karyotype.

  17. Le monde quantique

    CERN Document Server

    Aspect, A; Bensaude-Vincent, B; Castiel, A; Chevalley, C; Darrigol, O; Deligeorges, S; D'Espagnat, B; Laloë, F; Lévy-Leblond, J-M; Messiah, A; Paty, M; Vuillemin, J; Wheaton, B R

    1984-01-01

    Le monde quantique La physique quantique, après trois quarts de siècle, n'en finit pas d'être moderne. Elle est présente quotidiennement dans les laboratoires où les physiciens étudient atomes, noyaux et particules. Elle est entrée dans l'industrie où lasers, transistors et supraconducteurs lui doivent d'exister. Et elle continue à alimenter le débat philosophique sur la nature de la réalité dont elle montre la non-séparabilité fondamentale. Ses concepts de base, son développement, ses applications, ses controverses sont ici présentés par une pléiade de physiciens, d'historiens et de philosophes.

  18. Le charme slave

    Directory of Open Access Journals (Sweden)

    Antonella Mauri

    2012-09-01

    Full Text Available Antonella Mauri analyse l’image des femmes slaves immigrées en Italie telle qu’elle apparaît à travers la publicité, la littérature romanesque (La ballata dei lavavetri de Peter Del monte, Luce Profuga de Valerio Aiolli, Pornokiller de Bruno Ventavoli, le cinéma, la bande dessinée (Danilo Maramotti, image qu’elle oppose aux résultats d’une enquête qu’elle a menée sur le terrain. Elle s’interroge en particulier sur la permanence des stéréotypes liés à la femme slave.

  19. Le Nordais on schedule

    International Nuclear Information System (INIS)

    Anon.

    1998-01-01

    The first phase of the Le Nordais wind farm project in the Gaspe Peninsula in Quebec is on schedule. It was announced that the project's first turbines will be turning by September 1998. Hydro-Quebec has agreed to buy power from the 100 MW wind farm. The Le Nordais consortium plans to have 76,750 kW turbines in service in Cap-Chat by December 1998. Many of the foundations for the towers are poured and a substation is under construction. The turbines that are currently in use come from Denmark, but 20 of the 76 turbines being slated for installation this year will come from NEG Micon Canada Inc.'s assembly plant in Quebec. The Quebec government is providing a $5.6 million grant for their production and for turbine assembly in Quebec. During phase two, an additional 57 turbines will be installed in Matane by the end of 1999. 1 fig

  20. Le forme del fondo

    Directory of Open Access Journals (Sweden)

    Michel Maffesoli

    2004-12-01

    Full Text Available Non è vero che la natura ha paura del vuoto. Forse addirittura si completa. Il vuoto è anche una modalità dell'essere. È possibile nidificarvisi, avvolgersi pigramente e, così, proteggersi dall'angoscia del tempo che passa. Il vuoto delle apparenze è, in alcuni momenti, una delle forme d'espressione della vita sociale. Oltretutto occorre saperle riconoscere. Certamente, abbiamo tutti un'esistenza personale, ma siamo, ugualmente, i rappresentanti, a volte anche le vittime, di uno "spirito comune", forse anche di un "inconscio collettivo" che si è costituito di secolo in secolo. E, molto spesso, quando crediamo di esprimere le nostre idee, siamo soltanto dei portavoce, comparse di un vasto "theatrum mundi" dalle dimensioni infinite.

  1. Garder le rythme

    OpenAIRE

    Arnaud-Demir, Françoise

    2015-01-01

    Chez les Alévis de Turquie, hommes et femmes se réunissent pour de longues assemblées nocturnes, le cem ou « cérémonie collective », sous la houlette d’un guide spirituel appelé dede (« grand-père, ancêtre »), lui-même assisté par des bardes (aşık) et divers officiants. Ces cérémonies se composent de chants et de danses accompagnés au luth saz. Près de Divriği, dans la province de Sivas, cette danse rituelle, le semah (d’un étymon arabe signifiant « écoute »), applique un schéma complexe, alt...

  2. Le CRDI en Mongolie

    International Development Research Centre (IDRC) Digital Library (Canada)

    touchent la steppe de même que les régions forestières et montagneuses. Utilisation des technologies numériques. Dès le début des années 1990, grâce à des subventions et à des conseils techniques du CRDI, un fournisseur local de services de communication de données, Datacom, a pu fournir l'accès Internet à la ...

  3. Le CRDI au Ghana

    International Development Research Centre (IDRC) Digital Library (Canada)

    pour prévenir le paludisme, des études ayant démontré que leur utilisation pouvait réduire considérablement la mortalité infantile. Les chercheurs ont également suggéré aux gouvernements différents moyens pour inciter les gens à acheter les moustiquaires et à les utiliser correctement. Les TI au service de la démocratie.

  4. Le CRDI en Chine

    International Development Research Centre (IDRC) Digital Library (Canada)

    les employés du secteur non structuré ont de meilleures conditions de travail. □ les citoyens influencent les décisions relatives aux dépenses publiques. Soutien accordé par le CRDI depuis 1981. 222 activités d'une valeur de 59 millions CAD. Chercheurs et agriculteurs s'emploient à améliorer les moyens de subsistance.

  5. Le CRDI en Tunisie

    International Development Research Centre (IDRC) Digital Library (Canada)

    les citoyens arabes sont plus présents sur Internet. Soutien accordé depuis 1975. 49 activités. 8 millions cad. Dans la foulée du Printemps arabe, les chercheurs conçoivent des réformes visant à assurer l'essor de la démocratie et en examinent la validité. CRDI centre de recherches pour le développement international.

  6. Le CRDI au Bangladesh

    International Development Research Centre (IDRC) Digital Library (Canada)

    d'agriculteurs ont trouvé des solutions de remplacement à la culture du tabac. Petit à petit, les agriculteurs améliorent ... réduire la pollution de l'air et à mieux utiliser l'eau. Soutien accordé par le CRDI depuis 1974 ... violence endémique, car la cause profonde du mécontentement — l'absence de démocra- tie plutôt que les ...

  7. Le CRDI en Colombie

    International Development Research Centre (IDRC) Digital Library (Canada)

    activités de longue haleine qui ont eu pour but d'appuyer la réinsertion des anciens combattants ... Internet à son programme d'insertion sociale des enfants de la rue victimes d'exploitation ... Des travaux subventionnés par le CRDI ont aidé une fondation à intégrer Internet à son programme d'insertion sociale des enfants ...

  8. Effect of acute acid-base disturbances on ErbB1/2 tyrosine phosphorylation in rabbit renal proximal tubules.

    Science.gov (United States)

    Skelton, Lara A; Boron, Walter F

    2013-12-15

    The renal proximal tubule (PT) is a major site for maintaining whole body pH homeostasis and is responsible for reabsorbing ∼80% of filtered HCO3(-), the major plasma buffer, into the blood. The PT adapts its rate of HCO3(-) reabsorption (JHCO3(-)) in response to acute acid-base disturbances. Our laboratory previously showed that single isolated perfused PTs adapt JHCO3(-) in response to isolated changes in basolateral (i.e., blood side) CO2 and HCO3(-) concentrations but, surprisingly, not to pH. The response to CO2 concentration can be blocked by the ErbB family tyrosine kinase inhibitor PD-168393. In the present study, we exposed enriched rabbit PT suspensions to five acute acid-base disturbances for 5 and 20 min using a panel of phosphotyrosine (pY)-specific antibodies to determine the influence of each disturbance on pan-pY, ErbB1-specific pY (four sites), and ErbB2-specific pY (two sites). We found that each acid-base treatment generated a distinct temporal pY pattern. For example, the summated responses of the individual ErbB1/2-pY sites to each disturbance showed that metabolic acidosis (normal CO2 concentration and reduced HCO3(-) concentration) produced a transient summated pY decrease (5 vs. 20 min), whereas metabolic alkalosis produced a transient increase. Respiratory acidosis (normal HCO3(-) concentration and elevated CO2 concentration) had little effect on summated pY at 5 min but produced an elevation at 20 min, whereas respiratory alkalosis produced a reduction at 20 min. Our data show that ErbB1 and ErbB2 in the PT respond to acute acid-base disturbances, consistent with the hypothesis that they are part of the signaling cascade.

  9. TGF-α/HA complex promotes tympanic membrane keratinocyte migration and proliferation via ErbB1 receptor

    Energy Technology Data Exchange (ETDEWEB)

    Mei Teh, Bing, E-mail: bing.teh@earscience.org.au [Ear Sciences Centre, School of Surgery, The University of Western Australia, Nedlands, WA (Australia); Ear Science Institute Australia, Subiaco, WA (Australia); Department of Otolaryngology, Head, Neck and Skull Base Surgery, Sir Charles Gairdner Hospital, Nedlands, WA (Australia); Redmond, Sharon L. [Ear Sciences Centre, School of Surgery, The University of Western Australia, Nedlands, WA (Australia); Ear Science Institute Australia, Subiaco, WA (Australia); Shen, Yi [Ear Sciences Centre, School of Surgery, The University of Western Australia, Nedlands, WA (Australia); Ear Science Institute Australia, Subiaco, WA (Australia); Department of Otolaryngology, Head and Neck, Ningbo Lihuili Hospital (Ningbo Medical Centre), Ningbo, Zhejiang (China); Atlas, Marcus D. [Ear Sciences Centre, School of Surgery, The University of Western Australia, Nedlands, WA (Australia); Ear Science Institute Australia, Subiaco, WA (Australia); Department of Otolaryngology, Head, Neck and Skull Base Surgery, Sir Charles Gairdner Hospital, Nedlands, WA (Australia); Marano, Robert J.; Dilley, Rodney J. [Ear Sciences Centre, School of Surgery, The University of Western Australia, Nedlands, WA (Australia); Ear Science Institute Australia, Subiaco, WA (Australia)

    2013-04-01

    Tympanic membrane perforations are common and represent a management challenge to clinicians. Current treatments for chronic perforations involve a graft surgery and require general anaesthesia, including associated costs and morbidities. Bioactive molecules (e.g. growth factors, cytokines) play an important role in promoting TM wound healing following perforation and the use of growth factors as a topical treatment for tympanic membrane perforations has been suggested as an alternative to surgery. However, the choice of bioactive molecules best suited to promote wound healing has yet to be identified. We investigated the effects of hyaluronic acid, vitronectin, TGF-α, IL-24 and their combinations on migration, proliferation and adhesion of cultured human tympanic membrane-derived keratinocytes (hTM), in addition to their possible mechanisms of action. We found that TGF-α, TGF-α/HA and TGF-α/IL-24 promoted wound healing by significantly increasing both migration and proliferation. TGF-α and/or HA treated cells showed comparable cell–cell adhesion whilst maintaining an epithelial cell phenotype. With the use of receptor binding inhibitors for ErbB1 (AG1478) and CD44 (BRIC235), we revealed that the activation of ErbB1 is required for TGF-α/HA-mediated migration and proliferation. These results suggest factors that may be incorporated into a tissue-engineered membrane or directly as topical treatment for tympanic membrane perforations and hence reduce the need for a surgery. - Highlights: ► TGF-α, TGF-α/HA and TGF-α/IL-24 improved hTM keratinocyte migration and proliferation. ► TGF-α and/or HA maintained epithelial cell phenotype. ► TGF-α/HA-mediated migration and proliferation requires activation of ErbB1 receptor.

  10. An information theory approach for evaluating earth radiation budget (ERB) measurements - Nonuniform sampling of reflected shortwave radiation

    Science.gov (United States)

    Barkstrom, Bruce R.; Direskeneli, Haldun; Halyo, Nesim

    1992-01-01

    An information theory approach to examine the temporal nonuniform sampling characteristics of shortwave (SW) flux for earth radiation budget (ERB) measurements is suggested. The information gain is computed by computing the information content before and after the measurements. A stochastic diurnal model for the SW flux is developed, and measurements for different orbital parameters are examined. The methodology is applied to specific NASA Polar platform and Tropical Rainfall Measuring Mission (TRMM) orbital parameters. The information theory approach, coupled with the developed SW diurnal model, is found to be promising for measurements involving nonuniform orbital sampling characteristics.

  11. Intermittent hypoxia induces the proliferation of rat vascular smooth muscle cell with the increases in epidermal growth factor family and erbB2 receptor

    Energy Technology Data Exchange (ETDEWEB)

    Kyotani, Yoji, E-mail: cd147@naramed-u.ac.jp [Department of Pharmacology, Nara Medical University School of Medicine, Kashihara 634-8521 (Japan); Department of Pharmacy, Nara Medical University Hospital, Kashihara 634-8522 (Japan); Ota, Hiroyo [Second Department of Internal Medicine, Nara Medical University School of Medicine, Kashihara 634-8522 (Japan); Department of Biochemistry, Nara Medical University School of Medicine, Kashihara 634-8521 (Japan); Itaya-Hironaka, Asako; Yamauchi, Akiyo; Sakuramoto-Tsuchida, Sumiyo [Department of Biochemistry, Nara Medical University School of Medicine, Kashihara 634-8521 (Japan); Zhao, Jing; Ozawa, Kentaro; Nagayama, Kosuke; Ito, Satoyasu [Department of Pharmacology, Nara Medical University School of Medicine, Kashihara 634-8521 (Japan); Takasawa, Shin [Department of Biochemistry, Nara Medical University School of Medicine, Kashihara 634-8521 (Japan); Kimura, Hiroshi [Second Department of Internal Medicine, Nara Medical University School of Medicine, Kashihara 634-8522 (Japan); Uno, Masayuki [Department of Pharmacy, Nara Medical University Hospital, Kashihara 634-8522 (Japan); Yoshizumi, Masanori [Department of Pharmacology, Nara Medical University School of Medicine, Kashihara 634-8521 (Japan)

    2013-11-15

    Obstructive sleep apnea is characterized by intermittent hypoxia (IH), and associated with cardiovascular diseases, such as stroke and heart failure. These cardiovascular diseases have a relation to atherosclerosis marked by the proliferation of vascular smooth muscle cells (VSMCs). In this study, we investigated the influence of IH on cultured rat aortic smooth muscle cell (RASMC). The proliferation of RASMC was significantly increased by IH without changing the level of apoptosis. In order to see what induces RASMC proliferation, we investigated the influence of normoxia (N)-, IH- and sustained hypoxia (SH)-treated cell conditioned media on RASMC proliferation. IH-treated cell conditioned medium significantly increased RASMC proliferation compared with N-treated cell conditioned medium, but SH-treated cell conditioned medium did not. We next investigated the epidermal growth factor (EGF) family as autocrine growth factors. Among the EGF family, we found significant increases in mRNAs for epiregulin (ER), amphiregulin (AR) and neuregulin-1 (NRG1) in IH-treated cells and mature ER in IH-treated cell conditioned medium. We next investigated the changes in erbB family receptors that are receptors for ER, AR and NRG1, and found that erbB2 receptor mRNA and protein expressions were increased by IH, but not by SH. Phosphorylation of erbB2 receptor at Tyr-1248 that mediates intracellular signaling for several physiological effects including cell proliferation was increased by IH, but not by SH. In addition, inhibitor for erbB2 receptor suppressed IH-induced cell proliferation. These results provide the first demonstration that IH induces VSMC proliferation, and suggest that EGF family, such as ER, AR and NRG1, and erbB2 receptor could be involved in the IH-induced VSMC proliferation. - Highlights: ●In vitro system for intermittent hypoxia (IH) and sustained hypoxia (SH). ●IH, but not SH, induces the proliferation of rat vascular smooth muscle cell. ●Epiregulin m

  12. Le nouveau modèle africain | IDRC - International Development ...

    International Development Research Centre (IDRC) Digital Library (Canada)

    22 juil. 2011 ... L'annulation de la dette, un commerce plus équitable, davantage d'aide : voilà le plan d'action mondial dont on convient qu'il faut de toute urgence mettre en oeuvre en vue d'accélérer le développement en Afrique. Or, ce serait rater le bateau que de ne pas s'engager dans la voie tout autre que les ...

  13. Le Conseil des gouverneurs | CRDI - Centre de recherches pour le ...

    International Development Research Centre (IDRC) Digital Library (Canada)

    Le Conseil des gouverneurs guide le travail du CRDI en lui fournissant une orientation stratégique, en examinant ses activités et en approuvant ses budgets. Les gouverneurs – un maximum de 14 – sont nommés par le gouverneur en conseil du Canada pour un mandat d'au plus quatre ans, qui peut être reconduit. La Loi ...

  14. Sur le genre Apoleon, Gorh

    NARCIS (Netherlands)

    Fairmaire, L.

    1887-01-01

    Dans les »Notes from the Leyden Museum”, vol. VII (1885) p. 51, Mr. Gorham a décrit sous le nom d’ ’Apoleon un nouveau genre de Bostrychide, créé pour un insecte de Malacca, rencontré aussi au Laos, à Bornéo et à Sumatra, A. edax. Ce genre est identique avec le genre Dysides Perty, dont le type, D.

  15. Le regard anachronique

    Directory of Open Access Journals (Sweden)

    Jean-Paul Aubert

    2011-01-01

    Full Text Available Cet article a pour objet l’anachronisme dans le film historique. Il s’appuie sur l’étude du long métrage Goya à Bordeaux, réalisé en 1999 par le cinéaste espagnol Carlos Saura. Cette biographie filmée du peintre Francisco de Goya fait mieux que composer avec l’anachronisme inhérent à toute reconstitution historique. Il l’assume et le revendique. La mise en cause de la chronologie et l’effacement de l’Histoire prennent sens dans la perspective d’une réflexion originale sur l’Histoire de l’art conçue comme un dialogue entre les œuvres et entre les époques.Este artículo está dedicado al problema del anacronismo en las películas históricas. Se basa en el estudio de Goya en Burdeos, un largo metraje rodado en 1999 por el director de cine español Carlos Saura. Esta biografía de Goya no sólo se acomoda con el anacronismo propio de la reconstitución histórica sino que lo asume y lo reivindica. El cuestionamiento de la cronología y el desinterés por la Historia cobran un nuevo sentido en el marco de una reflexión original sobre la Historia del arte concebida como un diálogo entre las obras y entre las épocas.

  16. La piraterie sur le web

    CERN Multimedia

    2002-01-01

    Les échanges de toutes sortes sont facilités à l'extrême par le web: des forums, des vidéoconférences, le commerce à distance, ou tout simplement la célérité des courriers électroniques ou la convivialité des chats, tout cela participe de la société de communication. Une certaine partie du monde découvre le nouvel horizon des échanges quasi instantanés, mais... les transactions sur le web sont-elles vraiment s res?

  17. Le donne briganti

    OpenAIRE

    Cosco, Silvio

    2013-01-01

    Texto completo descargado desde Teseo Le donne briganti es una tesis interdisciplinaria, de carácter histórico-filológico con un enfoque de estudio de género. Es un trabajo que nace del interés por un argumento, el bandolerismo de la primera década del Reino de Italia, que durante mucho tiempo y a sabiendas, ha sido tratado como una reacción menor y criminal al proyecto de unificación italiana, callando las razones de las poblaciones meridionales afectada antes por la invasión y luego por...

  18. Travailler le vison

    OpenAIRE

    Gorre, Jean-François

    2007-01-01

    Dans notre société, la fourrure est porteuse de valeurs symboliques. D'autres travaux ont montré comment elle est l'expression du jeu entre nature et culture : investissement de la force de l'animal, expression du sauvage, marque de la domestication de la nature (Delort 1973, Pouchelle 1981). Notre propos sera différent. Nous étudierons dans le cadre du métier de fourreur, à travers une technique particulière, l'« allonge », la teneur de l'affrontement entre deux groupes socio-professionnels....

  19. Le CRDI au Bhoutan

    International Development Research Centre (IDRC) Digital Library (Canada)

    tance. Le collège a adopté une application. Web qui permet aux enseignants de créer des sites d'apprentissage en ligne, il a offert des cours en informatique aux enseignants et aux étudiants et il a conçu son propre site Web. Il a également établi neuf centres d'études régionaux dans des écoles. La mesure des progrès.

  20. A comprehensive, multi-scale dynamical model of ErbB receptor signal transduction in human mammary epithelial cells.

    Directory of Open Access Journals (Sweden)

    Tomáš Helikar

    Full Text Available The non-receptor tyrosine kinase Src and receptor tyrosine kinase epidermal growth factor receptor (EGFR/ErbB1 have been established as collaborators in cellular signaling and their combined dysregulation plays key roles in human cancers, including breast cancer. In part due to the complexity of the biochemical network associated with the regulation of these proteins as well as their cellular functions, the role of Src in EGFR regulation remains unclear. Herein we present a new comprehensive, multi-scale dynamical model of ErbB receptor signal transduction in human mammary epithelial cells. This model, constructed manually from published biochemical literature, consists of 245 nodes representing proteins and their post-translational modifications sites, and over 1,000 biochemical interactions. Using computer simulations of the model, we find it is able to reproduce a number of cellular phenomena. Furthermore, the model predicts that overexpression of Src results in increased endocytosis of EGFR in the absence/low amount of the epidermal growth factor (EGF. Our subsequent laboratory experiments also suggest increased internalization of EGFR upon Src overexpression under EGF-deprived conditions, further supporting this model-generated hypothesis.

  1. The negative cell cycle regulator, Tob (transducer of ErbB-2), is involved in motor skill learning

    International Nuclear Information System (INIS)

    Wang Xinming; Gao Xiang; Zhang Xuehan; Tu Yanyang; Jin Meilei; Zhao Guoping; Yu Lei; Jing Naihe; Li Baoming

    2006-01-01

    Tob (transducer of ErbB-2) is a negative cell cycle regulator with anti-proliferative activity in peripheral tissues. Our previous study identified Tob as a protein involved in hippocampus-dependent memory consolidation (M.L. Jin, X.M. Wang, Y.Y. Tu, X.H. Zhang, X. Gao, N. Guo, Z.Q. Xie, G.P. Zhao, N.H. Jing, B.M. Li, Y.Yu, The negative cell cycle regulator, Tob (Transducer of ErbB-2), is a multifunctional protein involved in hippocampus-dependent learning and memory, Neuroscience 131 (2005) 647-659). Here, we provide evidence that Tob in the central nervous system is engaged in acquisition of motor skill. Tob has a relatively high expression in the cerebellum. Tob expression is up-regulated in the cerebellum after rats receive training on a rotarod-running task. Rats infused with Tob antisense oligonucleotides into the 4th ventricle exhibit a severe deficit in running on a rotating rod or walking across a horizontally elevated beam

  2. Mammary gland cancer in a colony of beagle dogs: Inheritance, and p53 ampersand erbB-2 expression

    International Nuclear Information System (INIS)

    Kelly, G.; Griffith, W.C.; Muggenburg, Tierney, L.A.; Lechner, J.F.; Hahn, F.F.

    1994-01-01

    One American woman in nine will be diagnosed with breast cancer in her lifetime. This somber statistic translates into 182,000 new diagnoses and 46,000 deaths per year. Efforts to decrease breast cancer mortality have focused on early detection and improved treatment. Such efforts would be facilitated by the identification of individuals predisposed to the disease. A family history of the disease can increase a woman's risk for developing breast cancer by two- to six-fold. Inheritance of this disease is consistent with at least one susceptibility locus on chromosome 17 (17q12-21) with incomplete penetrance. However, other mechanisms of inherited susceptibility also contribute to the high incidence of the disease. The purpose of the present study was to characterize familial pattern of mammary cancer development in the dog colony. In addition, the expression of the p53 tumor supressor gene and c-erbB2 (p185 erbB2 ) oncogene proteins, which are frequently altered in human breast cancer, were examined in dogs susceptible and resistant to mammary cancer

  3. Le survivant sans le syndrome Schreber

    Directory of Open Access Journals (Sweden)

    Richard Figuier

    2006-09-01

    Full Text Available On a pensé la catastrophe, mais a-t-on suffisamment pensé la survivance et la figure du survivant ? Ce n'est pas un hasard si celle-ci est au centre de Masse et puissance, oeuvre dans laquelle Canetti interroge la « mauvaise » survivance responsable de la poursuite de la logique de guerre. Mais où trouver la « bonne » ? Revenir de la catastrophe ne suffit pas pour être un « survivant authentique », selon l'expression de Kafka. Il faut avoir dépassé, avec Primo Levi et Robert Antelme, l'opposition de la vie comme croissance continue et de la mort comme son horrible contraire, par le don, dans la pauvreté solidaire, de cette vie retrouvée.Hemos reflexionado acerca de la catástrofe, pero ¿hemos meditado lo suficiente sobre la supervivencia y el superviviente? No es una coincidencia si el superviviente es el tema principal de Masse et puissance, obra en la cual Canetti analiza la «mala» supervivencia responsable de la persistencia de la lógica de guerra ¿Dónde sin embargo podemos encontrar la «buena» supervivencia? Superar la catástrofe no es suficiente para ser un «auténtico superviviente», según Kafka. Es fundamental ir más allá, con Primo Levi y Robert Antelme, de la oposición entre la vida, como crecimiento continuo, y la muerte, como su espantoso contrario, mediante la donación de forma solidaria de esta vida reencontrada.Disaster is the theme of many studies, but what about survival and of the figure of the survivor? This issue is central in Mass and power, work in which Canetti questions the “bad” survival, responsible for the continuation of the logic of war. But is there any “good” survival? Coming back from the catastrophe is not enough to be an “authentic survivor”, according to Kafka’s expression. To achieve this, it is necessary to have exceeded, with PrimoLevi and Robert Antelme, the opposition of life as a continuous growth and of death as its horrible opposite, by the gift, in a

  4. Le Conseil des gouverneurs | CRDI - Centre de recherches pour le ...

    International Development Research Centre (IDRC) Digital Library (Canada)

    2 nov. 2010 ... La gouvernance du CRDI. Reddition de comptes, transparence et efficacité. Au cours de l'exercice 2009–2010, le Conseil des gouverneurs du CRDI a adopté un nouveau cadre stratégique quinquennal, Le développement par l'innovation. Pendant de nombreux mois, les gouverneurs et les membres de la ...

  5. Le rateau faucardeur relevable

    Directory of Open Access Journals (Sweden)

    ARRIGNON J.

    1976-07-01

    Full Text Available Un rateau monté sur deux bras mobiles à l'avant d'un bateau faucardeur permet de récupérer les végétaux coupés et de les déposer sur la berge. Le positionnement de la grille horizontale permet en outre l'enlèvement en profondeur des végétaux mous et notamment des algues filamenteuses ainsi que la récupération en surface des lentilles d'eau. La simplicité de la conception, la légèreté de l'outil, sa maniabilité et son coût modique s'associent à son efficacité pour le désigner comme une solution séduisante du problème de l'enlèvement des lentilles d'eau et des produits de faucardement dans les étangs et canaux.

  6. Le tournoi des ombres

    CERN Document Server

    Treille, Daniel

    2017-01-01

    Le lecteur, transporté avec le narrateur dans une région hors norme, est invité à partager sa fascination pour la beauté du lieu, à découvrir la chronique de son passé, rude et pittoresque. Il va côtoyer une galerie de personnages très attachants, mais aux destinées bousculées par l histoire, et assister à l agitation montante du présent dans un contexte d une actualité brûlante. Ce quatrième roman de Daniel Treille, mêlant hardiment les genres, du quotidien trivial au récit épique, de considérations géopolitiques à quelques avancées de la science moderne, confirme son talent à mener, d une écriture très aboutie, une histoire complexe, peuplée de héros singuliers

  7. Le principe roman

    CERN Document Server

    Ferrari, Jérôme

    2015-01-01

    Fasciné par la figure du physicien allemand Werner Heisenberg (1901-1976), fondateur de la mécanique quantique, inventeur du célèbre "principe d'incertitude" et Prix Nobel de physique en 1932, un jeune aspirant-philosophe désenchanté s'efforce, à l'aube du XXIe siècle, de considérer l'incomplétude de sa propre existence à l'aune des travaux et de la destinée de cet exceptionnel homme de sciences qui incarne pour lui la rencontre du langage scientifique et de la poésie, lesquels, chacun à leur manière, en ouvrant la voie au scandale de l'inédit, dessillent les yeux sur le monde pour en révéler la mystérieuse beauté que ne cessent de confisquer le matérialisme à l'œuvre dans l'Histoire des hommes.

  8. Vitamin E analogs trigger apoptosis in HER2/erbB2-overexpressing breast cancer cells by signaling via the mitochondrial pathway

    Czech Academy of Sciences Publication Activity Database

    Wang, X.-F.; Witting, P. K.; Salvatore, B.A.; Neužil, Jiří

    2005-01-01

    Roč. 326, č. 4 (2005), s. 282-289 ISSN 0006-291X Institutional research plan: CEZ:AV0Z5052915; CEZ:AV0Z50520514 Keywords : vitamin E analogs * apoptosis * ErbB2 Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 3.000, year: 2005

  9. Activation of MAPK overrides the termination of myelin growth and replaces Nrg1/ErbB3 signals during Schwann cell development and myelination

    NARCIS (Netherlands)

    M.E. Sheean (Maria); E. McShane (Erik); C. Cheret (Cyril); J. Walcher (Jan); T. Müller (Thomas); A. Wulf-Goldenberg (Annika); S. Hoelper (Soraya); A.N. Garratt (Alistair); M. Krüger (Markus); K. Rajewsky (Klaus); D.N. Meijer (Dies); W. Birchmeier (Walter); G.R. Lewin (Gary); M. Selbach (Matthias); C. Birchmeier (Carmen)

    2014-01-01

    textabstractMyelination depends on the synthesis of large amounts of myelin transcripts and proteins and is controlled by Nrg1/ErbB/Shp2 signaling. We developed a novel pulse labeling strategy based on stable isotope labeling with amino acids in cell culture (SILAC) to measure the dynamics of myelin

  10. Breast cancer cells can switch between estrogen receptor alpha and ErbB signaling and combined treatment against both signaling pathways postpones development of resistance

    DEFF Research Database (Denmark)

    Sonne-Hansen, Katrine; Norrie, Ida C; Emdal, Kristina Bennet

    2010-01-01

    The majority of breast cancers are estrogen responsive, but upon progression of disease other growth promoting pathways are activated, e.g., the ErbB receptor system. The present study focuses on resistance to the pure estrogen antagonist fulvestrant and strategies to treat resistant cells or even...

  11. Constitutively active ErbB2 regulates cisplatin-induced cell death in breast cancer cells via pro- and antiapoptotic mechanisms

    DEFF Research Database (Denmark)

    Sigurðsson, Haraldur H; Olesen, Christina Wilkens; Dybboe, Rie

    2015-01-01

    UNLABELLED: Despite the frequent expression of N-terminally truncated ErbB2 (ΔNErbB2/p95HER2) in breast cancer and its association with Herceptin resistance and poor prognosis, it remains poorly understood how ΔNErbB2 affects chemotherapy-induced cell death. Previously it was shown that ΔNErbB2...

  12. Exercise training and return to a well-balanced diet activate the neuregulin 1/ErbB pathway in skeletal muscle of obese rats.

    Science.gov (United States)

    Ennequin, Gaël; Boisseau, Nathalie; Caillaud, Kevin; Chavanelle, Vivien; Gerbaix, Maude; Metz, Lore; Etienne, Monique; Walrand, Stéphane; Masgrau, Aurélie; Guillet, Christelle; Courteix, Daniel; Niu, Airu; Li, Yi-Ping; Capel, Fréderic; Sirvent, Pascal

    2015-06-15

    Some studies suggest that neuregulin 1 (NRG1) could be involved in the regulation of skeletal muscle energy metabolism in rodents. Here we assessed whether unbalanced diet is associated with alterations of the NRG1 signalling pathway and whether exercise and diet might restore NRG1 signalling in skeletal muscle of obese rats. We show that diet-induced obesity does not impair NRG1 signalling in rat skeletal muscle. We also report that endurance training and a well-balanced diet activate the NRG1 signalling in skeletal muscle of obese rats, possibly via a new mechanism mediated by the protease ADAM17. These results suggest that some beneficial effects of physical activity and diet in obese rats could be partly explained by stimulation of the NRG1 signalling pathway. Some studies suggest that the signalling pathway of neuregulin 1 (NRG1), a protein involved in the regulation of skeletal muscle metabolism, could be altered by nutritional and exercise interventions. We hypothesized that diet-induced obesity could lead to alterations of the NRG1 signalling pathway and that chronic exercise could improve NRG1 signalling in rat skeletal muscle. To test this hypothesis, male Wistar rats received a high fat/high sucrose (HF/HS) diet for 16 weeks. At the end of this period, NRG1 and ErbB expression/activity in skeletal muscle was assessed. The obese rats then continued the HF/HS diet or were switched to a well-balanced diet. Moreover, in both groups, half of the animals also performed low intensity treadmill exercise training. After another 8 weeks, NRG1 and ErbB expression/activity in skeletal muscle were tested again. The 16 week HF/HS diet induced obesity, but did not significantly affect the NRG1/ErbB signalling pathway in rat skeletal muscle. Conversely, after the switch to a well-balanced diet, NRG1 cleavage ratio and ErbB4 amount were increased. Chronic exercise training also promoted NRG1 cleavage, resulting in increased ErbB4 phosphorylation. This result was

  13. 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

  14. Behavioral characterization of blocking the ErbB signaling during adolescent and adulthood in reward-liking (preference) and reward-related learning.

    Science.gov (United States)

    Tadmor, Hagar; Golani, Idit; Dvir, Eshkar; Kremer, Ilana; Shamir, Alon

    2017-05-30

    Adolescence is a critical period in brain development. During this critical period the seeking for hedonic activities is increased, and their activity signals are stronger than the regulatory signals of judgment and reasoning. We recently reported that alteration of ErbB signaling during this period led to elevated striatal dopamine levels and reduced preference for sweetness without affecting locomotor activity and exploratory behavior. In the current study, we extend our findings and explore whether inhibition of the ErbB pathway during adolescence or adulthood also affects alcohol preference (hedonic "liking"), avoidance learning, and motivational reward "wanting". We demonstrated that chronic administration of the pan-ErbB kinase inhibitor JNJ28871063 (JNJ) to adolescent mice, but not to adult mice, reduced alcohol preference compared with the saline-injected group, without affecting avoidance learning as measured by increasing concentrations of quinine in the bitter avoidance test. Adolescent JNJ-treated mice continue to demonstrate less alcohol preference in adulthood compared with their saline-injected controls. In addition, adolescent JNJ-treated mice and their saline-injected controls did not differ in the time they spent in the food-condition chamber, and in their preference for social odor. In contrast to adolescent JNJ- treated mice, blocking the pathway during adulthood alter the preference to natural reward. These data support our initial findings that interruption of the ErbB pathway during adolescence emerges in a reduced hedonic capacity that persists into adulthood, without disturbing avoidance and reward learning. In addition, this paper provides a further behavioral role of the ErbB signaling pathway in the reward system, and suggests a different time period for the involvement of the pathway in the "liking" and the "wanting" components of the system. Copyright © 2017 Elsevier B.V. All rights reserved.

  15. Le Milton de Toland

    Directory of Open Access Journals (Sweden)

    James C. BROWN

    2003-10-01

    Full Text Available Alors que l’œuvre de John Milton suscite encore de nombreuses critiques et interprétations, je vous propose un retour en arrière afin d’étudier l’un des premiers écrits biographiques dédié à la vie et à l’œuvre du poète anglais signé par le philosophe irlandais John Toland. Paru en 1698, Life of John Milton dresse un portrait plus complet que ceux que l’on trouve dans les précédentes biographies du poète anglais (Darbishire xxix. Ayant été l’un des premiers biographes de Milton, Toland a pub...

  16. Le Baratze (ou

    Directory of Open Access Journals (Sweden)

    Jacques Blot

    1998-01-01

    Full Text Available El círculo de piedras Mendizabal 7, de 8 metros de diámetro,   presenta una corona externa constituida de grandes bloques   hincados en la tierra, y otra interna y tangente, de elementos idénticos sólo puestos en el suelo. El cajón central está compuesto de cuatro losas y una tapa. No hay depósito de huesos ni de carbón de leña ; sólo se encuentran dos herraduras, entre las cuales una completa de tipo medieval, que podrían permitir de pensar en una construcción del círculo en el periodo histórico.

  17. Le tourisme alpin

    Directory of Open Access Journals (Sweden)

    Andrea Macchiavelli

    2009-06-01

    Full Text Available La forte croissance qu’ont connue les pays alpins dans les dernières décennies a surtout été fondée sur l’offre des activités du ski, avec comme conséquence, un massif développement immobilier, la multiplication d’infrastructures et l’extension des domaines. Aujourd’hui, le marché du ski semble arriver à saturation, la Convention alpine a mis un frein à la poursuite du développement des domaines skiables et on observe donc avec intérêt la diversification de l’offre soutenue par l’innovation. Après avoir rappelé les facteurs de changement en cours les plus significatifs dans le tourisme montagnard, l’article présente une grille interprétative de l’évolution des destinations touristiques alpines, identifiant les phases qui ont caractérisé son développement. Puis il propose une réflexion sur certaines conditions qui peuvent favoriser l’innovation dans le tourisme alpin, ainsi que sur les contradictions qui les accompagnent souvent. Dans la plupart des cas l’innovation est le résultat d’un processus qui a été lancé et qui s’est développé au sein de la communauté alpine, souvent favorisé et soutenu par des institutions nationales et internationales, et grâce auquel les difficultés structurelles qui ont déjà été abordées précédemment ont pu être surmontées avec succès.The spectacular increase in tourism in the Alps in recent decades has been founded mainly on the boom in skiing, resulting in both strong real estate development and an increasing array of infrastructures and ski runs. Today the ski market seems to have virtually reached saturation point and the winter sports sector needs to diversify its offer through innovation. After a review of the main factors of change in mountain tourism, the paper presents a grid for interpreting the life cycle of alpine destinations, identifying the phases that characterize their evolution. The conditions that may favour innovation in alpine

  18. Le grand inventaire

    Directory of Open Access Journals (Sweden)

    Michel Melot

    2012-05-01

    Full Text Available Depuis quarante ans qu’il existe, l’Inventaire général des monuments et des richesses artistiques de la France n’a pas seulement progressé, couvrant près de dix mille communes, documentant plus de vingt mille dans cinq millions de pages, trois millions de photographies, et cent mille dessins. Il est devenu ce que ses fondateurs désiraient qu’il fût. Il n’est pas une liste d’objets plus ou moins singuliers qu’on aurait oubliés, mais l’observation méthodique de l’émergence dans le monde de l’ar...

  19. Le citoyen rieur

    Directory of Open Access Journals (Sweden)

    Anna Rycman

    2009-11-01

    Full Text Available Dans la Pologne d’aujourd’hui, l’évolution des modèles d’engagement civique et politique s’opère plus particulièrement auprès des jeunes générations. Parmi les expériences nouvelles de participation politique, les nouvelles technologies de l’information et de la communication offrent des opportunités radicales de reconfigurer l’espace public. La jeunesse polonaise investit en masse le Web. Dans le flux de paroles affranchies circulant et dialoguant dans le cyberespace, nous nous intéressons ici au développement d’un discours qui emprunte au registre de la dérision et de la satire politiques. Une multitude de sites critiques, de nature apparemment contestataire, des sites d’opposition fondés sur le genre satirique, ont émergé comme réponse apportée à la situation politique. Cet espace public électronique représente une forme moderne de « folklore politique », contribuant au processus de socialisation des jeunes citoyens polonais.The laughing citizen. A modern form of civic commitment in democratic Poland?In present day Poland, the evolution of civic and political commitment models is above all the affaire of the younger generations. Among the current opportunities for political participation, the new information and communication technologies offer radical opportunities to reconfigure the public arena. Polish youth are flocking to the Web. Amongst the flux of frank points of views circulating and dialoguing in cyberspace, our interest here is the development of a discourse inspired by political and satirical derision. A multitude of critical, apparently anti-establishment, sites and general opposition sites using the satirical style have emerged as a response to the political situation. This public electronic space represents a modern form of « political folklore », contributing to the socialising processes of young polish citizens.El ciudadano que rie. ¿Nueva forma del compromiso cívico en la

  20. INVESTIR DANS LE SAVOIR : le soutien que le CRDI consent à des ...

    International Development Research Centre (IDRC) Digital Library (Canada)

    5 nov. 2010 ... ... 40 ans, le Cenre de recherches pour le développement international (CRDI), en plus d'appuyer des travaux de recherche dans l'ensemble des pays en développement, encourage des générations successives de jeunes chercheurs par l'entremise de son Programme de formation et de bourses (PFB).

  1. Lele des chefs traditionnels au Ghana : un modèle inspirant ...

    International Development Research Centre (IDRC) Digital Library (Canada)

    … en Afrique. À l'université, Ray pouvait étudier la politique canadienne ou la politique africaine. « J'ai cru que je comprendrais mieux mon pays si j'allais voir ce qui se passe ailleurs dans le monde, puis en tirais des leçons ...

  2. Expression of p53, Ki-67 and c-erb B2 in growth hormone-and/or prolactin-secreting pituitary adenomas Expressão de p53, Ki-67 e c-erb B2 em adenomas hipofisários secretores de prolactina e/ou hormônio de crescimento

    Directory of Open Access Journals (Sweden)

    Carlos Henrique A. Botelho

    2006-03-01

    Full Text Available The subcellular events implicated on the formation and behavior of pituitary adenomas are not fully understood. In this study we investigated the presence of p53, Ki-67 and c-erb B2 in 38 pituitary adenomas with immunohistochemical positivity for GH and prolactin (n=26; 68.4%, for prolactin (n=9; 23.7% and for GH (n=3. 7.8%. The analyses revealed the following results: 24 (63.2% tumors expressed variable positivity for c-erb B2, 11 (28.9% expressed p53 positivity and 11 (28.9% tumors were variably positive for Ki-67. Our results demonstrated a high percentage of GH/prolactin-, prolactin- and GH-secreting tumors with immunohistochemical positivity for c-erb B2. Once this membrane receptor is related to growth factors EGF and TGFalpha and both have a definite effect on tumor growth, our data suggest a possible role for c-erb B2 on the evolution of these tumors.Os eventos subcelulares implicados na formação e comportamento dos adenomas hipofisários não são completamente compreendidos. Neste estudo nós investigamos a presença de p53, Ki-67 e c-erb B2 em 38 adenomas hipofisários com positividade imuno-histoquímica para GH e prolactina (n=26, 68,4%, para prolactina (n=9, 23,7% e para GH (n=3, 7,8%. A análise revelou os seguintes resultados: 24 tumores (63,2% expressaram positividade variável para c-erb B2, 11 (28,9% expressaram positividade para p53 e 11 tumores (28,9% foram variavelmente positivos para Ki-67. Nossos resultados demonstraram elevada percentagem de tumores secretores de GH/prolactina, prolactina e GH com positividade imuno-histoquímica para c-erb B2. Desde que este receptor de membrana está relacionado aos fatores de crescimento EGF e TGFalfa e ambos têm efeito definido no crescimento tumoral, nossos dados sugerem possível função para o c-erb B2 na evolução destes tumores.

  3. Dans le tourbillon des particules

    CERN Document Server

    Zito, Marco

    2015-01-01

    Accélérateurs géants, détecteurs complexes, particules énigmatiques... La physique subatomique peut sembler bien intimidante pour le novice. Et pourtant, qui n a jamais entendu parler du boson de Higgs et du CERN, le laboratoire européen où il a été découvert en 2012 ? Nul besoin d être un spécialiste pour comprendre de quoi il s agit. Aujourd hui, une théorie extraordinairement élégante, le Modèle Standard, décrit tous les résultats des expériences dans le domaine. Trente-sept particules élémentaires et quatre forces fondamentales : c est tout ce dont nous avons besoin pour expliquer la matière et l Univers ! Ce livre, destiné à un large public, raconte sans équations le long parcours qui a abouti au Modèle Standard. Ce parcours, parfois sinueux, a été entamé lorsque les Grecs anciens, et peut-être d autres avant eux, ont imaginé que la matière est composée de petites « billes ». Il faudra attendre plusieurs siècles pour qu on réalise que la matière, à l échelle micros...

  4. Rapport sur le développement dans le monde

    International Development Research Centre (IDRC) Digital Library (Canada)

    Parlement International Development Research Centre Centre de recherches pour le développement international Centro Internacional de Investigaciones ..... Other donors include the Swedish International Development Cooperation Agency (Sida), the Norwegian Agency for Development Cooperation (Norad) and the ...

  5. Improving consistency of the ERB record measured by CERES scanners aboard Terra/Aqua/S-NPP satellites

    Science.gov (United States)

    Szewczyk, Z. Peter; Walikainen, Dale R.; Smith, Nitchie; Thomas, Susan; Priestley, Kory J.

    2017-10-01

    A purpose of this paper is to present verification of the consistency of unfiltered radiances measured by CERES instruments over their mission 2000-2016. The FM1 scanner on Terra, designated as the climate instrument, is used as a benchmark. The degradation modeling while the instruments on Terra and Aqua were operating in the RAPS mode is being revised, and the rate of the monthly degradation is shown to be 0.03%. The focus of this paper is on consistency between Terra CERES scanners, and it is a part of a broader investigation. Results of comparing FM2 and FM1 are reported for all-sky condition and selected scene types for shortwave and long-wave radiances based on Edition 4 ERBE-like (ES8) data product. Some scene type based results are also verified using an SSF product that contains imager (MODIS) information.

  6. The chicken c-erbA alpha-product induces expression of thyroid hormone-responsive genes in 3,5,3'-triiodothyronine receptor-deficient rat hepatoma cells

    DEFF Research Database (Denmark)

    Muñoz, A; Höppner, W; Sap, J

    1990-01-01

    To determine the capacity of the chicken c-erbA (cTR-alpha) gene product in regulating expression of known thyroid hormone-responsive genes, both the cTR-alpha and the viral v-erbA genes were expressed in FAO cells, a rat hepatoma cell line defective for functional thyroid hormone receptors. Upon...... nuclear expression of the cTR-alpha protein the cells become responsive to thyroid hormone, as detected by expression of a number of genes (malic enzyme, phosphoenolpyruvate carboxykinase, and Na+/K(+)-ATPase) reported to be indirectly induced by the hormone in vivo. In addition, our data show that the c......-erbA product directly activates the Moloney murine leukemia virus promoter in a ligand-dependent manner. The data show that the chicken c-erbA-alpha protein can modulate the expression of rat genes under either direct or indirect control by thyroid hormone....

  7. Le FIVB annonce le financement de huit autres projets | CRDI ...

    International Development Research Centre (IDRC) Digital Library (Canada)

    5 avr. 2018 ... Découvrez les derniers récents projets soutenus par le Fonds d'innovation en matière de vaccins pour le bétail : Maladie de Newcastle · Pleuropneumonie contagieuse caprine – cowdriose · Plateforme de modification génétique CRISPR/cas9 · Entérotoxémie, la bactérie Pasteurella et la fièvre de la vallée ...

  8. Exogenous HGF Bypasses the Effects of ErbB Inhibition on Tumor Cell Viability in Medulloblastoma Cell Lines.

    Directory of Open Access Journals (Sweden)

    Walderik W Zomerman

    Full Text Available Recent clinical trials investigating receptor tyrosine kinase (RTK inhibitors showed a limited clinical response in medulloblastoma. The present study investigated the role of micro-environmental growth factors expressed in the brain, such as HGF and EGF, in relation to the effects of hepatocyte growth factor receptor (MET and epidermal growth factor receptor family (ErbB1-4 inhibition in medulloblastoma cell lines. Medulloblastoma cell lines were treated with tyrosine kinase inhibitors crizotinib or canertinib, targeting MET and ErbB1-4, respectively. Upon treatment, cells were stimulated with VEGF-A, PDGF-AB, HGF, FGF-2 or EGF. Subsequently, we measured cell viability and expression levels of growth factors and downstream signaling proteins. Addition of HGF or EGF phosphorylated MET or EGFR, respectively, and demonstrated phosphorylation of Akt and ERK1/2 as well as increased tumor cell viability. Crizotinib and canertinib both inhibited cell viability and phosphorylation of Akt and ERK1/2. Specifically targeting MET using shRNA's resulted in decreased cell viability. Interestingly, addition of HGF to canertinib significantly enhanced cell viability as well as phosphorylation of Akt and ERK1/2. The HGF-induced bypass of canertinib was reversed by addition of crizotinib. HGF protein was hardly released by medulloblastoma cells itself. Addition of canertinib did not affect RTK cell surface or growth factor expression levels. This manuscript points to the bypassing capacity of exogenous HGF in medulloblastoma cell lines. It might be of great interest to anticipate on these results in developing novel clinical trials with a combination of MET and EGFR inhibitors in medulloblastoma.

  9. Le Valais et ses Reines

    Directory of Open Access Journals (Sweden)

    Alberto Campi

    2012-06-01

    Full Text Available Combat de ReinesAu premier plan (la corde dans la main, un propriétaire de vaches. Dans l'arène se trouve le rabatteur. Les Reines sur la photo sont des reines de première catégorie (ainsi que le montre le « I » sur leur cuisse .Dimanche 6 mai 2012, « Schakira », la vache numéro 42, a gagné, non sans polémique, le titre de Reine. Elle peut donc être considérée comme la Reine des Reines, titre qu’elle a gagné en se battant contre ses rivales dans différents combats, qui ont commencé pour Sch...

  10. Sur le chemin de Buchenwald

    OpenAIRE

    Bessière, Bernard

    2017-01-01

    En 1963, âgé de 37 ans, l’activiste communiste Jorge Semprún publie en français le roman Le Grand Voyage dans lequel il raconte le périple de 800 km qui l’avait conduit en train de Compiègne jusqu’à Buchenwald en septembre 1943. Il avait alors 19 ans. C’est dans ce camp de la mort situé près de Weimar – cité de Goethe, que Semprún admirait – qu’il sera interné jusqu’à sa libération par les troupes américaines en avril  1945. Pendant les quatre jours et cinq nuits de ce « grand voyage », le dé...

  11. Le bal du loup

    CERN Multimedia

    Happy Children's Home

    2013-01-01

    The Bord'eau amateur theatre group will graciously perform a play of their creation Le bal du loup Saturday 19 October 2013 at 20:00 Sunday 20 October at 17:00 in the Théâtre des Grottes Rue Louis Favre 43, 1201 Genève Children from age 12 upwards. Summary: The new-elected mayoress of a small village would like to clean up the town by prohibiting alcohol and getting rid of its prostitutes. Then along comes « Massimo Lupo » the pimp... The performances will be given to support the Happy Children's Home charity, which runs a foster-home in Pokhara for Nepali children:  http://www.happychildrenshome.org/ Admission : minimum charge of 10 CHF per person requested, to cover the cost of technical assistance and theatre rental. Any profit will be used solely for the foster-home. At the end of each performance members of the HCH charity will be happy to answer any questions you may have. The theatre has 86 seats, thank you for reserv...

  12. Cell cycle synchronization and BrdU incorporation as a tool to study the possible selective elimination of ErbB1 gene in the micronuclei in A549 cells

    International Nuclear Information System (INIS)

    Lauand, C.; Niero, E.L.; Dias, V.M.; Machado-Santelli, G.M.

    2015-01-01

    Lung cancer often exhibits molecular changes, such as the overexpression of the ErbB1 gene that encodes epidermal growth factor receptor (EGFR). ErbB1 amplification and mutation are associated with tumor aggressiveness and low response to therapy. The aim of the present study was to design a schedule to synchronize the cell cycle of A549 cell line (a non-small cell lung cancer) and to analyze the possible association between the micronuclei (MNs) and the extrusion of ErbB1 gene extra-copies. After double blocking, by the process of fetal bovine serum deprivation and vincristine treatment, MNs formation was monitored with 5-bromo-2-deoxyuridine (BrdU) incorporation, which is an S-phase marker. Statistical analyses allowed us to infer that MNs may arise both in mitosis as well as in interphase. The MNs were able to replicate their DNA and this process seemed to be non-synchronous with the main cell nuclei. The presence of ErbB1 gene in the MNs was evaluated by fluorescent in situ hybridization (FISH). ErbB1 sequences were detected in the MNs, but a relation between the MNs formation and extrusion of amplified ErbB1could not be established. The present study sought to elucidate the meaning of MNs formation and its association with the elimination of oncogenes or other amplified sequences from the tumor cells

  13. Cell cycle synchronization and BrdU incorporation as a tool to study the possible selective elimination of ErbB1 gene in the micronuclei in A549 cells

    Energy Technology Data Exchange (ETDEWEB)

    Lauand, C.; Niero, E.L.; Dias, V.M.; Machado-Santelli, G.M. [Departamento de Biologia Celular e do Desenvolvimento, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo, SP (Brazil)

    2015-03-06

    Lung cancer often exhibits molecular changes, such as the overexpression of the ErbB1 gene that encodes epidermal growth factor receptor (EGFR). ErbB1 amplification and mutation are associated with tumor aggressiveness and low response to therapy. The aim of the present study was to design a schedule to synchronize the cell cycle of A549 cell line (a non-small cell lung cancer) and to analyze the possible association between the micronuclei (MNs) and the extrusion of ErbB1 gene extra-copies. After double blocking, by the process of fetal bovine serum deprivation and vincristine treatment, MNs formation was monitored with 5-bromo-2-deoxyuridine (BrdU) incorporation, which is an S-phase marker. Statistical analyses allowed us to infer that MNs may arise both in mitosis as well as in interphase. The MNs were able to replicate their DNA and this process seemed to be non-synchronous with the main cell nuclei. The presence of ErbB1 gene in the MNs was evaluated by fluorescent in situ hybridization (FISH). ErbB1 sequences were detected in the MNs, but a relation between the MNs formation and extrusion of amplified ErbB1could not be established. The present study sought to elucidate the meaning of MNs formation and its association with the elimination of oncogenes or other amplified sequences from the tumor cells.

  14. Le CRDI dans les Philippines

    International Development Research Centre (IDRC) Digital Library (Canada)

    Le CRDI appuie la recherche dans les. Philippines depuis 1972. Le travail qu'y ont accompli des universités et des instituts de recherche vigoureux et la participation active de la société civile ont entraîné d'importantes améliorations dans les domaines de l'agriculture, du suivi de la pauvreté et de la gestion des forêts.

  15. Un oiseau "sabote" le CERN

    CERN Multimedia

    Colson, Sébastien

    2009-01-01

    Un oiseau, un simple oiseau, est parvenu à bloquer à lui tout seul l'accélérateur à particules à 3,7 milliards d'euros. UNe histoire quasiment bulresque qui a toutefois impacté le fonctionnement de la machine durant près de cinq jours, puisque c'est le système de refroidissement qui a été affecté. (1 page)

  16. Le cas de la Chine

    International Development Research Centre (IDRC) Digital Library (Canada)

    pwust

    Des changements récents dans le milieu de l'élaboration des politiques du pays semblent propices à la ... centrale, la Chine fait l'expérience de nouveaux partenariats d'aide au développement où .... 2 Le Service des prêts à des conditions libérales de la Banque d'import-export de Chine gère les prêts assortis de.

  17. Le livre sur le livre traité de documentation

    CERN Document Server

    Otlet, Paul

    2015-01-01

    Paul Otlet est considéré comme le père des sciences de l'information. Ouvrage fondateur et fondamental, le Traité de documentation. Le livre sur le livre (1934) est l'aboutissement de son travail inlassable pour rassembler, classer et partager les connaissances. Otlet y propose une remarquable synthèse du savoir sur le livre et le document en même temps qu'il anticipe Internet et l'hypertexte. La réédition du Traité de documentation, 70 ans après la disparition de son auteur, coïncide avec la réouverture du Mundaneum à Mons, où le fabuleux héritage documentaire légué par Paul Otlet et Henri La Fontaine est conservé. « Ici, la table de travail n'est plus chargée d'aucun livre. À leur place se dresse un écran et à portée un téléphone. Là-bas, au loin, dans un édifice immense, sont tous les livres et tous les renseignements. De là, on fait apparaître sur l'écran la page à lire pour connaître la réponse aux questions posées par téléphone. » Préfaces de Benoît Peeters (éc...

  18. Le modèle spatial de la capitale allemande

    Directory of Open Access Journals (Sweden)

    Antoine Laporte

    2013-06-01

    Full Text Available En Allemagne, en 1999, le Chancelier fédéral et son gouvernement ont quitté Bonn pour Berlin. Ce transfert du pouvoir est accompagné de celui d’une grande partie de l’appareil d’État et de la haute administration, et des fonctions qui leur sont traditionnellement attribuées comme la presse, les lobbys ou encore la diplomatie. Le déplacement du statut de capitale effective de l’Allemagne de Bonn à Berlin est le résultat des évolutions géopolitiques d’un pays ayant recouvré son unité et sa pleine et entière souveraineté. Installer le pouvoir exécutif et législatif à Berlin était une démarche hautement symbolique, visant à normaliser la position de l’ancienne capitale de la RDA et du IIIe Reich comme véritable centre politique de l’Allemagne. Or le déplacement des institutions fédérales n’est pas qu’un acte symbolique. Il entraîne également à l’échelle intra-urbaine des dynamiques très concrètes sur le tissu urbain et participe à la mise en place de nouvelles centralités dans la ville. En effet, le statut de capitale d’État prédestine l’agglomération à la coprésence de nombreuses fonctions urbaines spécifiques plus ou moins directement liées à l’exercice ou à la symbolique du pouvoir.

  19. 3. Le moraliste, le sociologue et le juge : objectivation et production de la connaissance

    OpenAIRE

    Noreau, Pierre

    2018-01-01

    Commedia del diritto Œuvre spécialement réalisée pour cet ouvrage par Maya Pankalla Le rapport qu’entretiennent les sciences sociales et le monde des valeurs est traversé par l’ambiguïté. Ce que nous pourrions appeler ici l’« engagement sociologique » de Guy Rocher témoigne de cette tension continue ; il exemplifie les relations complexes qui lient le mouvement de la pensée au monde de l’action. Comme il le rappelle lui-même dans ses entretiens avec Georges Khal, à la fin d’u...

  20. Le plomb, le cadmium et le mercure dans les produits de la mer

    OpenAIRE

    Thibaud, Yves

    1987-01-01

    Trois contaminants métalliques, toxiques vis-à-vis de l'homme : le plomb, le cadmium et le mercure, sont considérés sous l'angle de leur cheminement dans l'environnement, en particulier celui de l'accès au consommateur par les aliments d'origine marine. En plus des réglementations visant au contrôle des produits de la pêche destinés à la consommation et des mesures visant à limiter lés disséminations, il existe en France un système de surveillance continue des niveaux de contamination du litt...

  1. Le nouveau modèle africain | CRDI - Centre de recherches pour le ...

    International Development Research Centre (IDRC) Digital Library (Canada)

    22 juil. 2011 ... Or, ce serait rater le bateau que de ne pas s'engager dans la voie tout autre que les Africains proposent maintenant — à savoir se défaire du syndrome de la dépendance qui afflige l'Afrique depuis des décennies. Le Canada et les autres pays riches du Nord reconnaissent généralement qu'ils ne peuvent ...

  2. Lele des intervenants non gouvernementaux dans le ...

    International Development Research Centre (IDRC) Digital Library (Canada)

    Ce projet servira à déterminer les facteurs stratégiques et réglementaires qui ont contribué ou nui aux efforts visant à permettre aux fournisseurs non gouvernementaux de participer au renforcement des systèmes de santé. Lele des fournisseurs de ... Climate Change and Water Adaptation Options. The impacts of climate ...

  3. Evaluation of C-ErbB-2 Overexpression and Her-2/neu Gene Copy Number Heterogeneity in Barrett’s Adenocarcinoma

    Directory of Open Access Journals (Sweden)

    Axel Walch

    2000-01-01

    Full Text Available Amplifiction of the Her-2/neu gene is accompanied by overexpression of its cell surface receptor product, c‐erbB‐2 protein. To investigate the degree of intratumoural heterogeneity we applied immunohistochemistry in primary Barrett’s adenocarcinoma (BCA (n = 6 and dysplasia adjacent to the carcinoma (n = 4. In addition, fluorescence in situ hybridisation (FISH was performed in primary BCA (n=5 and dysplastic areas (n=4. For an objective evaluation digital image analysis and laser scanning microscopy were used. Five of six BCA showed a marked intratumoural heterogeneous staining pattern ranging from areas in which the tumour cells were negative or faintly positive to tumour areas with a strong staining of the entire membrane. Among the two dysplastic areas also a heterogenous staining pattern was observed. FISH analysis revealed marked heterogeneity of intratumoural gene copy number changes in all BCA showing populations with different fractions of cells with polysomy, low level amplification and high level amplification. One dysplasia showed a minor population with Her‐2/neu signal clusters. In conclusion, we observed marked intratumoural heterogeneity of c‐erbB‐2 protein overexpression and Her‐2/neu gene copy number in the majority of the primary BCA analyzed. Digital image analysis and laser scanning microscopy were helpful in quantifying the variations in protein expression and DNA copy number in individual tumour cells. The observed heterogeneity could hamper the exact diagnostic determination of the c‐erbB‐2 status in small biopsies and possibly influence the effectiveness of a potential c‐erbB‐2 targeting therapy.

  4. The pan-ErbB tyrosine kinase inhibitor canertinib induces caspase-mediated cell death in human T-cell leukemia (Jurkat) cells

    Energy Technology Data Exchange (ETDEWEB)

    Trinks, Cecilia, E-mail: Cecilia.trinks@liu.se [Division of Oncology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linkoeping University, Linkoeping (Sweden); Severinsson, Emelie A., E-mail: Emelie.severinsson@liu.se [Division of Oncology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linkoeping University, Linkoeping (Sweden); Holmlund, Birgitta, E-mail: Birgitta.holmlund@lio.se [Department of Oncology, County Council of Ostergoetland, Linkoeping (Sweden); Green, Anna, E-mail: Anna.green@liu.se [Division of Cell Biology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linkoeping University, Linkoeping (Sweden); Green, Henrik, E-mail: Henrik.green@liu.se [Clinical Pharmacology, Division of Drug Research, Department of Medical and Health Sciences, Faculty of Health Sciences, Linkoeping University, Linkoeping (Sweden); Joensson, Jan-Ingvar, E-mail: Jan-ingvar.jonsson@liu.se [Experimental Hematology Unit, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linkoeping University, Linkoeping (Sweden); Hallbeck, Anna-Lotta, E-mail: Anna-Lotta.Hallbeck@lio.se [Division of Oncology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linkoeping University, Linkoeping (Sweden); Department of Oncology, County Council of Ostergoetland, Linkoeping (Sweden); Walz, Thomas M., E-mail: Thomas.Walz@lio.se [Division of Oncology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linkoeping University, Linkoeping (Sweden); Department of Oncology, County Council of Ostergoetland, Linkoeping (Sweden)

    2011-07-08

    Highlights: {yields} Canertinib induces caspase-mediated apoptosis in T-cell leukemia cells in vitro. {yields} Canertinib mediates activation of the intrinsic apoptotic pathway. {yields} Canertinib induces apoptosis in an ErbB receptor independent manner. {yields} Lymphocyte specific proteins as well as survival kinases are inhibited. {yields} Canertinib may act as a multi-kinase inhibiting drug in human T-cell malignancies. -- Abstract: Canertinib is a novel ErbB-receptor inhibitor currently in clinical development for the treatment of solid tumors overexpressing ErbB-receptors. We have recently demonstrated that canertinib displays anti-proliferative and pro-apoptotic effects in human myeloid leukemia cells devoid of ErbB-receptors. The mechanism mediating these effects are however unknown. In this study, we show that canertinib is able to act as a multi-kinase inhibitor by inhibition of several intracellular kinases involved in T-cell signaling such as Akt, Erk1/2 and Zap-70, and reduced Lck protein expression in the human T-cell leukemia cell line Jurkat. Treatment with canertinib at a concentration of 2 {mu}M caused accumulation of Jurkat cells in the G{sub 1} cell cycle phase and increased doses induced apoptosis in a time-dependent manner. Apoptotic signs of treated cells were detected by Annexin V staining and cleavage of PARP, caspase-3, -8, -9, -10 and Bid. A subset of the pro-apoptotic signals mediated by canertinib could be significantly reduced by specific caspase inhibitors. Taken together, these results demonstrate the dual ability of canertinib to downregulate important signaling pathways and to activate caspase-mediated intrinsic apoptosis pathway in human T-cell leukemia cells.

  5. Disruption of the ErbB signaling in adolescence increases striatal dopamine levels and affects learning and hedonic-like behavior in the adult mouse.

    Science.gov (United States)

    Golani, Idit; Tadmor, Hagar; Buonanno, Andres; Kremer, Ilana; Shamir, Alon

    2014-11-01

    The ErbB signaling pathway has been genetically and functionally implicated in schizophrenia. Numerous findings support the dysregulation of Neuregulin (NRG) and epidermal growth factor (EGF) signaling in schizophrenia. However, it is unclear whether alterations of these pathways in the adult brain or during development are involved in the pathophysiology of schizophrenia. Herein we characterized the behavioral profile and molecular changes resulting from pharmacologically blocking the ErbB signaling pathway during a critical period in the development of decision making, planning, judgments, emotions, social cognition and cognitive skills, namely adolescence. We demonstrate that chronic administration of the pan-ErbB kinase inhibitor JNJ-28871063 (JNJ) to adolescent mice elevated striatal dopamine levels and reduced preference for sucrose without affecting locomotor activity and exploratory behavior. In adulthood, adolescent JNJ-treated mice continue to consume less sucrose and needed significantly more correct-response trials to reach the learning criterion during the discrimination phase of the T-maze reversal learning task than their saline-injected controls. In addition, JNJ mice exhibited deficit in reference memory but not in working memory as measured in the radial arm maze. Inhibition of the pathway during adolescence did not affect exploratory behavior and locomotor activity in the open field, social interaction, social memory, and reversal learning in adult mice. Our data suggest that alteration of ErbB signaling during adolescence resulted in changes in the dopaminergic systems that emerge in pathological learning and hedonic behavior in adulthood, and pinpoints the possible role of the pathway in the development of cognitive skills and motivated behavior. Copyright © 2014 Elsevier B.V. and ECNP. All rights reserved.

  6. Le clerc et le ménestrel

    OpenAIRE

    Szkilnik, Michelle

    2007-01-01

    Quand au début du XIVe siècle, un auteur inconnu imagine de raconter l’histoire d’un roi d’Angleterre tout aussi inconnu, Perceforest, il choisit « naturellement » la prose. « Naturellement » parce que le Perceforest se veut la pré-histoire du monde arthurien, qu’il prétend donc se rattacher, comme l’avait fait L’Estoire del Saint Graal, à l’avant des grands cycles en prose du XIIIe siècle, le Lancelot-Graal en particulier. Il opte donc pour le même mode d’écriture que les œuvres qu’il vient ...

  7. Steroid receptor expression and HER-2/neu (c-erbB-2) oncoprotein in the uterus of cats with cystic endometrial hyperplasia-pyometra complex.

    Science.gov (United States)

    Misirlioglu, D; Nak, D; Sevimli, A; Nak, Y; Ozyigit, M O; Akkoc, A; Cangul, I T

    2006-06-01

    The presence of oestrogen-alpha receptor (ER), progesterone receptor (PR), and HER-2/neu (c-erbB-2) oncoprotein in the uterine walls of 10 healthy cats and 20 subjects with cystic endometrial hyperplasia-pyometra (CEH-P) were evaluated. Lesions were graded according to the severity of cystic dilation, hyperplasia and inflammation, and were classified as normal, mild uterine hyperplasia and severe uterine hyperplasia. The ER, PR and c-erbB-2 expression in the endometrium, glandular epithelium, stromal fibroblasts and myometrial smooth muscle cells was quantified by immunohistochemistry. The ER, PR and c-erbB-2 staining patterns differed between normal uteri and uteri with CEH-P. The ER expression was tended to be higher in the endometrial surface and glandular epithelium in the severe hyperplasia group (P > 0.05) and significantly lower in the mild hyperplasia cases compared with normal endometrium (P pyometra, whereas PR plays a role in the pathogenesis of both CEH and pyometra.

  8. [Targeted tumor suppression by a secreted fusion protein consisting of anti- erbB2 antibody and reversed caspase-3 to SKBr3 cells].

    Science.gov (United States)

    Zhang, Li-hong; Jia, Lin-tao; Yu, Cui-juan; Qu, Ping; Dong, Hai-long; Zhao, Jing; Xu, Yan-ming; Wang, Cheng-Ji; Yang, An-gang

    2003-04-10

    To investigate the targeted killing effect to SKBr3 cells due to the expression of a secreted fusion protein consisting of anti-erbB2 antibody and reversed caspase-3. A recombinant plasmid pCMV-e23scFv-PEII-revcasp 3 was constructed by subcloning reversed caspase-3 gene to the downstream of anti-erbB2 antibody and transfected into Jurkat cells. The cell lines which secreted expressing fusion protein stably were selected. The fusion protein in media was detected by ELISA and the media was used to culture human breast cancer SKBr3 cells. The recombinant plasmids with liposomes was administrated to BALB/C nude mouses bearing SKBr3 tumor by intramuscular injection. The targetting effect of the recombinant fusion protein caspase-3 was detected by indirect immunofluorescence staining. Fusion protein can be expressed and secreted by Jurkat cells stably and kill SKBr3 cells. Significant prolonged survival time (prolonged by 72%) and inhibition of tumor growth in vivo (within inhibition ratio of 77%) were seen in the group administered with recombinant plasmids. Indirect immunofluorescence staining showed that the recombinant fusion protein caspase-3 has targetting effect. Secreted expression of the fusion protein consisting of anti-erbB2 antibody and reversed caspase-3 can targetedly induce SKBr3 cells to death.

  9. Activation of MAPK overrides the termination of myelin growth and replaces Nrg1/ErbB3 signals during Schwann cell development and myelination

    Science.gov (United States)

    Sheean, Maria E.; McShane, Erik; Cheret, Cyril; Walcher, Jan; Müller, Thomas; Wulf-Goldenberg, Annika; Hoelper, Soraya; Garratt, Alistair N.; Krüger, Markus; Rajewsky, Klaus; Meijer, Dies; Birchmeier, Walter; Lewin, Gary R.; Selbach, Matthias; Birchmeier, Carmen

    2014-01-01

    Myelination depends on the synthesis of large amounts of myelin transcripts and proteins and is controlled by Nrg1/ErbB/Shp2 signaling. We developed a novel pulse labeling strategy based on stable isotope labeling with amino acids in cell culture (SILAC) to measure the dynamics of myelin protein production in mice. We found that protein synthesis is dampened in the maturing postnatal peripheral nervous system, and myelination then slows down. Remarkably, sustained activation of MAPK signaling by expression of the Mek1DD allele in mice overcomes the signals that end myelination, resulting in continuous myelin growth. MAPK activation leads to minor changes in transcript levels but massively up-regulates protein production. Pharmacological interference in vivo demonstrates that the effects of activated MAPK signaling on translation are mediated by mTOR-independent mechanisms but in part also by mTOR-dependent mechanisms. Previous work demonstrated that loss of ErbB3/Shp2 signaling impairs Schwann cell development and disrupts the myelination program. We found that activated MAPK signaling strikingly compensates for the absence of ErbB3 or Shp2 during Schwann cell development and myelination. PMID:24493648

  10. Selective Inhibition of Tumor Growth by Clonal NK Cells Expressing an ErbB2/HER2-Specific Chimeric Antigen Receptor

    Science.gov (United States)

    Schönfeld, Kurt; Sahm, Christiane; Zhang, Congcong; Naundorf, Sonja; Brendel, Christian; Odendahl, Marcus; Nowakowska, Paulina; Bönig, Halvard; Köhl, Ulrike; Kloess, Stephan; Köhler, Sylvia; Holtgreve-Grez, Heidi; Jauch, Anna; Schmidt, Manfred; Schubert, Ralf; Kühlcke, Klaus; Seifried, Erhard; Klingemann, Hans G; Rieger, Michael A; Tonn, Torsten; Grez, Manuel; Wels, Winfried S

    2015-01-01

    Natural killer (NK) cells are an important effector cell type for adoptive cancer immunotherapy. Similar to T cells, NK cells can be modified to express chimeric antigen receptors (CARs) to enhance antitumor activity, but experience with CAR-engineered NK cells and their clinical development is still limited. Here, we redirected continuously expanding and clinically usable established human NK-92 cells to the tumor-associated ErbB2 (HER2) antigen. Following GMP-compliant procedures, we generated a stable clonal cell line expressing a humanized CAR based on ErbB2-specific antibody FRP5 harboring CD28 and CD3ζ signaling domains (CAR 5.28.z). These NK-92/5.28.z cells efficiently lysed ErbB2-expressing tumor cells in vitro and exhibited serial target cell killing. Specific recognition of tumor cells and antitumor activity were retained in vivo, resulting in selective enrichment of NK-92/5.28.z cells in orthotopic breast carcinoma xenografts, and reduction of pulmonary metastasis in a renal cell carcinoma model, respectively. γ-irradiation as a potential safety measure for clinical application prevented NK cell replication, while antitumor activity was preserved. Our data demonstrate that it is feasible to engineer CAR-expressing NK cells as a clonal, molecularly and functionally well-defined and continuously expandable cell therapeutic agent, and suggest NK-92/5.28.z cells as a promising candidate for use in adoptive cancer immunotherapy. PMID:25373520

  11. 6-Ethynylthieno[3,2-d]- and 6-ethynylthieno[2,3-d]pyrimidin-4-anilines as tunable covalent modifiers of ErbB kinases.

    Science.gov (United States)

    Wood, Edgar R; Shewchuk, Lisa M; Ellis, Byron; Brignola, Perry; Brashear, Ronald L; Caferro, Thomas R; Dickerson, Scott H; Dickson, Hamilton D; Donaldson, Kelly H; Gaul, Michael; Griffin, Robert J; Hassell, Anne M; Keith, Barry; Mullin, Robert; Petrov, Kimberly G; Reno, Michael J; Rusnak, David W; Tadepalli, Sarva M; Ulrich, John C; Wagner, Craig D; Vanderwall, Dana E; Waterson, Alex G; Williams, Jon D; White, Wendy L; Uehling, David E

    2008-02-26

    Analysis of the x-ray crystal structure of mono-substituted acetylenic thienopyrimidine 6 complexed with the ErbB family enzyme ErbB-4 revealed a covalent bond between the terminal carbon of the acetylene moiety and the sulfhydryl group of Cys-803 at the solvent interface. The identification of this covalent adduct suggested that acetylenic thienopyrimidine 6 and related analogs might also be capable of forming an analogous covalent adduct with EGFR, which has a conserved cysteine (797) near the ATP binding pocket. To test this hypothesis, we treated a truncated, catalytically competent form of EGFR (678-1020) with a structurally related propargylic amine (8). An investigation of the resulting complex by mass spectrometry revealed the formation of a covalent complex of thienopyrimidine 8 with Cys-797 of EGFR. This finding enabled us to readily assess the irreversibility of various inhibitors and also facilitated a structure-activity relationship understanding of the covalent modifying potential and biological activity of a series of acetylenic thienopyrimidine compounds with potent antitumor activity. Several ErbB family enzyme and cell potent 6-ethynyl thienopyrimidine kinase inhibitors were found to form covalent adducts with EGFR.

  12. Increased level of phosphorylated akt measured by chemiluminescence-linked immunosorbent assay is a predictor of poor prognosis in primary breast cancer overexpressing ErbB-2

    International Nuclear Information System (INIS)

    Cicenas, Jonas; Urban, Patrick; Vuaroqueaux, Vincent; Labuhn, Martin; Küng, Willy; Wight, Edward; Mayhew, Mark; Eppenberger, Urs; Eppenberger-Castori, Serenella

    2005-01-01

    Akt1, Akt2 and Akt3 kinases are downstream components of phosphoinositol 3-kinase derived signals from receptor tyrosine kinases, which influence cell growth, proliferation and survival. Akt2 overexpression and amplification have been described in breast, ovarian and pancreatic cancers. The present study was designed to investigate the prognostic significance of activated Akt in primary breast cancer and its association with other tumour biomarkers. Using a two-site chemiluminescence-linked immunosorbent assay, we measured the quantitative expression levels of total phosphorylated (P-S473) Akt (Akt1/Akt2/Akt3) on cytosol fractions obtained from fresh frozen tissue samples of 156 primary breast cancer patients. Akt phosphorylation was not associated with nodal status or ErbB-2 protein expression levels. High levels of phosphorylated Akt correlated (P < 0.01) with poor prognosis, and the significance of this correlation increased (P < 0.001) in the subset of patients with ErbB-2 overexpressing tumours. In addition, phosphorylated Akt was found to be associated with mRNA expression levels of several proliferation markers (e.g. thymidylate synthase), measured using quantitative real-time RT-PCR. Our findings demonstrate that, in breast cancer patients, Akt activation is associated with tumour proliferation and poor prognosis, particularly in the subset of patients with ErbB2-overexpressing tumours

  13. Selective inhibition of tumor growth by clonal NK cells expressing an ErbB2/HER2-specific chimeric antigen receptor.

    Science.gov (United States)

    Schönfeld, Kurt; Sahm, Christiane; Zhang, Congcong; Naundorf, Sonja; Brendel, Christian; Odendahl, Marcus; Nowakowska, Paulina; Bönig, Halvard; Köhl, Ulrike; Kloess, Stephan; Köhler, Sylvia; Holtgreve-Grez, Heidi; Jauch, Anna; Schmidt, Manfred; Schubert, Ralf; Kühlcke, Klaus; Seifried, Erhard; Klingemann, Hans G; Rieger, Michael A; Tonn, Torsten; Grez, Manuel; Wels, Winfried S

    2015-02-01

    Natural killer (NK) cells are an important effector cell type for adoptive cancer immunotherapy. Similar to T cells, NK cells can be modified to express chimeric antigen receptors (CARs) to enhance antitumor activity, but experience with CAR-engineered NK cells and their clinical development is still limited. Here, we redirected continuously expanding and clinically usable established human NK-92 cells to the tumor-associated ErbB2 (HER2) antigen. Following GMP-compliant procedures, we generated a stable clonal cell line expressing a humanized CAR based on ErbB2-specific antibody FRP5 harboring CD28 and CD3ζ signaling domains (CAR 5.28.z). These NK-92/5.28.z cells efficiently lysed ErbB2-expressing tumor cells in vitro and exhibited serial target cell killing. Specific recognition of tumor cells and antitumor activity were retained in vivo, resulting in selective enrichment of NK-92/5.28.z cells in orthotopic breast carcinoma xenografts, and reduction of pulmonary metastasis in a renal cell carcinoma model, respectively. γ-irradiation as a potential safety measure for clinical application prevented NK cell replication, while antitumor activity was preserved. Our data demonstrate that it is feasible to engineer CAR-expressing NK cells as a clonal, molecularly and functionally well-defined and continuously expandable cell therapeutic agent, and suggest NK-92/5.28.z cells as a promising candidate for use in adoptive cancer immunotherapy.

  14. Epidermal Growth Factor Cytoplasmic Domain Affects ErbB Protein Degradation by the Lysosomal and Ubiquitin-Proteasome Pathway in Human Cancer Cells

    Directory of Open Access Journals (Sweden)

    Aleksandra Glogowska

    2012-05-01

    Full Text Available The cytoplasmic domains of EGF-like ligands, including EGF cytoplasmic domain (EGFcyt, have important biological functions. Using specific constructs and peptides of human EGF cytoplasmic domain, we demonstrate that EGFcyt facilitates lysosomal and proteasomal protein degradation, and this coincided with growth inhibition of human thyroid and glioma carcinoma cells. EGFcyt and exon 22–23-encoded peptide (EGF22.23 enhanced procathepsin B (procathB expression and procathB-mediated lysosomal degradation of EGFR/ErbB1 as determined by inhibitors for procathB and the lysosomal ATPase inhibitor BafA1. Presence of mbEGFctF, EGFcyt, EGF22.23, and exon 23-encoded peptides suppressed the expression of the deubiqitinating enzyme ubiquitin C-terminal hydrolase-L1 (UCH-L1. This coincided with hyperubiquitination of total cellular proteins and ErbB1/2 and reduced proteasome activity. Upon small interfering RNA-mediated silencing of endogenously expressed UCH-L1, a similar hyperubiquitinylation phenotype, reduced ErbB1/2 content, and attenuated growth was observed. The exon 23-encoded peptide region of EGFcyt was important for these biologic actions. Structural homology modeling of human EGFcyt showed that this molecular region formed an exposed surface loop. Peptides derived from this EGFcyt loop structure may aid in the design of novel peptide therapeutics aimed at inhibiting growth of cancer cells.

  15. Le sacré sauvage

    Directory of Open Access Journals (Sweden)

    Roger Bastide

    2010-09-01

    Full Text Available Conférence prononcée le 13 septembre 1973 dans le cadre des Rencontres Internationales de Genève qui avaient pour thème cette année-là « Le besoin religieux ». Cette conférence figure dans les Actes de cette rencontre (Le Besoin religieux, Éditions de la Baconnière, Neuchâtel, 1974, pp. 123-145. Elle a été republiée dans un ouvrage posthume dont elle est l’éponyme, ouvrage édité par Henri Desroche (Paris, éditions Stock, 1975. Nous reproduisons ici le texte intégral original, avec l’aimable autorisation des Rencontres Internationales de Genève auxquelles SociologieS adresse ses remerciements.The wild sacredText of a lecture taken on November the 13th 1973 during the Rencontres Internationales de Genève whom theme was "The religious need". This lecture was first published in: Le Besoin religieux (La Baconnière Editions, Neuchâtel, 1974, pp. 123-145, and published once again in a posthumous book: Le sacré sauvage ("The wild sacred" edited by Henri Desroche (Paris, Stock Editions, 1975. It is reproduced here with the kind authorization of the Rencontres Internationales de Genève. SociologieS gives them sincere thanks.Le Sacré sauvage (Lo sagrado en el mundo primitivoConferencia efectuada el 13 de septiembre de 1973 en el marco de las Rencontres Internationales de Genève (Encuentros Internacionales de Ginebra que tenia como tema general la necesidad de la experiencia religiosa (“Le besoin religieux”, Éditions de la Baconnière, Neuchâtel, 1974, pp. 123-145. Esta conferencia fue publicada de nuevo en un trabajo póstumo que lleva el mismo título, editado por Henri Desroche (Paris, Éditions Stock, 1975. Reproducimos aquí la integralidad del texto original con la amable autorización de las Rencontres Internationales de Genève, a las cuales la revista SociologieS expresa su agradecimiento.

  16. Osteossarcomas humanos de alto grau: imunoexpressão de p53, erb-2 e P-glicoproteína, e correlação com o parâmetro anaplasia P-glycoprotein, erb2 and p53 expression in high-grade human osteosarcomas and their correlation with anaplasia

    Directory of Open Access Journals (Sweden)

    Maria Teresa de Seixas Alves

    2008-04-01

    Full Text Available INTRODUÇÃO: Osteossarcoma (OS, o mais freqüente tumor primário maligno do osso, tem comportamento local agressivo e alto índice de disseminação sistêmica. Os eventos que permitem o crescimento e a disseminação tumoral ainda permanecem controversos. Os estudos sobre a carcinogênese e a progressão dessa neoplasia, com base na imunoexpressão de c-erb-B2, P-glicoproteína (P-gp e p53, apresentam resultados conflitantes acerca do real valor prognóstico e suas correlações com parâmetros histológicos. A anaplasia, em neoplasias na infância, constitui parâmetro histológico de agressividade tumoral e quimiorresistência. Nos OS primários ou metastáticos, seu significado permanece controverso. Por outro lado, em outras neoplasias humanas, a expressão do c-erb-B2 relaciona-se com p53, grau nuclear e outros parâmetros de agressividade. OBJETIVO: Avaliar a imunoexpressão de p53, c-erb-B2 e P-gp em OS, correlacionando os par��metros entre si e com a presença de anaplasia. MÉTODO: O estudo incluiu 96 biópsias pré-quimioterapia de pacientes com OS de alto grau, diagnosticados entre 1991 e 2000. A pesquisa imuno-histoquímica de p53, P-gp e c-erb-B2 foi feita pela técnica da estreptoavidina-biotina-peroxidase. Foram considerados positivos os casos onde havia imunoexpressão em 10% ou mais das células neoplásicas. Somente colorações membranosa (para cerb-B2 e P-gp e nuclear (para p53 foram consideradas positivas. Anaplasia foi definida como no tumor de Wilms, sendo considerada presente ou ausente. RESULTADOS: Anaplasia pôde ser avaliada em 82/96 casos, estando presente em 29 (35,36%. Imunoexpressão de p53 foi detectada em 25 dos 60 casos (36,23%; de P-gp, em 30 dos 73 casos (41,1%; e de c-erb-B2, em 22 dos 55 casos (40%. Os resultados demonstraram associação entre as imunoexpressões de c-erb-B2 e p53 (p = 0,042, p53 e o parâmetro anaplasia (p = 0,015, anaplasia e Pg (p = 0.034 CONCLUSÕES: A imunoexpressão de p53, c-erb

  17. Le LHC, un tunnel cosmique

    CERN Document Server

    CERN. Geneva

    2009-01-01

    Et si la lumière au bout du tunnel du LHC était cosmique ? En d’autres termes, qu’est-ce que le LHC peut nous apporter dans la connaissance de l’Univers ? Car la montée en énergie des accélérateurs de particules nous permet de mieux appréhender l’univers primordial, chaud et dense. Mais dans quel sens dit-on que le LHC reproduit des conditions proches du Big bang ? Quelles informations nous apporte-t-il sur le contenu de l’Univers ? La matière noire est-elle détectable au LHC ? L’énergie noire ? Pourquoi l’antimatière accumulée au CERN est-elle si rare dans l’Univers ? Et si le CERN a bâti sa réputation sur l’exploration des forces faibles et fortes qui opèrent au sein des atomes et de leurs noyaux, est-ce que le LHC peut nous apporter des informations sur la force gravitationnelle qui gouverne l’évolution cosmique ? Depuis une trentaine d’années, notre compréhension de l’univers dans ses plus grandes dimensions et l’appréhension de son comportement aux plus peti...

  18. Le paludisme, le tsunami silencieux d'Afrique | IDRC - International ...

    International Development Research Centre (IDRC) Digital Library (Canada)

    12 janv. 2011 ... Dans un élan de compassion fort justifié, le monde s'est porté au secours des victimes du tsunami qui a touché récemment la région de l'océan Indien. Mais il ignore qu'un « tsunami silencieux », le paludisme, s'abat sans cesse sur l'Afrique et y fait chaque année plus de 1,5 million de victimes, surtout de ...

  19. Le même et le différent

    OpenAIRE

    Tixier, Nicolas

    2015-01-01

    À partir de Smoke de Paul Auster et Wayne Wang; International audience; Auggie Wren (joué par Harvey Keitel) tient un débit de tabac à Brooklyn au coin de la 16e rue et de Prospect Park West. Chaque matin il traverse le carrefour face à sa boutique et dispose avec attention, toujours au même endroit, son appareil photo sur un trépied. Il regarde sa montre, attend la bonne heure et appuie sur le déclencheur. Cette photo rejoindra un album où jour après jour, page après page, depuis de nombreus...

  20. Le Fleix – Bourg Ouest

    OpenAIRE

    Gineste, Marie-Christine

    2013-01-01

    Date de l'opération : 2009 (EX) Le projet d’extension d’une cantine scolaire est à l’origine de cette prescription. Il concerne une parcelle de 1 438 m2 située sur un replat de la terrasse holocène, en bordure d’un affluent de la Dordogne ; le Lasolle du Bost, dans le périmètre supposé de l’agglomération antique appelée « ville de Meille ». L’assiette du projet correspond au XIXe siècle à un secteur agricole non bâti. Deux tranchées ont été réalisées, occasionnant la découverte, surtout au no...

  1. Le Corbusier’s Dioramas

    Directory of Open Access Journals (Sweden)

    José Ramón Alonso Pereira

    2013-10-01

    Full Text Available AbstractLe Corbusier symbolizes the modern rational urbanism, whose rigorous effort of town planning demands a parallel effort of comprehension. It opposes to these contemporary urbanism that wish to perceive and to enjoy cities in a sensible way. Nevertheless, sentiment and reason are not adverses and Le Corbusier gives us at his  moment keys to intent a synthesis, joined them in a singular way by means of his ‘boîtes à miracles’ or ‘magic boxes’: those "architectural spectacles of synthesis" that he defined in 1951 Ciam. Here we try to approach to the first of those ‘spectacles’: the ‘diorama’, considering it as a corbusean strategy of mediation between rational and sensible in modern and contemporary city.Key wordsLe Corbusier, diorama, Ville Contemporaine, Plan Voisin, Plan Maciá

  2. La preuve par le nombre

    Directory of Open Access Journals (Sweden)

    Hélène Verdier

    2012-04-01

    Full Text Available S’il en était besoin, la question des usages et de la finalité des résultats de l’inventaire général pourrait être abordée par le nombre : nombre d’œuvres répertoriées, de communes inventoriées, de clichés photographiques réalisés, de dossiers, de consultations des notices dans les bases de données… Les additions aujourd’hui sont éloquentes, mais elles laissent dans l’ombre lele de l’inventaire qui, en mettant en œuvre une démarche systématique de connaissance, participe à l’ identificatio...

  3. Le front oriental de Lille

    Directory of Open Access Journals (Sweden)

    Étienne Poncelet

    2011-06-01

    Full Text Available De la porte d’eau de la Basse Deûle jusqu’au fort Saint-Sauveur, le front oriental de Lille, fortifié à l’époque espagnole, glisse ses courtines dans les entrelacs du périphérique et des gares. L’enjeu urbain actuel consiste à s’appuyer sur ces murs historiques pour « passer malgré tout » à travers cet écheveau urbain et retisser les fils de la continuité des promenades au cœur de la ville. Moins connus que le front occidental de la reine des citadelles, ces anciens espaces militaires sont une chance pour l’urbanisme de demain dont les opérations en cours de la Porte de Gand et de la Basse Deûle témoignent déjà.The east wall, at Lille, fortified during the period of Spanish occupation, extends from the Porte d'Eau de la Basse-Deûle to the Saint-Sauveur fort. Its curtain walls emerge today in a landscape of ring roads and railway territories. The issue today is to profit from these historic walls in order to make some sense of the urban chaos and to reinstate some urban continuity in the city-centre walkways. Although they are not as well known as the western wall of this major fortified city, these former military properties are an exciting opportunity for tomorrow's town-planners, as the operations already underway at the Porte de Gand et de la Basse Deûle suggest.

  4. ERBB2 in Cat Mammary Neoplasias Disclosed a Positive Correlation between RNA and Protein Low Expression Levels: A Model for erbB-2 Negative Human Breast Cancer

    Science.gov (United States)

    Abreu, Rui M. V.; Bastos, Estela; Amorim, Irina; Gut, Ivo G.; Gärtner, Fátima; Chaves, Raquel

    2013-01-01

    Human ERBB2 is a proto-oncogene that codes for the erbB-2 epithelial growth factor receptor. In human breast cancer (HBC), erbB-2 protein overexpression has been repeatedly correlated with poor prognosis. In more recent works, underexpression of this gene has been described in HBC. Moreover, it is also recognised that oncogenes that are commonly amplified or deleted encompass point mutations, and some of these are associated with HBC. In cat mammary lesions (CMLs), the overexpression of ERBB2 (27%–59.6%) has also been described, mostly at the protein level and although cat mammary neoplasias are considered to be a natural model of HBC, molecular information is still scarce. In the present work, a cat ERBB2 fragment, comprising exons 10 to 15 (ERBB2_10–15) was achieved for the first time. Allelic variants and genomic haplotype analyses were also performed, and differences between normal and CML populations were observed. Three amino acid changes, corresponding to 3 non-synonymous genomic sequence variants that were only detected in CMLs, were proposed to damage the 3D structure of the protein. We analysed the cat ERBB2 gene at the DNA (copy number determination), mRNA (expression levels assessment) and protein levels (in extra- and intra protein domains) in CML samples and correlated the last two evaluations with clinicopathological features. We found a positive correlation between the expression levels of the ERBB2 RNA and erbB-2 protein, corresponding to the intracellular region. Additionally, we detected a positive correlation between higher mRNA expression and better clinical outcome. Our results suggest that the ERBB2 gene is post-transcriptionally regulated and that proteins with truncations and single point mutations are present in cat mammary neoplastic lesions. We would like to emphasise that the recurrent occurrence of low erbB-2 expression levels in cat mammary tumours, suggests the cat mammary neoplasias as a valuable model for erbB-2 negative HBC

  5. ERBB2 in cat mammary neoplasias disclosed a positive correlation between RNA and protein low expression levels: a model for erbB-2 negative human breast cancer.

    Science.gov (United States)

    Santos, Sara; Baptista, Cláudia S; Abreu, Rui M V; Bastos, Estela; Amorim, Irina; Gut, Ivo G; Gärtner, Fátima; Chaves, Raquel

    2013-01-01

    Human ERBB2 is a proto-oncogene that codes for the erbB-2 epithelial growth factor receptor. In human breast cancer (HBC), erbB-2 protein overexpression has been repeatedly correlated with poor prognosis. In more recent works, underexpression of this gene has been described in HBC. Moreover, it is also recognised that oncogenes that are commonly amplified or deleted encompass point mutations, and some of these are associated with HBC. In cat mammary lesions (CMLs), the overexpression of ERBB2 (27%-59.6%) has also been described, mostly at the protein level and although cat mammary neoplasias are considered to be a natural model of HBC, molecular information is still scarce. In the present work, a cat ERBB2 fragment, comprising exons 10 to 15 (ERBB2_10-15) was achieved for the first time. Allelic variants and genomic haplotype analyses were also performed, and differences between normal and CML populations were observed. Three amino acid changes, corresponding to 3 non-synonymous genomic sequence variants that were only detected in CMLs, were proposed to damage the 3D structure of the protein. We analysed the cat ERBB2 gene at the DNA (copy number determination), mRNA (expression levels assessment) and protein levels (in extra- and intra protein domains) in CML samples and correlated the last two evaluations with clinicopathological features. We found a positive correlation between the expression levels of the ERBB2 RNA and erbB-2 protein, corresponding to the intracellular region. Additionally, we detected a positive correlation between higher mRNA expression and better clinical outcome. Our results suggest that the ERBB2 gene is post-transcriptionally regulated and that proteins with truncations and single point mutations are present in cat mammary neoplastic lesions. We would like to emphasise that the recurrent occurrence of low erbB-2 expression levels in cat mammary tumours, suggests the cat mammary neoplasias as a valuable model for erbB-2 negative HBC.

  6. ErbB2 and NFκB overexpression as predictors of chemoradiation resistance and putative targets to overcome resistance in muscle-invasive bladder cancer.

    Directory of Open Access Journals (Sweden)

    Fumitaka Koga

    Full Text Available Radical cystectomy for muscle-invasive bladder cancer (MIBC patients frequently impairs their quality of life (QOL due to urinary diversion. To improve their QOL, a bladder-sparing alternative strategy using chemoradiation has been developed. In bladder-sparing protocols, complete response (CR to induction chemoradiation is a prerequisite for bladder preservation and favorable survival. Thus predicting chemoradiation resistance and overcoming it would increase individual MIBC patients' chances of bladder preservation. The aim of this study is to investigate putative molecular targets for treatment aimed at improving chemoradiation response. Expression levels of erbB2, NFκB, p53, and survivin were evaluated immunohistochemically in pretreatment biopsy samples from 35 MIBC patients in whom chemoradiation sensitivity had been pathologically evaluated in cystectomy specimens, and associations of these expression levels with chemoradiation sensitivity and cancer-specific survival (CSS were investigated. Of the 35 patients, 11 (31% achieved pathological CR, while tumors in the remaining 24 patients (69% were chemoradiation-resistant. Multivariate analysis identified erbB2 and NFκB overexpression and hydronephrosis as significant and independent risk factors for chemoradiation resistance with respective relative risks of 11.8 (P = 0.014, 15.4 (P = 0.024 and 14.3 (P = 0.038. The chemoradiation resistance rate was 88.5% for tumors overexpressing erbB2 and/or NFκB, but only 11.1% for those negative for both (P <0.0001. The 5-year CSS rate was 74% overall. Through multivariate analysis, overexpression of erbB2 and/or NFκB was identified as an independent risk factor for bladder cancer death with marginal significance (hazard ratio 21.5, P = 0.056 along with chemoradiation resistance (P = 0.003 and hydronephrosis (P = 0.018. The 5-year CSS rate for the 11 patients achieving pathological CR was 100%, while that for the 24 with

  7. Ligeti, Le Grand Macabre (1978)

    OpenAIRE

    Amaral, Pedro

    2011-01-01

    Le Grand Macabre, de Györgi Ligeti, uma obra que, em plenos anos setenta, retoma e reinventa a grande tradição da ópera de repertório. Escrita para a Ópera de Estocolmo, estreada em Abril de 1978, Le Grand Macabre é uma das obras mais marcantes e uma das mais consagradas, internacionalmente, no plano da música dramática da segunda metade do século XX. Escrita a partir de uma peça do dramaturgo belga Michel de Ghelderode, “A Balada do Grande Macabro”, de 1934, a obra de Ligeti retoma um...

  8. Agir sur le gaspillage alimentaire

    OpenAIRE

    Jan, Sophie; Baron, Florence

    2016-01-01

    On estime aujourd'hui à 25% les pertes d'aliments post-récolte et en aval, en raison de leur altération par des microorganismes. L'étude menée ici illustre le risque d'altération engendré par une rupture dans la chaîne du froid, en prenant comme modèle un aliment liquide pasteurisé et réfrigéré, riche en nutriments et dont la température ne doit pas dépasser 4°C.

  9. Le developpement autocentre avec integration dans le marche ...

    African Journals Online (AJOL)

    -arabe, que l'Europe accepterait à cause de son intérêt à stabiliser les pays du sud de la Méditerranée sur le plan social et politique. Mots Clés: Industrialisation, Rente, Exportation de produits manufacturés, Coopération euro-arabe ...

  10. Humeral internal rotation osteotomy for the treatment of Erb-Duchenne-type obstetric palsy: clinical and radiographic results

    Science.gov (United States)

    Assunção, Jorge Henrique; Neto, Arnaldo Amado Ferreira; Benegas, Eduardo; Neto, Raul Bolliger; Prada, Flávia Santis; Malavolta, Eduardo Angeli; Gracitelli, Mauro Emilio Conforto; Camanho, Gilberto Luis

    2013-01-01

    OBJECTIVE: To evaluate the functional and radiographic results in patients undergoing shoulder anterior soft tissue stretching in association with open reduction and internal rotation osteotomy to centralize the humeral head as a treatment for Erb-Duchenne obstetric palsy sequelae. METHOD: A total of 35 patients underwent this surgical treatment, and the mean follow-up was 4.6 years. The Mallet scale was applied before and after the surgical procedure. A total of 20 patients underwent computed tomography to assess the glenoid version and humeral head subluxation. RESULTS: Functional improvement was achieved, as evidenced by an increase in the Mallet scale score from 12.14 to 16.46 (p<0.001). The correction of retroversion was achieved once the glenoid version ranged from -21.4 to -12 degrees (p<0.001). The humeral head subluxation improved from 6.5 to 35.2% (p<0.001). Patients older than 6 years of age did not achieve glenohumeral joint improvement with respect to dysplastic abnormalities. CONCLUSION: Internal rotation osteotomy in association with the stretching of anterior soft tissues of the shoulder in patients under the age of 7 years provided improvements in the function, retroversion, and subluxation of the glenohumeral joint. PMID:23917655

  11. Alterations in cell growth and signaling in ErbB3 binding protein-1 (Ebp1 deficient mice

    Directory of Open Access Journals (Sweden)

    Lee Myounghee

    2008-12-01

    Full Text Available Abstract Background The ErbB3 binding protein-1 (Ebp1 belongs to a family of DNA/RNA binding proteins implicated in cell growth, apoptosis and differentiation. However, the physiological role of Ebp1 in the whole organism is not known. Therefore, we generated Ebp1-deficient mice carrying a gene trap insertion in intron 2 of the Ebp1 (pa2g4 gene. Results Ebp1-/- mice were on average 30% smaller than wild type and heterozygous sex matched littermates. Growth retardation was apparent from Day 10 until Day 30. IGF-1 production and IGBP-3 and 4 protein levels were reduced in both embryo fibroblasts and adult knock-out mice. The proliferation of fibroblasts derived from Day 12.5 knock out embryos was also decreased as compared to that of wild type cells. Microarray expression analysis revealed changes in genes important in cell growth including members of the MAPK signal transduction pathway. In addition, the expression or activation of proliferation related genes such as AKT and the androgen receptor, previously demonstrated to be affected by Ebp1 expression in vitro, was altered in adult tissues. Conclusion These results indicate that Ebp1 can affect growth in an animal model, but that the expression of proliferation related genes is cell and context specific. The Ebp1-/- mouse line represents a new in vivo model to investigate Ebp1 function in the whole organism.

  12. Small Molecule Tyrosine Kinase Inhibitors of ErbB2/HER2/Neu in the Treatment of Aggressive Breast Cancer

    Directory of Open Access Journals (Sweden)

    Richard L. Schroeder

    2014-09-01

    Full Text Available The human epidermal growth factor receptor 2 (HER2 is a member of the erbB class of tyrosine kinase receptors. These proteins are normally expressed at the surface of healthy cells and play critical roles in the signal transduction cascade in a myriad of biochemical pathways responsible for cell growth and differentiation. However, it is widely known that amplification and subsequent overexpression of the HER2 encoding oncogene results in unregulated cell proliferation in an aggressive form of breast cancer known as HER2-positive breast cancer. Existing therapies such as trastuzumab (Herceptin® and lapatinib (Tyverb/Tykerb®, a monoclonal antibody inhibitor and a dual EGFR/HER2 kinase inhibitor, respectively, are currently used in the treatment of HER2-positive cancers, although issues with high recurrence and acquired resistance still remain. Small molecule tyrosine kinase inhibitors provide attractive therapeutic targets, as they are able to block cell signaling associated with many of the proposed mechanisms for HER2 resistance. In this regard we aim to present a review on the available HER2 tyrosine kinase inhibitors, as well as those currently in development. The use of tyrosine kinase inhibitors as sequential or combinatorial therapeutic strategies with other HER family inhibitors is also discussed.

  13. Humeral internal rotation osteotomy for the treatment of Erb-Duchenne-type obstetric palsy: clinical and radiographic results

    Directory of Open Access Journals (Sweden)

    Jorge Henrique Assunção

    2013-07-01

    Full Text Available OBJECTIVE: To evaluate the functional and radiographic results in patients undergoing shoulder anterior soft tissue stretching in association with open reduction and internal rotation osteotomy to centralize the humeral head as a treatment for Erb-Duchenne obstetric palsy sequelae. METHOD: A total of 35 patients underwent this surgical treatment, and the mean follow-up was 4.6 years. The Mallet scale was applied before and after the surgical procedure. A total of 20 patients underwent computed tomography to assess the glenoid version and humeral head subluxation. RESULTS: Functional improvement was achieved, as evidenced by an increase in the Mallet scale score from 12.14 to 16.46 (p<0.001. The correction of retroversion was achieved once the glenoid version ranged from -21.4 to -12 degrees (p<0.001. The humeral head subluxation improved from 6.5 to 35.2% (p<0.001. Patients older than 6 years of age did not achieve glenohumeral joint improvement with respect to dysplastic abnormalities. CONCLUSION: Internal rotation osteotomy in association with the stretching of anterior soft tissues of the shoulder in patients under the age of 7 years provided improvements in the function, retroversion, and subluxation of the glenohumeral joint.

  14. Rapport sur le développement dans le monde sur le thème du rôle ...

    International Development Research Centre (IDRC) Digital Library (Canada)

    ... rural et sont tributaires principalement de l'agriculture pour assurer leur subsistance. Ce projet permettra de veiller à ce qu'une place soit accordée aux travaux de recherche financés par le CRDI, aux points de vue différents et aux auteurs de l'hémisphère Sud dans le Rapport sur le développement dans le monde 2008.

  15. Le profil entrepreneurial : Facteur discriminant du developpement ...

    African Journals Online (AJOL)

    Le développement économique est un objectif majeur pour tout pays. Selon le classement établi par le Forum économique mondial, le développement économique dépend du niveau du PIB per capita et de la part des exportations des biens minéraux dans l'exportation totale. A partir de la base de données GEM Algérie, ...

  16. Quand le dentier devient danger!

    Science.gov (United States)

    Sadak, Nouzha; Herrak, Laila; Achachi, Leila; El Ftouh, Mustapha

    2017-01-01

    Bien que rare chez l'adulte, l'inhalation de corps étranger (CE) est un accident grave pouvant mettre en jeu le pronostic vital ou entrainer des séquelles importantes. Nous rapportons l'observation d'un patient de 50 ans, sans antécédents pathologiques particuliers, qui s'est présentée aux urgences pour douleur thoracique, toux intermittente et dyspnée d'effort, six jours après avoir inhalé, accidentellement, sa prothèse dentaire en plastique lors d'un repas. L'examen clinique était sans particularités. La radiographie thoracique ainsi que l'ASP ne montraient pas d'anomalie. Une bronchoscopie souple sous anesthésie générale a permis de visualiser le CE au niveau du tronc intermédiaire et l'extraction a été réalisée avec succès évitant ainsi le recours à un geste beaucoup plus invasif. La radiographie standard peut s'avérer utile en visualisant les CE radio-opaque ou par des signes indirects évoquant la présence d'un CE, mais le recours à la bronchoscopie à visée diagnostique et thérapeutique est primordial. PMID:28904706

  17. Nanostructures pour le développement de vaccins contre le virus de ...

    International Development Research Centre (IDRC) Digital Library (Canada)

    Institut national de la recherche agronomique (France). Ce projet est financé par le fonds d'innovation en vaccins pour le bétail, un partenariat entre la fondation Bill et Melinda Gates, Affaires Mondiales Canada et le Centre de recherches pour le ...

  18. Le Kenya nomme le titulaire de sa première chaire de recherche

    International Development Research Centre (IDRC) Digital Library (Canada)

    14 avr. 2016 ... De concert avec le CRDI, la National Commission for Science, Technology and Innovation (NACOSTI) du Kenya a inauguré sa première chaire de recherche à Nairobi, le 31 mars 2015. Le professeur Fabian Omoding Esamai, qui dirige actuellement le College of Health Sciences de la Moi University, a été ...

  19. Le LHC, priorité absolue

    CERN Multimedia

    Huet, S

    2002-01-01

    Le LHC, sa mise en est repoussee a 2007 quand les physiciens esperaient 2006. Le CERN a sous-estime les couts, environ 11% pour les 1 200 aimants supraconducteurs. Les Etats membres n'augmenteront pas leurs subventions, il propose donc cette semaine un plan drastique : tout pour le LHC (1/2 page).

  20. Le CERN ouvre ses entrailles au public

    CERN Multimedia

    2004-01-01

    "Le CERN se lance dans une grande opération de relations publiques pour son cinquantième anniversaire. Le centre de recherche organisera une journée portes ouvertes le 16 octobre. Quelque 50 sites pourrant être visités" (1/2 page)

  1. LE CORBUSIER: CONCURSOS Y PALACIOS / Le Corbusier: competitions and palaces

    Directory of Open Access Journals (Sweden)

    Fernando Zaparaín Hernández

    2012-11-01

    Full Text Available RESUMEN Cuando Le Corbusier ya había pasado de los cuarenta años se enfrentó a dos concursos internacionales: el Palacio de las Naciones en Ginebra (1926–31 y el Palacio de los Soviets en Moscú (1931–32 con los que intentaba acceder a grandes encargos de estado con mayor escala urbana en los que poner a prueba su ideario moderno sobre arquitectura y urbanismo. En ambos casos estuvo entre los vencedores pero por conveniencia e indecisión, los poderes políticos optaron por soluciones academicistas. Al conocer las decisiones definitivas, Le Corbusier y todos sus contactos del Movimiento Moderno orquestaron diversas polémicas ante los medios de comunicación y los gobernantes por entender que el progreso se veía lastrado por el triunfo de propuestas reaccionarias. Mediante el estudio de la correspondencia con personas particulares como Moser, Giedion, Colly o Stonorov, conservada en la Fundación Le Corbusier, se analizan las relaciones y el tono ideológico en torno a aquellas protestas. En esos textos quedan reflejados los principales rasgos que caracterizan la modernidad como su internacionalización, la seguridad en la propia misión, la defensa de lo nuevo o el método dialéctico. SUMMARY When Le Corbusier had already passed the age of forty he confronted two international competitions: the Palais des Nations in Geneva (1926–1931 and the Palace of the Soviets in Moscow (1931–32, with which he attempted to access large state commissions, with greater urban scale, in which to test his ideas about modern architecture and urbanism. In both cases he was among the winners, but through convenience and indecision the political powers opted for solutions from academicians. Upon knowing the final decisions, Le Corbusier and all his contacts in the Modern Movement orchestrated several controversies with the media, and the people in power, to convey that progress seemed burdened by the triumph of reactionary proposals. The relationships

  2. LE CORBUSIER: CONCURSOS Y PALACIOS / Le Corbusier: competitions and palaces

    Directory of Open Access Journals (Sweden)

    Fernando Zaparaín Hernández

    2012-11-01

    Full Text Available RESUMEN Cuando Le Corbusier ya había pasado de los cuarenta años se enfrentó a dos concursos internacionales: el Palacio de las Naciones en Ginebra (1926–31 y el Palacio de los Soviets en Moscú (1931–32 con los que intentaba acceder a grandes encargos de estado con mayor escala urbana en los que poner a prueba su ideario moderno sobre arquitectura y urbanismo. En ambos casos estuvo entre los vencedores pero por conveniencia e indecisión, los poderes políticos optaron por soluciones academicistas. Al conocer las decisiones definitivas, Le Corbusier y todos sus contactos del Movimiento Moderno orquestaron diversas polémicas ante los medios de comunicación y los gobernantes por entender que el progreso se veía lastrado por el triunfo de propuestas reaccionarias. Mediante el estudio de la correspondencia con personas particulares como Moser, Giedion, Colly o Stonorov, conservada en la Fundación Le Corbusier, se analizan las relaciones y el tono ideológico en torno a aquellas protestas. En esos textos quedan reflejados los principales rasgos que caracterizan la modernidad como su internacionalización, la seguridad en la propia misión, la defensa de lo nuevo o el método dialéctico.SUMMARY When Le Corbusier had already passed the age of forty he confronted two international competitions: the Palais des Nations in Geneva (1926–1931 and the Palace of the Soviets in Moscow (1931–32, with which he attempted to access large state commissions, with greater urban scale, in which to test his ideas about modern architecture and urbanism. In both cases he was among the winners, but through convenience and indecision the political powers opted for solutions from academicians. Upon knowing the final decisions, Le Corbusier and all his contacts in the Modern Movement orchestrated several controversies with the media, and the people in power, to convey that progress seemed burdened by the triumph of reactionary proposals. The relationships and

  3. Publications | Page 95 | CRDI - Centre de recherches pour le ...

    International Development Research Centre (IDRC) Digital Library (Canada)

    Le CRDI et la lutte contre le paludisme. DOCUMENT D'INFORMATION. Le paludisme tue un enfant africain toutes les 30 secondes. Avec le VIH/sida et la tuberculose, le paludisme est l'un des principaux problèmes de santé publique menaçant le.

  4. pour le trimestre qui a pris fin le 30 septembre 2017

    International Development Research Centre (IDRC) Digital Library (Canada)

    Sophie Comeau

    30 sept. 2017 ... Régi par la Loi sur le Centre de recherches pour le développement international (1970), le Centre de recherches pour le développement international (le Centre ou CRDI) vise à « lancer, encourager, appuyer et mener des recherches sur les problèmes des régions du monde en voie de développement et ...

  5. Reflexion sur le climat, l'effet de serre et le rechauffement global ...

    African Journals Online (AJOL)

    Le climat de la Terre est largement influencé par l'état de son atmosphère. Le rayonnement solaire jouerait un rôle primordial dans la climatologie terrestre certes, néanmoins, il n'est plus en mesure à lui tout seul d'expliquer le climat qui prédomine, en moyenne, à la surface de la terre. L'effet de serre serait le phénomène ...

  6. Rapport financier trimestriel pour le trimestre qui a pris fin le 31 ...

    International Development Research Centre (IDRC) Digital Library (Canada)

    Office 2004 Test Drive User

    31 déc. 2016 ... Lʼinformation et les divulgations contenues dans le Rapport annuel 2015-2016 sʼappliquent au trimestre sur lequel porte le présent rapport trimestriel, sauf indication contraire. Budget 2016-2017 révisé. Le Conseil des gouverneurs a approuvé le budget 2016-2017 avant le début de lʼexercice. Cʼest.

  7. Le contrôle de gestion des entreprises familiales : un contrôle non-financiarisé ?

    OpenAIRE

    Barbelivien, Dominique

    2016-01-01

    Nous examinons la tendance décrite dans la littérature quant à la financiarisation de la fonction de contrôle de gestion en nous appuyant sur le cas d’une entreprise de taille intermédiaire familiale. Nous constatons que le contrôle de gestion dans le cas étudié correspond à une rationalisation des décisions opérationnelles et développons les raisons qui peuvent expliquer la persistance d’un contrôle de gestion très opérationnel. Le contexte d’entreprise familiale dans laquelle il y a confusi...

  8. Bulletin #109 | CRDI - Le Centre de recherches pour le ...

    International Development Research Centre (IDRC) Digital Library (Canada)

    ... offres d'emploi. Appel à propositions de recherche sur les villes résilientes en Amérique latine. Date butoir : 13 juin 2016. Programme de recherche sur le virus Zika Canada-Amérique latine et Caraïbes Date butoir : 12 juillet 2016. POSSIBILITÉS D'EMPLOIS Agent de ressources humaines · Analyste des opérations de TI.

  9. Le cosmos et le lotus confessions d'un astrophysicien

    CERN Document Server

    Trinh, Xuan Thuan

    2011-01-01

    Que nous dit vraiment la science sur la nature de l'univers, sur son origine et son avenir ? Par quel mystère le langage mathématique, pure création de l'esprit humain, se révèle-t-il aussi performant pour nous décrire les phénomènes physiques, de l'infiniment petit à l'infiniment grand ? S'il existe un ordre du monde, ce que nous en disent la physique quantique et la théorie de la relativité est-il compatible avec ce qu'enseigne le bouddhisme ? Et que peut-on en conclure concernant notre propre vie ? A ces questions passionnantes et à beaucoup d'autres, le célèbre astrophysicien Trinh Xuan Thuan répond ici d'une façon personnelle, en s'appuyant sur son expérience. Son itinéraire l'a placé d'emblée à la confluence de trois cultures : issu d'une famille de lettrés vietnamiens imprégnée de traditions bouddhiste et confucéenne, il a reçu une éducation à la française puis une formation scientifique à l'américaine. Une telle richesse de points de vue lui permet d'apporter, non pas de...

  10. Le futur du travail | CRDI - Centre de recherches pour le ...

    International Development Research Centre (IDRC) Digital Library (Canada)

    12 juin 2017 ... Une base de données probantes est nécessaire afin de trouver des solutions stratégiques et sociales appropriées aux divers défis que posent ces nouveaux modes de travail. La recherche sur l'innovation en matière d'éducation et le renforcement des capacités seront également essentiels pour assurer la ...

  11. Effect of estradiol on estrogen receptor-alpha gene expression and activity can be modulated by the ErbB2/PI 3-K/Akt pathway.

    Science.gov (United States)

    Stoica, Gerald E; Franke, Thomas F; Moroni, Maria; Mueller, Susette; Morgan, Elisha; Iann, Mary C; Winder, Abigail D; Reiter, Ronald; Wellstein, Anton; Martin, Mary Beth; Stoica, Adriana

    2003-09-11

    Epidermal growth factor (EGF), insulin-like growth factor-I (IGF-I), and heregulin-beta1 (HRG-beta1), can modulate the expression and activity of the estrogen receptor-alpha (ER-alpha) via the phosphatidylinositol 3-kinase (PI 3-K)/Akt pathway in the ER-alpha-positive breast cancer cell line, MCF-7. Estradiol can also rapidly activate PI 3-K/Akt in these cells (nongenomic effect). The recent study examines whether Akt is involved in the ER-alpha regulation by estradiol (genomic effect). Stable transfection of parental MCF-7 cells with a dominant-negative Akt mutant, as well as the PI 3-K inhibitors wortmannin and LY 294,002, blocked the effect of estradiol on ER-alpha expression and activity by 70-80 and 55-63%, respectively. Stable transfection of MCF-7 cells with a constitutively active Akt mimicked the effect of estradiol. The changes in ER-alpha expression and activity were abrogated in response to estradiol by an arginine to cysteine mutation in the pleckstrin homology (PH) domain of Akt (R25C), suggesting the involvement of this amino acid in the interaction between Akt and ER-alpha. Experiments employing selective ErbB inhibitors demonstrate that the effect of estradiol on ER-alpha expression and activity is mediated by ErbB2 and not by EGFR. Moreover, anchorage-dependent and -independent growth assays, cell cycle and membrane ruffling analyses showed that Akt exerts estrogen-like activity on cell growth and membrane ruffling and that a selective ErbB2 inhibitor, but not anti-ErbB2 antibodies directed to the extracellular domain, can block these effects. In the presence of constitutively active Akt, tamoxifen only partially inhibits cell growth. In contrast, in cells stably transfected with either a dominant-negative Akt or with R25C-Akt, as well as in parental cells in the presence of a selective ErbB2 inhibitor, the effect of estradiol on anchorage-dependent and -independent cell growth was inhibited by 50-75 and 100%, respectively. Dominant-negative Akt

  12. Análise da expressão imuno-histoquímica de c-erbB-2 e EGFR em carcinoma epidermóide de esôfago Immunohistochemical expression of c-erbB-2 and EGFR in esophageal squamous cell carcinoma

    Directory of Open Access Journals (Sweden)

    Yukie Sato

    2007-08-01

    Full Text Available INTRODUÇÃO: O carcinoma epidermóide de esôfago (CEE possui alta incidência em nosso país, com altas taxas de mortalidade. A família dos receptores do fator epitelial de crescimento (EGFR é composta por quatro membros, e muitos estudos têm sido direcionados para a expressão de EGFR e c-erbB-2, com implicações terapêuticas. OBJETIVO: Investigar as expressões imuno-histoquímicas de EGFR e c-erbB-2 e correlacioná-las a aspectos clinicopatológicos em casos de CEE. MATERIAL E MÉTODOS: Para esse estudo, dados clinicopatológicos de 613 CEE foram revistos. A imunoistoquímica foi feita utilizando anticorpo policlonal para c-erbB-2 e monoclonal para EGFR em 597 e 585 casos, respectivamente. Os casos representados por peças cirúrgicas foram distribuídos em três blocos de parafina de tissue microarray (TMA, inseridos em duplicata; aqueles com biópsias foram analisados em corte convencional. Todos foram classificados de acordo com intensidade e padrão de marcação de membrana das células tumorais. RESULTADOS: As expressões de c-erbB-2 e EGFR foram observadas em 42,4% e 77,6% dos casos, respectivamente. Observou-se correlação estatisticamente significativa entre as expressões de c-erbB-2 (p = 0,04 e EGFR (p = 0,01 e grau histológico. Ambos os marcadores foram significativamente mais expressos em casos bem/moderadamente diferenciados do que nos pouco diferenciados/indiferenciados. Embora não tenha sido significativa, houve uma tendência de associação entre superexpressão de c-erbB-2 e sítio do tumor, em que casos positivos ocorreram com mais freqüência no terço médio do esôfago. Nenhuma correlação significativa foi verificada entre essas proteínas e sobrevida global. CONCLUSÃO: Os resultados podem sugerir um papel primordial para essas proteínas na diferenciação tumoral em CEE.INTRODUCTION: Esophageal squamous cell carcinoma (ESCC is highly prevalent in Brazil, and responsible for high mortality index. The

  13. Polypeptide-based nanogels co-encapsulating a synergistic combination of doxorubicin with 17-AAG show potent anti-tumor activity in ErbB2-driven breast cancer models.

    Science.gov (United States)

    Desale, Swapnil S; Raja, Srikumar M; Kim, Jong Oh; Mohapatra, Bhopal; Soni, Kruti S; Luan, Haitao; Williams, Stetson H; Bielecki, Timothy A; Feng, Dan; Storck, Matthew; Band, Vimla; Cohen, Samuel M; Band, Hamid; Bronich, Tatiana K

    2015-06-28

    ErbB2-driven breast cancers constitute 20-25% of the cases diagnosed within the USA. The humanized anti-ErbB2 monoclonal antibody, Trastuzumab (Herceptin™; Genentech), with chemotherapy is the current standard of treatment. Novel agents and strategies continue to be explored, given the challenges posed by Trastuzumab-resistance development in most patients. The HSP90 inhibitor, 17-allylaminodemethoxygeldanamycin (17-AAG), which induces ErbB2 degradation and attenuates downstream oncogenic signaling, is one such agent that showed significant promise in early phase I and II clinical trials. Its low water solubility, potential toxicities and undesirable side effects observed in patients, partly due to the Cremophor-based formulation, have been discouraging factors in the advancement of this promising drug into clinical use. Encapsulation of 17-AAG into polymeric nanoparticle formulations, particularly in synergistic combination with conventional chemotherapeutics, represents an alternative approach to overcome these problems. Herein, we report an efficient co-encapsulation of 17-AAG and doxorubicin, a clinically well-established and effective modality in breast cancer treatment, into biodegradable and biocompatible polypeptide-based nanogels. Dual drug-loaded nanogels displayed potent cytotoxicity in a breast cancer cell panel and exerted selective synergistic anticancer activity against ErbB2-overexpressing breast cancer cell lines. Analysis of ErbB2 degradation confirmed efficient 17-AAG release from nanogels with activity comparable to free 17-AAG. Furthermore, nanogels containing both 17-AAG and doxorubicin exhibited superior antitumor efficacy in vivo in an ErbB2-driven xenograft model compared to the combination of free drugs. These studies demonstrate that polypeptide-based nanogels can serve as novel nanocarriers for encapsulating 17-AAG along with other chemotherapeutics, providing an opportunity to overcome solubility issues and thereby exploit its full

  14. MiR-193b, downregulated in Ewing Sarcoma, targets the ErbB4 oncogene to inhibit anchorage-independent growth.

    Directory of Open Access Journals (Sweden)

    Colin Moore

    Full Text Available Ewing Sarcoma is an aggressive, oncofusion-driven, malignant neoplasm of bone and soft tissue affecting predominantly children and young adults. Seeking to identify potential novel therapeutic targets/agents for this disease, our previous studies uncovered microRNAs regulated by EWS/Fli1, the most common oncofusion, with growth modulatory properties. In the present study, we sought to identify EWS/Fli1-repressed, growth suppressive, microRNAs potentially amenable to replacement in Ewing Sarcoma cells. Eight microRNAs (143, 153, 184, 193b, 195, 203, 206 and 223 were selected for evaluation as EWS/Fli1-repressed and underexpressed in Ewing Sarcoma cells, and reported to be growth suppressive in other pediatric or/and adult cancers. The selected miRs, and appropriate non-targeting controls, were introduced into two different Ewing Sarcoma cell lines (A673 and SK-ES-1, and effects on growth were examined using a high and low-density growth assay. MiR-193b was growth inhibitory in both assays and cell lines. In subsequent analyses, we found that stable overexpression of miR-193b also inhibits anchorage-independent growth in both A673 and SK-ES-1 cells. We further show that miR-193b negatively regulates expression of the ErbB4 oncogene in A673 and SK-ES-1 cells, and that depletion of ErbB4 is itself inhibitory to anchorage-independent growth in the same cell lines. Together, our studies show that the EWS/Fli1-repressed miR-193b is growth suppressive in Ewing Sarcoma, and identify ErbB4 as a target gene and candidate mediator of this growth suppression.

  15. Le glaive de la parole

    Directory of Open Access Journals (Sweden)

    Luce Marchal-Albert

    2006-09-01

    Full Text Available Chacun sait, selon le mot de Pierre Viret, « en quelle confusion est la Chrestienté » au xvie siècle en Europe. C’est le deuxième quart du siècle qui nous intéressera ici, et en particulier l’année 1545, qui constitue une année charnière qui voit vaciller l’Église romaine, flamber et culminer la chasse aux hérétiques en même temps qu’elle voit la jeune Église réformée se renforcer et se positionner avec succès dans un champ religieux plus que chaotique. Les ouvrages polémiques réformés écrits...

  16. Prendre le pli des techniques

    OpenAIRE

    Latour, Bruno

    1983-01-01

    À partir de la notion de mode d’existence développée par Gilbert Simondon et surtout par Etienne Souriau, il est possible d’aborder la question de la technique sans se laisser arrêter par la présence excessive de l’un de ses résultats : les objets techniques. On peut alors essayer de définir le mode propre de la technique comme un mouvement, un projet, un plissage, une forme très particulière de transcendance, qui n’a pas reçu en philosophie le traitement que mérite son importance et son ubiq...

  17. Le sette meraviglie del cosmo

    CERN Document Server

    Narlikar, Jayant V

    2004-01-01

    Tra giganti, "nane" e stelle che esplodono in cielo, un vademecum per scoprire il cosmo e i misteri che lo abitano. Lasciati alle spalle i confini sicuri della Terra e del Sistema solare, assistiamo a un'esplosione continua di fenomeni inaspettati. L'universo si svela nel suo continuo mutamento, cresce in fascino e complessità via via che ci addentriamo nei suoi spazi profondi. Tramite esempi semplici, aneddoti umoristici e una prosa cristallina, Vishnu Narkilar racconta l'emozione di fronte alle sorprese del cosmo. Le "sette meraviglie" sono i fenomeni misteriosi che si nascondono dietro le stelle che punteggiano il cielo, una schiera di eventi spettacolari che per secoli hanno sfidato la curiosità umana ed eluso ogni spiegazione.

  18. Le CRDI au Sri Lanka

    International Development Research Centre (IDRC) Digital Library (Canada)

    Le CRDI appuie la recherche au Sri. Lanka depuis 1973. Il s'est d'abord concentré sur l'amélioration des pratiques agricoles. Par exemple, grâce à la mise au point d'un système de rizi - culture permettant d'exploiter les pluies de mousson, les riziculteurs ont triplé leurs rendements en quatre ans. Ils ont été nombreux à ...

  19. Le jumelage de journalistes scientifiques

    International Development Research Centre (IDRC) Digital Library (Canada)

    Cathy Egan

    Les questions scientifiques suscitent de plus en plus de doutes, d'angoisse et de discorde chez le grand public. Les profanes, peut-être plus encore que les scientifiques, s'interrogent et s'obstinent sur les causes du réchauffement planétaire, l'innocuité des organismes génétiquement modifiés (OGM) dans les aliments ou ...

  20. A new solvate of afatinib, a specific inhibitor of the ErbB family of tyrosine kinases

    Directory of Open Access Journals (Sweden)

    Matthias Zeller

    2017-03-01

    Full Text Available Afatinib (systematic name: N-{4-(3-chloro-4-fluoroanilino-7-[(tetrahydrofuran-3-yloxy]quinazolin-6-yl}-4-(dimethylaminobut-2-enamide, is a specific inhibitor of the ErbB family of tyrosine kinases. The free base form crystallizes from acetonitrile as a mixed water–acetonitrile solvent, C24H25ClFN5O3·0.25C2H3N·2H2O. It crystallizes with two independent molecules (A and B in the asymmetric unit of the chiral space group P4212, but exhibits close to perfect pseudo-inversion symmetry, emulating P4/ncc that relates the two molecules to each other. Exact inversion symmetry is however broken by swapping of oxygen and CH2 moieties of the outer tetrahydrofuranyl substituents of the two independent molecules. This can, in turn, be traced back to C—H...N and C—H...O interactions of the acetonitrile solvent molecules with the tetrahydrofuran oxygen and CH2 units. In the crystal, neighboring molecules are connected via N—H...O hydrogen bonds between the secondary amine and the amide keto O atom. Additional hydrogen bonds are formed through the water solvent molecules, which are engaged in O—H...O and O—H...N hydrogen bonds connecting to the dimethylamino N atom, the amide keto O atom, and one of the quinazoline N atoms of a neighboring molecule, leading to an intricate three-dimensional hydrogen-bonded superstructure. There are two types of channels stretching along the direction of the c axis; one along the fourfold rotational axis, occupied by acetonitrile solvent molecules situated on that axis, and parallel channels which are not occupied by any solvent.

  1. Georges et le big bang

    CERN Document Server

    Hawking, Lucy; Parsons, Gary

    2011-01-01

    Georges et Annie, sa meilleure amie, sont sur le point d'assister à l'une des plus importantes expériences scientifiques de tous les temps : explorer les premiers instants de l'Univers, le Big Bang ! Grâce à Cosmos, leur super ordinateur, et au Grand Collisionneur de hadrons créé par Éric, le père d'Annie, ils vont enfin pouvoir répondre à cette question essentielle : pourquoi existons nous ? Mais Georges et Annie découvrent qu'un complot diabolique se trame. Pire, c'est toute la recherche scientifique qui est en péril ! Entraîné dans d'incroyables aventures, Georges ira jusqu'aux confins de la galaxie pour sauver ses amis...Une plongée passionnante au coeur du Big Bang. Les toutes dernières théories de Stephen Hawking et des plus grands scientifiques actuels.

  2. Le principe non bis in idem et le droit communautaire

    OpenAIRE

    Hedabou, Aziz

    2018-01-01

    Le principe non bis in idem est une garantie fondamentale qui interdit que les mêmes faits soit poursuivi et puni deux fois. Il est reconnu par tous les droits internes et “appartient aux droit universel des nations”. Dès lors, sa lettre et son esprit ne sont plus cantonnés au droit interne et ont tendance à s’internationaliser. En droit communautaire, l’étude du principe non bis in idem peut être envisagée sous trois angles différents. D’abord en droit pénal international unilatéral où chaqu...

  3. Contester le mariage forcé : mettre en place la ligne de défense et le ...

    International Development Research Centre (IDRC) Digital Library (Canada)

    Le droit civil en matière de mariage est la Loi spéciale sur le mariage, qui permet aux parties de différentes religions de se marier sans changer de religion. Elle exige le consentement explicite des deux partenaires pour que le mariage soit possible. Le consentement demeure le point central de la loi sur le mariage; ...

  4. LE SECTEUR INFORMEL EN ALGERIE : APPROCHES, ACTEURS ...

    African Journals Online (AJOL)

    du respect des lois et des règlements et de l'Etat de droit de façon générale. 1.4. L'approche du secteur informel selon le Bureau International du Travail (BIT) ... qui ne tiennent pas une comptabilité complète et dont la person- l'importation…) mais également dans le secteur immobilier dont le fonctionnement est informel.

  5. Peut-on voyager dans le temps ?

    CERN Multimedia

    CERN. Geneva

    2008-01-01

    La possibilité de voyager dans le temps est régulièrement évoquée par les magazines scientifiques (et parfois même par les scientifiques). Elle est également le sujet de nombreux romans de science-fiction. Nous discuterons d’abord du sens qu’on peut donner à l’expression « voyager dans le temps », puis nous expliciterons ce que la physique contemporaine dit à ce propos.

  6. Télécharger le PDF

    International Development Research Centre (IDRC) Digital Library (Canada)

    Le CRDI finance la recherche dans les pays en développement afin de réduire la pauvreté, soutenant ainsi l'objectif des activités de dévelop- pement international du Canada. Le Centre favorise la croissance et le développement et encourage la communication des connaissances aux responsables des politiques, aux ...

  7. Le CRDI en Égypte

    International Development Research Centre (IDRC) Digital Library (Canada)

    afin d'y favoriser la croissance et le développement. Il en résulte des solutions locales, novatrices et durables, qui offrent des choix aux personnes qui en ont le plus besoin et font changer les choses. Centre de recherches pour le développement international. CP 8500, Ottawa (Ontario) Canada K1G 3H9. 1012 alexandrie.

  8. Le CRDI en Éthiopie

    International Development Research Centre (IDRC) Digital Library (Canada)

    'une crise. À long terme, toutefois, elle peut entraîner la dépendance et saper le système local de production de semences. Dans le cadre d'une étude menée de 2005 à 2008, des chercheurs s ubventionnés par le CRDI ont constaté que l'on ...

  9. Cytotoxicity of a natural anthraquinone (Aloin) against human breast cancer cell lines with and without ErbB-2: topoisomerase IIalpha coamplification.

    Science.gov (United States)

    Esmat, Amr Y; Tomasetto, Catherine; Rio, Marie-Christine

    2006-01-01

    In the present study the cytotoxic activity of aloin, a natural anthracycline from Aloe plant, is reported against two human breast cancer cell lines; without (MCF-7) and with (SKBR-3) erbB-2-topoIIalpha coamplification. MCF-7cell line was shown to be more sensitive to aloin than SKBR-3 demonstrated by MTT and clonogenic assays, from which IC50 and 50% ICF values are reported to be 60 microg/ml, respectively, in the former cell line and as high as 150 and 80 microg/ml, respectively, in the latter, which are still far below the maximum tolerated dose of the compound. The effect of aloin is suggested to be brought about by more than one mechanism depending on the dose level and tumor phenotype. This was demonstrated by flow cytometric analysis, fluorescence microscopy and western blot analysis, which revealed that aloin at higher concentrations caused a reduction in the proportion of cells undergoing mitosis by induction of apoptosis, inhibition of topo II alpha protein expression and downregulation of cyclin B1 protein expression in MCF-7 cell line, whereas erbB-2 protein expression was not affected. Topo IIalpha protein expression was mildly downregulated in SKBR-3 cell line at higher concentrations only.

  10. Valuing Heritage in Macau: On Contexts and Processes of Urban Conservation Kulturelles Erbe in Macau: Zu Rahmenbedingungen und Prozessen städtischer Denkmalpflege

    Directory of Open Access Journals (Sweden)

    Thomas Chung

    2009-04-01

    Full Text Available This paper examines the evolving values of urban heritage in Macau in terms of the various conservation approaches and mechanisms employed, and the shifting emphases on heritage and development within the context of continuity and change in Macau. Accumulated over four centuries of cultural interchange, the richly layered Historic Centre of the former Portuguese-administered outpost attained World Heritage status in 2005. After situating the problem pertaining to the multifaceted nature of heritage valorisation, the city’s trajectory of urban conservation leading up to the 1999 retrocession will be traced, and germane issues concerning heritage management vis-à-vis effects of post-handover urban developments assessed. As the latest culmination of value imbalances and conflicts arising from urban change, the Guia Lighthouse controversy will be critically appraised to speculate on a timely re-evaluation of Macau’s heritage conservation process. Der vorliegende Beitrag untersucht die sich wandelnde Haltung in Macau zum eigenen kulturellen Erbe, und zwar mit Blick auf die verschiedenen Konservierungsansätze und die dazu angewandten Methoden sowie auf die unterschiedliche Bedeutung von Kulturellem Erbe und Entwicklung im Kontext von Kontinutät und Wandel in der Stadt.

  11. miR-205-5p-mediated downregulation of ErbB/HER receptors in breast cancer stem cells results in targeted therapy resistance.

    Science.gov (United States)

    De Cola, A; Volpe, S; Budani, M C; Ferracin, M; Lattanzio, R; Turdo, A; D'Agostino, D; Capone, E; Stassi, G; Todaro, M; Di Ilio, C; Sala, G; Piantelli, M; Negrini, M; Veronese, A; De Laurenzi, V

    2015-07-16

    The ErbB tyrosine kinase receptor family has been shown to have an important role in tumorigenesis, and the expression of its receptor members is frequently deregulated in many types of solid tumors. Various drugs targeting these receptors have been approved for cancer treatment. Particularly, in breast cancer, anti-Her2/EGFR molecules represent the standard therapy for Her2-positive malignancies. However, in a number of cases, the tumor relapses or progresses thus suggesting that not all cancer cells have been targeted. One possibility is that a subset of cells capable of regenerating the tumor, such as cancer stem cells (CSCs), may not respond to these therapeutic agents. Accumulating evidences indicate that miR-205-5p is significantly downregulated in breast tumors compared with normal breast tissue and acts as a tumor suppressor directly targeting oncogenes such as Zeb1 and ErbB3. In this study, we report that miR-205-5p is highly expressed in BCSCs and represses directly ERBB2 and indirectly EGFR leading to resistance to targeted therapy. Furthermore, we show that miR-205-5p directly regulates the expression of p63 which is in turn involved in the EGFR expression suggesting a miR-205/p63/EGFR regulation.

  12. Le corps dans l'Antiquité

    Directory of Open Access Journals (Sweden)

    Sophie Lalanne

    2008-06-01

    Full Text Available Ouvrages générauxLaqueur Thomas, La fabrique du sexe. Essai sur le corps et le genre en Occident, trad. fr., Paris, Gallimard, 1992.Feher Michel, Naddaff Ramona, Tazi Nadia, Fragments for a History of the Human Body, 3 volumes, New York, Zone Books, 1989.Le Corps dans l’AntiquitéBodiou Lydie, Frère Dominique, Mehl Véronique dir., L’expression des corps. Gestes, attitudes, regards dans l’iconographie antique, Rennes, Presses Universitaires de Rennes, 2006.Bonnard Jean-Baptiste, Le complexe de ...

  13. Le marketing : quelle contribution au bien commun ?

    OpenAIRE

    Béji-Bécheur, Amina

    2015-01-01

    National audience; Partons d'un constat : le marketing est né pour servir l'entreprise capitaliste et le développement de ses marchés. Le but ultime étant la création de richesses et par ricochet le bien-être des populations. Un ensemble d'outils marketing ont été créés pour accompagner les enjeux de performance économique des entreprises. Reprenant les travaux de Jean-Claude Moisdon (Du mode d'existence des outils de gestion, les instruments de gestion à l'épreuve de l'organisation 1), ces o...

  14. Le marketing cherche ses marques

    OpenAIRE

    Hentschel, Dieter

    2018-01-01

    Voici maintenant dix ans que, dans le cadre d’une politique continue de diversification des formations offertes aux germanistes, l’IAA a mis en place un enseignement de marketing. Cette innovation n’est pas restée sans suite, puisqu’elle a abouti au repositionnement du DESS « économie et Société dans les pays de langue allemande » qui s’appelle désormais « Gestion et marketing franco-allemands ». L’objectif a été de proposer aux étudiants une formation professionnalisante qui corresponde aux ...

  15. Le CRDI et la lutte contre le paludisme | CRDI - Centre de ...

    International Development Research Centre (IDRC) Digital Library (Canada)

    22 juil. 2011 ... D'autres interventions luttent également contre le paludisme, notamment les moustiquaires imprégnées d'insecticide et les médicaments visant à prévenir le ... Le CRDI appuie le GCRAI depuis les années 1970 et participe avec SIMA au financement de la recherche sur les interactions complexes entre ...

  16. Lele du langage de programmation dans la réalisation de code ...

    African Journals Online (AJOL)

    Lele du langage de programmation dans la réalisation de code de qualité, les cas de Delphi et C++ Nous discutons dans ce papier lele du langage de programmation dans la production d'un code de qualité. La qualité d'un code peut être atteinte en respectant certains critères simples au niveau de la programmation ...

  17. Le

    NARCIS (Netherlands)

    de Beer, P.T.; Luttikhuizen, R.; Barbier, J.C.; Gautii, J.

    1998-01-01

    Interventions ` visie ` la fois iconomique et sociale, les politiques publiques de l'emploi (PPE) de chaque pays trouvent leur logique dans une relation itroite avec chacun des systhmes nationaux de protection sociale. La premihre partie de cet ouvrage est consacrie ` la prisentation de cas

  18. Le CRDI participe à la lutte mondiale contre le VIH/sida | CRDI ...

    International Development Research Centre (IDRC) Digital Library (Canada)

    15 juil. 2014 ... Le Centre de recherches pour le développement international (CRDI), organisme canadien, a été l'un des premiers bailleurs de fonds à vocation internationale à reconnaître que le VIH/sida constituait un problème de développement important.

  19. Le CRDI participe à la lutte mondiale contre le VIH/sida | IDRC ...

    International Development Research Centre (IDRC) Digital Library (Canada)

    15 juil. 2014 ... Le Centre de recherches pour le développement international (CRDI), organisme canadien, a été l'un des premiers bailleurs de fonds à vocation internationale à reconnaître que le VIH/sida constituait un problème de développement important.

  20. Konversion des kulturellen Erbes für die Forschung: Volltextbeschaffung und -bereitstellung als Aufgabe der Bibliotheken

    Directory of Open Access Journals (Sweden)

    Thomas Stäcker

    2014-12-01

    Full Text Available Mit der Transformation des gedruckten Buch zum elektronischen Text verändern sich zentrale Rahmenbedingungen der Bibliothek. Die theoretischen Grundlagen des ‚Buches‘ müssen unter dem Gesichtspunkt des Digitalen neu durchdacht und auf ihre praktischen Konsequenzen hin geprüft werden. Vor allem die Transitivität, spezifische Schriftlichkeit und Prozessierbarkeit elektronischer Texte sind Eigenschaften, die Konsequenzen für eine ganze Reihe bibliothekarischer Kernaufgaben haben. Mit Blick auf das kulturelle Erbe, das in Bibliotheken verwahrt wird, stellt sich die Aufgabe, auf diesen Paradigmenwechsel angemessen zu reagieren und Sorge dafür zu tragen, dass das schriftliche und gedruckte Kulturgut auch in einer adäquaten maschinenlesbaren Form zur Verfügung steht. Nach gut 10 Jahren erfolgreicher Imagedigitalisierung muss daher jetzt, nach der Entwicklung entsprechender Techniken der nächste Schritt zur Herstellung, Aufbereitung und Bereitstellung von Volltext getan werden, um neuen, sich aus der digitalen Wende ergebenden Forschungsanforderungen und Forschungsfragen, die sich mit Begriffen wie Stilometrie, Clusteranalyse, Topic Modeling etc. verbinden, zu genügen. Den Bibliotheken wächst vor diesem Hintergrund in der Transformation des schriftlichen Kulturgutes und Bereitstellung von Volltexten eine neue Aufgabe zu. Sie können darin einen wichtigen Beitrag zum Aufbau einer Infrastruktur für eine digital arbeitende Geistes- und Kultwissenschaft bzw. die Digital Humanities leisten. The transformation of the book into an electronic text has led to constitutive changes in the functional frameworks of the library. Basic concepts of the notion of the ‘book’ have to be reconsidered and to be evaluated in view of the practical consequences. Above all, the transitivity of such texts, the specific mode of writing employed, and their ability to be processed are aspects that have considerable impact on several core tasks of the library. In

  1. The Na+/H+ exchanger NHE1, but not the Na+, HCO3- cotransporter NBCn1, regulates motility of MCF7 breast cancer cells expressing constitutively active ErbB2

    DEFF Research Database (Denmark)

    Lauritzen, Gitte; Stock, Christian-Martin; Lemaire, Justine

    2012-01-01

    We and others have shown central roles of the Na(+)/H(+) exchanger NHE1 in cell motility. The aim of this study was to determine the roles of NHE1 and of the Na(+), HCO(3)(-) cotransporter NBCn1 in motility of serum-starved MCF-7 breast cancer cells expressing constitutively active ErbB2 (¿NErbB2...

  2. Expression of the clock gene Rev-erbα in the brain controls the circadian organisation of food intake and locomotor activity, but not daily variations of energy metabolism

    NARCIS (Netherlands)

    Sen, Satish; Dumont, Stéphanie; Sage-Ciocca, Dominique; Reibel, Sophie; de Goede, Paul; Kalsbeek, Andries; Challet, Etienne

    2018-01-01

    The nuclear receptor REV-ERBα is part of the molecular clock mechanism and is considered to be involved in a variety of biological processes within metabolically active peripheral tissues as well. To investigate whether Rev-erbα (also known as Nr1d1) in the brain plays a role in the daily variations

  3. Dohmen, Dieter, Erbes, Annegret, Fuchs, Kathrin & Günzel, Juliane (2008). Was wissen wir über Nachhilfe? Sachstand und Auswertung der Forschungsliteratur zu Angebot, Nachfrage und Wirkungen. Bielefeld: Bertelsmann, 150 S. [Rezension

    OpenAIRE

    Mayr, Thomas

    2014-01-01

    Rezension von Dohmen, Dieter, Erbes, Annegret, Fuchs, Kathrin & Günzel, Juliane (2008). Was wissen wir über Nachhilfe? Sachstand und Auswertung der Forschungsliteratur zu Angebot, Nachfrage und Wirkungen. Bielefeld: Bertelsmann, 150 S. 29,90 EUR, ISBN 978-3763936656

  4. L'analyse des semences d'arachide fermières pour le contrôle de ...

    African Journals Online (AJOL)

    Le manque de semences sélectionnées en qualité satisfaisante et en quantités suffisantes est une contrainte majeure à la production de l'arachide (Arachis hypogea L.) en Afrique centrale. La multiplication de semences en milieu paysan est le moyen de propagation le plus rapide, le moins cher et le plus durable.

  5. Aharon Appelfeld et Philip Roth : le réel, l’imaginaire, le double et le fantastique

    OpenAIRE

    Toren, Orly

    2014-01-01

    C’est la marge étroite entre « le réel et l’imaginaire » selon le titre de l’essai de Masha Itzhaki sur Appelfeld que nous souhaiterions explorer à partir de la relation entre Le Temps des prodiges d’Appelfeld et Opération Shylock de Philip Roth. Si la vrai/fausse « confession » de Roth se présente comme le détournement vertigineux des codes du fantastique, de l’autobiographie et de l’autofiction, le roman d’Appelfeld pousse les limites du réalisme par l’interrogation que suscite son titre én...

  6. L’Association du personnel, le TREF, le Comité des Finances et le Conseil du CERN

    CERN Multimedia

    Staff Association

    2016-01-01

    L’Association du personnel, forte de son approche participative et consensuelle, recherche toujours le meilleur accord possible pour l’Organisation et son personnel. Pour ce faire, discussions et concertation avec la Direction, travail d’explication et de persuasion au TREF et ailleurs auprès des délégués des États membres sont nos principaux atouts. TREF (Tripartite Employment Conditions Forum), un Forum d’échanges, de discussions « L’objectif du Forum est d’améliorer le processus de prise de décision  en donnant aux personnes concernées la possibilité et le temps de comprendre pleinement la position de tous les participants. » (CERN/RTG/8) Le Forum tripartite sur les conditions d’emploi (TREF), créé par le Conseil du CERN en juin 1994, est composé de r...

  7. Le contrôle de gestion environnementale d'une entreprise

    OpenAIRE

    Marquet-Pondeville, Sophie

    2001-01-01

    Dans cette recherche, nous étudions comment s’opère le contrôle de gestion environnementale. Cette problématique est abordée dans une perspective contingente et nous proposons un modèle théorique qui met en évidence l’impact de certaines variables sur les systèmes de contrôle de la gestion environnementale. Certains liens présents dans ce modèle sont discutés à travers une étude de cas.

  8. Le facteur humain et la sûreté de fonctionnement dans le ...

    African Journals Online (AJOL)

    Notre contribution porte sur lele fondamental du facteur humain dans le management intégré des risques d'une part et du rôle déterminant qu'il peut avoir à jouer pour que la sûreté de fonctionnement réponde à sa propriété d'autre part. Un rôle illustré à travers une analyse de risque dans un complexe de Gaz Naturel ...

  9. Le Hodler d'Iéna

    OpenAIRE

    2017-01-01

    Suites de la protestation contre le bombardement de la cathédrale de Reims. Nouvelle proposition de M. Gunsburger pour le rachat du tableau de Hodler "Départ des étudiants d'Iéna pour la guerre de libération contre Napoléon en 1813".

  10. L'astronomie dans le monde

    Science.gov (United States)

    Manfroid, J.

    2008-09-01

    Fragmentation et astéroïdes binaires; Astéroïde géocroiseur triple; Rosetta sort de son hibernation; Messenger; Transit lunaire vu par Deep Impact; Titan; Phobos; Phoenix; Einstein avait raison; Le ballet des taches rouges; Le poids des lentilles;

  11. Le barrage des trois Gorges (Chine

    Directory of Open Access Journals (Sweden)

    Luc Merchez

    1999-09-01

    Full Text Available Le barrage des Trois Gorges, en construction sur le Yangzijiang, sera le plus grand barrage au monde. Le gigantisme du projet et sa médiatisation croissante en Occident permettent d'en saisir les enjeux environnementaux et humains. On analyse les grandes caractéristiques du projet et ses conséquences premières avant d'aborder le travail de recherche de l'équipe SIG de l'IGA de Grenoble qui vise à préparer la relocalisation de plus d'un million d'habitants, et à modéliser les impacts démographiques et sociaux.

  12. Le Premier Amendement : un mythe

    Directory of Open Access Journals (Sweden)

    Claude‑Jean Bertrand

    2006-03-01

    Full Text Available Ce papier, plein de verve, d’humeur et d’humour, pose, comme sait si bien le faire l’auteur, des questions profondes sous une apparence paradoxale. Il a été présenté lors d’un colloque sur le Premier amendement organisé à l’Université Lumière-Lyon 2 les 17 et 18 janvier 2003. Certaines communications ont été publiées dans le volume XXIV, n°1 (2003, « Le premier amendement : un modèle américain des libertés » (sous la direction de Vincent Michelot de la Revue Tocqueville.

  13. Cisjordanie et Gaza | CRDI - Centre de recherches pour le ...

    International Development Research Centre (IDRC) Digital Library (Canada)

    Le conflit qui perdure et la violence politique ont aggravé le stress chez les adolescents, qui constituent près de la moitié de la population de la Cisjordanie. La violence politique et le conflit qui perdure ont aggravé le stress chez les adolescents. Le problème a été analysé dans le cadre de travaux menés en collaboration ...

  14. Le lien retrouvé

    Directory of Open Access Journals (Sweden)

    Luis Antonio Bittar Venturi

    2009-06-01

    Full Text Available Les ressources naturelles sont les principales médiatrices de la relation homme-nature, se situant à l´interface entre les dimensions sociale et naturelle. Cette thématique favorise donc la ré-intégration entre la géographie physique et humaine, dans la mesure où elle amène le chercheur à une vraie analyse géographique, celle qui considère, en même temps, les aspects humains et naturels pour la compréhension du territoire ou, si l’on préfère, de l´espace géographique. C´est dans ce contexte i...

  15. Comprendre le territoire de Venise

    Directory of Open Access Journals (Sweden)

    Lorena Rocca

    2013-05-01

    Full Text Available Le projet de recherche PANDORA - PArticipatory Networks and Databases fOr sustainable Research and Assessment (www.feempandora.it – de la Fondation Eni Enrico Mattei repose sur une démarche innovante de recherche action invitant à la participation de tous grâce aux Nouvelles Technologies de l’Information et de la Communication (TIC. A partir de l’analyse des pratiques collaboratives sur Internet, un espace en ligne a été créé afin de diffuser des informations et des données sur la ville mais surtout, de recueillir des avis, des idées et des solutions alternatives permettant d’atteindre les objectifs d’un développement urbain durable et co-construit.

  16. Le Point sur... Astronomie IV

    Science.gov (United States)

    Pecker, J.-C.

    Cet ouvrage regroupe des articles de mise au point sollicités par le rédacteur en chef de la rubrique Astronomie des Comptes rendus de l'Académie des sciences. Les textes se proposent de faire découvrir aux lecteurs, dans les principales disciplines de l'astronomie, les résultats les plus remarquables des dernières années.Leurs auteurs sont des spécialistes participant activement à l'accroissement des connaissances dans des domaines faisant l'objet de recherches intensives. Ces mises au point sur des questions particulièrement importantes de l'astronomie sont rédigées soit en français, soit en anglais et accompagnées d'une bibliographie détaillée.

  17. Le Point sur... Astronomie III

    Science.gov (United States)

    Pecker, J.-C.

    Ce fascicule contient l'ensemble des textes du débat sur la cosmologie du big-bang entre Joseph Silk, Jayant V. Narlikar, arbitrés par Jean-Claude Pecker. Il regroupe également des articles de mise au point sollicités par le rédacteur en chef de la rubrique Astronomie des Comptes rendus de l'Académie des sciences. Les textes se proposent de faire découvrir aux lecteurs, dans les principales disciplines de l'astronomie, les résultats les plus remarquables des dernières années. Ces mises au point sur des questions particulièrement importantes de l'astronomie sont rédigées soit en francais, soit en anglais et accompagnèes d'une bibliographie dètaillèe.

  18. Two Paired "Le Chatelier" Reactions

    Science.gov (United States)

    Cawley, John J.

    1995-07-01

    We have created a two-week, two hour-per-week cyclic experiment, which pairs two reactions. These reactions, the acid catalyzed esterification to yield n-amyl acetate and the base catalyzed hydrolysis of n-amyl acetate are intended to serve as a first and last experiment respectively, of the second-semester laboratory for liberal arts students. Because of time constraints, we have modified these experiments so that no distillation is performed as a purification step. The notion of achieving yields beyond the equilibrium value is discussed in terms of the pragmatics of removing one of the products of an equilibrium. Because of this "Le Chatelier" aspect of each reaction, each of them may be pushed in practicality to completion, which is well beyond the equilibrium value expectation. Because of the cycle, the chemistry may be done on a scale well beyond the microscale approach with little loss of material.

  19. Le Squatteur, le Gentrifieur et le Promoteur. Une leçon de la géographie

    Directory of Open Access Journals (Sweden)

    Laurent Matthey

    2005-03-01

    Full Text Available Posées sur mon bureau : deux photos. Je les regarde. Silencieusement, je les décris et les commente. La première a été prise en novembre 1997. Angle rue Jean-Violette, rue Prévost-Martin, à Genève. On y voit un immeuble, ancien, des échafaudages. Entre cet immeuble et celui qui lui fait face, on a tendu des fanions verts, bleus, orange. Son rez-de-chaussée a été repeint dans une teinte un peu brique. La seconde date d’avril 2005. C’est le même immeuble, presque dix ans plus tard, rénové. Jaun...

  20. Des maux pour le taire

    OpenAIRE

    Dussy, Dorothée; Caisne, Léonore Le

    2011-01-01

    Cette enquête ethnographique effectuée dans une association parisienne d’entraide aux victimes d’inceste montre que les enfants sexuellement abusés par un familier doivent se construire sur une double approche de la réalité sociale : d’un côté un discours dominant qui prône l’interdit de l’inceste et le respect des valeurs ordinaires, de l’autre l’expérience quotidienne des viols perpétrés par un de ceux qui transmettent ces valeurs. Grâce à un annonciateur, l’inceste perd son caractère anomi...

  1. Le surpoids, l'obésité et le contrôle glycémique chez les diabétiques ...

    African Journals Online (AJOL)

    utilisation et du stockage des sucres apportés par l'alimentation, sa prise en charge est assurée par le suivi du surpoids et l'obésité et le contrôle glycémique régulier. L'objectif de ce travail était l'étude du surpoids, l'obésité et le contrôle glycémique ...

  2. Le Mahdi dans le Maghreb médiéval

    Directory of Open Access Journals (Sweden)

    Michael Brett

    2009-05-01

    Full Text Available Dans le monde islamique médiéval, l'Afrique du Nord fut le centre principal du mahdisme, qui y inspira deux des trois grandes révolutions qui unifièrent le Maghreb entre le IV/Xe et le Vl/XIIe siècles : celle des Fatimides au Xe et celle des Almohades au XIIe siècle. La forme islamique du messianisme judéo-chrétien, le mahdisme, attendait l'arrivée d'un second Muhammad pour inaugurer un âge d'or ; mais il souffrait aussi d'une hésitation entre un royaume de ce monde ou du monde à venir, entre un homme envoyé par Dieu ou un être divin. Son succès au Maghreb était le fruit de son appel aux fidèles à conquérir le monde, moyennant une prédication militante adressée à des populations tribales pour les persuader de se soumettre à la discipline militaire imposée par un prophète. Dans les deux cas, néanmoins, la prédication et son accomplissement se divisèrent entre un annonciateur comparable à Saint Jean-Baptiste et « l'homme né pour être roi ». Dans le cas des Fatimides, le roi fut le mahdi lui-même ; mais dans le cas des Almohades, le mahdi fut le prophète qui ouvrit la voie à son calife, destiné au gouvernement du monde. Après la désintégration de l'empire almohade au XIIIe siècle, le mahdisme se réduisit au Maghreb à un millénarisme inefficace, mais revint au pouvoir au XVIe avec la dynastie saadienne au Maroc. Ici encore, comme dans le cas d'Abdelkader en Algérie au XIXe siècle, le mahdisme se fonda sur la même distinction entre prophète et roi ; mais, au cours du XXe siècle, il a été remplacé par le nationalisme comme force politique efficace.

  3. [Expression of erythroblastic leukemia viral oncogene homolog 3 (ErbB-3) binding protein-1, matrix metalloproteinases, eplthelial cadherin in adenoid cystic carcinoma and correlation analysis].

    Science.gov (United States)

    Sun, Jian; Yu, You-cheng; Luo, Yi-xi; Tian, Zhen

    2012-12-01

    To investigate the expression of ErbB-3 binding protein-1 (EBP-1), matrix metalloproteinase 9 (MMP-9) and E-cadherin (E-cad) in adenoid cystic carcinoma and their correlation. Immunohistochemistry(PV6000 method) was used to detect EBP-1, MMP-9 and E-cad expression in 66 cases of adenoid cystic carcinoma tissues and matched para-cancerous normal tissues. In this study all cases were successfully followed up. The positive expression rate of EBP-1 in adenoid cystic carcinoma tissues was 85%. EBP-1 expression was significantly correlated to pathological pattern and clinical stage (P correlation between EBP-1 and E-cad expression, and positive correlation between EBP-1 and MMP-9. EBP-1 and its correlation with MMP-9 and E-cad may be used as useful indicators for clinical assessment of tumor biological behavior and prognosis in patients with adenoid cystic carcinoma.

  4. Identification of a novel circadian clock modulator controlling BMAL1 expression through a ROR/REV-ERB-response element-dependent mechanism.

    Science.gov (United States)

    Lee, Jiyeon; Lee, Seungbeom; Chung, Sooyoung; Park, Noheon; Son, Gi Hoon; An, Hongchan; Jang, Jaebong; Chang, Dong-Jo; Suh, Young-Ger; Kim, Kyungjin

    2016-01-15

    Circadian rhythms, biological oscillations with a period of about 24 h, are maintained by an innate genetically determined time-keeping system called the molecular circadian clockwork. Despite the physiological and clinical importance of the circadian clock, development of small molecule modulators targeting the core clock machinery has only recently been initiated. BMAL1, a core clock gene, is controlled by a ROR/REV-ERB-response element (RORE)-dependent mechanism, which plays an important role in stabilizing the period of the molecular circadian clock. Therefore, we aimed to identify a novel small molecule modulator that regulates Bmal1 gene expression in RORE-dependency, thereby influencing the molecular feedback loop of the circadian clock. For this purpose, we carried out a cell-based screen of more than 1000 drug-like compounds, using a luciferase reporter driven by the proximal region of the mouse Bmal1 promoter. One compound, designated KK-S6, repressed the RORE-dependent transcriptional activity of the mBmal1 promoter and reduced endogenous BMAL1 protein expression. More importantly, KK-S6 significantly altered the amplitude of circadian oscillations of Bmal1 and Per2 promoter activities in a dose-dependent manner, but barely affected the period length. KK-S6 effectively decreased mRNA expression of metabolic genes acting downstream of REV-ERBα, Pai-1 and Citrate synthase, that contain RORE cis-element in their promoter. KK-S6 likely acts in a RORE-dependent manner by reinforcing the REV-ERBα activity, though not by the same mechanism as known REV-ERB agonists. In conclusion, the present study demonstrates that KK-S6 functions as a novel modulator of the amplitude of molecular circadian rhythms by influencing RORE-mediated BMAL1 expression. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

  5. Stability of the recombinant anti‑erbB2 scFv‑Fc‑interleukin‑2 fusion protein and its inhibition of HER2‑overexpressing tumor cells.

    Science.gov (United States)

    Du, Yu-Jia; Lin, Ze-Min; Zhao, Ying-Hua; Feng, Xiu-Ping; Wang, Chang-Qing; Wang, Gang; Wang, Chun-Di; Shi, Wei; Zuo, Jian-Ping; Li, Fan; Wang, Cheng-Zhong

    2013-02-01

    The anti‑erbB2 scFv‑Fc‑IL‑2 fusion protein (HFI) is the basis for development of a novel targeted anticancer drug, in particular for the treatment of HER2‑positive cancer patients. HFI was fused with the anti‑erbB2 antibody and human IL‑2 by genetic engineering technology and by antibody targeting characteristics of HFI. IL‑2 was recruited to target cells to block HER2 signaling, inhibit or kill tumor cells, improve the immune capacity, reduce the dose of antibody and IL‑2 synergy. In order to analyse HFI drug ability, HFI plasmid stability was verified by HFI expression of the trend of volume changes. Additionally, HFI could easily precipitate and had progressive characteristics and thus, the buffer system of the additive phosphate‑citric acid buffer, arginine, Triton X‑100 or Tween‑80, the establishment of a microfiltration, ion exchange, affinity chromatography and gel filtration chromatography‑based purification process were explored. HFI samples were obtained according to the requirements of purity, activity and homogeneity. In vivo, HFI significantly delayed HER2 overexpression of non‑small cell lung cancer (Calu‑3) in human non‑small cell lung cancer xenografts in nude mice, and the inhibition rate was more than 60% (Pbreast cancer (FVB/neu) transgenic mouse tumor growth in 1 mg/kg of the HFI dose group, and in the following treatment the 400 mm3 tumors disappeared completely. Combined with other HFI test data analysis, HFI not only has good prospects, but also laid the foundation for the development of antibody‑cytokine fusion protein‑like drugs.

  6. : Le Goff, Annales and National Historical Traditions:

    OpenAIRE

    Rucquoi, Adeline

    1994-01-01

    Version originale de l'article traduit en anglais (mal) et publié sous le titre (dû à l'éditeur) "Spanish Medieval History and the Annales: Between Franco and Marx"; International audience; Influencia ejercida por las obras de Jacques Le Goff y la llamada "escuela de los Annales" sobre la historiografía española (1950-1990); Influence des travaux de Jacques Le Goff et de l'"école" des Annales sur l'historiographie espagnole (1950-1990)

  7. Le Corbusier, Alfred Roth y el color

    Directory of Open Access Journals (Sweden)

    Angelica Fernández-Morales

    2014-07-01

    Full Text Available This article discusses the relationship between Le Corbusier and Alfred Roth, a member of the Paris office between 1927 and 1928. It also deals with the influence that this period had with reference to an important factor in Roth’s professional development, as in Le Corbusier’s later works: the use of colour in his architecture. This article takes the position that Roth, given his close friendship with Mondrian, was an important figure in turning Le Corbusier’s work towards greater use of primary colours and aesthetic neoplasticism.

  8. Le Great Limpopo Transfrontier Park

    Directory of Open Access Journals (Sweden)

    Nadia Belaidi

    2008-10-01

    Full Text Available Cet article a pour objet de présenter quelques problématiques d'une recherche sur la construction d’un mécanisme de valorisation sociale de la protection de l’environnement : l’ordre public écologique. Cette étude s’appuie sur une expérience récente et originale en Afrique australe : la création de Parcs pour la Paix dont relève le Great Limpopo Transfrontier Park. Ces parcs sont officiellement consacrés à la protection et à la conservation de la diversité biologique, des ressources naturelles et culturelles qui y sont associées, ainsi qu’à la promotion de la coopération et de la Paix qu’elle soit civile, sociale, économique ou culturelle. La logique de construction de ces parcs repose sur l’idée que l’articulation des zones de conservation facilite la résolution de conflits territoriaux – de toutes sortes – en transformant les préoccupations environnementales en objet de coopération entre des juridictions politiques diverses. C’est précisément le schéma du concept juridique objet de nos travaux : l’ordre public écologique. Aussi peut-on se demander si le GLTP, en particulier, (peut constitue(r une illustration concrète de ce mécanisme et permettre d’atteindre la Paix recherchée, favorisant ainsi les processus de développement ?This article aims to present some problems of researches on the construction of a mechanism of social valorisation of the environmental protection: ecological public order. This study leans on a recent and original experience in southern Africa: the creation of Peace Park like the Great Limpopo Transfrontier Park (GLTP. These parks are officially dedicated to the protection and to the preservation of biological diversity, natural and cultural resources which are associated with it, as well as in the promotion of the cooperation and the peace. The peace looked for in these parks is not only the opposite of the war but it is also social, economic and cultural peace

  9. Structure and expression of two nuclear receptor genes in marsupials: insights into the evolution of the antisense overlap between the α-thyroid hormone receptor and Rev-erbα

    Directory of Open Access Journals (Sweden)

    Brown M Scott

    2010-12-01

    Full Text Available Abstract Background Alternative processing of α-thyroid hormone receptor (TRα, NR1A1 mRNAs gives rise to two functionally antagonistic nuclear receptors: TRα1, the α-type receptor, and TRα2, a non-hormone binding variant that is found only in mammals. TRα2 shares an unusual antisense coding overlap with mRNA for Rev-erbα (NR1D1, another nuclear receptor protein. In this study we examine the structure and expression of these genes in the gray short-tailed opossum, Monodelphis domestica, in comparison with that of eutherian mammals and three other marsupial species, Didelphis virginiana, Potorous tridactylus and Macropus eugenii, in order to understand the evolution and regulatory role of this antisense overlap. Results The sequence, expression and genomic organization of mRNAs encoding TRα1 and Rev-erbα are very similar in the opossum and eutherian mammals. However, the sequence corresponding to the TRα2 coding region appears truncated by almost 100 amino acids. While expression of TRα1 and Rev-erbα was readily detected in all tissues of M. domestica ages 0 days to 18 weeks, TRα2 mRNA was not detected in any tissue or stage examined. These results contrast with the widespread and abundant expression of TRα2 in rodents and other eutherian mammals. To examine requirements for alternative splicing of TRα mRNAs, a series of chimeric minigenes was constructed. Results show that the opossum TRα2-specific 5' splice site sequence is fully competent for splicing but the sequence homologous to the TRα2 3' splice site is not, even though the marsupial sequences are remarkably similar to core splice site elements in rat. Conclusions Our results strongly suggest that the variant nuclear receptor isoform, TRα2, is not expressed in marsupials and that the antisense overlap between TRα and Rev-erbα thus is unique to eutherian mammals. Further investigation of the TRα and Rev-erbα genes in marsupial and eutherian species promises to yield

  10. Structure and expression of two nuclear receptor genes in marsupials: insights into the evolution of the antisense overlap between the α-thyroid hormone receptor and Rev-erbα

    Science.gov (United States)

    2010-01-01

    Background Alternative processing of α-thyroid hormone receptor (TRα, NR1A1) mRNAs gives rise to two functionally antagonistic nuclear receptors: TRα1, the α-type receptor, and TRα2, a non-hormone binding variant that is found only in mammals. TRα2 shares an unusual antisense coding overlap with mRNA for Rev-erbα (NR1D1), another nuclear receptor protein. In this study we examine the structure and expression of these genes in the gray short-tailed opossum, Monodelphis domestica, in comparison with that of eutherian mammals and three other marsupial species, Didelphis virginiana, Potorous tridactylus and Macropus eugenii, in order to understand the evolution and regulatory role of this antisense overlap. Results The sequence, expression and genomic organization of mRNAs encoding TRα1 and Rev-erbα are very similar in the opossum and eutherian mammals. However, the sequence corresponding to the TRα2 coding region appears truncated by almost 100 amino acids. While expression of TRα1 and Rev-erbα was readily detected in all tissues of M. domestica ages 0 days to 18 weeks, TRα2 mRNA was not detected in any tissue or stage examined. These results contrast with the widespread and abundant expression of TRα2 in rodents and other eutherian mammals. To examine requirements for alternative splicing of TRα mRNAs, a series of chimeric minigenes was constructed. Results show that the opossum TRα2-specific 5' splice site sequence is fully competent for splicing but the sequence homologous to the TRα2 3' splice site is not, even though the marsupial sequences are remarkably similar to core splice site elements in rat. Conclusions Our results strongly suggest that the variant nuclear receptor isoform, TRα2, is not expressed in marsupials and that the antisense overlap between TRα and Rev-erbα thus is unique to eutherian mammals. Further investigation of the TRα and Rev-erbα genes in marsupial and eutherian species promises to yield additional insight into the

  11. Le soleil devient un mythe

    Directory of Open Access Journals (Sweden)

    Ildikó Lőrinszky

    2009-01-01

    Full Text Available Partant d’une phrase énigmatique datant de 1858 et puisée dans la Correspondance de Flaubert, cet article s’interroge sur la relation entre soleil et mythe, qui constituera l’un des éléments clefs de la dimension mythologique de Salammbô. Il se propose d’examiner la façon dont cette question apparaît dans deux ouvrages représentatifs des études mythographiques : d’une part, L’Origine de tous les cultes de Charles-François Dupuis, d’autre part, Les Religions de l’Antiquité..., publié sous les noms de Frédéric Creuzer et de son adaptateur français, Joseph-Daniel Guigniault. La version française de la grande synthèse de Creuzer, assortie d’une série importante de planches, a été richement exploitée par Flaubert au cours de la genèse du roman carthaginois. Dans Salammbô, le mythe apparaît sous de multiples formes. L’analyse de ce texte peut nous amener à réfléchir sur le « bon usage » du mythe auquel chaque créateur (et chaque lecteur se trouve nécessairement confronté.Starting from an enigmatic phrase in Flaubert’s correspondence, dating from 1858, this article examines the relation between the Sun and myth, which constitutes one of the key elements of the mythological dimension of Salammbô. It especially focuses on the treatment of this question in two representative works of mythographic studies, The Origin of All Religious Worship by Charles-François Dupuis, and Les Religions de l’Antiquité..., the French adaptation of Frédéric Creuzer’s Symbolik und Mythologie der alten Völker by Joseph-Daniel Guigniault. The French version of Creuzer’s great synthesis, supplied with a remarkable set of prints, was abundantly consulted by Flaubert when writing his Carthaginian novel. In Salammbô, myth takes on various forms. Analyzing this text might lead one to reconsider “the right way” to use myths — a problem all writers (and readers find themselves confronted with.

  12. Les ERP changent-ils le contrôle de gestion ?

    OpenAIRE

    Meyssonnier, François; Pourtier, Frédéric

    2005-01-01

    L'intégration de l'information de gestion dans le cadre d'ERP se généralise et le contrôle de gestion s'effectue maintenant la plupart du temps en environnement ERP dans les grandes entreprises. Un état de l'art est effectué relativement à l'impact des ERP aussi bien sur les concepts et les outils du contrôle de gestion que sur la fonction et lele des contrôleurs de gestion. La démarche de recherche, fondée sur dix études de cas dans une approche intermédiaire entre les monographies qualit...

  13. Vers une plus grande collaboration régionale — le CRDI appuie le ...

    International Development Research Centre (IDRC) Digital Library (Canada)

    26 janv. 2011 ... Bien qu'ils aient souvent de la difficulté à se démarquer face à la véritable dynamo économique qu'est la Chine, des pays tels que le Laos, le Cambodge et le Vietnam, qui tentaient d'échapper à la guerre il y a à peine 25 ans, connaissent une croissance explosive encore plus remarquable. Renaissance ...

  14. Démocratie et le développement dans le monde arabe | CRDI ...

    International Development Research Centre (IDRC) Digital Library (Canada)

    Extrants. Rapports. Democracy and development in the Arab world : final technical report, Sep. 15, 2006 - Sep. 15, 2009. Téléchargez le PDF. Contenus connexes. Le CRDI « analyse l'autonomisation des femmes » lors d'une conférence à l'Université McGill. Les conclusions d'un programme financé par le CRDI au ...

  15. ÉTUDE DE CAS — Cuba : Le logement et le capital humain à Cuba ...

    International Development Research Centre (IDRC) Digital Library (Canada)

    10 janv. 2011 ... ÉTUDE DE CAS — Cuba : Le logement et le capital humain à Cuba .... Elle reconnaît qu'il existe des liens inéluctables entre les humains et les milieux biophysique, social et économique qui ont des répercussions sur la santé des gens », explique le Dr Mariano Bonet, l'un des chercheurs de l'équipe et ...

  16. pour le trimestre qui a pris fin le 30 juin 2014

    International Development Research Centre (IDRC) Digital Library (Canada)

    Office 2004 Test Drive User

    30 juin 2014 ... d'information financière (normes IFRS). Toutes les sommes sont exprimées en dollars canadiens. Le CRDI recommande de lire ce rapport en parallèle avec les états financiers intermédiaires résumés, non audités (qui débutent à la page 11). L'information et les divulgations contenues dans le Rapport ...

  17. pour le trimestre qui a pris fin le 30 septembre 2014

    International Development Research Centre (IDRC) Digital Library (Canada)

    Office 2004 Test Drive User

    30 sept. 2014 ... d'information financière (normes IFRS). Toutes les sommes sont exprimées en dollars canadiens. Le CRDI recommande de lire ce rapport en parallèle avec les états financiers intermédiaires résumés, non audités (qui débutent à la page 11). L'information et les divulgations contenues dans le Rapport ...

  18. pour le trimestre qui a pris fin le 30 juin 2012

    International Development Research Centre (IDRC) Digital Library (Canada)

    Office 2004 Test Drive User

    30 juin 2012 ... dans le Rapport annuel 2011-2012 du CRDI s'appliquent au trimestre sur lequel porte le présent rapport trimestriel à moins d'une mise à jour fournie aux présentes. Résultats. Aperçu de la situation financière. (pour la période de trois mois qui a pris fin le 30 juin 2012). 0. 10. 20. 30. 40. 50. 60. 70. Produits.

  19. Rapport financier trimestriel pour le trimestre qui a pris fin le 31 ...

    International Development Research Centre (IDRC) Digital Library (Canada)

    Sophie Comeau

    31 déc. 2011 ... Le Centre de recherches pour le développement international. CRDI , qui est un élément clé de l'aide internationale du. Canada depuis 1970, appuie des travaux de recherche dans les pays en développement afin d'y favoriser la croissance et le développement. Il veille aussi à promouvoir la diffusion.

  20. Le « modèle germanique » Français

    OpenAIRE

    Lefebvre , Armelle

    2009-01-01

    Resume Le concept d?Allemagne permet de reveler, selon une approche , l?ampleur des desaccords ayant preside a la definition du concept d?Etat en France. De ce dernier, l?on aborde divers emplois qu?illustrent des modeles d?Etat. Le opere ainsi dans un debat qui est le creuset de la connaissance politique moderne, avec ses apories: celles de la souverainete externe, de l?ordre interetatique, de la confederation. L?article expose alo...

  1. 205 Le Role de la Litterature dans le Developpement de la Nation ...

    African Journals Online (AJOL)

    Ike Odimegwu

    du plaisir en même temps qu'il le moralise. Elle fait naître dans ses lecteurs ou dans son audience des .... développement de l'esprit>>(319)Par cette définition nous comprenons que le développement signale qu'il du progrès ... qu'elle est une œuvre de l'imagination qui aide l'homme à transcender le monde physique.

  2. Droits d'auteur | CRDI - Centre de recherches pour le ...

    International Development Research Centre (IDRC) Digital Library (Canada)

    Droits d'auteur détenus par le CRDI Sauf indication contraire, les droits d'auteur relatifs aux documents mis en ligne sur le présent site Web sont détenus par le Centre de recherches pour le développement international (CRDI).

  3. Publications | Page 200 | CRDI - Centre de recherches pour le ...

    International Development Research Centre (IDRC) Digital Library (Canada)

    Le CRDI collabore avec les chercheurs et les établissements des pays en développement au renforcement des capacités locales par le truchement du financement, de la mise en commun des connaissances et de la ... Le partage de l''information et des techniques de la communication favorise le développement durable.

  4. Publications | Page 103 | CRDI - Centre de recherches pour le ...

    International Development Research Centre (IDRC) Digital Library (Canada)

    Le FIE 2008 fait avancer le cadre écobiosocial de l'OMS. Le Programme spécial de recherche et de formation concernant les maladies tropicales (TDR) de l'OMS a élaboré le concept du champ « écobiosocial », qui combine les perspectives écologiques, biologiques et sociales « pour mieux.

  5. Publications | Page 17 | CRDI - Centre de recherches pour le ...

    International Development Research Centre (IDRC) Digital Library (Canada)

    Publication du rapport de BSR sur le travail des enfants en Birmanie. Le CRDI finance plusieurs projets de recherche sur les facteurs expliquant le travail des enfants, incluant le rapport intitulé 'Child labor in Myanmar's Garment Sector' écrit récemment par l'organisme Business for Social Responsibility (BSR).

  6. Jan Potocki et le "Gothic Novel"

    Science.gov (United States)

    Finne, Jacques

    1970-01-01

    Establishes a parallel between the supernatural and fantastic qualities of Le Comte Jan Potocki's literary works, and the English gothic novels by comparing the elements of terror, mysterious atmosphere, and the supernatural beings involved. (DS)

  7. Savoir gérer le mal

    Directory of Open Access Journals (Sweden)

    Michel Maffesoli

    2015-09-01

    Full Text Available Le sens commun, conservatoire immémorial de la sagesse humaine « sait », de savoir incorporé, que le mal, l’ombre, la mort, la douleur sont des caractéristiques essentielles de l’existence en son entièreté. Dès lors les créatures quelles qu’elles soient, sont des manifestations de la vie et, dès lors, méritent une attitude « compassionnelle », fraternelle, parce qu’ensemble elles constituent le flux vital. C’est ainsi que l’on peut comprendre l’utilité sociale de ces divers « mondes intermédiaires » que sont les croyances, religieuses ou philosophiques, au « double », au « daimon », aux esprits et autres figures tutélaires ou effrayantes. Elles aident à vivre, au jour le jour, la souffrance en la communalisant.

  8. Nuevo León

    Directory of Open Access Journals (Sweden)

    Laura Nelly Medellín Mendoza

    2006-01-01

    Full Text Available El ensayo analiza la transición política nuevoleonesa a partir de un contexto de liberalización política. En Nuevo León el régimen político autoritario fue cediendo en el plano electoral, dada la presión que conjuntamente la sociedad política y la sociedad civil ejercieron por lograr reglas democráticas. Este avance gradual permitió garantizar un organismo electoral confiable y que determinó en buena medida la garantía de la alternancia en 1997. El pan fue el partido que capitalizó el bono democrático, pero una vez en la responsabilidad de gobierno, no pudo ampliar el proceso de liberalización política al mediatizar las reformas electorales y no comprometerse para sacar del atolladero legislativo las iniciativas que garantizaban mecanismos de participación ciudadana: referéndum y plebiscito.

  9. le des universités dans le renforcement des technologies de l ...

    International Development Research Centre (IDRC) Digital Library (Canada)

    le des universités dans le renforcement des technologies de l'information et de la communication au service du développement (TIC-D) en Asie. Jusqu'à maintenant, les efforts déployés dans le secteur de l'enseignement supérieur ont surtout été axés sur le téléapprentissage, l'apprentissage électronique et différentes ...

  10. Rapport financier trimestriel pour le trimestre qui a pris fin le 31 ...

    International Development Research Centre (IDRC) Digital Library (Canada)

    Office 2004 Test Drive User

    31 déc. 2015 ... Budget 2015-2016 révisé. Le Conseil a approuvé le budget 2015-2016 avant le début de lʼexercice. Cʼest sur ce budget que sont fondées les sommes budgétaires qui ont été présentés dans le Rapport annuel. 2014-2015. En octobre, on a revu les prévisions budgétaires initiales en tenant compte des.

  11. Le modèle de l’erreur humaine de James Reason

    OpenAIRE

    Larouzée, Justin; Guarnieri, Franck; Besnard, Denis

    2014-01-01

    Ce papier de recherche a pour objet de revenir en détail sur les travaux de recherche du psychologue anglais James Reason, mondialement célèbre pour sa taxonomie de l’erreur humaine et son modèle étiologique de l’accident immensément connu sous le nom de Swiss Cheese Model (SCM) ou Modèle du Fromage Suisse. Ce papier de recherche est une synthèse du parcours scientifique de Reason, il revient aussi sur la conception du modèle et ses évolutions, il traite de ses usages, apports et limites. Il ...

  12. la lutte contre le SIDA au Cameroun

    African Journals Online (AJOL)

    Chantel

    à une action efficace et courageuse, à la mesure de l'enjeu. De nombreuses ..... des médicaments à un niveau toujours prohibitif. Tableau 2 indique les ... Les femmes et les jeunes paient le plus lourd tribut à l'épidémie (Kuate Defo, 1998). En effet, les 3/5 des personnes infectées sont des femmes et le tiers des personnes ...

  13. Le déficit de filles

    International Development Research Centre (IDRC) Digital Library (Canada)

    qui veulent former un couple idéal. D'autre part, les chercheuses indiquent que le céli- bat des femmes est perçu comme une « aberration totale ». Tous les répondants ont fait, à ce sujet, des remarques semblables : même la personne la plus riche du monde, disent-ils, ne peut assumer le far- deau financier qu'impose une ...

  14. Quand la musique donne le ton

    DEFF Research Database (Denmark)

    Reeh, Henrik

    2017-01-01

    Le lycée Sainte-Anne de Copenhague est un établissement réputé pour les résultats de ses élèves et pour être le foyer d’une intense tradition chorale et musicologique. L’article interroge les parcours de 32 élèves d’une même classe, tous reçus au baccalauréat 2014 avec une option musique et...

  15. Le désordre du monde

    African Journals Online (AJOL)

    sulaiman.adebowale

    interfère dans le désordre du monde. Globalement, une négligence des aspects collectifs planétaires par rap- port à des intérêts nationaux toujours surdéterminés conduit à l'entropie. Cela débouche sur le désordre, au regard des questions qui nécessitent un consensus, un accord et une démarche collective sans (auto) ...

  16. Le Chatelier principle in replicator dynamics

    OpenAIRE

    Allahverdyan, Armen E.; Galstyan, Aram

    2011-01-01

    The Le Chatelier principle states that physical equilibria are not only stable, but they also resist external perturbations via short-time negative-feedback mechanisms: a perturbation induces processes tending to diminish its results. The principle has deep roots, e.g., in thermodynamics it is closely related to the second law and the positivity of the entropy production. Here we study the applicability of the Le Chatelier principle to evolutionary game theory, i.e., to perturbations of a Nas...

  17. Le CRDI au Népal

    International Development Research Centre (IDRC) Digital Library (Canada)

    Les chercheurs ont aidé les agriculteurs de Kulekhani à adopter la pisciculture en cage. CRDI. Centre De reCherChes pour le Développement internAtionAl. Le CRDI au Népal. Grâce à l'appui du CRDI. □ les collectivités s'adaptent aux changements climatiques. □ les agriculteurs de l'Himalaya améliorent leurs moyens.

  18. Le cas du Brésil

    International Development Research Centre (IDRC) Digital Library (Canada)

    pwust

    de biocarburants (particulièrement l'éthanol et le biodiesel). Les tendances actuelles donnent à croire que les projets reliés à l'énergie et aux biocarburants deviendront particulièrement importants sous peu. Outre ces domaines traditionnels, les projets en Afrique ont ciblé l'éducation, le développement des entreprises, les ...

  19. Transparence | CRDI - Centre de recherches pour le ...

    International Development Research Centre (IDRC) Digital Library (Canada)

    La transparence est un élément clé de l'engagement du gouvernement du Canada envers le gouvernement ouvert, dont l'objectif est d'améliorer l'accès aux données, aux renseignements et aux échanges. Le CRDI s'emploie à la transparence en fournissant des renseignements sur son site Web, dans ses publications, ...

  20. Le CRDI en Cisjordanie et à Gaza

    International Development Research Centre (IDRC) Digital Library (Canada)

    Stress des adolescents et conflit qui perdure. En Cisjordanie, la violence politique et le conflit qui perdure ont aggravé le stress chez les adolescents, qui constituent près de la moitié de la population. À Ramallah, plus de 3 000 adolescents de 15 à 17 ans ont été interrogés par des chercheurs de l'Université de Birzeit et de ...

  1. Le cas de l'Inde

    International Development Research Centre (IDRC) Digital Library (Canada)

    pwust

    le développement, l'Inde doit réduire la proportion de personnes vivant en deçà du seuil de pauvreté de 37,5 %, en. 1990, à 18,75 % ... exemple, à la suite du tsunami en Asie, en 2004, c'est le premier ministre qui a décidé de porter assistance. Pour ces types d'opérations, les forces militaires et paramilitaires indiennes.

  2. dynamiques migratoires et rapport avec le

    African Journals Online (AJOL)

    qui s'était illustré sur le campus par sa violence, notamment l'agression des étudiants au restaurant et en cité universitaires (sans aucune réaction de ... venant de l'extérieur), dans des actions de parrainage (le président du Tocsin a été choisi comme parrain par la promotion 2002 de l'École nationale du service social de ...

  3. Le juge administratif et le sens des images. Les mutations des techniques contentieuses du contrôle des visas d’exploitation

    OpenAIRE

    Mercier, Jérémy

    2017-01-01

    A la suite des affaires Nymphomaniac, La Vie d'Adèle, Antichrist, Love, SAW 3D Chapitre final, Cinquante Nuances de Grey, Bang Gang : une histoire d'amour moderne, Les Huit Salopards et Salafistes, l'affaire Sausage Party a mis en évidence un élément central dans le raisonnement du juge administratif : l'argumentation sur les images et sur le sens de leur contenu, impliquant un affinement progressif de son contrôle théorique de l'effet produit sur le spectateur. Le contentieux relatif au syst...

  4. Le patrimoine et ses outils de gestion

    CERN Document Server

    Garcin, J

    2001-01-01

    Les principale taches de gestion du Patrimoine immobilier du CERN sont la saisie des données, leur mise à jour, l'archivage et la mise à disposition des informations. Les outils de gestion actuels : Le Système de Gestion de Base de Données Relationnelles alphanumérique ORACLE permet de gérer toutes les informations du Patrimoine, sur le réseau du CERN. Le logiciel de dessin Graphique MICROSTATION (Bentley) a été installé dans la division ST depuis fin 1991. Les plans de situation des sites, des bâtiments et locaux, des espaces confinés ont été réalisés avec ce logiciel. Les outils de demain : La mise en place du SIG (Système d'Information Graphique) STAR a été réalisée en 1993. Le transfert des plans de locaux de MICROSTATION vers STAR est en cours depuis une année environ. Le dessin de la cartographie des réseaux de canalisations Eaux Usées et Eaux Pluviales est en cours de réalisation. Le Web est l'outil de consultation de l'information par les utilisateurs.

  5. Dans le grand collisionneur du CERN

    CERN Document Server

    AUTHOR|(CDS)2051256

    2014-01-01

    Ce livre fait pénétrer le lecteur non initié dans l’instrument scientifique le plus grand du monde. D’ailleurs, le web fut précisément inventé à Genève en vue d’une collaboration aussi gigantesque. Résultat de vingt ans de recherche, le LHC, Grand collisionneur de hadrons, est l’anneau de 26,7 km creusé sous la frontière francosuisse, où sont accélérés, en sens opposés, des paquets de particules jusqu’à des vitesses et des énergies extrêmes. Ainsi la physique s’est-elle engagée dans une étape nouvelle de nos connaissances. Après les grandes découvertes de l’univers et de la réalité microscopique du siècle dernier, le collisionneur nous fait progresser aujourd’hui dans un «nuage de probabilités» aux frontières de l’antimatière. Dans une bousculade de particules, voici le champ convoité du boson de Higgs. Mario Campanelli, professeur associé à l’Université de Londres et collaborateur au projet ATLAS du LHC, propose, dans cet ouvrage, de s’introduire pas �...

  6. Activité antérieure – Le Kenya nomme le titulaire de sa première ...

    International Development Research Centre (IDRC) Digital Library (Canada)

    14 avr. 2016 ... De concert avec le CRDI, la National Commission for Science, Technology and Innovation (NACOSTI) du Kenya a inauguré sa première chaire de recherche à Nairobi, le 31 mars 2015. Le professeur Fabian Omoding Esamai, qui dirige actuellement le College of Health Sciences de la Moi University, a été ...

  7. Livres | Page 21 | CRDI - Centre de recherches pour le ...

    International Development Research Centre (IDRC) Digital Library (Canada)

    ISBN: 190239142X. Le débat des semences volume 2 : Solutions pour les lois nationales régissant le contrôle des ressources génétiques et des innovations biologiques. Le Débat des semences met les lecteurs au courant de ce qui a changé — sur le plan scientifique, politique et environnemental — depuis la publication ...

  8. Le Projet d’Ole Lando sur les Contrats

    DEFF Research Database (Denmark)

    Holle, Marie-Louise

    2017-01-01

    En 2016 le projet de recherche le plus important jusqu’à présent sur le droit nordique des contrats a pris fin et un livre, de presque 400 pages, en a marqué l’aboutissement. Le résultat du projet est un « restatement » tel qu’il existe aux États-Unis. Le Restatement porte sur les règles et les...

  9. Contribution de l'échographie dans le dépistage et le diagnostic des ...

    African Journals Online (AJOL)

    échographie dans le dépistage et le diagnostic des lésions mammaires à Yaoundé, Cameroun. Il s'agissait de décrire les anomalies cliniques, échogra- phiques, éventuellement anatomopathologiques pour des lésions suspectes et les confronter.

  10. Le point sur le sida, l'alimentation et la nutrition | CRDI - Centre de ...

    International Development Research Centre (IDRC) Digital Library (Canada)

    agriculture et l'alimentation ( FAO ), Stuart Gillespie a passé six mois à étudier le lien entre le VIH/sida et la sécurité alimentaire. Il a vite compris que l'épidémie risquait d'avoir, à long terme, des répercussions désastreuses sur la ...

  11. Pour que brûle le feu du changement | IDRC - International ...

    International Development Research Centre (IDRC) Digital Library (Canada)

    7 déc. 2010 ... Le programme Recherche pour la lutte mondiale contre le tabac (RMCT) du CRDI aide des chercheurs des pays en développement à contrer l'influence des géants de l'industrie du tabac aux ressources financières colossales.

  12. Le FIE 2008 fait avancer le cadre écobiosocial de l'OMS | CRDI ...

    International Development Research Centre (IDRC) Digital Library (Canada)

    10 mai 2011 ... Le Programme spécial de recherche et de formation concernant les maladies tropicales (TDR) de l'OMS a élaboré le concept du champ « écobiosocial », qui combine les perspectives écologiques, biologiques et sociales « pour mieux comprendre la dynamique des maladies infectieuses à transmission ...

  13. Contribution de l'échographie dans le dépistage et le diagnostic des ...

    African Journals Online (AJOL)

    Contribution de l'échographie dans le dépistage et le diagnostic des cancers du sein : une expérience de Yaoundé, Cameroun. GE Guegang, TI Sandjong, PM Tebeu, BA Temgoua, Z Sando, JR Moulion, A Atem, E Mboudou, J Yomi, A Doh, FJ Gonsu ...

  14. Changer le travail des animaux, pour changer le travail des humains

    OpenAIRE

    Porcher, Jocelyne

    2016-01-01

    Animaux et hommes construisent des liens par le travail, explique l’auteure de cette tribune. Il existe même un « travailler » de l’animal, où celui-ci s’investit et recherche du sens. Réfléchir au travail des animaux, c’est aussi s’interroger sur le travail humain.

  15. Le SRAS, le sida, et la santé publique | IDRC - International ...

    International Development Research Centre (IDRC) Digital Library (Canada)

    22 juil. 2011 ... Certaines de ces leçons portent sur les interactions complexes entre la biologie, la culture et le pouvoir. D'autres traitent des moyens de .... HIV prevention policy in China. IDRC-funded research is using mathematical modelling to influence local and national policies in China to reduce HIV transmission.

  16. Juan Goytisolo: Le soi, le monde et la création littéraire

    Directory of Open Access Journals (Sweden)

    Pablo Romero Alegría

    2010-01-01

    Full Text Available Reseña de la obra: Yannick Llored. Le soi, le monde et la création littéraire. Presses Universitaires du Septentrion. Villeneuve d’Ascq (Francia. 2009. 421 págs. ISBN: 978-2-75740-0089-0

  17. LE LIEN ENTRE FINANCE ET ECONOMIE ISLAMIQUES VIA LE MODELE PRINCIPIEL "ZR"

    OpenAIRE

    BELABES, ABDERRAZAK

    2010-01-01

    A l'heure où certains évoquent l'intégration de la finance islamique à la finance globale, et d'autres rattachent la finance islamique à des thèmes en vogue telles que la finance éthique, la finance participative ou la finance socialement responsable, le présent papier explore le lien entre finance et économie islamiques à partir du modèle principiel "ZR", c’est-à-dire "Zakât" et "Ribâ". Ce modèle montre que les principes invariants de Zakât et Ribâ jouent un rôle central dans l’établissement...

  18. Le patrimoine astronomique provençal

    Science.gov (United States)

    Rous, M.; Figon, P.; Guyot, S.

    2012-12-01

    L'OSU OAMP/Institut Pythéas porte les missions de conservation, inventaire et valorisation du patrimoine. Suite à la fusion de l'Observatoire de Marseille et du Laboratoire d'Astronomie Spatiale en 2000 pour créer le Laboratoire d'Astrophysique de Marseille, le déménagement des équipes sur le site de Château-Gombert en 2008 a soulevé le problème du devenir des collections des deux sites d'origine. Nous ferons le bilan des actions passées en matière de conservation et de valorisation de ce riche patrimoine : versement à l'inventaire général du Ministère de la Culture, classement de 22 instruments au titre des Monuments Historiques, inventaire et numérisation des archives anciennes, montage d'expositions et réalisation du catalogue Telescopium, 400 ans de lunettes et de télescopes. Nous présenterons les actions en cours: mesures de conservation préventive, inventaire des archives et des instruments. Nous parlerons enfin des projets: création d'un espace d'exposition permanente, participation à des expositions temporaires.

  19. Temperature-moisture biases in ECMWF analyses based on clear sky longwave simulations constrained by SSMI and MSU measurements and comparisons to ERBE estimates

    Science.gov (United States)

    Sohn, Byung-Ju

    1994-01-01

    Clear sky longwave radiation fluxes for the summer of 1988 and winter of 1989 have been simulated with a radiative transfer model that includes detailed treatment of atmospheric gas absorption. The input data to the model are humidity and temperature profiles from European Center for Medium-Range Weather Forecasts (ECMWF) analyses and surface temperature measurements from the International Satellite Cloud Climatology Project. To reduce the inherent uncertainties in humidity profiles, the ECMWF moisture fields have been adjusted, based on the climatological relationship between the moisture profile and total precipitable water (PW), so that the ECMWF PW is equal to that derived from Special Sensor Microwave Imager (SSMI) data. SSMI and ECMWF PW patterns are generally similar, but significant differences in magnitude are found in the low latitudes, particularly over the subtropical oceans in the Southern Hemisphere. At the same time the tropospheric brightness temperature (T(sub B)) at 53.74 GHz has been computed using a microwave transfer model with ECMWF temperature and humidity fields as inputs. The comparison of computed T(sub B) with the Microwave Sounding Unit (MSU) channel 2 T(sub B) revealed differences larger than 1.5 K over most of the oceans, suggesting that the ECMWF model atmosphere has a cold bias. Maximum biases greater than 3 K are found in low latitudes. After removing the bias from the ECMWF temperature field, a new set of temperature profiles yielding brightness temperature equal to MSU channel 2 T(sub B) has been obtained. Simulation results clearly demonstrate that inclusion of satellite estimates of PW and T(sub B) enhances the accuracy of the clear sky LW flux simulation, substantially reducing the differences from Earth Radiation Budget Experiment (ERBE) estimates. Global averages indicate that the model-derived top-of-atmosphere (TOA) clear sky fluxes from the adjusted moisture and temperature profiles are in very good agreement with

  20. Le mal et ses complots imaginaires

    OpenAIRE

    Frankfurter, David

    2012-01-01

    Les récits d’abus rituels sataniques que les médias ont largement diffusés, aux États-Unis et au Royaume-Uni, entre le début des années 1980 et la fin des années 1990, soutenaient le parallèle avec les allégations avancées, durant l’Antiquité et au début des Temps modernes, contre les chrétiens, les hérétiques, les juifs ou les sorcières. Quelle est la nature de ces parallèles ? Cet article examine plusieurs types de modèles convoqués lors de diverses occurrences historiques des peurs panique...

  1. Le catch, la domestication du risque

    Directory of Open Access Journals (Sweden)

    Jeremy Lacoste

    2015-09-01

    Full Text Available Cet article vise à questionner les logiques de gestion, réappropriation et détournement du risque à travers le catch. Il s’appuie sur la monographie d’un club de la région parisienne observée durant huit mois. Parce que la discipline est à mi-chemin entre la sportivité théâtrale et la scénarisation pugilistique, elle pioche dans le registre de la représentation. Ainsi, art de la surenchère et du pastiche, le catch constitue un terreau majeur pour déconstruire les figures du risque.

  2. Le littoral face aux changements climatiques

    OpenAIRE

    Mulot, Vanessa; Vigneron, Anne-Laure; Lambert-Hadid, Marie-Laure

    2011-01-01

    Le changement climatique et l’anthropisation du littoral accentuent le risque de submersion marine sur l’ensemble des côtes. Malgré l’élévation en cours du niveau des mers, l’attractivité du littoral ne décroît pas malgré la connaissance du risque. Ce risque aggravera dans les années à venir les enjeux liés à la submersion marine, parmi lesquels le danger pour les vies humaines, comme l’a malheureusement illustré l’actualité (Xynhia), mais aussi la question de la propriété des biens et des te...

  3. Les Brulures Chimiques Par Le Laurier Rose

    OpenAIRE

    Bakkali, H.; Ababou, M.; Nassim Sabah, T.; Moussaoui, A.; Ennouhi, A.; Fouadi, F.Z.; Siah, S.; Ihrai, H.

    2010-01-01

    Le laurier rose ou Nerium oleander est un arbuste qui pousse naturellement dans les régions méditerranéennes. Au Maroc on le trouve dans les lieux humides. Il est réputé par ses risques de toxicité systémique en cas d'empoisonnement à cause de la présence de deux alcaloïdes, surtout l'oléandrine. La littérature illustre des cas d'utilisation locale des feuilles de cette plante contre la gale, les hémorroïdes et les furoncles. Nous rapportons deux cas de brûlures chimiques par le laurier rose ...

  4. Influence du soleil sur le climat

    OpenAIRE

    Bard, Édouard

    2013-01-01

    Variations du forçage radiatif solaire Il a fallu attendre la fin des années 70 pour obtenir les premières données précises sur l’irradiance solaire mesurée à partir des satellites. La « constante solaire », introduite par le physicien français Claude Pouillet en 1838, fluctue à court terme et son cycle de 11 ans se caractérise par une variation de l’irradiance totale d’environ 0,1 %. Paradoxalement, l’éclairement augmente avec le nombre de taches solaires : les taches assombrissent le Soleil...

  5. Farid Ameur, Le Ku Klux Klan

    OpenAIRE

    Laberge, Yves

    2018-01-01

    S’il existe de nombreuses études en anglais sur le Ku Klux Klan, et notamment celles — percutantes — de Stetson Kennedy (1916-2011), qui avait réussi à infiltrer cette organisation, on en trouve relativement peu en langue française. De ce fait, la réédition de cette monographie de l’historien Farid Ameur tombe à point nommé. Mouvement social d’extrême-droite prônant le racisme et la suprématie blanche, le KKK a une histoire secrète qui est de ce fait difficile à raconter de manière exhaustive...

  6. Le jeu de la création : Le mangeur (2005 de Ying Chen

    Directory of Open Access Journals (Sweden)

    Nicole Dunham

    2013-11-01

    Full Text Available Le théoricien James Hans définit le jeu comme une déconstruction structurante, un processus de perpétuelle remise en question. Dans Le Mangeur (2005 de Ying Chen, la narratrice revit un épisode d’une de ses vies passées où elle meurt mangée, avalée, par son père, descendant dans le « tunnel » du ventre de ce dernier. Cependant, suite à cet événement, elle se retrouve dans un autre espace-temps où elle rencontre son mari, A.. Une équivalence s’établit dans le roman entre les éléments suivants : le ventre du père, les tableaux peints par ce dernier et l’espace-temps de A., et la fenêtre. Ces éléments deviennent des aires de jeu, remettant en question les concepts de l’intérieur et de l’extérieur et du créateur et de l’œuvre. En nous servant du texte « Le Tunnel » écrit par Ying Chen, nous démontrerons que cette notion du jeu s’applique également à l’ensemble de son œuvre.

  7. O labor secreto de Le Corbusier

    OpenAIRE

    Alexandre Hector Benoit

    2014-01-01

    Após iniciar sua trajetória como pintor junto às vanguardas parisienses do cubismo e do purismo, Le Corbusier cessa em 1923, aos olhos do público, tal atividade, mantendo-a regular e sistemática como um trabalho exclusivo seu. Afora algumas poucas exposições menores e discretas, Le Corbusier permanece cerca de 30 anos pintando sem expor até que, em 1948, inicia o redescobrimento do que veio a chamar de seu \\"labor secreto\\". Esse processo de retomada da pintura como a \\"virtude profunda\\" de ...

  8. LE MARCHE FINANCIER EN ALGERIE : SITUATION ET ...

    African Journals Online (AJOL)

    Administrateur

    Dans les pays en transition, la performance du marché financier apparaît loin des espérances suscitées. Le marché financier dont le début de la mise en place en Algérie remonte à 1995, peut-il se construire dans une économie dominée par la rente pétro- lière et par un système bancaire public sclérosé, omniprésent et ...

  9. Le language des masques burkinabè

    African Journals Online (AJOL)

    hond

    2 juil. 2007 ... Les masques, dont le côté festif, esthétique et touristique retient encore l'attention des jeunes, tendent à « s'épurer » de leur ésotérisme qui leur donnait une âme grave. Ainsi « allégés », les masques risquent de tomber dans le folklore ; ils risquent même. 23 Millogo_F 03.pmd. 2/7/2007, 1:40 PM. 330 ...

  10. Le continu contre l'espace

    Science.gov (United States)

    Salanskis, Jean-Michel

    Disons pour conclure que, en tout état de cause, la façon de concevoir philosophiquement le conflit du continu et de l'espace que nous avons trouvée chez Hegel n'est pas homogène avec le style et les modalités de la pensée mathématique: 1) d'une part, le lien classique, le lien de référence entre continu et espace en mathématiques n'est pas que l'espace serait premier et privé de pensée, et le continu second, venant dissoudre l'espace en apportant la qualité, l'infini et la pensée, mais tout au contraire, il consiste en ce que l'espace est fondé sur l'abîme infinitaire du continu ; 2) d'autre part, l'éventuel divorce entre l'espace et le continu dans l'aire mathématique n'est pas celui d'une réflexivité purement conceptuelle du continu avec un positivisme géométrique, n'équivaut pas à une rupture disciplinaire ; il est plutôt le symptôme de la dérive d'une herméneutique à l'égard d'une autre, au sein d'un continent juridique commun définissant la discipline (la mathématique ensembliste), cette dérive pouvant, à la limite, induire une refonte de ce sol juridique, sans que jamais il soit question pour autant de nier l'unité des mathématiques, à comprendre ici comme l'unité ultime de responsabilité de la communauté mathématique à l'égard des trois questions Qu'est-ce que l'espace?”, “Qu'est-ce que le continu?” et “Qu'est-ce que l'infini?”.

  11. et le développement La

    International Development Research Centre (IDRC) Digital Library (Canada)

    été réalisée, le service postal venait de mettre en place un système automatisé de transferts monétaires par voie élec- tronique à l'intérieur du pays, mais il offrait un service international restreint. À la fin de 2007, l'Uzbekistan. Pochtasi a intégré officiellement le système financier inter- national de l'Union postale universelle, ...

  12. L'astronomie dans le monde

    OpenAIRE

    Manfroid, Jean

    2004-01-01

    comètes en pagaille; Recherche d'astéroïdes; Voisinage galactique; Titan en X; Titan à haute résolution; Alignement parfait dans le Sagittaire; Où est la lune de Sedna; SgrA*; Première image d'une planète extrasolaire?; Deux Jupiter chauds; Cycles stellaires; Le trou noir de M87; Un nouveau bras pour la Voie LactÃée; L'étoile la plus massive jamais observée!

  13. Particularites des accidents vasculaires cerebraux chez le ...

    African Journals Online (AJOL)

    Une revue de la littérature nous a permis de relever les particularités des AVC chez le diabétique. Résultats L'AVC peut être révélateur du diabète dans 20% des cas, ... Le dépistage du diabète doit être systématique chez tout patient présentant un AVC. A la phase aiguë, l'hyperglycémie doit être traitée énergiquement.

  14. Le stéréotype dans le roman policier

    Directory of Open Access Journals (Sweden)

    Marion François

    2009-12-01

    Full Text Available Le roman policier offre à l’étude du stéréotype une grande variété de redondances, lexicales et structurelles, qui permettent d’éclairer le concept même de genre, en fait issu du constat de stéréotypie. Il est également manifeste que contrairement aux idées reçues, les clichés font du texte policier un texte littéraire, parce qu’ils naissent d’images associées, distinctes de la réalité, qui révèlent d’ailleurs le cheminement même de l’écriture. Par ailleurs ces images jouent un rôle fondamental dans le plaisir du lecteur, comme dans les contes de fées de notre enfance. Les clichés ouvrent la porte des fantasmes : le stéréotype rejoignant l’archétype, les clichés policiers réactivent de nombreux mythes, le texte évoquant l’Autre Scène. Le constat de stéréotypie provoque l’écriture, en particulier parodique, et stimule le renouvellement et l’essaimage des clichés dans toutes sortes de textes, qui bénéficieront de la présence du déjà-lu, laquelle donne au lecteur une assise pour affronter l’inconnu et une expérience pour apprécier la nouveauté.

  15. Indicadores de Prognóstico em Câncer de Mama com Axila Negativa: Receptor de Estrógeno e Expressão de P53 e de c-erbB-2 Prognostic Indicators In Lymph Node-Negative Breast Cancer: Estrogen Receptor and P53 and c-erbB-2 Protein Expression

    Directory of Open Access Journals (Sweden)

    Adriana Harter Teixeira Bolaséll

    2000-08-01

    Full Text Available Objetivo: avaliar o valor prognóstico do receptor de estrógeno e da expressão das proteínas p53 e c-erbB-2 no câncer de mama com axila negativa. Métodos: foi realizado estudo imuno-histoquímico em material incluido em parafina, do arquivo do Instituto de Pesquisas Cito-Oncológicas (IPCO da Fundação Faculdade Federal de Ciências Médicas de Porto Alegre (FFFCMPA, de 50 casos de câncer de mama sem comprometimento dos linfonodos axilares, em mulheres menopausadas, tratadas na Irmandade da Santa Casa de Porto Alegre (ISCMPA e no Hospital Santa Rita de Porto Alegre (HSR de janeiro 1990 a dezembro de 1994. Para análise estatística foram utilizados os testes de c² com correção de Yates, teste exato de Fisher e curvas de sobrevida pelo método de Kaplan-Meier comparados pelo teste log rank. O seguimento médio das pacientes foi de 3,6 anos (3,1-4,5. Dos 50 casos, 14 apresentaram recidiva no período observado. Resultados: a média de idade foi 61 anos (variação de 46 a 78 anos. A mastectomia radical modificada (MRM foi realizada em 35 pacientes (70% e 15 (30% foram submetidas a setorectomia com esvaziamento axilar e posterior radioterapia. Metade das pacientes que apresentaram recidiva apresentaram-na nos três primeiros anos após o diagnóstico. O tamanho médio do tumor foi 2,8 cm (1,98-3,13 e o tipo histológico mais freqüente foi o carcinoma ductal infiltrante de tipo histológico não-especial (92%, conforme a graduação histológica de Bloom e Richardson, sendo 3 grau I (6,6%, 35 grau II (76% e 8 grau III (17,4%; nos tumores que recidivaram não houve nenhum grau I, 9 (25,7% eram grau II e 3 (37,5% eram grau III. Em relação ao prognóstico, a taxa de intervalo livre de doença foi menor quando da associação de tumor pouco diferenciado (grau III com receptor de estrógeno negativo (p = 0,006, p53 positivo (p = 0,006 e c-erbB-2 positivo (p = 0,001. Conclusão: mulheres menopausadas com câncer de mama sem comprometimento

  16. Le Peer to Peer: Vers un Nouveau Modèle de Civilization

    Directory of Open Access Journals (Sweden)

    Michel Bauwens

    2006-06-01

    Full Text Available Le « peer to peer » est la dynamique intersubjective caractéristique des réseaux distribués. Le but de cet essai est de montrer qu'il s'agit d'une véritable nouvelle forme d’organisation sociale, apte à produire et échanger des biens, à créer de la valeur. Celle-ci est la conséquence d'un nouvel imaginaire social, et possède le potentiel de devenir le pilier d'un nouveau mode d'économie politique, voire d'un nouveau type de civilisation. Pour cela, nous allons d'abord définir le P2P, décrire en bref ces manifestations, et le différencier d'autres modalités d'échange intersubjectif tel que le marché, la hiérarchie, l'économie du don.Comme principale modalité P2P nous distinguons: Les processus de production P2P, comme troisième mode de production, qui n'est ni géré par un mode hiérarchique ou par l'état, ni répondant à des impératifs de profit ou qui sont modulés par le biais des prix. Les processus de gouvernance P2P, qui gouverne ces processus de production. Les formes de propriété P2P, qui sont destine a empecher l’appropriation prive de cette production pour le commun.Afin d’examiner les characteristiques de cette nouvelle dynamique sociale, nous utilisons la typologie intersubjective de l’anthropologue Alan Page Fisque, qui distingue: 1. l'échange égalitaire (Equality Matching, c..a.d l’economie du don. 2. La relation d’autorité (Authority Ranking tel qu’elle s’exprime dans le mode hierarchique. 3. le marché (Market Pricing. 4. la participation commune (Communal Shareholding.En conclusion, nous examinons les possibilites d’expansion de ce nouveau mode sociale et son insertion dans l’economie capitaliste, en nous nous posons la question: le P2P peut-il etre concu comme alternative sociale et economique aux modeles existants.

  17. L'Inde : où est le milieu ? | CRDI - Centre de recherches pour le ...

    International Development Research Centre (IDRC) Digital Library (Canada)

    1 avr. 2011 ... Mais ils n'ont pas créé les emplois « fiables » dont l'Inde a désespérément besoin. Le travail peu rémunéré demeure un problème de taille sur le marché du travail indien. Pourtant, l'étude réalisée par M. Mazumdar sur la pauvreté, la croissance et l'inégalité montre que le nombre d'Indiens vivant dans la ...

  18. Thermal Orbital Environmental Parameter Study on the Propulsive Small Expendable Deployer System (ProSEDS) Using Earth Radiation Budget Experiment (ERBE) Data

    Science.gov (United States)

    Sharp, John R.; McConnaughey, Paul K. (Technical Monitor)

    2002-01-01

    The natural thermal environmental parameters used on the Space Station Program (SSP 30425) were generated by the Space Environmental Effects Branch at NASA's Marshall Space Flight Center (MSFC) utilizing extensive data from the Earth Radiation Budget Experiment (ERBE), a series of satellites which measured low earth orbit (LEO) albedo and outgoing long-wave radiation. Later, this temporal data was presented as a function of averaging times and orbital inclination for use by thermal engineers in NASA Technical Memorandum TM 4527. The data was not presented in a fashion readily usable by thermal engineering modeling tools and required knowledge of the thermal time constants and infrared versus solar spectrum sensitivity of the hardware being analyzed to be used properly. Another TM was recently issued as a guideline for utilizing these environments (NASA/TM-2001-211221) with more insight into the utilization by thermal analysts. This paper gives a top-level overview of the environmental parameters presented in the TM and a study of the effects of implementing these environments on an ongoing MSFC project, the Propulsive Small Expendable Deployer System (ProSEDS), compared to conventional orbital parameters that had been historically used.

  19. Combined use of anti-ErbB monoclonal antibodies and erlotinib enhances antibody-dependent cellular cytotoxicity of wild-type erlotinib-sensitive NSCLC cell lines

    Directory of Open Access Journals (Sweden)

    Cavazzoni Andrea

    2012-12-01

    Full Text Available Abstract Background The epidermal growth factor receptor (EGFR is an established target for anti-cancer treatment in different tumour types. Two different strategies have been explored to inhibit this pivotal molecule in epithelial cancer development: small molecules TKIs and monoclonal antibodies. ErbB/HER-targeting by monoclonal antibodies such as cetuximab and trastuzumab or tyrosine-kinase inhibitors as gefitinib or erlotinib has been proven effective in the treatment of advanced NSCLC. Results In this study we explored the potential of combining either erlotinib with cetuximab or trastuzumab to improve the efficacy of EGFR targeted therapy in EGFR wild-type NSCLC cell lines. Erlotinib treatment was observed to increase EGFR and/or HER2 expression at the plasma membrane level only in NSCLC cell lines sensitive to the drug inducing protein stabilization. The combined treatment had marginal effect on cell proliferation but markedly increased antibody-dependent, NK mediated, cytotoxicity in vitro. Moreover, in the Calu-3 xenograft model, the combination significantly inhibited tumour growth when compared with erlotinib and cetuximab alone. Conclusion Our results indicate that erlotinib increases surface expression of EGFR and/or HER2 only in EGFR-TKI sensitive NSCLC cell lines and, in turns, leads to increased susceptibility to ADCC both in vitro and in a xenograft models. The combination of erlotinib with monoclonal antibodies represents a potential strategy to improve the treatment of wild-type EGFR NSCLC patients sensitive to erlotinib.

  20. La science, la littérature, le rituel: le vrai dire et le plus que mentir

    Directory of Open Access Journals (Sweden)

    Panagiotis Christias

    2005-03-01

    Full Text Available Le scientifique promet la vérité sans être en mesure d'accomplir sa promesse tandis que l'écrivain promet de mentir mais par son mensonge, il fait plus que mentir. Il ne dit certainement pas la vérité, car la vérité n'est pas sa préoccupation première. Voilà comment nous pouvons résumer les deux attitudes, condamnées à un antagonisme stérile par l'attitude positiviste moderne. Compte tenu donc de l'intention fondatrice de la science, de sa promesse donc originaire et fondatrice, la science doit dire la vérité et rien que la vérité. Ce qui, de l'aveu même de cette même science, est impossible. [...] La littérature se permet de reconstruire des mondes par-delà le vrai et le faux. [...] Un récit littéraire ne demande pas la consécration de la vérité, ne demande pas à être suivi parce que vrai, n'impose rien et n'attend rien. Sa vraie destinée est l'errance et sa vraie conscience est celle de sa dissémination. Celui qui renonce à la prétention de vérité renonce en même temps à la volonté de dominer. Dominer signifie créer un espace de vérité dans lequel celui qui énonce la vérité est le maître légitime de ceux qui sont dans le champ de la conception du monde dont cette vérité est la pierre angulaire.

  1. Perspectives | Page 3 | CRDI - Centre de recherches pour le ...

    International Development Research Centre (IDRC) Digital Library (Canada)

    Des experts du CRDI examinent les questions et les approches sur lesquelles se penchent les acteurs du développement international, ainsi que lele de la recherche dans la mise au point de solutions.

  2. Pronto chi parla. Cesare e le intercettazioni telefoniche

    Directory of Open Access Journals (Sweden)

    Paolo Caponi

    2010-03-01

    Full Text Available Pronto chi parla. Cesare e le intercettazioni telefoniche (Ugo Guspini, L’orecchio del regime. Le intercettazioni telefoniche al tempo del fascismo, Milano, Mursia, 1973, pp. 262 di Paolo Caponi

  3. Publications | Page 102 | CRDI - Centre de recherches pour le ...

    International Development Research Centre (IDRC) Digital Library (Canada)

    En mars 2004, le ministre ougandais de l'Éducation et des sports, Kiddhu Makubuya, et le... Biodiversité et santé : Tuons-nous les plantes qui peuvent nous guérir ? Enrhumé ? Vite, de l'échinacée. Le stress vous tenaille ? Prenez un peu de ginseng. Vous êtes inquiet et déprimé ? Le millepertuis devrait vous requinquer.

  4. Mexico : tous les projets | CRDI - Centre de recherches pour le ...

    International Development Research Centre (IDRC) Digital Library (Canada)

    Au cours des 15 dernières années, des efforts ont été déployés par le gouvernement, la société civile, le secteur privé et les organisations internationales dans le but de relever les défis auxquels sont confrontés les peuples autochtones, et tout particulièrement les femmes dans certains cas, dans le système ...

  5. Publications | Page 179 | CRDI - Centre de recherches pour le ...

    International Development Research Centre (IDRC) Digital Library (Canada)

    Lele de l'énergie dans le développement rural. Hisham Zerriffi n'a aucun mal à énumérer les bienfaits de l'électrification des zones rurales : une ... Enterrer la hache de guerre : le CRDI appuie un processus de paix inédit. La plupart des gens pensent que la paix est un état dans lequel soit il « ne se produit rien de ...

  6. Publications | Page 177 | CRDI - Centre de recherches pour le ...

    International Development Research Centre (IDRC) Digital Library (Canada)

    Lele de l'énergie dans le développement rural. Hisham Zerriffi n'a aucun mal à énumérer les bienfaits de l'électrification des zones rurales : une ... Enterrer la hache de guerre : le CRDI appuie un processus de paix inédit. La plupart des gens pensent que la paix est un état dans lequel soit il « ne se produit rien de ...

  7. Plaidoyer pour le lavage de nez dans les pathologies naso ...

    African Journals Online (AJOL)

    Le lavage de nez permet l'humidification des muqueuses partant favorise le nettoyage mucociliaire en enlevant voire diminuant les croutes favorise leur élimination et ainsi la guérison en réduisant le recours aux antibiotiques [4-10]. Sans danger, le lavage de nez est bien tolérée tant chez les enfants que chez les adultes.

  8. La nouvelle politique concernant le salaire minimum au Myanmar ...

    International Development Research Centre (IDRC) Digital Library (Canada)

    20 avr. 2016 ... Au cours de la dernière décennie, le marché du travail asiatique a été marqué par des augmentations du salaire minimum. Alors que la Chine et le Vietnam ont augmenté leur salaire minimum au cours des 10 dernières années, le Bangladesh et le Cambodge ont adopté un salaire minimum dans les deux ...

  9. Publications | Page 59 | CRDI - Centre de recherches pour le ...

    International Development Research Centre (IDRC) Digital Library (Canada)

    Le rapport régional de 2012 du projet Global Entrepreneurship Monitor (GEM), qui porte sur l'Afrique subsaharienne, est le premier à examiner les dynamiques d'entrepreneuriat dans la région. Il a été lancé à Lusaka, en Zambie, le 19 novembre 2013. Les données recueillies par le Zimbabwe sur la pauvreté : un apport ...

  10. Gestion du Centre | CRDI - Centre de recherches pour le ...

    International Development Research Centre (IDRC) Digital Library (Canada)

    Le Comité de gestion du Centre (CGC) est composé des membres de la haute direction du CRDI, notamment les directeurs de nos quatre bureaux régionaux et de nos principaux secteurs de programme. Le CGC travaille en collaboration avec le président afin de soutenir la recherche pour le développement, lui fournissant ...

  11. Le stockage thermique par chaleur latente

    OpenAIRE

    Martin, F.; Nicolas, Jacques

    1988-01-01

    L'article présente le principe du stockage d'énergie par transformation de phase ainsi que les matériaux employés (composés organiques, sels hydratés et matériaux à transformation solide-solide) et les différents types d'échangeurs. Peer reviewed

  12. Le Chatelier's principle in replicator dynamics.

    Science.gov (United States)

    Allahverdyan, Armen E; Galstyan, Aram

    2011-10-01

    The Le Chatelier principle states that physical equilibria are not only stable, but they also resist external perturbations via short-time negative-feedback mechanisms: a perturbation induces processes tending to diminish its results. The principle has deep roots, e.g., in thermodynamics it is closely related to the second law and the positivity of the entropy production. Here we study the applicability of the Le Chatelier principle to evolutionary game theory, i.e., to perturbations of a Nash equilibrium within the replicator dynamics. We show that the principle can be reformulated as a majorization relation. This defines a stability notion that generalizes the concept of evolutionary stability. We determine criteria for a Nash equilibrium to satisfy the Le Chatelier principle and relate them to mutualistic interactions (game-theoretical anticoordination) showing in which sense mutualistic replicators can be more stable than (say) competing ones. There are globally stable Nash equilibria, where the Le Chatelier principle is violated even locally: in contrast to the thermodynamic equilibrium a Nash equilibrium can amplify small perturbations, though both types of equilibria satisfy the detailed balance condition.

  13. Le Francais Moderne: Part I, French.

    Science.gov (United States)

    Dade County Public Schools, Miami, FL.

    Instructional objectives of the Dade County Public Schools Quinmester Program in French for use with "Le Francais Moderne: Part 1" focus on the development of vocabulary and mastery of grammatical structures. The formation of the passe compose with "avoir," object pronouns, the present tense of regular "-ir" verbs,…

  14. ON THE LE CHATELIER-SAMUELSON PRINCIPLE

    OpenAIRE

    ANDERSON, Richard K.; TAKAYAMA, Akira

    1992-01-01

    This paper obtains a method to derive the Le Chatelier-Samuelson Principle. Not only is it simpler and more straightforward than other methods in the literature, but also it enables us to obtain important results which are not readily accessible otherwise.

  15. Le Chatelier's Principle, Temperature Effects, and Entropy.

    Science.gov (United States)

    Campbell, J. Arthur

    1985-01-01

    One of the most useful methods of understanding chemical equilibria is provided by Le Chatelier's principle. The relationships between this principle, temperature, and entropy are discussed. Tables with thermodynamic data for some net reactions commonly used to illustrate the principle and for reactions involving gases are included. (JN)

  16. Le Chatelier--Right or Wrong?

    Science.gov (United States)

    Helfferich, Friedrich G.

    1985-01-01

    Presents a class exercise designed to find out how well students understand the nature and consequences of the mass action law and Le Chatelier's principle as applied to chemical equilibria. The exercise relates to a practical situation and provides simple relations for maximizing equilibrium quantities not found in standard textbooks. (JN)

  17. Le Chatelier's principle in replicator dynamics

    Science.gov (United States)

    Allahverdyan, Armen E.; Galstyan, Aram

    2011-10-01

    The Le Chatelier principle states that physical equilibria are not only stable, but they also resist external perturbations via short-time negative-feedback mechanisms: a perturbation induces processes tending to diminish its results. The principle has deep roots, e.g., in thermodynamics it is closely related to the second law and the positivity of the entropy production. Here we study the applicability of the Le Chatelier principle to evolutionary game theory, i.e., to perturbations of a Nash equilibrium within the replicator dynamics. We show that the principle can be reformulated as a majorization relation. This defines a stability notion that generalizes the concept of evolutionary stability. We determine criteria for a Nash equilibrium to satisfy the Le Chatelier principle and relate them to mutualistic interactions (game-theoretical anticoordination) showing in which sense mutualistic replicators can be more stable than (say) competing ones. There are globally stable Nash equilibria, where the Le Chatelier principle is violated even locally: in contrast to the thermodynamic equilibrium a Nash equilibrium can amplify small perturbations, though both types of equilibria satisfy the detailed balance condition.

  18. Microscopic Description of Le Chatelier's Principle

    Science.gov (United States)

    Novak, Igor

    2005-01-01

    A simple approach that "demystifies" Le Chatelier's principle (LCP) and simulates students to think about fundamental physical background behind the well-known principles is presented. The approach uses microscopic descriptors of matter like energy levels and populations and does not require any assumption about the fixed amount of substance being…

  19. (Mycosphaerella fijiensis Morelet) chez le bananier plantain

    African Journals Online (AJOL)

    SARAH

    31 mars 2014 ... Aguirre MC, Castano- zapata J, Valencia JA, Zuluaga. LE, Arce C, 1988 a. Interaccion de. Mycosphaerella fijiensis Morelet y M. musicola. Leach en siete genotipos de la Sigatoka negra en la zonacafetera colombiana. Pp. 192-220 in. Memorias del Seminaio Internacional sobre P roduction de Platano.

  20. Le rêve dans la psychanalyse

    Czech Academy of Sciences Publication Activity Database

    Pechar, Jiří

    2016-01-01

    Roč. 12, č. 3 (2016), s. 1-5 ISSN 1336-6556 Institutional support: RVO:67985955 Keywords : psychoanalysis * dream-work * condensation * displacement * screen-memory * Freud Subject RIV: AA - Philosophy ; Religion http://www.ostium.sk/sk/le-r%c8%87ve-dans-la-psychanalyse/