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Sample records for blieck stanislas loboziak

  1. Alcohol Consumption, Beverage Preference, and Diet in Middle-Aged Men from the STANISLAS Study

    Directory of Open Access Journals (Sweden)

    Bernard Herbeth

    2012-01-01

    Full Text Available The question about differences in dietary patterns associated with beer, wine, and spirits is still unresolved. We used diet data from 423 middle-aged males of the STANISLAS Study. Using adjusted values for covariates, we observed a negative significant association between increasing alcohol intakes and the consumption of milk, yogurt, and fresh/uncured cheese, sugar and confectionery, vegetables and fruits, and a significant positive relationship with cheese, meat and organs, pork-butcher's meat, and potatoes. In addition, the first dietary pattern identified by factor analysis (characterized a more prudent diet was inversely related to alcohol intakes. Conversely, when analyzing daily consumption of specific food groups and diet patterns according to beverage preference (wine, beer, and spirits, no significant difference was observed. In conclusion, in this sample of middle-aged French males, there was a linear trend between increasing alcohol intakes and worsening of quality of diet, while no difference was observed according to beverage preference.

  2. Metabolic syndrome-related composite factors over 5 years in the STANISLAS family study: genetic heritability and common environmental influences.

    Science.gov (United States)

    Herbeth, Bernard; Samara, Anastasia; Ndiaye, Coumba; Marteau, Jean-Brice; Berrahmoune, Hind; Siest, Gérard; Visvikis-Siest, Sophie

    2010-06-03

    We estimated genetic heritability and common environmental influences for various traits related to metabolic syndrome in young families from France. At entrance and after 5 years, nineteen traits related to metabolic syndrome were measured in a sample of families drawn from the STANISLAS study. In addition, 5 aggregates of these traits were identified using factor analysis. At entrance, genetic heritability was high (20 to 44%) for plasma lipids and lipoproteins, uric acid, fasting glucose, and the related clusters "risk lipids" and "protective lipids". Intermediate or low genetic heritability (less than 20%) was shown for triglycerides, adiposity indices, blood pressure, hepatic enzyme activity, inflammatory makers and the related clusters: "liver enzymes", "adiposity/blood pressure" and "inflammation". Moreover, common environmental influences were significant for all the parameters. With regard to 5-year changes, polygenic variance was low and not statistically significant for any of the individual variables or clusters whereas shared environment influence was significant. In these young families, genetic heritability of metabolic syndrome-related traits was generally lower than previously reported while the common environmental influences were greater. In addition, only shared environment contributed to short-term changes of these traits. Copyright 2010 Elsevier B.V. All rights reserved.

  3. Le Foyer social de Mbandaka (Coquilhatville) | Lufungula Lewono ...

    African Journals Online (AJOL)

    Le Foyer social de Mbandaka (Coquilhatville). Stanislas Lufungula Lewono. Abstract. (Annales Æquatoria, 21 (2000): 19-32). Full Text: EMAIL FULL TEXT EMAIL FULL TEXT · DOWNLOAD FULL TEXT DOWNLOAD FULL TEXT · AJOL African Journals Online. HOW TO USE AJOL... for Researchers · for Librarians ...

  4. Lille – 28-30 rue des Fossés

    OpenAIRE

    Blieck, Gilles

    2013-01-01

    Date de l'opération : 1991 (SP) Inventeur(s) : Blieck Gilles Cette intervention sur un terrain attenant constituait le second volet de l’opération de la place Rihour [ (Fig. n°1 : Plan général. Localisation des zones fouillées), site I]. Elle a permis de compléter les observations précédentes notamment en ce qui concerne la genèse de cette fortification. La défense paraît avoir reposé, dans un premier temps, sur un simple fossé de 8,50 m de large sur 1,10 m de profondeur. Le débordement régu...

  5. The Brain Prize 2014: complex human functions.

    Science.gov (United States)

    Grigaityte, Kristina; Iacoboni, Marco

    2014-11-01

    Giacomo Rizzolatti, Stanislas Dehaene, and Trevor Robbins were recently awarded the 2014 Grete Lundbeck European Brain Research Prize for their 'pioneering research on higher brain mechanisms underpinning such complex human functions as literacy, numeracy, motivated behavior and social cognition, and for their effort to understand cognitive and behavioral disorders'. Why was their work highlighted? Is there anything that links together these seemingly disparate lines of research? Copyright © 2014 Elsevier Ltd. All rights reserved.

  6. Activité antérieure – Améliorer la recherche sur les systèmes de ...

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

    15 avr. 2016 ... M. Félix Boa Yapo, directeur général de la santé de la Côte d'Ivoire, a ouvert la séance de consultation, en compagnie de Stanislas Kambour, directeur des systèmes de recherche et de renseignements sur la santé de l'OOAS, et de Chantal de Varennes, ambassadrice du Canada auprès de la République ...

  7. Cognition, attention et conscience : la synchronie dans l’esprit

    OpenAIRE

    Ward, Lawrence

    2011-01-01

    Professeur à British Columbia University (Vancouver, Canada), invité par l’Assemblée des professeurs à l’initiative des Prs Alain Berthoz et Stanislas Dehaene, a donné en mai 2010, quatre conférences intitulées « Cognition, attention et conscience : la synchronie dans l’esprit »

  8. Number sense how the mind creates mathematics

    CERN Document Server

    Dehaene, Stanislas

    2011-01-01

    Our understanding of how the human brain performs mathematical calculations is far from complete, but in recent years there have been many exciting breakthroughs by scientists all over the world. Now, in The Number Sense, Stanislas Dehaene offers a fascinating look at this recent research, in an enlightening exploration of the mathematical mind. Dehaene begins with the eye-opening discovery that animals--including rats, pigeons, raccoons, and chimpanzees--can perform simple mathematical calculations, and that human infants also have a rudimentary number sense. Dehaene suggests that this rudime

  9. 30. L’empire de la raison

    OpenAIRE

    2018-01-01

    La pensée politique de Stanislas Leszczynski (1677–1766), roi de Pologne puis duc de Lorraine, est faite d’un mélange de pragmatisme et d’idéalisme : pour vivre en paix avec ses voisins, un État doit savoir s’en faire craindre ; mais il n’exercera durablement son empire que par la sagesse de ses lois et la vertu de son souverain. Dans l’Entretien d’un Européen avec un insulaire du Royaume de Dumocala, il fait dialoguer un voyageur, dont le vaisseau a fait naufrage sur une terre australe incon...

  10. Consciousness and the brain deciphering how the brain codes our thoughts

    CERN Document Server

    Dehaene, Stanislas

    2014-01-01

    How does our brain generate a conscious thought? And why does so much of our knowledge remain unconscious? Thanks to clever psychological and brain-imaging experiments, scientists are closer to cracking this mystery than ever before. In this lively book, Stanislas Dehaene describes the pioneering work his lab and the labs of other cognitive neuroscientists worldwide have accomplished in defining, testing, and explaining the brain events behind a conscious state. We can now pin down the neurons that fire when a person reports becoming aware of a piece of information and understand the crucial role unconscious computations play in how we make decisions. The emerging theory enables a test of consciousness in animals, babies, and those with severe brain injuries. A joyous exploration of the mind and its thrilling complexities, Consciousness and the Brain will excite anyone interested in cutting-edge science and technology and the vast philosophical, personal, and ethical implications of finally quantifying cons...

  11. Obesity and metabolic features associated with long-term developing diastolic dysfunction in an initially healthy population-based cohort.

    Science.gov (United States)

    Chau, Kénora; Girerd, Nicolas; Magnusson, Martin; Lamiral, Zohra; Bozec, Erwan; Merckle, Ludovic; Leosdottir, Margret; Bachus, Erasmus; Frikha, Zied; Ferreira, João Pedro; Després, Jean-Pierre; Rossignol, Patrick; Boivin, Jean-Marc; Zannad, Faiez

    2018-04-21

    Diastolic dysfunction (DD) is increasingly common. However, its metabolic determinants are poorly known. This study aims to determine which metabolic and inflammatory features predict DD in initially healthy adults. We prospectively analyzed the association between metabolic features and DD in 728 initially healthy adults aged 30-60 from Eastern France enrolled in the STANISLAS population-based cohort. Clinical and biological cardiovascular features were collected at baseline (1994-1995). DD was assessed twenty years later (2011-2016) by echocardiography using current international guidelines. For replication purposes, 1463 subjects from the Malmö Preventive Project cohort were analyzed. In the STANISLAS cohort, 191 subjects (26.2%) developed DD. In age-sex-adjusted logistic models, significant predictors of DD were body mass index (BMI, odds ratio for 1-standard-deviation increase (OR) 1.28, 95% CI 1.08-1.52), waist circumference (WC, OR 1.48, 95% CI 1.18-1.84), waist-hip ratio (OR 1.53, 95% CI 1.16-2.02), systolic blood pressure (OR 1.19, 95% CI 1.00-1.43) and triglycerides (TG, OR 1.18, 95% CI 1.00-1.40). Subjects with elevated WC (> 80th percentile) and TG (> 50th percentile) had a twofold higher DD risk (age-sex-adjusted odds ratio 2.00, 95% CI 1.20-3.31, P = 0.008), whereas no such interplay was observed for BMI. In the Malmö cohort, BMI was similarly associated with DD; participants with both elevated BMI and TG were at higher DD risk (age-sex-adjusted odds ratio 1.61, 95% CI 1.18-2.20, P = 0.002). Subjects with elevated WC and TG may have a higher long-term DD risk. Prevention targeting visceral obesity may help reduce the incidence of DD.

  12. Proceedings of the Nantes international secondary school meetings

    International Nuclear Information System (INIS)

    2012-03-01

    Since 2008, French and foreign secondary schools participate to radiation protection workshops led by teachers of these establishments in partnership with radiation protection experts and researchers. The aim of these workshops is to involve students in pluri-disciplinary activities in relation with the practical radiation protection culture. Each year, 100 to 150 students from about 15 French and foreign secondary schools participate to these workshops. This document brings together the available documents (slides) presented at the occasion of the 2012 meeting, held at the Ecole des Mines of Nantes (FR). The document gathers 20 presentations dealing with: - Nuclear medicine (Lycee Alienor d'Aquitaine - Poitiers (FR)); - Patients' radiation protection during a medical scanner examination (Externat des enfants nantais - Nantes (FR)); - Radiation protection of nuclear medicine personnel (Lycee Nicolas Appert - Nantes (FR)); - Radiation protection in therapeutic environment (Lycee Saint Stanislas - Nantes (FR)); - Radionuclide route from its injection to its elimination (Lycee Saint Stanislas (Nantes (FR)); - Radon in the geological heritage of Corsica (Lycee Paul Vincensini (Bastia (FR)); - History of radioactivity (Lycee Alienor d'Aquitaine (Poitiers (FR)); - Environmental monitoring around a nuclear facility (Lycee du Bois d'Amour (Poitiers (FR)); - Environmental monitoring and wastes (Lycee de l'Academie des Sciences de Chisinau (Moldavia)); - Dating by radioactive decay (Lycee Alienor d'Aquitaine (Poitiers (FR)); - Managing and storing the hospital radioactive wastes (Lycee Nicolas Appert - Nantes (FR)); - Radiation protection stakes in veterinary activities (Lycee Clemenceau - Nantes (FR)); - Why can we find radon in our houses and what are the consequences? (Lycee Paul Vincensini (Bastia (FR)); - Health impact of radon (Lycee Paul Vincensini (Bastia (FR)); - Nuclear power plant operation - a Civaux/Fukushima comparison (Lycee Alienor d'Aquitaine (Poitiers (FR

  13. Urojone-nic. Pojęcie zasady w Être, Monde, Imaginaire Stanislasa Bretona

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    Marcin POLAK

    2012-12-01

    Full Text Available A philosophical study of the concept of the principle was conducted by Stanislas Breton inhis two books: Du principe and Être, Monde Imaginaire, the first of which was dominated byits analytical and abstract style, while the second was speculative and imaginary. This articleundertakes the task of reconstructing the idea of the principle contained in the latter position.In the first part of the article the author presents two currents of thought concerning theprinciple: the ontological, which is based on the category of logos, and the ontomythological,for which the leading category is mythos. After discussing the differences between these twofields of thought and their corresponding fields of being, the author undertakes an attempt atdescribing the absolute source of reality – imaginary-nothing. The attempt is accompanied bya presentation of the way in which the ineffable principle produces the Word, whose originalexpression is prattle. The article concludes with an analysis of fable as the original form of expressionof the imaginary-nothing, from which arise the two trunks of rationality mentionedabove: the ontological and the ontomythological.

  14. Conference on the role of biomethane in the energy transition in France and in Germany

    International Nuclear Information System (INIS)

    Reizine, Stanislas; Edel, Matthias; Theobald, Olivier; Pierre, Frederic; Mestrel, Jean Marc; Grope, Johan; Scholwin, Frank; Eberlein, Jens; Renard, Suzanne; Trommler, Marcus; Demeusy, Tatiana; Chapelat, Nicolas; Lefebvre, Mathieu

    2015-01-01

    The French-German office for Renewable energies (OFAEnR) organised a conference on the role of biomethane in the energy transition in France and in Germany. In the framework of this French-German exchange of experience, about 110 participants exchanged views on the status of the legal framework and of the development of biomethane industry in the French and German energy transitions. This document brings together the available presentations (slides) made during this event: 1 - Biomethane injection in France - elaboration and implementation of the price structure (Stanislas Reizine); 2 - Biomethane framework conditions in Germany 3 - German Road-map for Biomethane (Matthias Edel); 4 - A vision for biomethane in France in 2030 - purified biogas injection in the natural gas network (Olivier Theobald); 5 - Biomethane produced by the Strasbourg-la Wantzenau waste water plant and injected into the GDS natural gas network (Frederic Pierre); 6 - Biomethane fuel in Lille city: 1995-2015 100% clean and renewable energy in transportation (Jean Marc Mestrel); 7 - Biomethane from organic waste and its utilisation (Johan Grope); 8 - Marketing of Biomethane to end consumers (Jens Eberlein); 9 - Developing new approaches to promote injection into the grid (Suzanne Renard); 10 - Demand driven power supply from Bioenergy - a balancing option for power distribution networks (Marcus Trommler); 11 - Flexible biogas production and its integration to power and gas grids (Tatiana Demeusy); 12 - A partnership for the development of Agricultural methanization plants around a single injection point (Nicolas Chapelat); 13 - Keynotes: biomethane development paths to favour (Mathieu Lefebvre)

  15. Gazettes sous influence : le Courrier du Bas-Rhin, la Gazette des Deux-Ponts et les sujets touchant la Russie vers 1770

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    Georges Dulac

    2016-11-01

    Full Text Available Vers 1770, la campagne anti-russe du gouvernement français tend à dégrader l’image de la Russie, ce qui lèse gravement ses intérêts, notamment quand elle doit emprunter pour financer la guerre avec la Turquie. Aussi le prince Dmitri Alexeevitch Golitsyn, ministre plénipotentiaire à La Haye, se montre-t-il alors très actif sur ce terrain. Sa correspondance avec Pétersbourg témoigne de ses efforts, aux effets inégaux, pour influer sur les informations diffusées par quelques journaux : principalement le Courrier du Bas-Rhin, publié par Jean Manzon à Trèves, sous contrôle prussien, et dans une moindre mesure les deux Gazettes des Deux-Ponts, l’une politique, l’autre littéraire. Le journaliste de Trèves, qui trouve son intérêt à prendre le parti de la Russie, met en œuvre en sa faveur un discours journalistique abondant et parfois très élaboré. Cependant, la ligne du journal subit des fluctuations sensibles, selon l’évolution de la situation et à la suite de diverses interventions, dont celles du roi de Prusse et d’autre part de Stanislas-Auguste, qui pensionne un temps le journaliste. La Gazette des deux Ponts pratique l’information orientée avec plus de finesse, et, comme la gazette littéraire, accorde une large place à la matière russe : mais sur le plan politique, son traitement reste le plus souvent sous influence française et répond rarement aux vœux de D. A. Golitsyn.

  16. Teorizações cognitivas sobre o processamento da leitura: contribuições das neurociências

    Directory of Open Access Journals (Sweden)

    Josa Coelho da Silva Irigoite

    2012-09-01

    Full Text Available http://dx.doi.org/10.5007/1984-8420.2012v13n3p106 As recentes descobertas das neurociências vêm respondendo muitas questões sobre a biologia do homem que o deixam apto para a aprendizagem da leitura e da escrita. As teorizações do psicólogo cognitivista Stanislas Dehaene (2012 sobre o ato de ler são exemplos disso e podem contribuir para as atividades escolares de leitura, sobretudo na fase de alfabetização. Esta resenha traz as principais descobertas desse estudioso, apresentadas na obra recém traduzida no Brasil, Os neurônios da leitura: como a ciência explica a nossa capacidade de ler. Nesse trabalho, o autor esmiúça o “mágico” processo da leitura, desde a decodificação até a atribuição de sentidos, trazendo a hipótese da reciclagem neuronial para explicar a aprendizagem dessa habilidade. Além disso, aponta uma região específica da leitura no cérebro, a occípito-temporal ventral esquerda, e descreve detalhadamente as características da leitura bem como o mecanismo cerebral em tal processo. Trata-se de um estudo cognitivo completo e detalhado sobre o processo da leitura, que merece ser conhecido pelos professores que trabalham com leitura em sala de aula, sobretudo os alfabetizadores.

  17. Lucas–Kanade fluid trajectories for time-resolved PIV

    International Nuclear Information System (INIS)

    Yegavian, Robin; Leclaire, Benjamin; Illoul, Cédric; Losfeld, Gilles; Champagnat, Frédéric

    2016-01-01

    We introduce a new method for estimating fluid trajectories in time-resolved PIV. It relies on a Lucas–Kanade paradigm and consists in a simple and direct extension of a two-frame estimation with FOLKI-PIV (Champagnat et al 2011 Exp. Fluids 50 1169–82). The so-called Lucas–Kanade Fluid Trajectories (LKFT) are assumed to be polynomial in time, and are found as the minimizer of a global functional, in which displacements are sought so as to match the intensities of a series of images pairs in the sequence, in the least-squares sense. All pairs involve the central image, similar to other recent time-resolved approaches (FTC (Lynch and Scarano 2013 Meas. Sci. Technol . 24 035305) and FTEE (Jeon et al 2014 Exp. Fluids 55 1–16)). As switching from a two-frame to a time-resolved objective simply amounts to adding terms in a functional, no significant additional algorithmic element is required. Similar to FOLKI-PIV the method is very well suited for GPU acceleration, which is an important feature as computational complexity increases with the image sequence size. Tests on synthetic data exhibiting peak-locking show that increasing the image sequence size strongly reduces both associated bias and random error, and that LKFT has a remaining total error comparable to that of FTEE on this case. Results on case B of the third PIV challenge (Stanislas et al 2008 Exp. Fluids 45 27–71) also show its ability to drastically reduce the error in situations with low signal-to-noise ratio. These results are finally confirmed on experimental images acquired in the near-field of a low Reynolds number jet. Strong reductions in peak-locking, spatial and temporal noise compared to two-frame estimation are also observed, on the displacement components themselves, as well as on spatial or temporal derivatives, such as vorticity and material acceleration. (paper)

  18. Systemic inflammatory response syndrome and model for end-stage liver disease score accurately predict the in-hospital mortality of black African patients with decompensated cirrhosis at initial hospitalization: a retrospective cohort study

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    Mahassadi AK

    2018-04-01

    Full Text Available Alassan Kouamé Mahassadi,1 Justine Laure Konang Nguieguia,1 Henriette Ya Kissi,1 Anthony Afum-Adjei Awuah,2 Aboubacar Demba Bangoura,1 Stanislas Adjeka Doffou,1 Alain Koffi Attia1 1Medicine and Hepatogastroenterology Unit, Centre Hospitalier et Universitaire de Yopougon, Abidjan, Côte d’Ivoire; 2Kumasi Centre for Collaborative Research in Tropical Medicine, Kumasi, Ghana Background: Systemic inflammatory response syndrome (SIRS and model for end-stage liver disease (MELD predict short-term mortality in patients with cirrhosis. Prediction of mortality at initial hospitalization is unknown in black African patients with decompensated cirrhosis.Aim: This study aimed to look at the role of MELD score and SIRS as the predictors of morbidity and mortality at initial hospitalization.Patients and methods: In this retrospective cohort study, we enrolled 159 patients with cirrhosis (median age: 49 years, 70.4% males. The role of Child–Pugh–Turcotte (CPT score, MELD score, and SIRS on mortality was determined by the Kaplan–Meier method, and the prognosis factors were assessed with Cox regression model.Results: At initial hospitalization, 74.2%, 20.1%, and 37.7% of the patients with cirrhosis showed the presence of ascites, hepatorenal syndrome, and esophageal varices, respectively. During the in-hospital follow-up, 40 (25.2% patients died. The overall incidence of mortality was found to be 3.1 [95% confidence interval (CI: 2.2–4.1] per 100 person-days. Survival probabilities were found to be high in case of patients who were SIRS negative (log-rank test= 4.51, p=0.03 and in case of patients with MELD score ≤16 (log-rank test=7.26, p=0.01 compared to the patients who were SIRS positive and those with MELD score >16. Only SIRS (hazard ratio (HR=3.02, [95% CI: 1.4–7.4], p=0.01 and MELD score >16 (HR=2.2, [95% CI: 1.1–4.3], p=0.02 were independent predictors of mortality in multivariate analysis except CPT, which was not relevant in our study

  19. Proceedings of the 2013 Valence international secondary school meetings

    International Nuclear Information System (INIS)

    2013-03-01

    (Nantes (FR)); - Hospital wastes and the protection of sewer maintenance personnel (Lycee Saint Stanislas (Nantes (FR)); - Nuclear and radiation protection training courses (Eric Liatard - UJF); - Nuclear and radiation protection training courses (Paul Livolsi - CEA INSTN); - Advanced nuclear technologies and nuclear fear: scientific, technological, political, economical and social aspects (Lycee Prometeu-Prim (Moldavia)); - Philosophical playlets (Lycee Notre-Dame (Boulogne-Billancourt (FR)); - Radiation protection at the regional level and economic profitability: the bases of a friendly agreement (Lycee de l'Academie des Sciences - Chisinau (Moldavia)) - Use of radiations by customs (Lycee Marie Curie (Echirolles (FR)); - What is tritium and how to be efficiently protected against it? (Lycee Marie Curie (Echirolles (FR))

  20. The earliest phases of the parish church of Saint Margaret and Saint Stanislaus in Żębocin

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    Sławomir Dryja

    2012-12-01

    Full Text Available The paper has been based on archaeological and architectural exploration of the church in Żębocin carried out in 2011. Żębocin, a village in the Miechów district and the Proszowice deanery, had its beginnings reportedly in the mid-11th century. However, the first squire of Żębocin documented in historical sources was Tomko, coat of arms unknown, mentioned in 1384. According to tradition, the first church in the village, which has not survived, was built in the years 1059–1071 and consecrated by St. Stanislas of Szczepanów. In a local legend, the wife of knight Mikołaj of Żębocin took shelter in the tower of a stone church in Żębocin during the unrest in the reign of Boleslaus the Brave. The stone foundation under the north-eastern corner of the chancel belonged probably to a stone building, its function unknown, which may have stood there already in those turbulent times. The extant church, erected in the mid-13th century or soon afterwards, was a small single-nave structure with a chancel closed with a straight wall, built from bricks (with a wendian bond pattern on its elevation on stone foundations. It combined two styles: Romanesque (as shown by the surviving splayed window in the northern elevation of the chancel and Gothic (the brick ogival frame in the northern elevation of the nave. The important question whether the church had a tower from the start and where that tower was located remains undecided; the tower could have been incorporated into the body of the nave from the west or built above the chancel; it could also have been added afterwards, in the 16th century at the latest. Reportedly, the church in Żębocin once had a defensive character and was located in knights’ fortified town. Its founder may have been a progenitor of the Strzemieńczyk or the Odrowąż families. It should be remembered that Romanesque single-nave “village” churches built on a simple plan are quite frequent in Central Europe; there are

  1. HCVerso1 and 2: faldaprevir with deleobuvir (BI 207127 and ribavirin for treatment-naïve patients with chronic hepatitis C virus genotype-1b infection

    Directory of Open Access Journals (Sweden)

    Sarrazin C

    2016-11-01

    Full Text Available Christoph Sarrazin,1 Francesco Castelli,2 Pietro Andreone,3 Maria Buti,4 Massimo Colombo,5 Stanislas Pol,6 Filipe Calinas,7 Massimo Puoti,8 Antonio Olveira,9 Mitchell Shiffman,10 Jerry O Stern,11 George Kukolj,12 Michael Roehrle,13 Stella Aslanyan,11 Qiqi Deng,11 Richard Vinisko,11 Federico J Mensa,11 David R Nelson,14 on behalf of the HCVerso1 and 2 study groups 1Department of Internal Medicine 1, JW Goethe University Hospital, Frankfurt, Germany; 2Department of Infectious and Tropical Diseases, University of Brescia, Brescia, 3Department of Medical and Surgical Sciences, Università di Bologna and Azienda Ospedaliero-Universitaria, Policlinico Sant‘Orsola-Malpighi, Bologna, Italy; 4Department of Internal Medicine, Hospital Universitari Vall d’Hebron and CIBERehd del Instituto Carlos III, Barcelona, Spain; 5Division of Gastroenterology and Hepatology, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy; 6University Paris Descartes, Department of Hepatology, Hospital Cochin, APHP and INSERM UMS-20, Institut Pasteur, Paris, France; 7Department of Gastroenterology, Centro Hospitalar de Lisboa Central, Lisbon, Portugal; 8Department of Infectious Diseases, AO Ospedale Niguarda Cà Granda, Milan, Italy; 9Liver Unit, Hospital Universitario La Paz, CIBERehd, Madrid, Spain; 10Liver Institute of Virginia, Bon Secours Health System, Richmond, VA, USA; 11Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT, USA; 12Boehringer Ingelheim Ltd/Ltée, Burlington, ON, Canada; 13Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany; 14Clinical and Translational Science Institute, University of Florida, Gainesville, FL, USA Abstract: The interferon-free combination of once-daily faldaprevir 120 mg, twice-daily deleobuvir 600 mg, and weight-based ribavirin was evaluated in two Phase III studies (HCVerso1, HCVerso2 in hepatitis C virus genotype-1b-infected, treatment-naïve patients, including

  2. Pharmacokinetics and safety of DTS-108, a human oligopeptide bound to SN-38 with an esterase-sensitive cross-linker in patients with advanced malignancies: a Phase I study

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    Coriat R

    2016-11-01

    Full Text Available Romain Coriat,1 Sandrine J Faivre,2 Olivier Mir,3 Chantal Dreyer,2 Stanislas Ropert,3 Mohammed Bouattour,2 Robert Desjardins,4 François Goldwasser,3 Eric Raymond5 1Gastroenterology and Digestive Oncology Unit, Cochin Teaching Hospital, Université Paris Descartes Sorbonne Paris Cité, Paris, 2Department of Medical Oncology, Beaujon Teaching Hospital, Université Paris Diderot, Paris 7, Clichy, 3Department of Medical Oncology, Cochin Teaching Hospital, Université Paris Descartes Sorbonne Paris Cité, Paris, France; 4Drais Pharmaceuticals, Bridgewater, NJ, USA; 5Groupe Hospitalier Paris Saint-Joseph, Paris, France Background: DTS-108 is a hydrosoluble prodrug, where the SN-38 moiety is covalently linked to a 20-amino acid vector peptide by a specific esterase-sensitive cross-linker, releasing 7-ethyl-10-hydroxycampthotecin (SN-38 by esterase bond cleavage. Methods: The pharmacokinetics of DTS-108, adverse events graded according to NCI-CTCv3.1, dose-limiting toxicities at cycle 1, the maximum tolerated dose (MTD, and the recommended Phase II dose (RP2D of intravenous DTS-108 (1–2 hours every 2 weeks were evaluated in a first-in-human Phase I study in patients with advanced/metastatic carcinomas, according to an accelerated dose escalation design. SN-38 and SN-38 glucuronide (SN-38G levels were evaluated with fluorescence high-performance liquid chromatography (HPLC test, then liquid chromatography–tandem mass spectrometry (LC/MS/MS methods. Results: Forty-two patients received DTS-108 across 14 dosing cohorts (range 3–416 mg/m2. At 416 mg/m2, three out of six patients had grade 4 neutropenia thereby defining the MTD and the RP2D at 313 mg/m2. Fluorescence HPLC was inaccurate to quantify DTS-108 and its metabolites (SN-38 and SN-38G. New processes and analytical LC/MS/MS methods for testing SN-38 were implemented. At a dose of 313 mg/m2, mean DTS-108, SN-38, and SN-38G area under the plasma concentration–time curve to infinity