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51 results on '"MESH: Polyethylene Glycols"'

1. PEGylated Protamine Letrozole Nanoparticles: A Promising Strategy to Combat Human Breast Cancer via MCF-7 Cell Lines

Author

Muhammad Tafhim Khan, Zia Uddin, Muhammad Arslan Javed, Nabi Shah, Hamid Bashir, Ahson Jabbar Shaikh, Muhammad Shahid Riaz Rajoka, Muhammad Imran Amirzada, Muhammad Hassham Hassan Bin Asad, Institut de neurophysiopathologie (INP), and Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Article Subject, Breast Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, General Biochemistry, Genetics and Molecular Biology, Polyethylene Glycols, Humans, Protamines, MESH: Particle Size, Particle Size, Drug Carriers, MESH: Humans, General Immunology and Microbiology, technology, industry, and agriculture, MESH: Protamines, General Medicine, MESH: MCF-7 Cells, MESH: Drug Carriers, MESH: Polyethylene Glycols, MESH: Letrozole, Letrozole, MCF-7 Cells, Nanoparticles, Female, MESH: Female, MESH: Breast Neoplasms, MESH: Nanoparticles
Abstract

The objective of the study was to develop PEGylated protamine letrozole nanoparticles to combat human breast cancer by modifying the release pattern of letrozole. Breast cancer is amongst the most prevalent diseases in women due to overactivity of human epidermal growth factor receptor 2 (HER2). PEG-protamine letrozole nanoparticle formulation was designed and optimized to alter the release pattern of the drug. The size, morphology, and structure of PEG-protamine letrozole NP were characterized by FTIR, XRD, Zetasizer, and SEM analysis. The result showed the PEG-protamine letrozole nanoparticles were irregular in shape and have size ranging from 258 nm to 388 nm, polydispersity index 0.114 to 0.45, zeta potential of 11.2 mV, and entrapment efficiency 89.93%. XRD studies have confirmed that the crystal structure of letrozole has become amorphous. The drug release study maintained the prolonged release for 72 hours. Moreover, the PEG-protamine letrozole NPs displayed a strong anticancer action compared to MCF-7 cells with an IC50 70 μM for letrozole and 50 μM for PEG-protamine letrozole NPs. Overall, our results indicate that letrozole PEG-protamine NPs alter the release profile of letrozole, which could be an excellent approach for overcoming letrozole resistance in human breast cancer.

Published
2022
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2. Intérêts du polyetheretherketone en odontologie prothétique

Author

Polycarpe, Marjorie, Aix-Marseille Université - Faculté des sciences médicales et paramédicales (AMU SMPM), Aix Marseille Université (AMU), and Frédéric Silvestri

Subjects
MESH: Matériaux dentaires, MESH: Cétones, Odontologie prothétique, PEEK, Implantologie, Matériaux, MESH: Prothèses dentaires, [SDV.MHEP.CHI]Life Sciences [q-bio]/Human health and pathology/Surgery, MESH: Polyéthylène glycols
Abstract

Currently, new biomaterials are appearing in dentistry. Polyetheretherketone (PEEK), first used in the aerospace industry and then widely used in the medical field, particularly in orthopedic surgery, is trying to make a place in prosthetic dentistry. This work presents, in a first part, the different chemical, thermal, mechanical and biocompatibility properties that make this material interesting for a clinical application in dentistry. The second part presents the use of PEEK in the different fields of prosthetic dentistry whichare implantology (implant, abutment, healing screw...), joint prosthesis and removable prosthesis (partial and complete). The application protocols and the contribution of computeraided design and manufacture are discussed. The third part proposes a discussion of this material and its possibility of development in the field of dentistry.; Actuellement, de nouveaux biomatériaux font leur apparition en odontologie. Le polytheretherketone (PEEK) tout d’abord utilisé dans l’industrie aérospatiale puis largement répandue dans le domaine médical notamment dans les chirurgies orthopédiques, tente de se faire une place en odontologie prothétique. Ce travail présente, dans une première partie, les différentes propriétés chimiques, thermiques, mécaniques et de biocompatibilité qui rendent ce matériau intéressant pour une application clinique en odontologie. La deuxième partie présente l’utilisation du PEEK dans les différents domaines de l’odontologie prothétique que sont l’implantologie (implant, pilier, vis de cicatrisation…), prothèse conjointe et prothèse adjointe (partielle et complète). Les protocoles de mise en œuvre ainsi que l’apport de la conception-fabrication assistée par ordinateur y sont évoqués. La troisième partie propose une discussion autour de ce matériau et ses perspectives de développement dans le domaine de l’odontologie.

Published
2020

3. Investigation of cationized triblock and diblock poly(ε-caprolactone)-co-poly(ethylene glycol) copolymers for oral delivery of enoxaparin: In vitro approach

Author

Anne Sapin-Minet, Philippe Maincent, Pimchanok Charoongchit, Jiraphong Suksiriworapong, Shirui Mao, Varaporn Buraphacheep Junyaprasert, Siriraj Hospital, Mahidol University, Mahidol University [Bangkok], Shenyang Pharmaceutical University, Cibles thérapeutiques, formulation et expertise pré-clinique du médicament (CITHEFOR), and Université de Lorraine (UL)

Subjects
Poly(ε-carprolactone)-co-poly(ethylene glycol) copolymers, MESH: Cell Death, Cell Membrane Permeability, [SDV]Life Sciences [q-bio], Administration, Oral, Nanoparticle, Polymer architecture, 02 engineering and technology, 01 natural sciences, Biochemistry, Polyethylene Glycols, Cationic copolymer, chemistry.chemical_compound, Drug Delivery Systems, Copolymer, MESH: Cell Membrane Permeability, [PHYS]Physics [physics], Cell Death, Temperature, Biomaterial, General Medicine, 021001 nanoscience & nanotechnology, MESH: Polyesters, MESH: Temperature, Oral delivery, MESH: Administration, Oral, MESH: Caco-2 Cells, 0210 nano-technology, Caprolactone, Biotechnology, MESH: Enoxaparin, Materials science, Surface Properties, Polyesters, MESH: Drug Delivery Systems, Biomedical Engineering, MESH: Imaging, Three-Dimensional, 010402 general chemistry, Biomaterials, Imaging, Three-Dimensional, Cations, PEG ratio, Polymer chemistry, Humans, MESH: Drug Liberation, [CHIM]Chemical Sciences, MESH: Particle Size, Particle Size, Enoxaparin, MESH: Cations, Molecular Biology, MESH: Surface Properties, MESH: Humans, Cationic polymerization, 0104 chemical sciences, Drug Liberation, MESH: Polyethylene Glycols, chemistry, Nanoparticles, Caco-2 Cells, Ethylene glycol, Nuclear chemistry
Abstract

In this study, poly( e -caprolactone)-co-poly(ethylene glycol) copolymers grafted with a cationic ligand, propargyltrimethyl ammonium iodide (PTA), to fabricate the cationized triblock (P(CatCLCL) 2 -PEG) and diblock (P(CatCLCL)-mPEG) copolymers were investigated their potential use for oral delivery of enoxaparin (ENX). Influences of various PTA contents and different structures of the copolymers on molecular characteristics, ENX encapsulation, particle characteristics, and capability of drug transport across Caco-2 cells were elucidated. The results showed that P(CatCLCL) 2 -PEG and P(CatCLCL)-mPEG copolymers self-aggregated and encapsulated ENX into spherical particles of ∼200–450 nm. The increasing amount of PTA on the copolymers increased encapsulation efficiency of over 90%. The ENX release from both types of the cationized copolymer particles was pH-dependent which was retarded at pH 1.2 and accelerated at pH 7.4, supporting the drug protection in the acidic environment and possible release in the blood circulation. The toxicity of ENX-loaded particles on Caco-2 cells decreased when decreasing the amount of PTA. The triblock and diblock particles dramatically enhanced ENX uptake and transport across Caco-2 cells as compared to the ENX solution. However, the different structures of the copolymers slightly affected ENX transport. These results suggested that P(CatCLCL) 2 -PEG and P(CatCLCL)-mPEG copolymers would be potential carriers for oral delivery of ENX. Statement of Significance The anionic drugs such as proteins, peptides or polysaccharides are generally administered via invasive route causing patient incompliance and high cost of hospitalization. The development of biomaterials for non-invasive delivery of those drugs has gained much attention, especially for oral delivery. However, they have limitation due to non-biocompatibility and poor drug bioavailability. In this study, the novel poly( e -caprolactone)-co-poly(ethylene glycol) copolymers grafted with propargyltrimethyl ammonium iodide, a small cationic ligand, were introduced to use as a carrier for oral delivery of enoxaparin, a highly negatively charged drug. The study showed that these cationized copolymers could achieve high enoxaparin entrapment efficiency, protect drug release in an acidic environment and enhance enoxaparin permeability across Caco-2 cells, the intestinal cell model. These characteristics of the cationized copolymers make them a potential candidate for oral delivery of anionic drugs for biomaterial applications.

Published
2017

4. Poly ethylene glycol (PEG)-Related controllable and sustainable antidiabetic drug delivery systems

Author

Ding Ying, Jiang Liu, Litao Zhang, Peng Yu, Yongmin Zhang, Yupeng Fu, Tianjin University of Science and Technology (TUST), Institut Parisien de Chimie Moléculaire (IPCM), Chimie Moléculaire de Paris Centre (FR 2769), Institut de Chimie du CNRS (INC)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Chimie du CNRS (INC)-École normale supérieure - Paris (ENS Paris), and Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Poly ethylene glycol, MESH: Diabetes Mellitus, Biocompatibility, MESH: Drug Delivery Systems, MESH: Molecular Structure, Nanotechnology, macromolecular substances, Polyethylene glycol, stimulating responsive release, 01 natural sciences, Micelle, Polyethylene Glycols, 03 medical and health sciences, chemistry.chemical_compound, Drug Delivery Systems, MESH: Hypoglycemic Agents, Drug Discovery, PEG ratio, Diabetes Mellitus, Humans, Hypoglycemic Agents, drug delivery system, sustainable release, Therapy efficacy, Micelles, 030304 developmental biology, Pharmacology, Drug Carriers, 0303 health sciences, MESH: Humans, Molecular Structure, antidiabetic, 010405 organic chemistry, Chemistry, Organic Chemistry, MESH: Micelles, technology, industry, and agriculture, General Medicine, [SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences, PEG, 0104 chemical sciences, 3. Good health, MESH: Drug Carriers, MESH: Polyethylene Glycols, Drug delivery, Self-healing hydrogels
Abstract

International audience; Diabetes mellitus is one of the most challenging threats to global public health. To improve the therapy efficacy of antidiabetic drugs, numerous drug delivery systems have been developed. Polyethylene glycol (PEG) is a polymeric family sharing the same skeleton but with different molecular weights which is considered as a promising material for drug delivery. In the delivery of antidiabetic drugs, PEG captures much attention in the designing and preparation of sustainable and controllable release systems due to its unique features including hydrophilicity, biocompatibility and biodegradability. Due to the unique architecture, PEG molecules are also able to shelter delivery systems to decrease their immunogenicity and avoid undesirable enzymolysis. PEG has been applied in plenty of delivery systems such as micelles, vesicles, nanoparticles and hydrogels. In this review, we summarized several commonly used PEG-contained antidiabetic drug delivery systems and emphasized the advantages of stimuli-responsive function in these sustainable and controllable formations.

Published
2021

5. Freeze drying of polyelectrolyte complex nanoparticles: Effect of nanoparticle composition and cryoprotectant selection

Author

Carlos Medina, Lidia Tajber, Anita Umerska, Maria Jose Santos-Martinez, Krzysztof J. Paluch, Owen I. Corrigan, Cibles thérapeutiques, formulation et expertise pré-clinique du médicament (CITHEFOR), Université de Lorraine (UL), Trinity College Dublin, and University of Bradford

Subjects
MESH: Chondroitin Sulfates, MESH: Freeze Drying, [SDV]Life Sciences [q-bio], Pharmaceutical Science, Nanoparticle, Protamine, 02 engineering and technology, 030226 pharmacology & pharmacy, Polyethylene Glycols, Chitosan, Freeze-drying, chemistry.chemical_compound, Cryoprotective Agents, 0302 clinical medicine, Protamines, Hyaluronic Acid, [PHYS]Physics [physics], Coacervate, Chemistry, Chondroitin Sulfates, MESH: Cryoprotective Agents, 021001 nanoscience & nanotechnology, Polyelectrolyte, MESH: Chitosan, MESH: Cell Survival, MESH: Caco-2 Cells, 0210 nano-technology, Chondroitin, MESH: Trehalose, Cryoprotectant, Cell Survival, macromolecular substances, 03 medical and health sciences, PEG ratio, Humans, [CHIM]Chemical Sciences, MESH: Humans, Polyelectrolyte complex nanoparticle, MESH: Hyaluronic Acid, technology, industry, and agriculture, Trehalose, MESH: Protamines, Hyaluronate, Chemical engineering, MESH: Polyethylene Glycols, Freeze drying, Nanoparticles, Caco-2 Cells, Ethylene glycol, MESH: Nanoparticles
Abstract

International audience; This work investigates the impact of nanoparticle (NP) composition and effectiveness of cryo-/lyo-protectants in a freeze drying process, which was employed to convert liquid dispersions of polyelectrolyte complex (PEC) NPs into completely redispersible powders. PEC NPs, with and without peptide, were produced by complex coacervation. The cryo-/lyo-protectants investigated were mannitol, trehalose (TRE) and poly(ethylene glycol) (PEG). The solid state of lyophilised powders was studied by thermal analysis and X-ray diffraction. Cytotoxicity studies were done by MTS assay and flow cytometry. The presence of a cryoprotectant was essential to achieve a successful powder reconstitution. The concentration of TRE was optimised for each type of PEC NPs. Protamine- and hyaluronate-based NPs reconstituted better than chitosan- and chondroitin sulphate-based NPs, respectively. PEG polymers were found to be more effective cryoprotectants than TRE and best results were achieved using co-freeze drying of NPs with TRE and PEG. These ternary NPs/TRE/PEG samples were crystalline, with expected better storage stability. PEG polymers were well tolerated by Caco-2 cells, with the exception of linear PEG 10 kDa. This work shows that, as regards the formulation design and maximising NP loading in the dried product, optimisation of the cryoprotectant type and content is needed as it is highly dependent not only on the type of polyelectrolyte pair in the PEC, but also the polyions ratio.

Published
2018

6. Self-aggregation of cationically modified poly( ε -caprolactone) 2 - co -poly(ethylene glycol) copolymers: Effect of cationic grafting ligand and poly( ε -caprolactone) chain length

Author

Varaporn Buraphacheep Junyaprasert, Pimchanok Charoongchit, Anne Sapin-Minet, Philippe Maincent, Kittisak Sripha, Shirui Mao, Jiraphong Suksiriworapong, Department of Pharmacy, Faculty of Pharmacy, Mahidol University, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Mahidol University, School of Pharmacy, Shenyang Pharmaceutical University, Cibles thérapeutiques, formulation et expertise pré-clinique du médicament (CITHEFOR), and Université de Lorraine (UL)

Subjects
Poly(ε-caprolactone)-co-poly(ethylene glycol), MESH: Hydrogen-Ion Concentration, Materials science, MESH: Pharmaceutical Preparations, [SDV]Life Sciences [q-bio], Bioengineering, 02 engineering and technology, 010402 general chemistry, 01 natural sciences, MESH: Spectroscopy, Fourier Transform Infrared, Cationic copolymer, Biomaterials, Self-aggregation, MESH: Transition Temperature, chemistry.chemical_compound, MESH: Osmolar Concentration, PEG ratio, Polymer chemistry, Zeta potential, Copolymer, MESH: Ligands, [CHIM]Chemical Sciences, MESH: Particle Size, MESH: Cations, chemistry.chemical_classification, [PHYS]Physics [physics], Particle properties, Click chemistry, MESH: Magnetic Resonance Spectroscopy, MESH: Molecular Weight, MESH: Calorimetry, Differential Scanning, Cationic polymerization, Polymer, 021001 nanoscience & nanotechnology, MESH: Polyesters, 0104 chemical sciences, MESH: Drug Carriers, chemistry, MESH: Polyethylene Glycols, Mechanics of Materials, Particle size, 0210 nano-technology, Caprolactone, Ethylene glycol
Abstract

International audience; Cationic copolymers have been attractive to investigate due to their potential to complexation with anionic drugs and expected to use in the pharmaceutical application. In this study, the modified poly(ε-caprolactone)2-co-poly(ethylene glycol) copolymers (P(CL)2-PEG) were successfully synthesized by click reaction. The amount of small molecular cationic ligand, propargyltrimethyl ammonium iodide, was varied and grafted onto various mole ratios of P(CL) to PEG. The effects of P(CL) chain length and amount of the grafting cationic ligand on physicochemical properties of polymers and particles were studied. The number-average molecular weights of the copolymers grafted with cationic ligand were found ranging between 10,000 and 23,000g/mol as investigated by NMR. From DSC study, the results showed that the grafting ligand affected thermal behaviors of the copolymers by increasing the glass transition temperature and decreasing the melting temperature of the copolymers. Furthermore, these cationic copolymers could self-aggregate with their critical aggregation concentration depending on mole ratios of hydrophilic to hydrophobic portions. The particles containing higher amounts of the cationic ligand tended to aggregate in both acidic and basic pH environment and at high salt concentration. Additionally, particle size, size distribution (PdI), and morphology of self-assembling particles varied depending on P(CL) chain length and the amount of the grafting cationic ligand. The synthesized cationic copolymer showed a capability to encapsulate a high negatively charged drug, enoxaparin, with an encapsulation efficiency of 87%. After drug incorporation, the particles substantially changed in size, shape, PdI, and zeta potential to become more suitable for drug delivery. These cationic copolymers with flexible properties will be the candidate for further development as carriers for the delivery of negatively charged drugs.

Published
2017

7. Potency, safety, and pharmacokinetics of the NS3/4A protease inhibitor BI201335 in patients with chronic HCV genotype-1 infection

Author

Christian Trepo, Michael P. Manns, David Wright, Jose Luis Calleja, Peter W. White, Chan-Loi Yong, Stanislas Pol, George Kukolj, Jerry O. Stern, Marc Bourlière, Maurizio Bonacini, Thomas Berg, Wulf Otto Boecher, Yves Benhamou, Gerhard G. Steinmann, Joe Scherer, Department of Gastroenterology, Hepatology and Endocrinology (MHH), Hannover Medical School [Hannover] (MHH), Hôpital saint joseph, Service d' Hépato-gastroentérologie, Service d'Hépato-Gastro-Entérologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service d'hépatologie médicale [CHU Cochin], Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), California Pacific medical research center institute, Pacific medical center, Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), IFR Laennec (IL), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Department of Psychiatry and Behavioural Neurosciences, McMaster University [Hamilton, Ontario]-Offord Centre for Child Studies, University Clinic, University Clinic, Leipzig, Hospital universitano Puerta de Hierro, hospital universitano puerta de hierro, Service d'Hépato-Gastroentérologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], CHU Cochin [AP-HP]-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Centre de Recherche en Cancérologie de Lyon (CRCL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Department of Gastroenterology, Hepatology and Endocrinology ( MHH ), Hannover Medical School [Hannover] ( MHH ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP], Institut Cochin ( UM3 (UMR 8104 / U1016) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Cochin [AP-HP], Centre de Recherche en Cancérologie de Lyon ( CRCL ), Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), IFR Laennec ( IL ), Institut National de la Recherche Agronomique ( INRA ) -Université Claude Bernard Lyon 1 ( UCBL ), and Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] ( UJM ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS )

Subjects
Male, Aminoisobutyric Acids, Hepacivirus, MESH : Viral Load, Viral Nonstructural Proteins, medicine.disease_cause, Gastroenterology, MESH : Hepacivirus, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, Polyethylene Glycols, MESH: Recombinant Proteins, chemistry.chemical_compound, 0302 clinical medicine, MESH : Thiazoles, Pegylated interferon, MESH : Female, MESH: Double-Blind Method, MESH: Hepacivirus, MESH : Viral Nonstructural Proteins, 0303 health sciences, MESH: Middle Aged, MESH: Protease Inhibitors, MESH: Drug Resistance, Viral, biology, MESH : Polyethylene Glycols, Intracellular Signaling Peptides and Proteins, MESH : Adult, Middle Aged, Viral Load, Hepatitis C, Recombinant Proteins, MESH : Antiviral Agents, 3. Good health, MESH : Drug Resistance, Viral, MESH: Oligopeptides, Quinolines, MESH : Interferon-alpha, Female, 030211 gastroenterology & hepatology, MESH : Carrier Proteins, MESH: Interferon-alpha, MESH: Viral Load, Oligopeptides, Viral load, medicine.drug, Pegylated Interferon Alfa, MESH : Oligopeptides, Adult, MESH: Antiviral Agents, medicine.medical_specialty, MESH : Protease Inhibitors, Proline, MESH : Recombinant Proteins, MESH : Male, Hepatitis C virus, MESH: Thiazoles, MESH: Carrier Proteins, [SDV.CAN]Life Sciences [q-bio]/Cancer, Interferon alpha-2, Antiviral Agents, 03 medical and health sciences, Double-Blind Method, Leucine, MESH: Ribavirin, Internal medicine, Drug Resistance, Viral, Ribavirin, medicine, MESH : Double-Blind Method, Humans, MESH : Middle Aged, Protease Inhibitors, Protease inhibitor (pharmacology), 030304 developmental biology, MESH: Hepatitis C, MESH: Humans, Hepatology, business.industry, MESH : Humans, Interferon-alpha, MESH: Adult, MESH : Hepatitis C, biology.organism_classification, MESH: Male, MESH : Ribavirin, Thiazoles, MESH: Polyethylene Glycols, chemistry, Faldaprevir, Immunology, MESH: Viral Nonstructural Proteins, Carrier Proteins, business, MESH: Female
Abstract

International audience; BACKGROUND & AIMS: BI201335 is a highly specific and potent HCV protease inhibitor. This multiple rising dose trial evaluated antiviral activity and safety in chronic HCV genotype-1 patients. METHODS: Thirty-four treatment-naïve patients were randomized to monotherapy with placebo or BI201335 at 20-240 mg once-daily for 14 days, followed by combination with pegylated interferon alfa/ribavirin (PegIFN/RBV) through Day 28. Nineteen treatment-experienced patients received 48-240 mg BI201335 once-daily with PegIFN/RBV for 28 days. HCV-RNA was measured with Roche COBAS TaqMan. RESULTS: In treatment-naïve patients, median maximal viral load (VL) reductions during 14-day monotherapy were -3.0, -3.6, -3.7, and -4.2 log(10) for the 20, 48, 120, and 240 mg groups. VL breakthroughs (≥1 log(10) from nadir) were seen in most patients on monotherapy and were caused by NS3/4A variants (R155K, D168V) conferring in vitro resistance to BI201335. Adding PegIFN/RBV at Days 15-28 led to continuous viral load reductions in most patients. In treatment-experienced patients, treatment with BI201335 and PegIFN/RBV achieved VL

Published
2011

8. Ribavirin in chronic hepatitis C: past and future

Author

Pierre Marquet, François Denis, Sophie Alain, Véronique Loustaud-Ratti, Annick Rousseau, Biologie moléculaire et cellulaire des microorganismes (EA3175), Université de Limoges (UNILIM)-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Bactériologie, Virologie, Hygiène [CHU Limoges], CHU Limoges, Pharmacologie des Immunosuppresseurs et de la Transplantation (PIST), Université de Limoges (UNILIM)-CHU Limoges-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université de Limoges (UNILIM)

Subjects
MESH: Antiviral Agents, Microbiology (medical), Hepacivirus, Treatment outcome, Alpha interferon, Antiviral Agents, Microbiology, MESH: Drug Synergism, Drug synergism, Polyethylene Glycols, chemistry.chemical_compound, Text mining, Chronic hepatitis, MESH: Drug Monitoring, MESH: Ribavirin, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Virology, Ribavirin, Humans, Medicine, MESH: Hepacivirus, ComputingMilieux_MISCELLANEOUS, MESH: Treatment Outcome, MESH: Humans, biology, business.industry, Interferon-alpha, Drug Synergism, Hepatitis C, Chronic, biology.organism_classification, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, MESH: Hepatitis C, Chronic, MESH: Drug Therapy, Combination, Treatment Outcome, Infectious Diseases, MESH: Polyethylene Glycols, chemistry, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Drug Therapy, Combination, Drug Monitoring, MESH: Interferon-alpha, business
Abstract

International audience

Published
2009

9. Treatment of hepatitis C-associated mixed cryoglobulinemia vasculitis

Author

Patrice Cacoub, Aurélien Delluc, J.C. Piette, David Saadoun, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Groupe d'Etude de la Thrombose de Bretagne Occidentale (GETBO), Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO), Département de Médecine Interne et Pneumologie [Brest] (DMIP - Brest), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Biologie et thérapeutique des pathologies immunitaires (BTPI), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Service de médecine interne [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Université de Brest (UBO)-Institut Brestois Santé Agro Matière (IBSAM)

Subjects
viruses, Fulminant, Gastroenterology, Polyethylene Glycols, MESH: Antibodies, Monoclonal, MESH: Recombinant Proteins, Antibodies, Monoclonal, Murine-Derived, 0302 clinical medicine, hemic and lymphatic diseases, B-Lymphocytes, MESH: Vasculitis, MESH: Immunologic Factors, Antibodies, Monoclonal, Glomerulonephritis, Hepatitis C, Cryoglobulinemia, Recombinant Proteins, MESH: Hepatitis C, Chronic, 3. Good health, Purpura, 030211 gastroenterology & hepatology, Rituximab, MESH: Interferon-alpha, medicine.symptom, Vasculitis, medicine.drug, MESH: Antiviral Agents, medicine.medical_specialty, MESH: Cryoglobulinemia, Alpha interferon, Interferon alpha-2, Antiviral Agents, 03 medical and health sciences, Rheumatology, MESH: Ribavirin, MESH: B-Lymphocytes, Internal medicine, Ribavirin, medicine, Humans, Immunologic Factors, 030203 arthritis & rheumatology, MESH: Humans, business.industry, Interferon-alpha, Hepatitis C, Chronic, medicine.disease, MESH: Polyethylene Glycols, MESH: Antibodies, Monoclonal, Murine-Derived, Immunology, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

International audience; PURPOSE OF REVIEW: Hepatitis C virus infection is the main cause of mixed cryoglobulinemia vasculitis. The disease expression of mixed cryoglobulinemia vasculitis is variable, ranging from mild clinical symptoms (purpura, arthralgia) to fulminant life-threatening complications (glomerulonephritis, widespread vasculitis). Treatment of hepatitis C virus-mixed cryoglobulinemia vasculitis may target either the viral trigger (hepatitis C virus) or the downstream B-cell arm of autoimmunity. This review focuses on recent advances in our understanding of the treatment of hepatitis C virus-mixed cryoglobulinemia vasculitis. RECENT FINDINGS: Aggressive antiviral therapy with Peg-IFNalpha and ribavirin should be considered as induction therapy for hepatitis C virus-mixed cryoglobulinemia vasculitis with mild to moderate disease severity and activity. In patients presenting with severe disease, an induction phase of immunosuppression is often necessary while awaiting the generally slow response to antiviral treatments. Combination therapy with rituximab and Peg-IFNalpha plus ribavirin appears logical as it may target both the viral trigger (hepatitis C virus) and cryoglobulin-producing B-cells. SUMMARY: Antiviral therapy and rituximab are the main therapeutic options in hepatitis C virus-mixed cryoglobulinemia vasculitis. Further studies are needed to better define the therapeutic strategy.

Published
2008

10. Water-Soluble Pegylated Quantum Dots: From a Composite Hexagonal Phase to Isolated Micelles

Author

Marie-Josèphe Brienne, Fouzia Boulmedais, Thierry Gacoin, Isabelle Arnal, Patrick Bauchat, Franck Artzner, Maxime Dahan, Valérie Marchi-Artzner, Institut des Sciences Chimiques de Rennes (ISCR), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Ecole Nationale Supérieure de Chimie de Rennes (ENSCR)-Centre National de la Recherche Scientifique (CNRS), Institut Charles Sadron (ICS), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Matériaux et nanosciences d'Alsace, Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Université de Strasbourg (UNISTRA)-Réseau nanophotonique et optique, Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Université de Strasbourg (UNISTRA), Interactions cellulaires et moléculaires (ICM), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS), Groupe matière condensée et matériaux (GMCM), Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Institut de Physique de Rennes (IPR), Laboratoire de physique de la matière condensée (LPMC), École polytechnique (X)-Centre National de la Recherche Scientifique (CNRS), Laboratoire Kastler Brossel (LKB (Lhomond)), Fédération de recherche du Département de physique de l'Ecole Normale Supérieure - ENS Paris (FRDPENS), École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Ecole Nationale Supérieure de Chimie de Rennes (ENSCR)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Chimie des interactions moléculaires (CIM), Centre National de la Recherche Scientifique (CNRS), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS), École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS-PSL), De Villemeur, Hervé, Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Ecole Nationale Supérieure de Chimie de Rennes (ENSCR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA), Université Pierre et Marie Curie - Paris 6 (UPMC)-Fédération de recherche du Département de physique de l'Ecole Normale Supérieure - ENS Paris (FRDPENS), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), and Centre National de la Recherche Scientifique (CNRS)-École polytechnique (X)

Subjects
[SDV]Life Sciences [q-bio], MESH: Molecular Structure, Aucun, Electrons, MESH: Spectrum Analysis, 02 engineering and technology, chemistry, 010402 general chemistry, 01 natural sciences, Micelle, Polyethylene Glycols, chemistry.chemical_compound, Microscopy, Electron, Transmission, Liquid crystal, Phase (matter), Quantum Dots, Amphiphile, MESH: Water, Electrochemistry, General Materials Science, Micelles, Spectroscopy, MESH: Electrons, Chromatography, Molecular Structure, Spectrum Analysis, MESH: Micelles, Hexagonal phase, Water, Mesophase, MESH: Quantum Dots, Surfaces and Interfaces, Gallate, 021001 nanoscience & nanotechnology, Condensed Matter Physics, Lipids, MESH: Lipids, 0104 chemical sciences, [CHIM.THEO]Chemical Sciences/Theoretical and/or physical chemistry, [SDV] Life Sciences [q-bio], MESH: Solubility, [CHIM.THEO] Chemical Sciences/Theoretical and/or physical chemistry, Solubility, MESH: Polyethylene Glycols, Chemical engineering, MESH: Microscopy, Electron, Transmission, 0210 nano-technology, Ethylene glycol
Abstract

We present a simple method based on the dispersion of fluorescent quantum dots (QD) into a liquid crystal phase that provides either nanostructured material or isolated QD micelles depending on water concentration. The liquid-crystal phase was obtained by using a gallate amphiphile with a poly(ethylene glycol) chain as the polar headgroup, named I. The hydration of QD/I mixtures resulted in the formation of a composite hexagonal phase identified by small-angle X-ray scattering and by polarized light and fluorescence optical microscopy, showing a homogeneous distribution of fluorescence within hexagonal phase. This composite mesophase can be converted into isolated QD-I micelles by dilution in water. The fluorescent QD-I micelles, purified by size exclusion chromatography, are well monodisperse with a hydrodynamic diameter of 20-30 nm. Moreover, these QD do not show any nonspecific adsorption on lipid or cell membranes. By simply adjusting the water content, the PEG gallate amphiphile I provides a simple method to prepare a self-organized composite phase or pegylated water soluble QD micelles for biological applications. journal article research support, non-u.s. gov't 2006 Nov 07 imported

Published
2006

11. Hyaluronic acid nanohydrogels as a useful tool for BSAO immobilization in the treatment of melanoma cancer cells

Author

Montanari, Elita, Capece, Sabrina, Di Meo, Chiara, Meringolo, Martina, Coviello, Tommasina, Agostinelli, Enzo, Matricardi, Pietro, Department of Drug Chemistry and Technologies, Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome], Department of Biochemical Sciences 'Rossi Fanelli', Institut Pasteur, Fondation Cenci Bolognetti - Istituto Pasteur Italia, Fondazione Cenci Bolognetti, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome], This work was financially supported by Sapienza University of Rome ‘‘Ricerche Universitarie’’ 2011, no. C26A119N2S (P.M.), by the Italian MIUR(Ministero dell’Istruzione, dell’Università e della Ricerca, and E.A.), by Istituto Superiore di Sanità a ‘‘Project Italy-USA’’ (E.A.), and byIstituto Pasteur-Fondazione Cenci Bolognetti (E.A.).

Subjects
MESH: Oxidation-Reduction, MESH: Cell Death, MESH: Cell Line, Tumor, MESH: Enzymes, Immobilized, MESH: Melanoma, [SDV]Life Sciences [q-bio], Static Electricity, Nanogels, [SDV.CAN]Life Sciences [q-bio]/Cancer, MESH: Polyethyleneimine, Hydrogel, Polyethylene Glycol Dimethacrylate, Polyethylene Glycols, MESH: Cholesterol, Cell Line, Tumor, Animals, Humans, Polyethyleneimine, MESH: Animals, MESH: Particle Size, Hyaluronic Acid, Particle Size, Melanoma, MESH: Static Electricity, MESH: Hydrogel, MESH: Humans, MESH: Hyaluronic Acid, Cell Death, Enzymes, Immobilized, MESH: Cattle, Cholesterol, MESH: Polyethylene Glycols, MESH: Amine Oxidase (Copper-Containing), Cattle, Amine Oxidase (Copper-Containing), Oxidation-Reduction
Abstract

International audience; An alternative anticancer therapy based on the use of bovine serum amine oxidase (BSAO), an enzyme that converts polyamines over-expressed in malignant cells, into hydrogen peroxide and aldehyde(s), thus inducing high cytotoxicity in cancer cells, was recently proposed. With the aim of improving the system efficacy by exploiting a nanotechnology approach, BSAO is covalently immobilized onto injectable nanohydrogels (NHs) based on cholesterol-graft-hyaluronic acid (HA-CH), a biocompatible conjugate that spontaneously leads to self-assembled structures in aqueous solutions. In this study, the physicochemical properties of the HA-CH-based NHs and the NHs cytocompatibility are reported. The properties of the NHs-BSAO system are also studied in terms of protein residual activity, both in vitro and on a model melanoma cell line.

Published
2013

12. Continuous versus intermittent treatment strategies during primary HIV-1 infection: the randomized ANRS INTERPRIM Trial

Author

Goujard, Cécile, Emilie, Dominique, Roussillon, Caroline, Godot, Véronique, Rouzioux, Chrisitine, Venet, Alain, Colin, Céline, Pialoux, Gilles, Girard, Pierre-Marie, Boilet, Valérie, Chaix, Marie-Laure, Galanaud, Pierre, Chene, Geneviève, Michelet, Christian, Service de médecine interne et maladies infectieuses, Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, Centre de recherche en épidémiologie et santé des populations (CESP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Cytokines, chimiokines et immunopathologie, Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM), Epidémiologie et Biostatistique [Bordeaux], Université Bordeaux Segalen - Bordeaux 2-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Virologie [CHU Necker], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Régulation de la réponse immune, infection VIH-1 et autoimmunité, Service des maladies infectieuses et tropicales [CHU Tenon], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Tenon [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Services des Maladies Infectieuses et Tropicales [CHU Saint-Antoine], CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut de recherche en santé, environnement et travail (Irset), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Institut National de la Santé et de la Recherche Médicale (INSERM)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Université d'Angers (UA), French National Agency forResearch on AIDS and ViralHepatitis (ANRS), ANRS-112 INTERPRIM Study Group, Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Tenon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université Paris-Sud - Paris 11 ( UP11 ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Bicêtre, Centre de recherche en épidémiologie et santé des populations ( CESP ), Université de Versailles Saint-Quentin-en-Yvelines ( UVSQ ) -Université Paris-Sud - Paris 11 ( UP11 ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Paris-Sud - Paris 11 ( UP11 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Bordeaux Segalen - Bordeaux 2-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale ( INSERM ), CHU Necker - Enfants Malades [AP-HP]-Assistance publique - Hôpitaux de Paris (AP-HP), Service des maladies infectieuses et tropicales, Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Tenon [APHP], Service des maladies infectieuses et tropicales [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Saint-Antoine [APHP], Institut de recherche, santé, environnement et travail ( Irset ), Université d'Angers ( UA ) -Université de Rennes 1 ( UR1 ), and Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -École des Hautes Études en Santé Publique [EHESP] ( EHESP ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ) -Université des Antilles ( UA )

Subjects
CD4-Positive T-Lymphocytes, Male, antiretroviral treatment, MESH : Viral Load, CD8-Positive T-Lymphocytes, Lymphocyte Activation, Polyethylene Glycols, MESH: HIV-1, MESH: Recombinant Proteins, 0302 clinical medicine, Pegylated interferon, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Immunology and Allergy, Medicine, MESH : Female, MESH : DNA, Viral, 030212 general & internal medicine, MESH: Anti-HIV Agents, MESH: Treatment Outcome, Response rate (survey), 0303 health sciences, MESH: Middle Aged, MESH : Acquired Immunodeficiency Syndrome, treatment interruption, MESH : Polyethylene Glycols, virus diseases, MESH: CD4-Positive T-Lymphocytes, interferon, MESH: Follow-Up Studies, Middle Aged, Viral Load, MESH : Adult, MESH : CD8-Positive T-Lymphocytes, MESH: CD8-Positive T-Lymphocytes, Recombinant Proteins, 3. Good health, [ SDV.MHEP.MI ] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Treatment Outcome, Infectious Diseases, MESH : CD4-Positive T-Lymphocytes, primary infection, MESH : Interferon-alpha, Female, MESH: Interferon-alpha, MESH: Viral Load, Viral load, MESH : HIV-1, medicine.drug, Adult, Cart, medicine.medical_specialty, Anti-HIV Agents, MESH : Recombinant Proteins, MESH : Male, MESH : Drug Administration Schedule, Immunology, CD4-CD8 Ratio, Alpha interferon, MESH : Treatment Outcome, Interferon alpha-2, MESH: Drug Administration Schedule, Drug Administration Schedule, 03 medical and health sciences, Immune system, Internal medicine, Antiretroviral treatment, Humans, MESH : Middle Aged, MESH: Lymphocyte Activation, MESH : Lymphocyte Activation, 030304 developmental biology, MESH: Acquired Immunodeficiency Syndrome, Acquired Immunodeficiency Syndrome, MESH: Humans, business.industry, MESH : Anti-HIV Agents, MESH : Humans, Interferon-alpha, MESH : Follow-Up Studies, MESH: Adult, MESH: Male, Surgery, MESH: DNA, Viral, MESH: Polyethylene Glycols, MESH : CD4-CD8 Ratio, DNA, Viral, HIV-1, MESH: CD4-CD8 Ratio, business, MESH: Female, CD8, Follow-Up Studies
Abstract

International audience; OBJECTIVES: The ANRS-112 INTERPRIM trial assessed whether fixed-cycles of antiretroviral treatment interruption (ART-STI) combined or not with pegylated interferon alpha-2b (peg-IFN) could lower viral load and achieve a healthier immune system in patients diagnosed during primary HIV-1-infection (PHI). DESIGN AND METHODS: Patients were randomized to receive either continuous ART (cART) during 72 weeks, or cART during 36 weeks followed by three ART-STIs, or the same ART-STIs associated with peg-IFN during the first 14 weeks and each interruption (ART-STI-IFN). Treatment was stopped at week 72. Final evaluation was based on plasma HIV-RNA level 6 months after the last treatment interruption. RESULTS: Eighty-seven percent of patients achieved undetectable HIV-RNA at week 32, with no deleterious impact of sequential treatment interruptions (STIs). Viral rebounds during interruptions were lower in the ART-STI-IFN than in the ART-STI group and during the second and third interruptions compared with the first one. However, HIV-RNA levels, CD4 T-cell counts and CD4 T/CD8 T ratios were similar between groups after the 6-month interruption, with a persistent effect on CD4 T cells and total cell-associated HIV-DNA levels. Predictive factors of virological outcome were HIV-RNA and HIV-DNA levels at PHI and HIV-DNA levels at treatment interruption. HIV-specific responses did not differ between strategies and were not associated with outcome. Forty-eight percent of patients experienced treatment resumption during long-term follow-up without difference between groups. CONCLUSION: When initiated during PHI, STIs associated or not with IFN did not result in a different outcome as compared to cART. All regimens showed a high response rate and a sustained immunological benefit after cessation.

Published
2012

13. Treatment of recurrent HCV infection following liver transplantation: results of a multicenter, randomized, versus placebo, trial of ribavirin alone as maintenance therapy after one year of PegIFNα-2a plus ribavirin

Author

Philippe Wolf, Didier Samuel, Karim Boudjema, Christophe Duvoux, Lionel Rostaing, Olivier Boillot, Claire Vanlemmens, Yvon Calmus, Martine Neau-Cransac, Jean Gugenheim, Danielle Botta-Fridlund, Georges Philippe Pageaux, François Durand, Olivier Chazouillères, Sébastien Dharancy, L. Samelson, Service de Chirurgie Digestive, Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Pôle Recherche Clinique-Santé Publique [Mondor], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor, Service de Chirurgie Générale et Transplantation Multi Organes, CHU Strasbourg, Service de Néphrologie - Hypertension Artérielle Dialyse - Transplantation, Service d'hépatologie, Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Hôpital Claude Hurriez, CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Foie, métabolismes et cancer, Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), French National Direction for Clinical Research (Direction de la Recherche Clinique), Roche Pharma France., CHU Toulouse [Toulouse]-Hôpital de Rangueil, CHU Toulouse [Toulouse], Service d'hépatologie [Saint-Antoine], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )

Subjects
Liver Cirrhosis, Male, medicine.medical_treatment, MESH: Logistic Models, Hepacivirus, Liver transplantation, Kidney, Gastroenterology, MESH: Cyclosporine, Polyethylene Glycols, Placebos, MESH: Recombinant Proteins, MESH: Genotype, chemistry.chemical_compound, 0302 clinical medicine, Maintenance therapy, Recurrence, MESH: Double-Blind Method, MESH: Hepacivirus, MESH: Treatment Outcome, 0303 health sciences, MESH: Middle Aged, Hepatitis C virus, virus diseases, Hepatitis C, Induction Chemotherapy, Middle Aged, Viral Load, MESH: Induction Chemotherapy, Recombinant Proteins, 3. Good health, MESH: Maintenance Chemotherapy, Treatment Outcome, Cyclosporine, 030211 gastroenterology & hepatology, Drug Therapy, Combination, Female, MESH: Immunosuppressive Agents, MESH: Interferon-alpha, MESH: Liver Cirrhosis, MESH: Viral Load, Viral load, Immunosuppressive Agents, MESH: Antiviral Agents, medicine.medical_specialty, MESH: Liver Transplantation, Combination therapy, Genotype, MESH: Placebos, Placebo, Antiviral Agents, Tacrolimus, Maintenance Chemotherapy, 03 medical and health sciences, Double-Blind Method, MESH: Ribavirin, Internal medicine, Viral response, Ribavirin, medicine, MESH: Tacrolimus, Humans, Peginterferon, Erythropoietin, 030304 developmental biology, MESH: Hepatitis C, Intention-to-treat analysis, MESH: Humans, Hepatology, business.industry, Interferon-alpha, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, MESH: Kidney, medicine.disease, Fibrosis, digestive system diseases, MESH: Male, Liver Transplantation, MESH: Recurrence, MESH: Drug Therapy, Combination, Logistic Models, chemistry, MESH: Polyethylene Glycols, Immunology, business, MESH: Female
Abstract

International audience; BACKGROUND & AIMS: We aimed at determining the effect of maintenance therapy with ribavirin alone, after a year of combined peginterferon-alfa 2a (PegIFNα-2a) and ribavirin therapy, on viral response and liver histology after liver transplantation (LT). METHODS: Hundred and one patients with recurrent HCV and a minimum of stage 1 fibrosis (METAVIR scoring), 1-5years after LT, were enrolled. PegIFNα-2a and ribavirin were initiated at 90 μg/wk and 600 mg/d, respectively, then increased or adjusted as a function of tolerance. At 12 months, combination therapy was discontinued and patients were randomized to ribavirin or placebo for a further 12 months. Growth factor use was permitted. RESULTS: At 18 months, a sustained virological response (SVR) was obtained in 47.9% of patients in Per Protocol (PP) analysis, and was higher in patients with genotype 2 or 3 than in patients with genotype 1 or 4, in patients with genotypes 1+4 receiving ciclosporine than in those receiving tacrolimus, in patients with worse renal function, in those having received EPO, in patients with lower weight, and in those with lower viral load at 3 months. Using logistic regression, only the early viral response, recipient weight and renal function were independently associated with better SVR. SVR, viral load, activity, and fibrosis scores were similar, at M18 and M30, in patients randomized to ribavirin, or to placebo. CONCLUSIONS: A PP SVR was achieved in 47.9% of patients with established recurrent hepatitis C after LT. Maintenance therapy with ribavirin alone does not improve the virological response or the histological parameters.

Published
2012

14. Factors that predict response of patients with hepatitis C virus infection to boceprevir

Author

Poordad, Fred, Bronowicki, Jeanpierre, Gordon, Stuart C., Zeuzem, Stefan, Jacobson, Ira M., Sulkowski, Mark S., Poynard, Thierry, Morgan, Timothy R., Molony, Cliona, Pedicone, Lisa D., Sings, Heather L., Burroughs, Margaret H., Sniukiene, Vilma, Boparai, Navdeep, Goteti, Venkata S., Brass, Clifford A., Albrecht, Janice K., Bacon, Bruce R., Sprint, 2, Respond, 2 Investigators, Taliani, Gloria, Cedars-Sinai Medical Center, Centre Hospitalier Universitaire de Nancy (CHU Nancy), Université Henri Poincaré - Nancy 1 (UHP), Henry Ford Hospital, Goethe-University Frankfurt am Main, Weill Medical College of Cornell University [New York], California State University [Long Beach] (CSULB ), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Merck & Co. Inc, Saint Louis University (SLU), Hepatology and Liver Transplantation, Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Johann Wolfgang Goethe University Medical Center, Service d'Hépato-Gastro-Entérologie [CHU Pitié-Salpêtrière], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Poordad, F, Bronowicki, JP, Gordon, SC, Zeuzem, S, Jacobson, IM, Sulkowski, MS, Poynard, T, Morgan, TR, Molony, C, Pedicone, LD, Sings, HL, Burroughs, MH, Sniukiene, V, Boparai, N, Goteti, VS, Brass, CA, Albrecht, JK, Bacon, BR, Craxi, A, and SPRINT-2 and RESPOND-2 Investigators

Subjects
Male, Cirrhosis, MESH: Logistic Models, Hepacivirus, MESH: Risk Assessment, Gastroenterology, Polyethylene Glycols, MESH: Recombinant Proteins, MESH: Genotype, 0302 clinical medicine, Odds Ratio, Prospective Studies, MESH: Treatment Outcome, Response to Therapy, 0303 health sciences, MESH: Polymorphism, Single Nucleotide, virus diseases, 3. Good health, MESH: RNA, Viral, HCV, Drug Therapy, Combination, 030211 gastroenterology & hepatology, Clinical Trial, Genetic, Prognostic Factors, Adult, Antiviral Agents, Biomarkers, Canada, Europe, Female, Genotype, Hepatitis C, Humans, Interferon-alpha, Interleukins, Logistic Models, Multivariate Analysis, Phenotype, Polymorphism, Single Nucleotide, Proline, RNA, Viral, Recombinant Proteins, Ribavirin, Risk Assessment, Risk Factors, Time Factors, Treatment Outcome, United States, Viral Load, Viral load, medicine.medical_specialty, MESH: Interleukins, Interferon alpha-2, MESH: Phenotype, 03 medical and health sciences, Drug Therapy, MESH: Ribavirin, MESH: Canada, Boceprevir, Polymorphism, MESH: Proline, MESH: Humans, MESH: Adult, Odds ratio, medicine.disease, digestive system diseases, Clinical trial, chemistry, Immunology, MESH: Female, medicine.disease_cause, chemistry.chemical_compound, Interferon, MESH: Risk Factors, MESH: Hepacivirus, Viral, Single Nucleotide, Combination, MESH: Interferon-alpha, MESH: Viral Load, medicine.drug, MESH: Antiviral Agents, Hepatitis C virus, MESH: Multivariate Analysis, Internal medicine, medicine, MESH: United States, 030304 developmental biology, MESH: Hepatitis C, Hepatology, business.industry, MESH: Time Factors, MESH: Biological Markers, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, MESH: Prospective Studies, MESH: Male, MESH: Odds Ratio, MESH: Drug Therapy, Combination, MESH: Polyethylene Glycols, RNA, Interferons, MESH: Europe, business
Abstract

Background & Aims Little is known about factors associated with a sustained virologic response (SVR) among patients with hepatitis C virus (HCV) infection to treatment with protease inhibitors. Methods Previously untreated patients (from the Serine Protease Inhibitor Therapy 2 [SPRINT-2] trial) and those who did not respond to prior therapy (from the Retreatment with HCV Serine Protease Inhibitor Boceprevir and PegIntron/Rebetol 2 [RESPOND-2] trial) received either a combination of peginterferon and ribavirin for 48 weeks or boceprevir, peginterferon, and ribavirin (triple therapy) after 4 weeks of peginterferon and ribavirin (total treatment duration, 28–48 wk). A good response to interferon was defined as a ≥1 log 10 decrease in HCV RNA at week 4; a poor response was defined as a 10 decrease. We used multivariate regression analyses to identify baseline factors of the host (including the polymorphism interleukin [ IL ]- 28B rs12979860) associated with response. The polymorphism IL - 28B rs8099917 also was assessed. Results In the SPRINT-2 trial, factors that predicted a SVR to triple therapy included low viral load (odds ratio [OR], 11.6), IL-28B genotype (rs 12979860 CC vs TT and CT; ORs, 2.6 and 2.1, respectively), absence of cirrhosis (OR, 4.3), HCV subtype 1b (OR, 2.0), and non-black race (OR, 2.0). In the RESPOND-2 trial, the only factor significantly associated with a SVR was previous relapse, compared with previous nonresponse (OR, 2.6). Most patients with rs12979860 CC who received triple therapy had undetectable levels of HCV RNA by week 8 (76%–89%), and were eligible for shortened therapy. In both studies, IL-28B rs12979860 CC was associated more strongly with a good response to interferon than other baseline factors; however, a ≥1 log 10 decrease in HCV-RNA level at week 4 was associated more strongly with SVR than IL-28B rs12979860. Combining the rs8099917 and rs12979860 genotypes does not increase the association with SVR. Conclusions The CC polymorphism at IL-28B rs12979860 is associated with response to triple therapy and can identify candidates for shorter treatment durations. A ≥1 log 10 decrease in HCV RNA at week 4 of therapy is the strongest predictor of a SVR, regardless of polymorphisms in IL-28B . ClinicalTrials.gov; numbers NCT00705432 and NCT00708500.

Published
2012

15. The treatment response of chronically hepatitis C virus-infected patients depends on interferon concentration but not on interferon gene expression in peripheral blood mononuclear cells

Author

Gilles Duverlie, Cédric Coulouarn, Etienne Brochot, Véronique Descamps, Isabelle Duchaussoy, Sandrine Castelain, Dominique Capron, Agnès Baron, Catherine François, Eric Nguyen-Khac, Laboratoire de Virologie [CHU Amiens], CHU Amiens-Picardie, Unité de Virologie clinique et fondamentale (UVCF), Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie, Foie, métabolismes et cancer, Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Service d'Hépatogastroentérologie, Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )

Subjects
Male, Hepacivirus, medicine.disease_cause, Polyethylene Glycols, MESH: Recombinant Proteins, chemistry.chemical_compound, 0302 clinical medicine, Interferon, Gene expression, Pharmacology (medical), MESH: Hepacivirus, MESH: Treatment Outcome, 0303 health sciences, MESH: Middle Aged, biology, Middle Aged, Viral Load, MESH: Gene Expression Regulation, Recombinant Proteins, 3. Good health, MESH: Hepatitis C, Chronic, MESH: Leukocytes, Mononuclear, Treatment Outcome, Infectious Diseases, Drug Therapy, Combination, Female, 030211 gastroenterology & hepatology, MESH: Interferon-alpha, MESH: Viral Load, Viral load, medicine.drug, Adult, MESH: Antiviral Agents, Hepatitis C virus, Alpha interferon, Interferon alpha-2, Antiviral Agents, Peripheral blood mononuclear cell, 03 medical and health sciences, MESH: Ribavirin, Ribavirin, medicine, Humans, 030304 developmental biology, Pharmacology, MESH: Humans, business.industry, Body Weight, Interferon-alpha, MESH: Adult, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Hepatitis C, Chronic, biology.organism_classification, MESH: Male, MESH: Body Weight, MESH: Drug Therapy, Combination, Gene Expression Regulation, chemistry, MESH: Polyethylene Glycols, Immunology, Leukocytes, Mononuclear, business, MESH: Female
Abstract

The current treatment of chronic hepatitis C is based on pegylated alpha interferon (PEG-IFN-α) and ribavirin. The aim of this study was to identify biological and clinical variables related to IFN therapy that could predict patient outcome. The study enrolled 47 patients treated with PEG-IFN and ribavirin combined therapy. The interferon concentration was measured in serum by a bioassay. The expression of 93 interferon-regulated genes in peripheral blood mononuclear cells was quantified by real-time quantitative reverse transcription-PCR (RT-PCR) before and after 1 month of treatment. The interferon concentration in the serum was significantly lower in nonresponders than in sustained virological responders. Moreover, a significant correlation was identified between interferon concentration and interferon exposition as well as body weight. The analysis of interferon-inducible genes in peripheral blood mononuclear cells among the genes tested did not permit the prediction of treatment outcome. In conclusion, the better option seems to be to treat patients with weight-adjusted PEG-IFN doses, particularly for patients with high weight who are treated with PEG-IFN-α2a. Although the peripheral blood mononuclear cell samples are the easiest to obtain, the measurement of interferon-inducible genes seems not be the best strategy to predict treatment outcome.

Published
2012

16. Sustained virological response after 14-day treatment with danoprevir and 48-week treatment with pegylated interferon-α2a (40 KD) plus ribavirin

Author

Nathalie Boyer, Georges-Philippe Pageaux, Regine Rouzier, Christophe Carenco, Patrick Marcellin, Yves Benhamou, Dominique Guyader, Dominique Larrey, Service d'hépatologie, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-CHU Saint-Eloi, Foie, métabolismes et cancer, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Diderot - Paris 7 (UPD7)-Hôpital Beaujon, Service d'Hépato-Gastroentérologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Hôpital Beaujon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service d'Hépato-Gastro-Entérologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Saint Eloi (CHRU Montpellier), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)

Subjects
Cyclopropanes, Male, Time Factors, Nucleoside analog, MESH: Sulfonamides, Hepacivirus, Isoindoles, Pharmacology, 01 natural sciences, Gastroenterology, Polyethylene Glycols, Virological response, MESH: Recombinant Proteins, MESH: Genotype, chemistry.chemical_compound, 0302 clinical medicine, Pegylated interferon, Pharmacology (medical), MESH: Hepacivirus, Drug combination, MESH: Treatment Outcome, MESH: Aged, Sulfonamides, MESH: Middle Aged, Danoprevir, Middle Aged, Viral Load, Recombinant Proteins, 3. Good health, MESH: Hepatitis C, Chronic, Treatment Outcome, Infectious Diseases, Antineoplastic agent, Pegylated form, Day treatment, Drug Therapy, Combination, Female, 030211 gastroenterology & hepatology, Interferon alpha 2a, MESH: Interferon-alpha, MESH: Viral Load, medicine.drug, Adult, MESH: Antiviral Agents, medicine.medical_specialty, Genotype, Lactams, Proline, Combination therapy, Lactams, Macrocyclic, MESH: Drug Administration Schedule, Antiviral Agents, Drug Administration Schedule, 03 medical and health sciences, MESH: Ribavirin, Internal medicine, Ribavirin, medicine, Humans, Antiviral, Cytokine, Aged, Retrospective Studies, MESH: Humans, MESH: Lactams, business.industry, MESH: Time Factors, Interferon-alpha, MESH: Adult, MESH: Retrospective Studies, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Hepatitis C, Chronic, MESH: Male, 0104 chemical sciences, Discontinuation, Treatment, 010404 medicinal & biomolecular chemistry, Regimen, MESH: Drug Therapy, Combination, chemistry, MESH: Polyethylene Glycols, business, MESH: Female
Abstract

Background Danoprevir (RG7227) is an inhibitor of the HCV NS3/4A protease. In two Phase Ib studies of treatment-naive patients with chronic HCV genotype 1 infection, danoprevir administration for 14 days was associated with HCV RNA median reduction reaching 3.8 log10 in monotherapy and 5.7 log10 in combination therapy with pegylated interferon (PEG-IFN)-α2a (40 KD) plus ribavirin (RBV). After the protocol-defined phase, patients were free to continue with PEG-IFN/RBV. Sustained virological response (SVR) was evaluated in patients who continued treatment with PEG-IFN/RBV. Methods Retrospective analysis of the patients who received a 14-day monotherapy regimen with danoprevir (100 or 200 mg every 8 or 12 h), or 14-day triple therapy with danoprevir (100, 200 or 300 mg every 8 h, or 400, 600 or 900 mg every 12 h) with PEG-IFN-α2a (40 KD; 180 mg/ week subcutaneously) and RBV (1,000–1,200 mg/day) followed by PEG-IFN-α2a (40 KD; 180 μg/week subcutaneously) and RBV (1,000–1,200 mg/day) for 46 weeks (triple therapy group) for a total of 48 weeks (monotherapy group). Results Data were collected from 15 patients with danoprevir monotherapy and 24 patients with danoprevir-based triple therapy. Virological results are expressed using an intention-to-treat principle. Premature treatment discontinuation occurred in five patients. Rapid virological response (RVR; week 4) rate was 50% and 69.6% and SVR rate was 60% and 70.8% in the mono-therapy and triple therapy groups, respectively. RVR was highly predictive of SVR (>90%; HCV RNAConclusions The addition of danoprevir for 14 days to PEG-IFN/RBV treatment results in a high SVR rate in HCV genotype 1 treatment-naive patients.

Published
2012

17. Pharmacological exposure to ribavirin: a key player in the complex network of factors implicated in virological response and anaemia in hepatitis C treatment

Author

Loustaud-Ratti, Véronique, Carrier, Paul, Rousseau, Annick, Maynard, Marianne, Babany, Gérard, Alain, Sophie, Trépo, Christian, De Ledinghen, Victor, Bourlière, Marc, Pol, Stanislas, Di Martino, Vincent, Zarski, Jean-Pierre, Pinta, Alexandrina, Sautereau, Denis, Marquet, Pierre, Renseigné, Non, Service d'Hépato-Gastro-Entérologie et Nutrition [CHU Limoges], CHU Limoges, Pharmacologie des Immunosuppresseurs et de la Transplantation (PIST), Université de Limoges (UNILIM)-CHU Limoges-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'hépato-gastro-enterologie, Hospices Civils de Lyon (HCL), Produits Roche, Roche, Service de Bactériologie, Virologie, Hygiène [CHU Limoges], Equipe 16, IFR Laennec (IL), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre de Recherche en Cancérologie de Lyon (CRCL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service d'Hépato-Gastro-Entérologie, CHU Bordeaux [Bordeaux]-Hôpital Saint-André, Hôpital saint joseph, Service d' Hépato-gastroentérologie, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service d'hépatologie médicale [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Cochin [AP-HP], Agents pathogènes et inflammation - UFC (EA 4266) (API), Université de Franche-Comté (UFC), Service d'hépatologie, Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon)-Hôpital Jean Minjoz-Université de Franche-Comté (UFC), Département d'hépato-gastroentérologie, Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble, Institut d'oncologie/développement Albert Bonniot de Grenoble (INSERM U823), Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire Roche, Laboratoire Roche [Boulogne-Billancourt], Service de Pharmacologie, toxicologie et pharmacovigilance [CHU Limoges], CHU Cochin [AP-HP]-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503)-Université de Limoges (UNILIM)-CHU Limoges, Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Léon Bérard [Lyon]-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Université de Franche-Comté (UFC), CHU Grenoble-Université Grenoble Alpes (UGA), Pharmacologie des Immunosuppresseurs et de la Transplantation ( PIST ), Université de Limoges ( UNILIM ) -CHU Limoges-Génomique, Environnement, Immunité, Santé, Thérapeutique ( GEIST FR CNRS 3503 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Hospices Civils de Lyon ( HCL ), IFR Laennec ( IL ), Institut National de la Recherche Agronomique ( INRA ) -Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] ( UJM ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Recherche Agronomique ( INRA ) -Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] ( UJM ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Centre de Recherche en Cancérologie de Lyon ( CRCL ), Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Institut Cochin ( UM3 (UMR 8104 / U1016) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Cochin [AP-HP], Agents pathogènes et inflammation - UFC (EA 4266) ( API ), Université de Franche-Comté ( UFC ), Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ) -Hôpital Jean Minjoz-Université de Franche-Comté ( UFC ), Université Joseph Fourier - Grenoble 1 ( UJF ) -CHU Grenoble, Institut d'oncologie/développement Albert Bonniot de Grenoble ( INSERM U823 ), and Université Joseph Fourier - Grenoble 1 ( UJF ) -CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale ( INSERM )

Subjects
MESH: Anemia, MESH: Pyrophosphatases, Hepacivirus, MESH : Viral Load, MESH : Hepacivirus, Polyethylene Glycols, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, MESH: Recombinant Proteins, chemistry.chemical_compound, 0302 clinical medicine, Medicine, MESH: Hepacivirus, Pyrophosphatases, media_common, 0303 health sciences, biology, MESH : Polyethylene Glycols, Gastroenterology, virus diseases, Anemia, Hepatitis C, Viral Load, Recombinant Proteins, MESH : Antiviral Agents, 3. Good health, MESH : Interferon-alpha, Drug Therapy, Combination, 030211 gastroenterology & hepatology, MESH: Interferon-alpha, MESH: Viral Load, Viral load, Drug, MESH: Antiviral Agents, MESH: Interleukins, MESH : Recombinant Proteins, MESH : Anemia, media_common.quotation_subject, Alpha interferon, [SDV.CAN]Life Sciences [q-bio]/Cancer, Interferon alpha-2, Antiviral Agents, Virus, 03 medical and health sciences, MESH: Ribavirin, Ribavirin, Humans, MESH : Pyrophosphatases, 030304 developmental biology, MESH: Hepatitis C, MESH: Humans, Hepatology, business.industry, Interleukins, MESH : Drug Therapy, Combination, MESH : Humans, Interferon-alpha, MESH : Hepatitis C, biology.organism_classification, medicine.disease, Virology, MESH : Ribavirin, MESH: Drug Therapy, Combination, chemistry, MESH: Polyethylene Glycols, Pharmacodynamics, Immunology, Interferons, MESH : Interleukins, business
Abstract

International audience; Ribavirin remains today a pivotal drug in the treatment of hepatitis C; in standard double therapy, as well as in triple combination with direct antiviral agents, ribavirin reduces relapse and can double the sustained virological response obtained with peginterferon alone or in association with direct antiviral agents. In the complex network of interacting factors determining sustained virological response independently of known predictive factors related to host and virus, two modern tools are emerging: polymorphisms in the IL28B gene and very early exposure to ribavirin. The use of a pharmacokinetic-pharmacodynamic model of early ribavirin exposure to adjust the dose individually would help promote a safer ribavirin use and improve sustained virological response. The variability of the influence of ribavirin exposure on anaemia is probably genetically determined; however, the low prevalence of the implicated protective alleles of the inosine triphosphate pyrophosphatase gene could explain their lack of influence on sustained virological response.

Published
2011

18. Toward characterizing seed vigor in alfalfa through proteomic analysis of germination and priming

Author

Dominique Job, Claudette Job, Rafika Yacoubi, Maya Belghazi, Wided Chaïbi, Physiologie des plantes et des champignons lors de l'infection, Bayer Cropscience-Centre National de la Recherche Scientifique (CNRS), Centre de recherche en neurobiologie - neurophysiologie de Marseille (CRN2M), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Unité de Recherche de Biologie et Physiologie Cellulaires Végétales, and Université de Tunis El Manar (UTM)

Subjects
0106 biological sciences, Proteomics, MESH: Sodium Chloride, Proteome, Protein metabolism, Germination, Priming (agriculture), MESH: Germination, Sodium Chloride, 01 natural sciences, Biochemistry, Salinity stress, Polyethylene Glycols, 03 medical and health sciences, chemistry.chemical_compound, Stress, Physiological, Electrophoresis, Gel, Two-Dimensional, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], MESH: Stress, Physiological, 030304 developmental biology, Plant Proteins, MESH: Medicago sativa, 2. Zero hunger, 0303 health sciences, biology, MESH: Plant Proteins, MESH: Proteomics, food and beverages, General Chemistry, Metabolism, 15. Life on land, biology.organism_classification, MESH: Electrophoresis, Gel, Two-Dimensional, MESH: Proteome, Agronomy, chemistry, MESH: Polyethylene Glycols, MESH: Seeds, Seedling, Seedlings, Seeds, Stress conditions, MESH: Seedling, 010606 plant biology & botany, Medicago sativa
Abstract

International audience; Alfalfa, the most widely grown leguminous crop in the world, is generally exposed to severe salinity stress in Tunisia, notably affecting its germination performance. Toward a better understanding of alfalfa seed vigor, we have used proteomics to characterize protein changes occurring during germination and osmopriming, a pretreatment that accelerates germination and improves seedling uniformity particularly under stress conditions. The data revealed that germination was accompanied by dynamic changes of 79 proteins, which are mainly involved in protein metabolism, cell structure, metabolism, and defense. Comparative proteomic analysis also revealed 63 proteins specific to osmopriming, 65 proteins preferentially varying during germination, and 14 proteins common to both conditions. Thus, the present study unveiled the unexpected finding that osmopriming cannot simply be considered as an advance of germination-related processes but involves other mechanisms improving germination such as the mounting of defense mechanisms enabling osmoprimed seeds to surmount environmental stresses potentially occurring during germination. The present results therefore provide novel avenues toward understanding the mechanisms of invigoration of low vigor seeds by priming treatments that are widely used both in commercial applications and in developing countries (on farm seed priming) to better control crop yields.

Published
2011

19. Treatment of chronic hepatitis C patients with the NS3/4A protease inhibitor danoprevir (ITMN-191/RG7227) leads to robust reductions in viral RNA: a phase 1b multiple ascending dose study

Author

Porter Steven B, Regine Rouzier, Lawrence M. Blatt, Alain Patat, Stefan Zeuzem, Patrick F. Smith, Bradford Williamson Ziegler, Dominique Guyader, Dominique Larrey, Patrick Marcellin, Scott D. Seiwert, Nicole Forestier, Johann Wolfgang Goethe University Medical Center, CHU Montpellier, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Microenvironnement et remodelage, Centre Hospitalier Universitaire [Rennes]-Foie, métabolismes et cancer, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Service d'hépatologie, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Diderot - Paris 7 (UPD7)-Hôpital Beaujon, InterMune, Inc. and Roche, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Hôpital Beaujon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), and Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )

Subjects
MESH: Sulfonamides, medicine.disease_cause, Gastroenterology, MESH: Recombinant Proteins, 0302 clinical medicine, Pegylated interferon, MESH: Double-Blind Method, MESH: Hepacivirus, MESH: Aged, 0303 health sciences, MESH: Middle Aged, MESH: Drug Resistance, Viral, Danoprevir, virus diseases, 3. Good health, MESH: Hepatitis C, Chronic, Direct antiviral, MESH: RNA, Viral, HCV, 030211 gastroenterology & hepatology, Viral disease, MESH: Interferon-alpha, MESH: Viral Load, Viral load, medicine.drug, MESH: Antiviral Agents, medicine.medical_specialty, MESH: Serine Proteinase Inhibitors, Hepatitis C virus, Cmax, MESH: Carrier Proteins, 03 medical and health sciences, Pharmacokinetics, MESH: Ribavirin, Internal medicine, medicine, Protease inhibitor (pharmacology), MESH: Humans, Hepatology, MESH: Lactams, 030306 microbiology, business.industry, ITMN-191, MESH: Adult, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Virology, digestive system diseases, MESH: Male, Protease inhibitor, MESH: Polyethylene Glycols, MESH: Alanine Transaminase, MESH: Viral Nonstructural Proteins, business, MESH: Female
Abstract

International audience; BACKGROUND & AIMS: Danoprevir is a potent and selective inhibitor of the hepatitis C virus (HCV) NS3/4A serine protease. The present study assessed the safety, pharmacokinetics, and antiviral activity of danoprevir in a randomized, placebo-controlled, 14-day multiple ascending dose study in patients with chronic HCV genotype 1 infection. METHODS: Four cohorts of treatment-naïve (TN) patients (100 mg q12 h, 100 mg q8 h, 200 mg q12 h, 200 mg q8 h) and one cohort of non-responders (NR) to prior pegylated interferon alfa-ribavirin treatment (300 mg q12 h) were investigated. RESULTS: Danoprevir was safe and well tolerated; adverse events were generally mild, transient and were not associated with treatment group or dose level. Danoprevir displayed a slightly more than proportional increase in exposure with increasing daily dose and was rapidly eliminated from the plasma compartment. Maximal decreases in HCV RNA were: -3.9 log(10)IU/ml and -3.2 log(10)IU/ml in TN receiving 200 mg q8 h and 200 mg q12 h, respectively. End of treatment viral decline in these two cohorts was within 0.1 log(10)IU/ml of the viral load nadir. HCV RNA reduction in NR was more modest than that observed in upper dose TN cohorts. The overall incidence of viral rebound was low (10/37) and was associated with the R155K substitution in NS3 regardless of the HCV subtype. CONCLUSIONS: Danoprevir was safe and well tolerated when administered for 14 days in patients with chronic HCV genotype 1 infection. Treatment resulted in sustained, multi-log(10) IU/ml reductions in HCV RNA in upper dose cohorts. These results support further clinical evaluation of danoprevir in patients with chronic HCV.

Published
2011

20. New functional degradable and bio-compatible nanoparticles based on poly(malic acid) derivatives for site-specific anti-cancer drug delivery

Author

Thierry Benvegnu, Ghizlane Chetouani, Julia Y. Ljubimova, Eggehard Holler, Sandrine Cammas-Marion, Véronique Laurent, Pascal Loyer, Zhi Wei Huang, Le Corre, Morgane, Institut des Sciences Chimiques de Rennes (ISCR), Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Ecole Nationale Supérieure de Chimie de Rennes (ENSCR)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Foie, métabolismes et cancer, Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Drug Delivery and Nanomedicine Laboratory, Cedars-Sinai Medical Center, Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Ecole Nationale Supérieure de Chimie de Rennes (ENSCR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA), Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )

Subjects
Polymers, Degradable polyesters, Malates, Pharmaceutical Science, Nanoparticle, 02 engineering and technology, Polyethylene Glycols, chemistry.chemical_compound, Mice, Drug Delivery Systems, Organic chemistry, MESH: Animals, Cytotoxicity, MESH: Static Electricity, Cell Line, Transformed, 0303 health sciences, Molecular Structure, Poly(malic acid) derivatives, In vitro cytotoxicity, Carbocyanines, 021001 nanoscience & nanotechnology, MESH: Fluorescent Dyes, MESH: Polymers, Polyester, MESH: Cell Survival, Drug delivery, MESH: Carbocyanines, Functional polymers, 0210 nano-technology, In vitro cellular uptake, MESH: Cell Line, Tumor, Cell Survival, Surface Properties, MESH: Molecular Structure, MESH: Drug Delivery Systems, Static Electricity, Biotin, Antineoplastic Agents, Article, 03 medical and health sciences, MESH: Doxorubicin, Cell Line, Tumor, PEG ratio, MESH: Biotin, Animals, Humans, MESH: Particle Size, MESH: Cell Line, Transformed, Particle Size, MESH: Mice, MESH: Malates, 030304 developmental biology, Fluorescent Dyes, MESH: Surface Properties, MESH: Humans, technology, industry, and agriculture, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Fibroblasts, Combinatorial chemistry, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, chemistry, MESH: Polyethylene Glycols, Degradable functional nanoparticles, MESH: Fibroblasts, Doxorubicin, MESH: Antineoplastic Agents, Nanoparticles, Malic acid, Ethylene glycol, MESH: Nanoparticles
Abstract

International audience; Design of an efficient site-specific drug delivery system based on degradable functional polymers still remains challenging. In this work, we synthesized and characterized three degradable functional polyesters belonging to the poly(malic acid) family: the poly(benzyl malate) (PMLABe), the poly(ethylene glycol)-b-poly(benzyl malate) (PEG(42)-b-PMLABe), the biotin-poly(ethylene glycol)-b-poly(benzyl malate) (Biot-PEG(62)-PMLABe). Starting from these building blocks, we were able to prepare the corresponding well-defined degradable functional nanoparticles whose toxicity was evaluated in vitro on normal and cancer cell lines. Results have evidenced that the prepared nanoparticles did not show any significant cytotoxicity even at high concentrations. A model anti-cancer drug (doxorubicin, Dox) or a fluorescent probe (1,1'-dioctadecyl-3,3,3',3'-tetramethylindodicarbocyanine, DiD oil) has been encapsulated into PMLABe, PEG(42)-PMLABe or Biot-PEG(62)-PMLABe based nanoparticles in order to evaluate, respectively, the in vitro cytotoxicity of Dox-loaded nanoparticles on normal and cancer cell lines and the ligand (biotin) effect on cellular uptake in vitro using mmt 060562 cell line. Dox-loaded PMLABe, PEG(42)-PMLABe or Biot-PEG(62)-PMLABe nanoparticles showed an in vitro cytotoxicity similar to that of free Dox. Moreover, the DiD oil loaded Biot-PEG(62)-PMLABe based nanoparticles showed a better in vitro cellular uptake than ligand-free DiD oil loaded nanoparticles. Both results evidence the great potential of such degradable functional poly(malic acid) derivatives for the design of highly efficient site-specific anti-cancer nanovectors.

Published
2011

21. Boceprevir for untreated chronic HCV genotype 1 infection

Author

Fredric Gordon, Mario Pirisi, Antonio Craxi, TRAN Albert, Mario ANGELICO, Nezam Afdhal, Conrado M Fernandez Rodriguez, Rafael Esteban, Jose Luis Calleja-Panero, Savino Bruno, Philippe Mathurin, Christopher Bowlus, Alessandra Mangia, Hugo E. Vargas, Steven Herrine, Peter Robert Galle, Hepatology and Liver Transplantation, Cedars-Sinai Medical Center, Gastroenterology-Hepatology, Certified Endoscopy Centers, School of Medicine, Saint Louis University, Azienda Ospedaliera Fatebenefratelli e Oftalmico, Department of Gastroenterology, Hepatology and Endocrinology (MHH), Hannover Medical School [Hannover] (MHH), Johns Hopkins University (JHU), Center for the Study of Hepatitis C, Weill Medical College of Cornell University [New York], University of Pennsylvania, Inova Fairfax Hospital, Center for Integrated Research, Betty and Guy Beatty, Merck, Whitehouse Station, Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), and University of Pennsylvania [Philadelphia]

Subjects
Male, MESH: Anemia, Hepacivirus, Gastroenterology, Telaprevir, Polyethylene Glycols, MESH: Recombinant Proteins, MESH: Genotype, chemistry.chemical_compound, 0302 clinical medicine, MESH: Double-Blind Method, MESH: Hepacivirus, genetics, hepatitis c, Beclabuvir, MESH: Treatment Outcome, 0303 health sciences, MESH: Middle Aged, interferon alfa-2b, Danoprevir, virus diseases, Anemia, General Medicine, Hepatitis C, Middle Aged, Viral Load, Recombinant Proteins, 3. Good health, MESH: Hepatitis C, Chronic, chronic, Treatment Outcome, MESH: RNA, Viral, RNA, Viral, 030211 gastroenterology & hepatology, Drug Therapy, Combination, Female, MESH: Interferon-alpha, MESH: Viral Load, medicine.drug, MESH: Antiviral Agents, Adult, medicine.medical_specialty, Serine Proteinase Inhibitors, Genotype, Proline, MESH: Serine Proteinase Inhibitors, Black People, Interferon alpha-2, Antiviral Agents, Article, 03 medical and health sciences, Double-Blind Method, MESH: Ribavirin, Boceprevir, Internal medicine, Ribavirin, medicine, Humans, Rapid Virologic Response, 030304 developmental biology, MESH: Humans, MESH: Proline, business.industry, Interferon-alpha, MESH: Adult, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Hepatitis C, Chronic, medicine.disease, Ombitasvir, MESH: Male, MESH: Drug Therapy, Combination, chemistry, MESH: Polyethylene Glycols, therapeutic use, Immunology, hepacivirus, humans, genotype, MESH: African Continental Ancestry Group, business, MESH: Female
Abstract

Background Peginterferon–ribavirin therapy is the current standard of care for chronic infection with hepatitis C virus (HCV). The rate of sustained virologic response has been below 50% in cases of HCV genotype 1 infection. Boceprevir, a potent oral HCV-protease inhibitor, has been evaluated as an additional treatment in phase 1 and phase 2 studies. Methods We conducted a double-blind study in which previously untreated adults with HCV genotype 1 infection were randomly assigned to one of three groups. In all three groups, peginterferon alfa-2b and ribavirin were administered for 4 weeks (the leadin period). Subsequently, group 1 (the control group) received placebo plus peginterferon–ribavirin for 44 weeks; group 2 received boceprevir plus peginterferon– ribavirin for 24 weeks, and those with a detectable HCV RNA level between weeks 8 and 24 received placebo plus peginterferon–ribavirin for an additional 20 weeks; and group 3 received boceprevir plus peginterferon–ribavirin for 44 weeks. Nonblack patients and black patients were enrolled and analyzed separately. Results A total of 938 nonblack and 159 black patients were treated. In the nonblack cohort, a sustained virologic response was achieved in 125 of the 311 patients (40%) in group 1, in 211 of the 316 patients (67%) in group 2 (P

Published
2011

22. A randomized study of pegylated liposomal doxorubicin versus continuous-infusion doxorubicin in elderly patients with acute lymphoblastic leukemia: the GRAALL-SA1 study

Author

Hunault-Berger, Mathilde, Leguay, Thibaut, Thomas, Xavier, Legrand, Ollivier, Huguet, Françoise, Bonmati, Caroline, Escoffre-Barbe, Martine, Legros, Laurence, Turlure, Pascal, Chevallier, Patrice, Larosa, Fabrice, Garban, Frederic, Reman, Oumedaly, Rousselot, Philippe, Dhédin, Nathalie, Delannoy, André, Lafage-Pochitaloff, Marina, Béné, Marie Christine, Ifrah, Norbert, Dombret, Hervé, Renseigné, Non, Service des maladies du sang, Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL), Laboratoire d'Hématologie [Purpan], Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Service d'hématologie clinique, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou, Institut de Biologie Valrose (IBV), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Service d'Hématologie clinique et thérapie cellulaire [CHU Limoges], CHU Limoges, Service d'hématologie, Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), TheREx, Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications, Grenoble - UMR 5525 (TIMC-IMAG), VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)-Département de cancérologie et d'hématologie, CHU Grenoble-Hôpital Michallon-CHU Grenoble-Hôpital Michallon, Hôpital de Jolimont, Haine-Saint-Paul and Cliniques Universitaires St Luc, Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Service d'Immunologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Service d'hématologie clinique [Avicenne], Université Paris 13 (UP13)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Avicenne [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Lymphocyte et cancer, IFR105-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service Hématologie - IUCT-Oncopole [CHU Toulouse], Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle IUCT [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Université de Rennes (UR)-Hôpital Pontchaillou, Université Nice Sophia Antipolis (1965 - 2019) (UNS), and Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Département de cancérologie et d'hématologie

Subjects
Male, Pharmacology, Gastroenterology, Dexamethasone, Polyethylene Glycols, 0302 clinical medicine, MESH: Aged, 80 and over, Antineoplastic Combined Chemotherapy Protocols, Cumulative incidence, MESH: Treatment Outcome, Aged, 80 and over, MESH: Aged, MESH: Middle Aged, Hematology, Middle Aged, Precursor Cell Lymphoblastic Leukemia-Lymphoma, 3. Good health, Survival Rate, MESH: Antineoplastic Combined Chemotherapy Protocols, Treatment Outcome, Vincristine, 030220 oncology & carcinogenesis, MESH: Dexamethasone, Toxicity, Female, Original Article, MESH: Neoplasm Recurrence, Local, medicine.drug, Adult, medicine.medical_specialty, Cyclophosphamide, MESH: Survival Rate, MESH: Vincristine, [SDV.CAN]Life Sciences [q-bio]/Cancer, 03 medical and health sciences, MESH: Doxorubicin, Internal medicine, medicine, Humans, Doxorubicin, Survival rate, Aged, MESH: Precursor Cell Lymphoblastic Leukemia-Lymphoma, MESH: Humans, business.industry, MESH: Cyclophosphamide, MESH: Adult, medicine.disease, MESH: Male, MESH: Polyethylene Glycols, Bacteremia, Liposomes, MESH: Liposomes, Neoplasm Recurrence, Local, business, MESH: Female, 030215 immunology
Abstract

International audience; BACKGROUND: The prognosis of acute lymphoblastic leukemia in the elderly is poor. The GRAALL-SA1 phase II, randomized trial compared the efficacy and toxicity of pegylated liposomal doxorubicin versus continuous-infusion doxorubicin in patients 55 years or older with Philadelphia chromosome-negative acute lymphoblastic leukemia. DESIGN AND METHODS: Sixty patients received either continuous-infusion doxorubicin (12 mg/m(2)/day) and continuous-infusion vincristine (0.4 mg/day) on days 1-4 or pegylated liposomal doxorubicin (40 mg/m(2)) and standard vincristine (2 mg) on day 1, accompanied by dexamethasone, followed at day 28 by a second cycle, reinforced by cyclophosphamide. End-points were safety, outcome and prognostic factors. RESULTS: Myelosuppression was reduced in the pegylated liposomal doxorubicin arm with shorter severe neutropenia (P=0.05), shorter severe thrombocytopenia (P=0.03), and fewer red blood cell transfusions (P=0.04). Grade 3/4 infections and Gram-negative bacteremia were reduced in the pegylated liposomal doxorubicin arm (P=0.04 and P=0.02, respectively). There was a trend towards fewer cardiac events among the patients who received pegylated liposomal doxorubicin (1/29 versus 6/31). The complete remission rate was 82% and, with a median follow-up of 4 years, median event-free survival and overall survival were 9 and 10 months, respectively. Despite the better tolerance of pegylated liposomal doxorubicin, no differences in survival were observed between the two arms, due to trends towards more induction refractoriness (17 versus 3%, P=0.10) and a higher cumulative incidence of relapse (52% versus 32% at 2 years, P=0.20) in the pegylated liposomal doxorubicin arm. CONCLUSIONS: With the drug schedules used in this study, pegylated liposomal doxorubicin did not improve the outcome of elderly patients with acute lymphoblastic leukemia despite reduced toxicities.

Published
2011

23. Gene transfer by histidylated lipopolyplexes: A dehydration method allowing preservation of their physicochemical parameters and transfection efficiency

Author

Olivier Lambert, Paul-Alain Jaffrès, Federico Perche, Patrick Midoux, Chantal Pichon, Mathieu Berchel, Centre de biophysique moléculaire (CBM), Université d'Orléans (UO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Chimie et Biologie des Membranes et des Nanoobjets (CBMN), École Nationale d'Ingénieurs des Travaux Agricoles - Bordeaux (ENITAB)-Institut de Chimie du CNRS (INC)-Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Chimie, Electrochimie Moléculaires et Chimie Analytique (CEMCA), Université de Brest (UBO)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), Université de Bordeaux (UB)-École Nationale d'Ingénieurs des Travaux Agricoles - Bordeaux (ENITAB)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Institut des Sciences Chimiques de Rennes (ISCR), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), and Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Ecole Nationale Supérieure de Chimie de Rennes (ENSCR)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Sucrose, Evaporation, Pharmaceutical Science, Nanoparticle, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, Polyethylene Glycols, chemistry.chemical_compound, MESH: Histidine, 0302 clinical medicine, Drug Stability, Luciferases, Firefly, Polylysine, MESH: Static Electricity, chemistry.chemical_classification, 0303 health sciences, Liposome, MESH: Drug Storage, Chemistry, Dextran Sulfate, Gene Transfer Techniques, Imidazoles, Polymer, Lipids, 030220 oncology & carcinogenesis, MESH: HEK293 Cells, MESH: Cryoelectron Microscopy, MESH: Imidazoles, Plasmids, Surface Properties, Drug Storage, Static Electricity, MESH: Gene Transfer Techniques, Transfection, 03 medical and health sciences, MESH: Plasmids, MESH: Drug Stability, medicine, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Histidine, Surface charge, Dehydration, MESH: Particle Size, Particle Size, 030304 developmental biology, MESH: Surface Properties, MESH: Dextran Sulfate, Chromatography, MESH: Humans, MESH: Luciferases, Firefly, MESH: Transfection, MESH: Sucrose, Cryoelectron Microscopy, medicine.disease, MESH: Lipids, MESH: Polylysine, HEK293 Cells, MESH: Polyethylene Glycols, Liposomes, Nucleic acid, MESH: Liposomes, Nanoparticles, MESH: Nanoparticles, Nuclear chemistry
Abstract

International audience; Lipid-Polycation-DNA complexes (LPD) is a promising non-viral system for nucleic acids delivery. Usually, LPD are prepared just before their use. In the present work, we have examined whether dehydration of a new type of LPD (named LPD100) might be a storage option. LPD100 comprises PEGylated histidylated polylysine/pDNA polyplexes and a liposomal formulation made with lipophosphoramidates containing N-methylimidazolium and histamine polar heads. LPD100 were dehydrated by evaporation, and the physicochemical parameters and transfection efficiency (TE) of reconstituted LPD100 were compared to that of fresh LPD100. LPD100 previously dehydrated in the presence of 20% saccharose, displayed comparable size and surface charge as freshly prepared LPD100 but gave a better TE. CryoTEM experiments showed that the reconstituted LPD100 exhibited a shape similar to fresh ones. Moreover, when LPD100 were prepared with dehydrated pDNA/polymer complexes and fresh liposomes, TE was as efficient as with fresh LPD100 while a small increase of their size were observed. These results demonstrate that evaporation of LPD100 in the presence of saccharose is a powerful method to store them for a long period of time.

Published
2011

24. A non-covalent peptide-based strategy for ex vivo and in vivo oligonucleotide delivery

Author

Crombez , Laurence, Morris , May C, Heitz , Frederic, Divita , Gilles, Centre de recherches de biochimie macromoléculaire ( CRBM ), Université Montpellier 1 ( UM1 ) -Université Montpellier 2 - Sciences et Techniques ( UM2 ) -IFR122-Centre National de la Recherche Scientifique ( CNRS ), Centre de recherche en Biologie Cellulaire (CRBM), and Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Université Montpellier 1 (UM1)

Subjects
Male, Peptide Nucleic Acids, MESH : Cell Line, MESH : Molecular Sequence Data, MESH : RNA, Messenger, Oligonucleotides, Cell-Penetrating Peptides, MESH: Amino Acid Sequence, MESH : RNA, Small Interfering, Polyethylene Glycols, Mice, Drug Delivery Systems, MESH: Oligonucleotides, MESH : Cell-Penetrating Peptides, MESH: RNA, Small Interfering, MESH: Animals, MESH : Female, RNA, Small Interfering, MESH: Cell-Penetrating Peptides, MESH: Peptides, MESH : Peptides, MESH : Amino Acid Sequence, MESH : Peptide Nucleic Acids, MESH : Polyethylene Glycols, RNA-Binding Proteins, MESH : Mice, Nude, MESH : Protein Binding, MESH: Oligopeptides, MESH : Drug Delivery Systems, Female, MESH : Transfection, Oligopeptides, MESH : Prostatic Neoplasms, Protein Binding, MESH : Oligopeptides, MESH: Cyclin B1, MESH : Male, Molecular Sequence Data, MESH: Drug Delivery Systems, MESH : RNA-Binding Proteins, Mice, Nude, MESH : Oligonucleotides, Transfection, Cell Line, MESH: Cell Adhesion, MESH: Peptide Nucleic Acids, MESH : Mice, Cell Adhesion, MESH: Mice, Nude, Animals, Humans, MESH: Protein Binding, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Amino Acid Sequence, RNA, Messenger, Cyclin B1, MESH: Mice, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: RNA, Messenger, MESH: Humans, MESH: Molecular Sequence Data, MESH: Transfection, MESH : Humans, Prostatic Neoplasms, MESH : Disease Models, Animal, MESH: Male, MESH: Cell Line, MESH : Cyclin B1, Disease Models, Animal, MESH : Cell Adhesion, MESH: RNA-Binding Proteins, MESH: Polyethylene Glycols, MESH : Nanoparticles, MESH: Prostatic Neoplasms, Nanoparticles, MESH : Animals, MESH: Disease Models, Animal, Peptides, MESH: Female, MESH: Nanoparticles
Abstract

International audience; The dramatic acceleration in identification of new nucleic acid-based therapeutic molecules such as short interfering RNA (siRNA) and peptide-nucleic acid (PNA) analogues has provided new perspectives for therapeutic targeting of specific genes responsible for pathological disorders. However, the poor cellular uptake of nucleic acids together with the low permeability of the cell membrane to negatively charged molecules remain major obstacles to their clinical development. Several non-viral strategies have been proposed to improve the delivery of synthetic short oligonucleotides both in cultured cells and in vivo. Cell-penetrating peptides constitute very promising tools for non-invasive cellular import of oligonucleotides and analogs. We recently described a non-covalent strategy based on short amphiphatic peptides (MPG8/PEP3) that have been successfully applied ex vivo and in vivo for the delivery of therapeutic siRNA and PNA molecules. PEP3 and MPG8 form stable nanoparticles with PNA analogues and siRNA, respectively, and promote their efficient cellular uptake, independently of the endosomal pathway, into a wide variety of cell lines, including primary and suspension lines, without any associated cytotoxicity. This chapter describes easy-to-handle protocols for the use of MPG-8 or PEP-3-nanoparticle technologies for PNA and siRNA delivery into adherent and suspension cell lines as well as in vivo into cancer mouse models.

Published
2011

25. A GEIL flow cytometry consensus proposal for quantification of plasma cells: Application to differential diagnosis between MGUS and myeloma

Author

Frébet, Elise, Abraham, Julie, Geneviève, Franck, Lepelley, Pascale, Daliphard, Sylvie, Bardet, Valérie, Amsellem, Sophie, Guy, Julien, Mullier, Francois, Durrieu, Francoise, Venon, Marie-Dominique, Leleu, Xavier, Jaccard, Arnaud, Faucher, Jean-Luc, Béné, Marie C, Feuillard, Jean, Renseigné, Non, Physiologie Moléculaire de la Réponse Immune et des Lymphoproliférations (PMRIL), Université de Limoges (UNILIM)-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503)-Centre National de la Recherche Scientifique (CNRS), Service d'Hématologie biologique [CHU Limoges], and CHU Limoges

Subjects
Pathology, MESH: Anemia, MESH: Remission Induction, MESH: Piperazines, MESH: Flow Cytometry, MESH: Multiple Myeloma, Monoclonal Gammopathy of Undetermined Significance, 0302 clinical medicine, immune system diseases, hemic and lymphatic diseases, MESH: Cytarabine, MESH: Proto-Oncogene Proteins c-abl, MESH: Treatment Outcome, MESH: Plasma Cells, MESH: Middle Aged, medicine.diagnostic_test, Flow Cytometry, 3. Good health, MESH: Reproducibility of Results, MESH: Antineoplastic Combined Chemotherapy Protocols, medicine.anatomical_structure, 030220 oncology & carcinogenesis, MESH: Survival Analysis, [SDV.IMM]Life Sciences [q-bio]/Immunology, Multiple Myeloma, MESH: Interferon Alfa-2a, medicine.medical_specialty, Validation study, Histology, MESH: Neutropenia, Plasma Cells, MESH: Stem Cells, MESH: Bone Marrow Neoplasms, Sensitivity and Specificity, Pathology and Forensic Medicine, Flow cytometry, Diagnosis, Differential, 03 medical and health sciences, MESH: Diagnosis, Differential, medicine, Humans, MESH: Thrombocytopenia, MESH: Humans, business.industry, MESH: Transcription, Genetic, MESH: Fusion Proteins, bcr-abl, Reproducibility of Results, MESH: Adult, Cell Biology, MESH: RNA, Neoplasm, Minimal residual disease, MESH: Sensitivity and Specificity, MESH: Male, Multicenter study, MESH: Polyethylene Glycols, MESH: Monoclonal Gammopathy of Undetermined Significance, MESH: Pyrimidines, Bone marrow, Differential diagnosis, business, Bone Marrow Neoplasms, MESH: Leukemia, Myeloid, Chronic-Phase, MESH: Female, 030215 immunology
Abstract

International audience; BACKGROUND:: Flow cytometry is the sole available technique for quantification of tumor plasma-cells in plasma-cell disorders, but so far, no consensus technique has been proposed. Here, we report on a standardized, simple, robust five color flow cytometry protocol developed to characterize and quantify bone marrow tumor plasma-cells, validated in a multicenter manner. METHODS:: CD36 was used to exclude red blood cell debris and erythroblasts, CD38 and CD138 to detect plasma-cells, immunoglobulin light chains, CD45, CD56, CD19, and CD117 + CD34 to simultaneously characterize abnormal plasma-cells and quantify bone marrow precursors. This approach was applied in nine centers to 229 cases, including 25 controls. RESULTS:: Tumor plasma-cells were detected in 96.8% of cases, all exhibiting an immunoglobulin peak over 1g/L. Calculation of a plasma-cells/precursors (PC/P) ratio allowed quantification of the plasma-cell burden independently from bone marrow hemodilution. The PC/P ratio yielded the best results in terms of sensitivity (81%) and specificity (84%) for differential diagnosis between MGUS and myeloma, when compared with other criteria. Combination of both the PC/P ratio and percentage of abnormal plasma-cells allowed the best differential diagnosis, but these criteria were discordant in 25% cases. Indirect calculation of CD19 negative PC/R ratio gave the best results in terms of sensitivity (87%). CONCLUSION:: This standardized multiparameter flow cytometric approach allows for the detection and quantification of bone marrow tumor plasma-cell infiltration in nearly all cases of MGUS and myeloma, independently of debris and hemodilution. This approach may also prove useful for the detection of minimal residual disease. © 2010 International Clinical Cytometry Society.

Published
2010

26. Improvement of HepG2/C3a cell functions in a microfluidic biochip

Author

Jean-Matthieu Prot, Anne Corlu, Caroline Aninat, Céline Brochot, Eric Leclerc, Cécile Legallais, Laurent Griscom, Florence Razan, Christiane Guillouzo, Bio-MIcroSystèmes et BioSensors (SATIE-BIOMIS), Systèmes d'Information et d'Analyse Multi-Echelles (SIAME), Systèmes et Applications des Technologies de l'Information et de l'Energie (SATIE), École normale supérieure - Cachan (ENS Cachan)-Université Paris-Sud - Paris 11 (UP11)-Institut Français des Sciences et Technologies des Transports, de l'Aménagement et des Réseaux (IFSTTAR)-École normale supérieure - Rennes (ENS Rennes)-Université de Cergy Pontoise (UCP), Université Paris-Seine-Université Paris-Seine-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Cachan (ENS Cachan)-Université Paris-Sud - Paris 11 (UP11)-Institut Français des Sciences et Technologies des Transports, de l'Aménagement et des Réseaux (IFSTTAR)-École normale supérieure - Rennes (ENS Rennes)-Université de Cergy Pontoise (UCP), Université Paris-Seine-Université Paris-Seine-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Centre National de la Recherche Scientifique (CNRS)-Systèmes et Applications des Technologies de l'Information et de l'Energie (SATIE), Université Paris-Seine-Université Paris-Seine-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Centre National de la Recherche Scientifique (CNRS), Razan, Florence, Biomécanique et génie biomédical (BIM), Centre National de la Recherche Scientifique (CNRS), Foie, métabolismes et cancer, Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université Paris-Seine-Université Paris-Seine-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Centre National de la Recherche Scientifique (CNRS), Institut National de l'Environnement Industriel et des Risques (INERIS), Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )

Subjects
MESH: Cell Death, MESH: Anemia, Glutamine, Cell, Microfluidics, 02 engineering and technology, Applied Microbiology and Biotechnology, MESH: Tissue Engineering, MESH: Recombinant Proteins, MESH: Hepatocytes, MESH: Microfluidics, MESH: Genotype, chemistry.chemical_compound, Tissue engineering, PDMS, MESH: Dimethylpolysiloxanes, MESH: Double-Blind Method, MESH: Hepacivirus, Biochip, ComputingMilieux_MISCELLANEOUS, MESH: Treatment Outcome, 0303 health sciences, MESH: Middle Aged, Cell Death, 021001 nanoscience & nanotechnology, MESH: Hepatitis C, Chronic, MESH: Glucose, medicine.anatomical_structure, Biochemistry, MESH: Cell Survival, MESH: RNA, Viral, MESH: Nylons, MESH: Interferon-alpha, 0210 nano-technology, MESH: Viral Load, Biotechnology, microfluidic biochip, MESH: Antiviral Agents, MESH: Serine Proteinase Inhibitors, Cell Survival, [SPI.NANO] Engineering Sciences [physics]/Micro and nanotechnologies/Microelectronics, Bioengineering, Biology, liver, Cell Line, 03 medical and health sciences, MESH: Gene Expression Profiling, MESH: Ribavirin, Albumins, medicine, Humans, Dimethylpolysiloxanes, [SPI.NANO]Engineering Sciences [physics]/Micro and nanotechnologies/Microelectronics, 030304 developmental biology, MESH: Glutamine, MESH: Humans, MESH: Proline, Tissue Engineering, Gene Expression Profiling, MESH: Adult, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, transcriptomic, Molecular biology, Fold change, In vitro, MESH: Male, MESH: Cell Line, MESH: Drug Therapy, Combination, Nylons, Glucose, chemistry, MESH: Polyethylene Glycols, Cell culture, Hepatocytes, MESH: African Continental Ancestry Group, MESH: Albumins, Xenobiotic, MESH: Female, Drug metabolism
Abstract

International audience; Current developments in tissue engineering and microtechnology fields allow the use of microfluidic biochip as microtools for in vitro investigations. In the present study, we describe the behavior of HepG2/C3a cells cultivated in a poly(dimethylsiloxane) (PDMS) microfluidic biochip coupled to a perfusion system. Cell culture in the microfluidic biochip for 96 h including 72 h of perfusion provoked a 24 h delay in cell growth compared to plate cultures. Inside the microfluidic biochip, few apoptosis, and necrosis were detected along the culture and 3D cell organization was observed. Regarding the hepatic metabolism, glucose and glutamine consumptions as well as albumin synthesis were maintained. A transcriptomic analysis performed at 96 h of culture using Affymetrix GeneChip demonstrated that 1,025 genes with a fold change above 1.8 were statistically differentially expressed in the microfluidic biochip cultures compared to plate cultures. Among those genes, phase I enzymes involved in the xenobiotic's metabolism such as the cytochromes P450 (CYP) 1A1/2, 2B6, 3A4, 3A5, and 3A7 were up-regulated. The CYP1A1/2 up-regulation was associated with the appearance of CYP1A1/2's activity evidenced by using EROD biotransformation assay. Several phase II enzymes such as sulfotransferases (SULT1A1 and SULT1A2), UDP-glucuronyltransferase (UGT1A1, UGT2B7) and phase III transporters (such as MDR1, MRP2) were also up-regulated. In conclusion, microfluidic biochip could and provide an important insight to exploring the xenobiotic's metabolism. Altogether, these results suggest that this kind of biochip could be considered as a new pertinent tool for predicting cell toxicity and clearance of xenobiotics in vitro.

Published
2010

27. Effectiveness of chronic hepatitis C treatment in drug users in routine clinical practice: results of a prospective cohort study

Author

Pascal, Melin, Michel, Chousterman, Thierry, Fontanges, Denis, Ouzan, Michel, Rotily, Jean-Philippe, Lang, Patrick, Marcellin, Patrice, Cacoub, Jean-Pierre, Zarski, Service d'hépatologie, Hôpital Beaujon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Service de médecine interne [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Biologie et thérapeutique des pathologies immunitaires (BTPI), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Hôpital Beaujon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Diderot - Paris 7 (UPD7)-Hôpital Beaujon, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], and Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)

Subjects
hepatitis C virus, Hepacivirus, medicine.disease_cause, MESH: Analgesics, Opioid, Polyethylene Glycols, Cohort Studies, peginterferon α-2b, MESH: Recombinant Proteins, chemistry.chemical_compound, 0302 clinical medicine, Quality of life, Surveys and Questionnaires, Prospective Studies, 030212 general & internal medicine, adherence, Prospective cohort study, MESH: Cohort Studies, media_common, MESH: Treatment Outcome, biology, Gastroenterology, Hepatitis C, Recombinant Proteins, 3. Good health, MESH: Hepatitis C, Chronic, Analgesics, Opioid, Treatment Outcome, MESH: Substance-Related Disorders, Drug Therapy, Combination, 030211 gastroenterology & hepatology, sustained virological response, MESH: Interferon-alpha, Cohort study, Drug, MESH: Antiviral Agents, medicine.medical_specialty, Substance-Related Disorders, ribavirin, media_common.quotation_subject, Hepatitis C virus, Interferon alpha-2, Antiviral Agents, Medication Adherence, 03 medical and health sciences, MESH: Ribavirin, Internal medicine, medicine, drug use, Hepatology, business.industry, Ribavirin, MESH: Questionnaires, Interferon-alpha, MESH: Quality of Life, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Hepatitis C, Chronic, MESH: Medication Adherence, medicine.disease, biology.organism_classification, MESH: Prospective Studies, MESH: Drug Therapy, Combination, routine clinical practice, chemistry, MESH: Polyethylene Glycols, Immunology, Quality of Life, business
Abstract

International audience; OBJECTIVE: Injection drug users are often excluded from hepatitis C virus (HCV) treatment. This study compares sustained virological response, adherence, and quality of life in patients with or without a history of illicit drug use in routine clinical practice. METHODS: This is a post-hoc analysis of a prospective, observational study conducted in 1860 patients who received peginterferon alpha-2b/ribavirin combination therapy. Nondrug users (NDUs) were defined as patients without a history of drug addiction; former drug users (FDUs) as patients who had stopped using illicit drugs or opioid maintenance therapy and active drug users (ADUs) as patients using illicit drugs or on opioid maintenance therapy. Virological response, adherence, and the health-related quality of life were assessed by the measure of HCV RNA in the serum, self-report and 36-item short-form health survey Questionnaire, respectively. RESULTS: The analyzed population included 1038 (56%) NDUs, 578 (31%) FDUs, and 244 (13%) ADUs. About 85% of ADUs were on opioid maintenance therapy and 25% used illicit drugs. Although ADUs had a more chaotic lifestyle and more psychiatric disorders, sustained virological response of ADUs (58%) did not differ from that of NDUs (49%) and FDUs (51%) (P=0.133). Adherence rates were 39% in NDUs and FDUs, and 37% in ADUs (P=0.883). Health-related quality of life was improved in the three groups after the end of treatment. CONCLUSION: Our study suggests that HCV therapy in ADUs on opioid maintenance therapy is as effective as in other HCV patients. The effectiveness of HCV therapy in illicit drug users needs to be evaluated in further studies.

Published
2010

28. Randomized trial of peginterferon alfa-2b and ribavirin for 48 or 72 weeks in patients with hepatitis C virus genotype 1 and slow virologic response

Author

Maria, Buti, Yoav, Lurie, Natalia G, Zakharova, Natalia P, Blokhina, Andrzej, Horban, Gerlinde, Teuber, Christoph, Sarrazin, Ligita, Balciuniene, Saya V, Feinman, Rab, Faruqi, Lisa D, Pedicone, Rafael, Esteban, S, Ryder, Department of Medicine, Clinicum, Hospital General, and Vall d'Hebron University Hospital [Barcelona]

Subjects
Male, Time Factors, Medizin, Hepacivirus, medicine.disease_cause, Gastroenterology, law.invention, Polyethylene Glycols, MESH: Recombinant Proteins, chemistry.chemical_compound, 0302 clinical medicine, Randomized controlled trial, law, INFECTION, Medicine, MESH: Hepacivirus, MESH: Treatment Outcome, MESH: Aged, MESH: Middle Aged, Hepatitis C, Middle Aged, Viral Load, PLUS RIBAVIRIN, Recombinant Proteins, 3. Good health, MESH: Hepatitis C, Chronic, Treatment Outcome, 030220 oncology & carcinogenesis, MESH: RNA, Viral, Peginterferon alfa-2b, RNA, Viral, 030211 gastroenterology & hepatology, Drug Therapy, Combination, Female, MESH: Interferon-alpha, MESH: Viral Load, Viral load, medicine.drug, MESH: Antiviral Agents, Adult, medicine.medical_specialty, Adolescent, Hepatitis C virus, Interferon alpha-2, Antiviral Agents, Drug Administration Schedule, 03 medical and health sciences, MESH: Ribavirin, Internal medicine, Ribavirin, Humans, Aged, MESH: Adolescent, MESH: Humans, Hepatology, business.industry, Body Weight, MESH: Time Factors, Interferon-alpha, MESH: Adult, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Hepatitis C, Chronic, medicine.disease, MESH: Male, Surgery, Discontinuation, MESH: Drug Therapy, Combination, COMBINATION THERAPY, chemistry, MESH: Polyethylene Glycols, 3121 General medicine, internal medicine and other clinical medicine, business, TREATMENT DURATION, MESH: Female
Abstract

International audience; UNLABELLED: The benefit of extending treatment duration with peginterferon (PEG-IFN) and ribavirin (RBV) from 48 weeks to 72 weeks for patients with chronic hepatitis C genotype 1 infection has not been well established. In this prospective, international, open-label, randomized, multicenter study, 1,428 treatment-naïve patients from 133 centers were treated with PEG-IFN alfa-2b (1.5 μg/kg/week) plus RBV (800-1,400 mg/day). Patients with detectable hepatitis C virus (HCV) RNA and a ≥2-log(10) drop in HCV RNA levels at week 12 (slow responders) were randomized 1:1 to receive 48 weeks (n = 86) or 72 weeks (n = 73) of treatment. Sustained virologic response (SVR) rates were 43% in slow responders treated for 48 weeks and 48% in slow responders treated for 72 weeks (P = 0.644). Relapse rates were similar in slow responders treated for 48 or 72 weeks (47% versus 33%, P = 0.169). The safety profile was similar in both treatment arms; serious adverse events leading to discontinuation of treatment were observed in 3.5% of slow responders treated for 48 weeks and 8.2% of those treated for 72 weeks. Among slow responders with a

Published
2010

29. Small and stable peptidic PEGylated quantum dots to target polyhistidine-tagged proteins with controlled stoichiometry

Author

Roland Le Borgne, Victor Roullier, Mathieu Pinot, Fouzia Boulmedais, Maxime Dahan, Michèle Baudy-Floc’h, Valérie Marchi-Artzner, Françoise Vignaux, Aurélien Dif, Frédéric M. Coquelle, Samuel Clarke, Zoher Gueroui, Pierre Neveu, Institut des Sciences Chimiques de Rennes (ISCR), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Ecole Nationale Supérieure de Chimie de Rennes (ENSCR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA), Institut Charles Sadron (ICS), Université de Strasbourg (UNISTRA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Réseau nanophotonique et optique, Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Matériaux et nanosciences d'Alsace (FMNGE), Institut de Chimie du CNRS (INC)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de Physique de Rennes (IPR), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS), Interactions cellulaires et moléculaires (ICM), Laboratoire Kastler Brossel (LKB (Lhomond)), Université Pierre et Marie Curie - Paris 6 (UPMC)-Fédération de recherche du Département de physique de l'Ecole Normale Supérieure - ENS Paris (FRDPENS), École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Processus d'Activation Sélective par Transfert d'Energie Uni-électronique ou Radiatif (UMR 8640) (PASTEUR), Université Pierre et Marie Curie - Paris 6 (UPMC)-Département de Chimie - ENS Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Institut de Génétique et Développement de Rennes (IGDR), Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Ecole Nationale Supérieure de Chimie de Rennes (ENSCR)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Université de Strasbourg (UNISTRA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Matériaux et Nanosciences Grand-Est (MNGE), Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Réseau nanophotonique et optique, Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS), Fédération de recherche du Département de physique de l'Ecole Normale Supérieure - ENS Paris (FRDPENS), École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), and De Villemeur, Hervé

Subjects
Light, Aucun, 02 engineering and technology, MESH: Movement, 01 natural sciences, Biochemistry, Microtubules, Polyethylene Glycols, Substrate Specificity, MESH: Histidine, Colloid and Surface Chemistry, Aspartic acid, Scattering, Radiation, MESH: Proteins, MESH: Animals, Peptide sequence, Gel electrophoresis, [PHYS.PHYS.PHYS-BIO-PH] Physics [physics]/Physics [physics]/Biological Physics [physics.bio-ph], Chemistry, MESH: Peptides, MESH: Microtubules, Protein Stability, MESH: Molecular Probes, MESH: Quantum Dots, 021001 nanoscience & nanotechnology, Ligand (biochemistry), Transport protein, [SDV.BBM.BP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biophysics, MESH: Staining and Labeling, Protein Transport, MESH: Cell Survival, analysis, chemistry, metabolism, 0210 nano-technology, Microtubule-Associated Proteins, MESH: Spectrometry, Fluorescence, MESH: Protein Transport, Microtubule-associated protein, Cell Survival, [PHYS.PHYS.PHYS-BIO-PH]Physics [physics]/Physics [physics]/Biological Physics [physics.bio-ph], Movement, [SDV.BBM.BP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biophysics, Spindle Apparatus, 010402 general chemistry, Catalysis, Microtubule, MESH: Protein Stability, Quantum Dots, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Animals, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Histidine, MESH: Scattering, Radiation, MESH: Mitotic Spindle Apparatus, MESH: Humans, Staining and Labeling, Proteins, General Chemistry, MESH: Light, 0104 chemical sciences, MESH: Extracellular Space, MESH: Hela Cells, Surface coating, MESH: Microtubule-Associated Proteins, Spectrometry, Fluorescence, MESH: Polyethylene Glycols, Molecular Probes, Biophysics, MESH: Substrate Specificity, Extracellular Space, Peptides, HeLa Cells
Abstract

The use of the semiconductor quantum dots (QD) as biolabels for both ensemble and single-molecule tracking requires the development of simple and versatile methods to target individual proteins in a controlled manner, ideally in living cells. To address this challenge, we have prepared small and stable QDs (QD-ND) using a surface coating based on a peptide sequence containing a tricysteine, poly(ethylene glycol) (PEG), and an aspartic acid ligand. These QDs, with a hydrodynamic diameter of 9 +/- 1.5 nm, can selectively bind to polyhistidine-tagged (histag) proteins in vitro or in living cells. We show that the small and monodisperse size of QD-ND allows for the formation of QD-ND/histag protein complexes of well-defined stoichiometry and that the 1:1 QD/protein complex can be isolated and purified by gel electrophoresis without any destabilization in the nanomolar concentration range. We also demonstrate that QD-ND can be used to specifically label a membrane receptor with an extracellular histag expressed in living HeLa cells. Here, cytotoxicity tests reveal that cell viability remains high under the conditions required for cellular labeling with QD-ND. Finally, we apply QD-ND complexed with histag end binding protein-1 (EB1), a microtubule associated protein, to single-molecule tracking in Xenopus extracts. Specific colocalization of QD-ND/EB1 with microtubules during the mitotic spindle formation demonstrates that QD-ND and our labeling strategy provide an efficient approach to monitor the dynamic behavior of proteins involved in complex biological functions. journal article research support, non-u.s. gov't 2009 Oct 21 imported

Published
2009

30. Ternary protein adsorption onto brushes: strong versus weak

Author

Avraham Halperin, Martin Kröger, Laboratoire Interdisciplinaire de Physique [Saint Martin d’Hères] (LIPhy), Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF), and Polymer Physics

Subjects
MESH: Serum Albumin, MESH: Solvents, 02 engineering and technology, Polyethylene glycol, Degree of polymerization, 010402 general chemistry, 01 natural sciences, Polyethylene Glycols, MESH: Linear Models, chemistry.chemical_compound, Adsorption, PEG ratio, Polymer chemistry, Electrochemistry, General Materials Science, MESH: Proteins, [SDV.IB.BIO]Life Sciences [q-bio]/Bioengineering/Biomaterials, Serum Albumin, Spectroscopy, MESH: Models, Chemical, technology, industry, and agriculture, Proteins, Surfaces and Interfaces, 021001 nanoscience & nanotechnology, Condensed Matter Physics, 0104 chemical sciences, Crystallography, Monomer, Models, Chemical, chemistry, Polymerization, MESH: Polyethylene Glycols, Linear Models, Solvents, MESH: Adsorption, 0210 nano-technology, Ternary operation, Protein adsorption
Abstract

International audience; Attractive interactions between proteins and polyethylene glycol (PEG) give rise to ternary adsorption within PEG brushes. Experimental evidence suggests two ternary adsorption modes: (i) weak, due to nonspecific weak attraction between PEG monomers and the surface of the protein, as exemplified by serum albumin and (ii) strong, due to strong binding of PEG segments to specific protein sites as it occurs for PEG antibodies, which can involve the terminal adsorption of free chain ends or backbone adsorption due to binding to interior chain segments. Ternary adsorption affects the capacity of brushes to repress protein adsorption. The strong adsorption of antibodies can trigger an immune response that may affect the biocompatibility of the surface. Theoretical adsorption isotherms and protein concentration profiles of the three cases are compared for "parabolic" brushes, allowing for the grafting density, 1/Sigma, and degree of polymerization of the PEG chains, N, as well as the volume and surface area of the proteins. The amount of adsorbed protein per unit area, Gamma, exhibits a mode-specific maximum in all three cases. For backbone and weak adsorption, Gamma approximately N, whereas for terminal adsorption, Gamma approximately N0. In every case, the concentration profile of adsorbed proteins, ctern(z), exhibits a maximum at zmax>0 that shifts outward as Sigma decreases; zmax=0 occurs only for weak and backbone adsorption at a high Sigma value.

Published
2009

31. Telaprevir and peginterferon with or without ribavirin for chronic HCV infection.: PROVE2: Telaprevir with PEG-IFN and RBV in HCV

Author

Hézode , Christophe, Forestier , Nicole, Dusheiko , Geoffrey, Ferenci , Peter, Pol , Stanislas, Goeser , Tobias, Bronowicki , Jean-Pierre, Bourlière , Marc, Gharakhanian , Shahin, Bengtsson , Leif, McNair , Lindsay, George , Shelley, Kieffer , Tara, Kwong , Ann, Kauffman , Robert, Alam , John, Pawlotsky , Jean-Michel, Zeuzem , Stefan, Service d'hépato-gastro-entérologie [APHP Henri Mondor], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Institut Mondor de recherche biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Dept. of Medicine I, J.W. Goethe University Hospital, Center for Hepatology, Royal Free Hospital-University College School of Medicine, Dept of internal medicine III, Medizinische Universität Wien = Medical University of Vienna, Institut Cochin (UMR_S567 / UMR 8104), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service d'hépatologie médicale [CHU Cochin], Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Dept. of Gastroenterology & Hepatology, University Hospital of Cologne [Cologne], Biologie Cellulaire et Moleculaire du Transport des Nutriments, Université Henri Poincaré - Nancy 1 (UHP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Hépato-gastro-entérologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Service d'Hépato-gastroentérologie, Assistance Publique - Hôpitaux de Marseille (APHM), Medicines Development Group (MDG), Vertex Pharmaceuticals, Centre National de Référence Virus des hépatites B, C et Delta, Institut National de la Transfusion Sanguine [Paris] (INTS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Hôpital Henri Mondor-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), University College School of Medicine-Royal Free Hospital [London, UK], Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ), Institut Mondor de recherche biomédicale ( IMRB ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ), Medical University of Vienna, Institut Cochin ( UMR_S567 / UMR 8104 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Cochin [AP-HP], Université Henri Poincaré - Nancy 1 ( UHP ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre Hospitalier Régional Universitaire de Nancy ( CHRU Nancy ), Assistance Publique - Hôpitaux de Marseille ( APHM ), Medicines Development Group ( MDG ), and Institut National de la Transfusion Sanguine [Paris] ( INTS ) -Assistance publique - Hôpitaux de Paris (AP-HP)

Subjects
MESH : Oligopeptides, MESH: Interferon Alfa-2a, MESH: Antiviral Agents, MESH : Hepatitis C, Chronic, MESH : Recurrence, MESH : Male, MESH : Drug Administration Schedule, MESH : Aged, MESH : Young Adult, MESH : Viral Load, MESH : Genotype, MESH: Drug Administration Schedule, MESH : Hepacivirus, MESH: Genotype, MESH: Ribavirin, MESH : RNA, Viral, MESH : Double-Blind Method, MESH : Middle Aged, MESH : Female, MESH: Double-Blind Method, MESH: Hepacivirus, MESH: Aged, MESH: Humans, MESH: Middle Aged, MESH : Drug Therapy, Combination, MESH : Humans, MESH : Polyethylene Glycols, virus diseases, MESH: Adult, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, MESH : Adult, MESH : Interferon Alfa-2a, digestive system diseases, MESH: Male, MESH : Antiviral Agents, MESH: Recurrence, MESH: Hepatitis C, Chronic, MESH : Ribavirin, MESH: Drug Therapy, Combination, MESH: Polyethylene Glycols, MESH: Young Adult, MESH: RNA, Viral, MESH: Oligopeptides, [ SDV.MHEP.HEG ] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, MESH: Viral Load, MESH: Female
Abstract

International audience; BACKGROUND: In patients with chronic infection with hepatitis C virus (HCV) genotype 1, treatment with peginterferon alfa and ribavirin for 48 weeks results in rates of sustained virologic response of 40 to 50%. Telaprevir is a specific inhibitor of the HCV serine protease and could be of value in HCV treatment. METHODS: A total of 334 patients who had chronic infection with HCV genotype 1 and had not been treated previously were randomly assigned to receive one of four treatments involving various combinations of telaprevir (1250 mg on day 1, then 750 mg every 8 hours), peginterferon alfa-2a (180 microg weekly), and ribavirin (dose according to body weight). The T12PR24 group (81 patients) received telaprevir, peginterferon alfa-2a, and ribavirin for 12 weeks, followed by peginterferon alfa-2a and ribavirin for 12 more weeks. The T12PR12 group (82 patients) received telaprevir, peginterferon alfa-2a, and ribavirin for 12 weeks. The T12P12 group (78 patients) received telaprevir and peginterferon alfa-2a without ribavirin for 12 weeks. The PR48 (control) group (82 patients) received peginterferon alfa-2a and ribavirin for 48 weeks. The primary end point, a sustained virologic response (an undetectable HCV RNA level 24 weeks after the end of therapy), was compared between the control group and the combined T12P12 and T12PR12 groups. RESULTS: The rate of sustained virologic response for the T12PR12 and T12P12 groups combined was 48% (77 of 160 patients), as compared with 46% (38 of 82) in the PR48 (control) group (P=0.89). The rate was 60% (49 of 82 patients) in the T12PR12 group (P=0.12 for the comparison with the PR48 group), as compared with 36% (28 of 78 patients) in the T12P12 group (P=0.003; P=0.20 for the comparison with the PR48 group). The rate was significantly higher in the T12PR24 group (69% [56 of 81 patients]) than in the PR48 group (P=0.004). The adverse events with increased frequency in the telaprevir-based groups were pruritus, rash, and anemia. CONCLUSIONS: In this phase 2 study of patients infected with HCV genotype 1 who had not been treated previously, one of the three telaprevir groups had a significantly higher rate of sustained virologic response than that with standard therapy. Response rates were lowest with the regimen that did not include ribavirin. (ClinicalTrials.gov number, NCT00372385.)

Published
2009

32. Telaprevir and peginterferon with or without ribavirin for chronic HCV infection

Author

Hézode, Christophe, Forestier, Nicole, Dusheiko, Geoffrey, Ferenci, Peter, Pol, Stanislas, Goeser, Tobias, Bronowicki, Jean-Pierre, Bourlière, Marc, Gharakhanian, Shahin, Bengtsson, Leif, Mcnair, Lindsay, George, Shelley, Kieffer, Tara, Kwong, Ann, Kauffman, Robert, Alam, John, Pawlotsky, Jean-Michel, Zeuzem, Stefan, Guellaen, Georges, Service d'hépato-gastro-entérologie [APHP Henri Mondor], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Institut Mondor de recherche biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Dept. of Medicine I, J.W. Goethe University Hospital, Center for Hepatology, University College School of Medicine-Royal Free Hospital [London, UK], Dept of internal medicine III, Medizinische Universität Wien = Medical University of Vienna, Institut Cochin (UMR_S567 / UMR 8104), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service d'hépatologie médicale [CHU Cochin], Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Dept. of Gastroenterology & Hepatology, University Hospital of Cologne [Cologne], Biologie Cellulaire et Moleculaire du Transport des Nutriments, Université Henri Poincaré - Nancy 1 (UHP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Hépato-gastro-entérologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Service d'Hépato-gastroentérologie, Assistance Publique - Hôpitaux de Marseille (APHM), Medicines Development Group (MDG), Vertex Pharmaceuticals, Centre National de Référence Virus des hépatites B, C et Delta, and Institut National de la Transfusion Sanguine [Paris] (INTS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)

Subjects
MESH: Aged, MESH: Interferon Alfa-2a, MESH: Antiviral Agents, MESH: Humans, MESH: Middle Aged, virus diseases, MESH: Adult, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, MESH: Drug Administration Schedule, digestive system diseases, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, MESH: Male, MESH: Recurrence, MESH: Hepatitis C, Chronic, MESH: Genotype, MESH: Drug Therapy, Combination, MESH: Polyethylene Glycols, MESH: Ribavirin, MESH: Young Adult, MESH: RNA, Viral, MESH: Oligopeptides, MESH: Double-Blind Method, MESH: Hepacivirus, MESH: Viral Load, MESH: Female
Abstract

International audience; BACKGROUND: In patients with chronic infection with hepatitis C virus (HCV) genotype 1, treatment with peginterferon alfa and ribavirin for 48 weeks results in rates of sustained virologic response of 40 to 50%. Telaprevir is a specific inhibitor of the HCV serine protease and could be of value in HCV treatment. METHODS: A total of 334 patients who had chronic infection with HCV genotype 1 and had not been treated previously were randomly assigned to receive one of four treatments involving various combinations of telaprevir (1250 mg on day 1, then 750 mg every 8 hours), peginterferon alfa-2a (180 microg weekly), and ribavirin (dose according to body weight). The T12PR24 group (81 patients) received telaprevir, peginterferon alfa-2a, and ribavirin for 12 weeks, followed by peginterferon alfa-2a and ribavirin for 12 more weeks. The T12PR12 group (82 patients) received telaprevir, peginterferon alfa-2a, and ribavirin for 12 weeks. The T12P12 group (78 patients) received telaprevir and peginterferon alfa-2a without ribavirin for 12 weeks. The PR48 (control) group (82 patients) received peginterferon alfa-2a and ribavirin for 48 weeks. The primary end point, a sustained virologic response (an undetectable HCV RNA level 24 weeks after the end of therapy), was compared between the control group and the combined T12P12 and T12PR12 groups. RESULTS: The rate of sustained virologic response for the T12PR12 and T12P12 groups combined was 48% (77 of 160 patients), as compared with 46% (38 of 82) in the PR48 (control) group (P=0.89). The rate was 60% (49 of 82 patients) in the T12PR12 group (P=0.12 for the comparison with the PR48 group), as compared with 36% (28 of 78 patients) in the T12P12 group (P=0.003; P=0.20 for the comparison with the PR48 group). The rate was significantly higher in the T12PR24 group (69% [56 of 81 patients]) than in the PR48 group (P=0.004). The adverse events with increased frequency in the telaprevir-based groups were pruritus, rash, and anemia. CONCLUSIONS: In this phase 2 study of patients infected with HCV genotype 1 who had not been treated previously, one of the three telaprevir groups had a significantly higher rate of sustained virologic response than that with standard therapy. Response rates were lowest with the regimen that did not include ribavirin. (ClinicalTrials.gov number, NCT00372385.)

Published
2009

33. Efficacy and safety of peginterferon alpha-2a/ribavirin in treatment-naive Cameroonian patients with chronic hepatitis C

Author

Eric Nerrienet, Michèle Tagni Sartre, Christophe Pasquier, Isabelle Timba, Patrice Tchendjou, Dominique Rousset, Richard Njouom, Centre Pasteur du Cameroun, Réseau International des Instituts Pasteur (RIIP), Institut Pasteur du Cambodge, Laboratoire d'Epidémiologie et de Santé Publique, and Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)

Subjects
Male, Hepacivirus, medicine.disease_cause, Polyethylene Glycols, MESH: Genotype, chemistry.chemical_compound, 0302 clinical medicine, Genotype, MESH: Hepacivirus, 030212 general & internal medicine, Cameroon, MESH: Treatment Outcome, MESH: Middle Aged, Hepatitis C, Middle Aged, Viral Load, Recombinant Proteins, MESH: Hepatitis C, Chronic, 3. Good health, Infectious Diseases, Treatment Outcome, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, 030211 gastroenterology & hepatology, Drug Therapy, Combination, Female, Viral disease, MESH: Viral Load, Peginterferon alfa-2a, medicine.drug, MESH: Antiviral Agents, MESH: Interferon Alfa-2a, Adult, Combination therapy, Hepatitis C virus, Interferon alpha-2, Antiviral Agents, 03 medical and health sciences, MESH: Ribavirin, Virology, Ribavirin, medicine, Humans, Adverse effect, MESH: Humans, business.industry, Interferon-alpha, MESH: Adult, MESH: Cameroon, Hepatitis C, Chronic, medicine.disease, MESH: Male, MESH: Drug Therapy, Combination, MESH: Polyethylene Glycols, chemistry, business, MESH: Female
Abstract

International audience; Data were examined from a day-to-day clinical practice in Yaounde, Cameroon to evaluate the efficacy and safety of peginterferon alfa-2a and ribavirin in treatment-naive Cameroonian patients with chronic hepatitis C. Ninety adults with chronic hepatitis C (mean age, 53 +/- 8 years; 79% males; 37.8% genotype 1; 23.3% genotype 2; and 38.9% genotype 4) were given at least 12 weeks of combination therapy between February 2003 and August 2007. Of these, 54 completed the treatment and the 24-week follow up. Subsequently, 18 continued treatment and 18 (20%) discontinued the treatment, 6 (6.7%) due to adverse effects. An intention-to-treat analysis showed that 38 (52.8%) had an end-of-treatment virologic response and 34 (47.2%) had a sustained virologic response. Sustained virologic response were significantly higher among patients with hepatitis C virus (HCV) genotype 2 (83.4%) than in those with genotype 1 (31%) or genotype 4 (42.3%) (P < 0.05). Non HCV-2 genotype, pretreatment fibrosis score >2, HCV RNA level >8.0 x 10(5) IU/ml and a non-virologic response at 12 weeks of treatment were associated with poor sustained virologic response (P < 0.05). Thus, HCV can be treated in a Sub-Saharan African country. It indicates that Cameroonian HCV-1 and -4 patients have a poorer sustained virologic response than the published results for Western and Middle-East countries. Virus subtype may influence the treatment outcome, since there is a great genetic diversity within Cameroonian HCV-1 and -4 genotypes.

Published
2008

34. Adjuvant therapy with pegylated interferon alfa-2b versus observation alone in resected stage III melanoma: final results of EORTC 18991, a randomised phase III trial

Author

Eggermont , Alexander M M, Suciu , Stefan, Santinami , Mario, Testori , Alessandro, Kruit , Wim H J, Marsden , Jeremy, Punt , Cornelis J A, Salès , François, Gore , Martin, Mackie , Rona, Kusic , Zvonko, Dummer , Reinhard, Hauschild , Axel, Musat , Elena, Spatz , Alain, Keilholz , Ulrich, Renseigné , Non, Aubin , François, Département de biologie et pathologie médicales [Gustave Roussy], Institut Gustave Roussy ( IGR ), Department of Medicine III, Charité, Campus Benjamin Franklin, Carcinogénèse épithéliale : facteurs prédictifs et pronostiques - UFC ( CEF2P / CARCINO ), Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ) -Université Bourgogne Franche-Comté ( UBFC ) -Université de Franche-Comté ( UFC ), Institut Gustave Roussy (IGR), Carcinogénèse épithéliale : facteurs prédictifs et pronostiques - UFC (EA 3181) (CEF2P / CARCINO), Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Other departments, Surgery, Medical Oncology, and University of Zurich

Subjects
Male, MESH: Observation, MESH : Aged, Observation, 2700 General Medicine, MESH : Observation, Gastroenterology, Polyethylene Glycols, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, MESH: Proportional Hazards Models, 0302 clinical medicine, Immune Regulation [NCMLS 2], Pegylated interferon, Interferon, Medicine, MESH : Female, Neoplasm Metastasis, Melanoma, MESH: Aged, 0303 health sciences, MESH: Middle Aged, interferon alfa-2b, melanoma, EORTC 18991, Hazard ratio, MESH : Polyethylene Glycols, 10177 Dermatology Clinic, MESH : Chemotherapy, Adjuvant, General Medicine, Middle Aged, MESH : Adult, Recombinant Proteins, 3. Good health, MESH : Antiviral Agents, Tolerability, Chemotherapy, Adjuvant, MESH: Chemotherapy, Adjuvant, 030220 oncology & carcinogenesis, MESH : Neoplasm Metastasis, MESH : Disease-Free Survival, Female, medicine.drug, Adult, MESH: Antiviral Agents, MESH: Interferon Alfa-2b, medicine.medical_specialty, Adolescent, MESH: Melanoma, MESH : Male, MESH : Melanoma, Alpha interferon, 610 Medicine & health, [SDV.CAN]Life Sciences [q-bio]/Cancer, Interferon alpha-2, Antiviral Agents, Disease-Free Survival, 03 medical and health sciences, Translational research [ONCOL 3], Interventional oncology [UMCN 1.5], Internal medicine, MESH : Adolescent, Adjuvant therapy, Humans, MESH : Middle Aged, Interferon alfa, Aged, Proportional Hazards Models, 030304 developmental biology, MESH: Adolescent, MESH: Humans, Intention-to-treat analysis, Hereditary cancer and cancer-related syndromes [ONCOL 1], business.industry, MESH : Humans, Interferon-alpha, MESH: Adult, MESH : Proportional Hazards Models, MESH : Interferon Alfa-2b, MESH: Neoplasm Metastasis, MESH: Male, Surgery, MESH: Polyethylene Glycols, MESH: Disease-Free Survival, business, MESH: Female
Abstract

Contains fulltext : 69569.pdf (Publisher’s version ) (Closed access) BACKGROUND: Any benefit of adjuvant interferon alfa-2b for melanoma could depend on dose and duration of treatment. Our aim was to determine whether pegylated interferon alfa-2b can facilitate prolonged exposure while maintaining tolerability. METHODS: 1256 patients with resected stage III melanoma were randomly assigned to observation (n=629) or pegylated interferon alfa-2b (n=627) 6 mug/kg per week for 8 weeks (induction) then 3 mug/kg per week (maintenance) for an intended duration of 5 years. Randomisation was stratified for microscopic (N1) versus macroscopic (N2) nodal involvement, number of positive nodes, ulceration and tumour thickness, sex, and centre. Randomisation was done with a minimisation technique. The primary endpoint was recurrence-free survival. Analyses were done by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00006249. FINDINGS: All randomised patients were included in the primary efficacy analysis. 608 patients in the interferon group and 613 patients in the observation group were included in safety analyses. The median length of treatment with pegylated interferon alfa-2b was 12 (IQR 3.8-33.4) months. At 3.8 (3.2-4.2) years median follow-up, 328 recurrence events had occurred in the interferon group compared with 368 in the observation group (hazard ratio 0.82, 95% CI 0.71-0.96; p=0.01); the 4-year rate of recurrence-free survival was 45.6% (SE 2.2) in the interferon group and 38.9% (2.2) in the observation group. There was no difference in overall survival between the groups. Grade 3 adverse events occurred in 246 (40%) patients in the interferon group and 60 (10%) in the observation group; grade 4 adverse events occurred in 32 (5%) patients in the interferon group and 14 (2%) in the observation group. In the interferon group, the most common grade 3 or 4 adverse events were fatigue (97 patients, 16%), hepatotoxicity (66, 11%), and depression (39, 6%). Treatment with pegylated interferon alfa-2b was discontinued because of toxicity in 191 (31%) patients. INTERPRETATION: Adjuvant pegylated interferon alfa-2b for stage III melanoma has a significant, sustained effect on recurrence-free survival.

Published
2008

35. Behaviors of keratinocytes and fibroblasts on films of PLA50-PEO-PLA50 triblock copolymers with various PLA segment lengths

Author

Henri Garreau, Michel Vert, Jean-Pierre Molès, Xavier Garric, Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM), Laboratoire de Dermatologie Moléculaire (EA3754), and Université Montpellier 1 (UM1)

Subjects
Ethylene Oxide, Keratinocytes, Magnetic Resonance Spectroscopy, Spectrophotometry, Infrared, Polymers, Cell Culture Techniques, Tetrazolium Salts, Human skin, 02 engineering and technology, 01 natural sciences, MESH: Tissue Engineering, Polyethylene Glycols, Contact angle, chemistry.chemical_compound, Copolymer, Glycolic acid, Skin, MESH: Ethylene Oxide, MESH: Polystyrenes, Adhesion, MESH: Tetrazolium Salts, respiratory system, 021001 nanoscience & nanotechnology, MESH: Keratinocytes, MESH: Polyesters, MESH: Polymers, 0210 nano-technology, Materials science, Polyesters, Biomedical Engineering, Biophysics, MESH: Thiazoles, Bioengineering, macromolecular substances, 010402 general chemistry, Biomaterials, stomatognathic system, MESH: Skin, Polymer chemistry, Humans, MTT assay, Lactic Acid, Cell adhesion, [SDV.IB.BIO]Life Sciences [q-bio]/Bioengineering/Biomaterials, MESH: Cell Culture Techniques, MESH: Humans, Tissue Engineering, Ethylene oxide, MESH: Spectrophotometry, Infrared, MESH: Magnetic Resonance Spectroscopy, technology, industry, and agriculture, Fibroblasts, equipment and supplies, Culture Media, 0104 chemical sciences, Thiazoles, chemistry, Chemical engineering, MESH: Polyethylene Glycols, MESH: Fibroblasts, MESH: Culture Media, Polystyrenes, MESH: Lactic Acid
Abstract

International audience; The growth of human primary keratinocytes and fibroblasts on PLA-PEO-PLA copolymer films was investigated as an intermediate stage of a strategy aimed at making implantable dermo-epidermal substitutes. Four PLA-PEO-PLA triblock copolymers with the same PEO block and different DL-lactic acid/ethylene oxide molar ratios (LA/EO) (0.8, 1.4, 1.8 and 2), were synthesized and characterized by 1H-nuclear magnetic resonance and infrared spectroscopy. The films made of these copolymers were more hydrophilic than PLA50 and than tissue culture polystyrene controls according to contact angles with water. Proliferation and adhesion of human skin cells were evaluated by MTT assay and by scanning electron microscopy. The presence of PEO in the triblock copolymers influenced cell adhesion and proliferation of fibroblasts, whereas keratinocyte adhesion and proliferation were not affected. These features emphasize the interest of PLA-PEO-PLA triblock copolymers to serve as better compounds than the racemic PLA previously investigated to make supports for human skin primary cells and scaffolds for skin engineering.

Published
2008

36. Predicting efficacy and safety outcomes in patients with hepatitis C virus genotype 1 and persistently 'normal' alanine aminotransferase levels treated with peginterferon alpha-2a (40KD) plus ribavirin

Author

Eric, Snoeck, Stephanos J, Hadziyannis, Claudio, Puoti, Mark G, Swain, Thomas, Berg, Patrick, Marcellin, Jean-Pierre, Zarski, Karin, Jorga, Stefan, Zeuzem, Exprimo NV, Henry Dunant Hospital, Department of Internal Medicine and Digestive Diseases, Marino General Hospital, University of Calgary, Campus Virchow-Klinikum, Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Service d'hépatologie, Hôpital Beaujon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Département de Gastroentérologie et hépatologie, Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-Hôpital Michallon, F. Hoffmann-La Roche [Basel], Saarland University [Saarbrücken], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Hôpital Beaujon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), and Duperray, Alain

Subjects
Male, MESH: Interferon Alfa-2a, MESH: Anemia, Drug-Related Side Effects and Adverse Reactions, Hepacivirus, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Interferon alpha-2, MESH: Drug Toxicity, Polyethylene Glycols, MESH: Dose-Response Relationship, Drug, MESH: Computer Simulation, MESH: Ribavirin, Ribavirin, Humans, Computer Simulation, MESH: Hepacivirus, MESH: Models, Theoretical, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, MESH: Treatment Outcome, MESH: Hepatitis C, MESH: Humans, Dose-Response Relationship, Drug, Interferon-alpha, virus diseases, Alanine Transaminase, Anemia, Models, Theoretical, Hepatitis C, Recombinant Proteins, digestive system diseases, MESH: Male, Treatment Outcome, MESH: Polyethylene Glycols, MESH: Alanine Transaminase, Female, MESH: Female
Abstract

International audience; BACKGROUND: Currently, the approved dosage of ribavirin has not been studied in patients with 'normal' alanine aminotransferase (ALT) levels. METHODS: Modelling and simulations were performed using generalised additive models (GAMs) to predict the incidence of anaemia and rate of sustained virological response (SVR) in patients with hepatitis C virus (HCV) genotype 1 and persistently 'normal' ALT levels treated with peginterferon alpha-2a (40KD) 180 microg/week plus ribavirin 1000/1200 mg/day for 48 weeks. RESULTS: Model-based simulations predicted that SVR rates would increase from 39 to 48% if patients with genotype 1 and persistently 'normal' ALT levels had received the standard weight-adjusted dose of ribavirin. This was similar to the predicted 49% SVR rate for genotype 1 patients with elevated ALT levels. The incidence of anaemia was predicted to increase from 13% to 23% in patients with persistently 'normal' ALT activity and was higher than that predicted for patients with elevated ALT levels; however, the difference appeared to be largely explained by the higher proportion of women in the former group. CONCLUSIONS: Simulations based on GAM suggest that regimens for patients with HCV genotype 1 should include the standard weight-adjusted dose of ribavirin, as similar SVR rates are predicted to be achieved, regardless of patients' ALT status at baseline.

Published
2008

37. Nano-emulsions and nanocapsules by the PIT method: an investigation on the role of the temperature cycling on the emulsion phase inversion

Author

Jean-Pierre Benoit, Nicolas Anton, Pascal Gayet, Patrick Saulnier, Ingénierie de la vectorisation particulaire, Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL), and Lemaire, Laurent

Subjects
MESH: Emulsions, Phase transition, Light, Dispersity, Pharmaceutical Science, Nanoparticle, 02 engineering and technology, 01 natural sciences, Polyethylene Glycols, Nonionic, Pulmonary surfactant, Nanotechnology, Scattering, Radiation, MESH: Nanotechnology, MESH: Technology, Pharmaceutical, Drug Carriers, Chemistry, Emulsion, Temperature, MESH: Surface-Active Agents, [SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences, 021001 nanoscience & nanotechnology, MESH: Temperature, [SDV.SP] Life Sciences [q-bio]/Pharmaceutical sciences, MESH: Stearic Acids, Emulsions, [SDV.IB]Life Sciences [q-bio]/Bioengineering, Rheology, 0210 nano-technology, Stearic Acids, Capsules, MESH: Electric Conductivity, Temperature cycling, 010402 general chemistry, PIT method, Phase Transition, Nanocapsules, Surface-Active Agents, Dynamic light scattering, MESH: Rheology, Technology, Pharmaceutical, MESH: Scattering, Radiation, [SDV.IB.BIO]Life Sciences [q-bio]/Bioengineering/Biomaterials, [SDV.IB] Life Sciences [q-bio]/Bioengineering, Electric Conductivity, MESH: Light, 0104 chemical sciences, Nano-emulsion, [SDV.IB.BIO] Life Sciences [q-bio]/Bioengineering/Biomaterials, Chemical engineering, MESH: Polyethylene Glycols, Nanoparticles, MESH: Phase Transition, MESH: Nanoparticles
Abstract

International audience; This paper focuses on the phenomenological understanding of temperature cycling process, applied to the phase inversion temperature (PIT) method. The role of this particular thermal treatment on emulsions phase inversion, as well as its ability to generate nano-emulsions have been investigated. In order to propose a general study, we have based our investigations on a given formulation of nano-emulsions classically proposed in the literature [Heurtault, B., Saulnier, P., Pech, B., Proust, J. E., Benoit, J.P., 2002. A novel phase inversion-based process for the preparation of lipid nanocarriers. Pharm. Res. 19, 875; Lamprecht, A., Bouligand, Y, Benoit, J.P., 2002. New lipid nanocapsules exhibit sustained release properties for amiodarone. J. Control. Release 84, 59-68], using a polyethoxylated model nonionic surfactant, a polyoxyehtylene-660-12-hydroxy stearate, stabilizing the emulsion composed of caprilic triglycerides (triglycerides medium chains), salt water (and also phospholipidic amphiphiles neutral for the formulation). Characterization of nano-emulsions was performed by dynamic light scattering (DLS) which provides the hydrodynamic diameter, but also the polydispersity index (PDI), as a fundamental criteria to judge the quality of the dispersion. Another aspect of the characterization was done following the emulsion inversion and structure by electrical conductivity through the temperature scan. Overall, the role such a temperature cycling process on the formulation of nano-emulsions appears to be relatively important, and globally enhanced as the surfactant concentration is lowered. Actually, both the hydrodynamic diameter and the PDI decrease as a function of the number and temperature cycles up to stabilize a steady state. Eventually, such a cycling process allows the generation of nano-emulsions in ranges of compositions largely expanded when compared with the classical PIT method. These general and interesting trends emerge from the results, are discussed and essentially explained by regarding the behavior of the nonionic surfactants towards the water/oil interface, linking partitioning coefficients, temperature variation, and surfactant water/oil interfacial concentration. In that way, this paper proposes new insights into the phenomena governing the PIT method, by originally investigating the temperature cycling process.

Published
2007

38. Simple and universal tool to remove on-line impurities in mono- or two-dimensional liquid chromatography-mass spectrometry analysis

Author

Jean Rossier, Anne-Marie Hesse, Joëlle Vinh, Paulo Marcelo, Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), and Université Paris sciences et lettres (PSL)

Subjects
Proteomics, Electrospray, Ion chromatography, Analytical chemistry, Mass spectrometry, 01 natural sciences, Biochemistry, High-performance liquid chromatography, Mass Spectrometry, Analytical Chemistry, Polyethylene Glycols, 03 medical and health sciences, Liquid chromatography–mass spectrometry, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], MESH: Models, Theoretical, 030304 developmental biology, MESH: Mass Spectrometry, 0303 health sciences, Chromatography, Elution, Chemistry, MESH: Peptides, MESH: Proteomics, 010401 analytical chemistry, Organic Chemistry, Reproducibility of Results, General Medicine, Reversed-phase chromatography, Models, Theoretical, 0104 chemical sciences, MESH: Reproducibility of Results, Two-dimensional chromatography, MESH: Polyethylene Glycols, Peptides, MESH: Chromatography, Liquid, Chromatography, Liquid
Abstract

International audience; Several recurrent problems have always hindered mono-dimensional liquid chromatography-mass spectrometry proteomic analyses. Polymer contamination is a major problem because polymers could co-elute with compounds of interest (peptides). In this case spectral suppression degrades dynamic range and sensitivity. Polyethylene glycol derivatives count among the major contaminants. They are targeted in this work. They are eluted at 35-40% acetonitrile from C18 phase in every single reversed-phase run. Moreover, they are also observed in two-dimensional liquid chromatography in every salt fraction. A simple and robust method is presented here for rapid and efficient on-line removal of these impurities using self-regenerating purification microdevices.

Published
2007

39. Hybrid gadolinium oxide nanoparticles: multimodal contrast agents for in vivo imaging

Author

Stéphane Roux, Jean-Luc Bridot, Jean-Luc Coll, Bassem Hiba, Marc Janier, Claire Billotey, Sophie Laurent, Luce Vander Elst, Olivier Tillement, Pascal Perriat, Robert N. Muller, Véronique Josserand, Anne-Charlotte Faure, Charlotte Rivière, Laboratoire de Physico-Chimie des Matériaux Luminescents (LPCML), Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Laboratoire de RMN, Université de Mons-Hainaut, NanoH-sas, Centre de Recherche et d'Application en Traitement de l'Image et du Signal (CREATIS), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-École Supérieure Chimie Physique Électronique de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut d'oncologie/développement Albert Bonniot de Grenoble (INSERM U823), Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), INSERM U823, équipe 5 (cibles diagnostiques ou thérapeutiques et vectorisation de drogues dans le cancer du poumon), Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Matériaux, ingénierie et science [Villeurbanne] (MATEIS), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA), Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Physico-Chimie des Matériaux Luminescents ( LPCML ), Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique ( CNRS ), Centre de Recherche et d'Application en Traitement de l'Image et du Signal ( CREATIS ), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon ( INSA Lyon ), Université de Lyon-Institut National des Sciences Appliquées ( INSA ) -Institut National des Sciences Appliquées ( INSA ) -École Supérieure Chimie Physique Électronique de Lyon-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Institut d'oncologie/développement Albert Bonniot de Grenoble ( INSERM U823 ), Université Joseph Fourier - Grenoble 1 ( UJF ) -CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Joseph Fourier - Grenoble 1 ( UJF ) -CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Joseph Fourier - Grenoble 1 ( UJF ) -CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Matériaux, ingénierie et science [Villeurbanne] ( MATEIS ), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique ( CNRS ) -Institut National des Sciences Appliquées de Lyon ( INSA Lyon ), Université de Lyon-Institut National des Sciences Appliquées ( INSA ) -Institut National des Sciences Appliquées ( INSA ), Hurbin, Amandine, Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Université de Lyon-Université de Lyon-École Supérieure de Chimie Physique Électronique de Lyon (CPE)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Fluorescence-lifetime imaging microscopy, MESH : Siloxanes, Nanoparticle, Contrast Media, Gadolinium, 02 engineering and technology, [SPI.MAT] Engineering Sciences [physics]/Materials, MESH : Gadolinium, 01 natural sciences, Biochemistry, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, Polyethylene Glycols, MESH: Magnetic Resonance Imaging, [SPI.MAT]Engineering Sciences [physics]/Materials, Paramagnetism, Mice, Colloid and Surface Chemistry, Nuclear magnetic resonance, Heterocyclic Compounds, MESH: Animals, Lung, medicine.diagnostic_test, Chemistry, MESH : Rats, MESH : Polyethylene Glycols, MESH : Mice, Nude, 021001 nanoscience & nanotechnology, Magnetic Resonance Imaging, Liver, Covalent bond, MESH : Organometallic Compounds, 0210 nano-technology, Preclinical imaging, MESH : Fluorescence, Siloxanes, MESH: Rats, MESH: Heterocyclic Compounds, MESH : Lung, Mice, Nude, [SDV.CAN]Life Sciences [q-bio]/Cancer, 010402 general chemistry, Catalysis, Fluorescence, [SDV.CAN] Life Sciences [q-bio]/Cancer, MESH : Magnetic Resonance Imaging, MESH: Contrast Media, PEG ratio, MESH : Mice, medicine, Organometallic Compounds, MESH: Mice, Nude, Animals, MESH: Lung, MESH: Siloxanes, MESH: Mice, MESH : Contrast Media, MESH: Fluorescence, MESH : Liver, Magnetic resonance imaging, MESH: Organometallic Compounds, General Chemistry, 0104 chemical sciences, Rats, MESH : Heterocyclic Compounds, MESH: Polyethylene Glycols, MESH : Nanoparticles, Nanoparticles, MESH : Animals, Luminescence, MESH: Gadolinium, MESH: Nanoparticles, MESH: Liver
Abstract

International audience; Luminescent hybrid nanoparticles with a paramagnetic Gd2O 3 core were applied as contrast agents for both in vivo fluorescence and magnetic resonance imaging. These hybrid particles were obtained by encapsulating Gd2O3 cores within a polysiloxane shell which carries organic fluorophores and carboxylated PEG covalently tethered to the inorganic network. Longitudinal proton relaxivities of these particles are higher than the positive contrast agents like Gd-DOTA which are commonly used for clinical magnetic resonance imaging. Moreover these particles can be followed up by fluorescence imaging. This study revealed that these particles suited for dual modality imaging freely circulate in the blood vessels without undesirable accumulation in lungs and liver.

Published
2007

40. Differential detergent resistance of the apical and basolateral NPPases: relationship with polarized targeting

Author

Delaunay, Jean-Louis, Breton, Michelyne, Goding, James, Trugnan, Germain, Maurice, Michèle, Trafic Membranaire et Signalisation Dans les Cellules Epitheliales, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Monash University [Malaysia]

Subjects
endocrine system, raft, MESH: Protein Transport, MESH: Mutation, MESH: Molecular Sequence Data, MESH: Rats, MESH: Pyrophosphatases, MESH: Membrane Microdomains, MESH: Polysorbates, MESH: Amino Acid Sequence, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, MESH: Cell Line, MESH: Dogs, detergent, MESH: Polyethylene Glycols, membrane microdomain, MESH: Octoxynol, apical targeting, MESH: Animals, MESH: Cell Polarity, MESH: Phosphoric Diester Hydrolases, MESH: Mice, MESH: Cell Membrane, MESH: Detergents
Abstract

34 pages; International audience; Targeting of glycosylphosphatidylinositol-anchored proteins to the apical surface of epithelial cells involves clustering in Triton X-100-resistant membrane microdomains or rafts. The role of these microdomains in sorting transmembrane proteins is more questionable because, unlike glycosylphosphatidylinositol-anchored proteins, apical transmembrane proteins are rather soluble in Triton X-100. They are, however, resistant to milder detergents such as Lubrol WX or Tween 20. It has been proposed that specific membrane microdomains, defined by resistance to these detergents, would carry transmembrane proteins to the apical surface. We have used MDCK cells stably transfected with the apical and basolateral pyrophosphatases/phosphodiesterases, NPP3 and NPP1, to examine the relationship between detergent resistance and apical targeting. The apically expressed wild-type NPP3 was insoluble in Lubrol WX whereas wild-type NPP1, which is expressed basolaterally, was essentially soluble. By using tail mutants and chimeric constructs that combine the cytoplasmic, transmembrane and extracellular domains of NPP1 and NPP3, we show that there is not a strict correlation between detergent resistance and apical targeting. Lubrol resistance is an intrinsic property of NPP3, which is acquired early during the biosynthetic process irrespective of its final destination, and depends on positively charged residues in its cytoplasmic tail.

Published
2007

41. Differential detergent resistance of the apical and basolateral NPPases: relationship with polarized targeting.: Lubrol insolubility and apical targeting

Author

Delaunay, Jean-Louis, Breton, Michelyne, Goding, James, Trugnan, Germain, Maurice, Michèle, Delaunay, Jean-Louis, Trafic Membranaire et Signalisation Dans les Cellules Epitheliales, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Monash University [Malaysia]

Subjects
endocrine system, raft, MESH: Protein Transport, MESH: Mutation, MESH: Molecular Sequence Data, MESH: Rats, MESH: Pyrophosphatases, MESH: Membrane Microdomains, MESH: Polysorbates, MESH: Amino Acid Sequence, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, MESH: Cell Line, MESH: Dogs, detergent, MESH: Polyethylene Glycols, membrane microdomain, MESH: Octoxynol, apical targeting, MESH: Animals, MESH: Cell Polarity, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, MESH: Phosphoric Diester Hydrolases, MESH: Mice, MESH: Cell Membrane, MESH: Detergents
Abstract

34 pages; International audience; Targeting of glycosylphosphatidylinositol-anchored proteins to the apical surface of epithelial cells involves clustering in Triton X-100-resistant membrane microdomains or rafts. The role of these microdomains in sorting transmembrane proteins is more questionable because, unlike glycosylphosphatidylinositol-anchored proteins, apical transmembrane proteins are rather soluble in Triton X-100. They are, however, resistant to milder detergents such as Lubrol WX or Tween 20. It has been proposed that specific membrane microdomains, defined by resistance to these detergents, would carry transmembrane proteins to the apical surface. We have used MDCK cells stably transfected with the apical and basolateral pyrophosphatases/phosphodiesterases, NPP3 and NPP1, to examine the relationship between detergent resistance and apical targeting. The apically expressed wild-type NPP3 was insoluble in Lubrol WX whereas wild-type NPP1, which is expressed basolaterally, was essentially soluble. By using tail mutants and chimeric constructs that combine the cytoplasmic, transmembrane and extracellular domains of NPP1 and NPP3, we show that there is not a strict correlation between detergent resistance and apical targeting. Lubrol resistance is an intrinsic property of NPP3, which is acquired early during the biosynthetic process irrespective of its final destination, and depends on positively charged residues in its cytoplasmic tail.

Published
2007

42. Transcriptome profiling uncovers metabolic and regulatory processes occurring during the transition from desiccation-sensitive to desiccation-tolerant stages in Medicago truncatula seeds

Author

Buitink, Julia, Leger, Jean J., Guisle, Isabelle, Vu, Benoit Ly, Wuillème, Sylvie, Lamirault, Guillaume, Le Bars, Alice, Le Meur, Nolwenn, Becker, Anke, Küster, Helge, Leprince, Olivier, Physiologie Moléculaire des Semences (PMS), Institut National de la Recherche Agronomique (INRA)-AGROCAMPUS OUEST, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), Physiopathologie et pharmacologie cellulaires et moléculaires, Université de Nantes (UN)-IFR26-Institut National de la Santé et de la Recherche Médicale (INSERM), Biologie des Semences (LBS), Institut National de la Recherche Agronomique (INRA)-Institut National Agronomique Paris-Grignon (INA P-G), Signalisation et Réponses aux Agents Infectieux et Chimiques (SeRAIC), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Ministère de l'Agriculture, de l'Alimentation, de la Pêche et des Affaires Rurales, Contrat Etat-Région 2000-2006, Conseil Général de Maine-et-Loire, Conseil Régional Pays de la Loire, CNRS, INSERM, INRA, Université de Rennes (UR), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-IFR140

Subjects
Sucrose, desiccation tolerance, MESH: Carbon, MESH: Germination, seeds, Polyethylene Glycols, MESH: Gene Expression Profiling, Gene Expression Regulation, Plant, C metabolism, Medicago truncatula, Cluster Analysis, RNA, Messenger, Desiccation, MESH: Gene Expression Regulation, Plant, MESH: Medicago truncatula, Oligonucleotide Array Sequence Analysis, Plant Proteins, MESH: RNA, Messenger, MESH: Plant Proteins, MESH: Kinetics, Gene Expression Profiling, MESH: Sucrose, food and beverages, MESH: Cluster Analysis, Carbon, Kinetics, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, germination, MESH: Polyethylene Glycols, MESH: Seeds, gene profiling, MESH: Oligonucleotide Array Sequence Analysis, MESH: Abscisic Acid, MESH: Desiccation, metabolism, Abscisic Acid
Abstract

International audience; To investigate regulatory processes and protective mechanisms leading to desiccation tolerance (DT) in seeds, 16086-element microarrays were used to monitor changes in the transcriptome of desiccation-sensitive 3-mm-long radicles of Medicago truncatula seeds at different time points during incubation in a polyethylene glycol (PEG) solution at -1.7 MPa, resulting in a gradual re-establishment of DT. Gene profiling was also performed on embryos before and after the acquisition of DT during maturation. More than 1300 genes were differentially expressed during the PEG incubation. A large number of genes involved in C metabolism are expressed during the re-establishment of DT. Quantification of C reserves confirms that lipids, starch and oligosaccharides were mobilised, coinciding with the production of sucrose during the early osmotic adjustment. Several clusters of gene profiles were identified with different time-scales. Genes expressed early during the PEG incubation belonged to classes involved in early stress and adaptation responses. Interestingly, several regulatory genes typically expressed during abiotic/drought stresses were also upregulated during maturation, arguing for the partial overlap of ABA-dependent and -independent regulatory pathways involved in both drought and DT. At later time points, in parallel to the re-establishment of DT, upregulated genes are comparable with those involved in late seed maturation. Concomitantly, a massive repression of genes belonging to numerous classes occurred, including cell cycle, biogenesis, primary and energy metabolism. The re-establishment of DT in the germinated radicles appears to concur with a partial return to the quiescent state prior to germination.

Published
2006

43. Surface-modified and conventional nanocapsules as novel formulations for parenteral delivery of halofantrine

Author

Vanessa Carla Furtado Mosqueira, Gillian Barratt, Philippe Legrand, Physico-chimie, pharmacotechnie, biopharmacie (PCPB), Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS), and Legrand, Philippe

Subjects
02 engineering and technology, 030226 pharmacology & pharmacy, Lecithin, Polyethylene Glycols, Diffusion, 0302 clinical medicine, Copolymer, Zeta potential, Organic chemistry, General Materials Science, Infusions, Parenteral, chemistry.chemical_classification, Drug Carriers, MESH: Diffusion, Polymer, 021001 nanoscience & nanotechnology, Condensed Matter Physics, MESH: Polyesters, 3. Good health, MESH: Drug Carriers, 0210 nano-technology, food.ingredient, Materials science, Surface Properties, Drug Compounding, Polyesters, Biomedical Engineering, Bioengineering, Capsules, [SDV.SP.PG] Life Sciences [q-bio]/Pharmaceutical sciences/Galenic pharmacology, Nanocapsules, 03 medical and health sciences, Antimalarials, food, MESH: Nanostructures, PEG ratio, MESH: Particle Size, Particle Size, MESH: Phenanthrenes, MESH: Surface Properties, MESH: Capsules, General Chemistry, Poloxamer, Phenanthrenes, Biodegradable polymer, MESH: Antimalarials, Nanostructures, MESH: Infusions, Parenteral, [SDV.SP.PG]Life Sciences [q-bio]/Pharmaceutical sciences/Galenic pharmacology, chemistry, Chemical engineering, MESH: Polyethylene Glycols, MESH: Drug Compounding
Abstract

The aim of this work was to develop a stable injectable formulation of the antimalarial drug halofantrine (Hf) based on nanocapsules (NC) prepared from biodegradable polymers with Miglyol® 810N as the oily core. Poly(D,L-lactide) PLA and its copolymers with poly(ethyleneglycol) (PLA-PEG) were used together with the surfactants poloxamer 188 and lecithin to yield NC with different surface properties. Highly efficient loading of the free base form of Hf was obtained; zeta potential measurements indicated that a part of the associated Hf was at the NC surface, interacting with the lecithin. NC were 150–250 nm in diameter and more stable on storage than nanoemulsions formed from oil and lecithin without polymer. The most stable NC, showing minimal size changes and flocculation, were those with a high density of 20-kDa PEG chains covalently grafted at the surface. Hf release from NC occurred mainly by partition with the external medium. In PBS, even when Tween 80 was added, release was limited to 20% of the total content, whatever the formulation. Addition of serum to the medium allowed complete and rapid release from PLA NC stabilized with adsorbed poloxamer 188, because of the high affinity of Hf for lipoproteins. However, the presence of covalently grafted PEG chains at the surface limited release by providing a hydrophilic steric barrier at the particle surface. A dense coverage with long PEG chains provided the best reduction of release. Such systems could constitute a long-circulating intravenous formulation of Hf for treating severe malaria.

Published
2006

44. PEGylation of microspheres for therapeutic embolization: preparation, characterization and biological performance evaluation

Author

Amina Lakrouf, Christine Vauthier, Daniel Scherman, Jean-Claude Chaumeil, Michel Bessodes, Faten Madani, Laboratoire de Pharmacie Galénique (LPG), Université Paris Descartes - Paris 5 (UPD5), Unité de Pharmacologie Chimique et Génétique (UPCG - UMR_S 640/UMR 8151), Centre National de la Recherche Scientifique (CNRS) - Institut National de la Santé et de la Recherche Médicale (INSERM) - Université Paris Descartes - Paris 5 (UPD5) - Institut des sciences du Médicament -Toxicologie - Chimie - Environnement (IFR71), Institut National de la Santé et de la Recherche Médicale (INSERM) - Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL (ENSCP) - Centre National de la Recherche Scientifique (CNRS) - Institut de Recherche pour le Développement (IRD) - Université Paris Descartes - Paris 5 (UPD5) - Institut National de la Santé et de la Recherche Médicale (INSERM) - Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL (ENSCP) - Centre National de la Recherche Scientifique (CNRS) - Institut de Recherche pour le Développement (IRD) - Université Paris Descartes - Paris 5 (UPD5), Physico-chimie, pharmacotechnie, biopharmacie (PCPB), Université Paris-Sud - Paris 11 (UP11) - Centre National de la Recherche Scientifique (CNRS), Service Recherche et Développement, Pharmacie Centrale des Hôpitaux de Paris, Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Institut des sciences du Médicament -Toxicologie - Chimie - Environnement (IFR71), Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Institut de Chimie du CNRS (INC), Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS), Génétique, Pharmacologie Chimique Et, Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut des sciences du Médicament -Toxicologie - Chimie - Environnement (IFR71), Institut de Recherche pour le Développement (IRD)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)

Subjects
MESH: Materials Testing, Scanning electron microscope, Biocompatible Materials, 02 engineering and technology, Polyethylene Glycols, chemistry.chemical_compound, MESH: Biocompatible Materials, MESH : Particle Size, Materials Testing, Copolymer, MESH : Surface Properties, Complement Activation, 0303 health sciences, MESH : Polyethylene Glycols, [SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences, 021001 nanoscience & nanotechnology, Blood proteins, MESH : Complement Activation, Embolization, Therapeutic, [SDV.SP] Life Sciences [q-bio]/Pharmaceutical sciences, Mechanics of Materials, Swelling, medicine.symptom, 0210 nano-technology, Materials science, MESH: Complement Activation, Surface Properties, Biophysics, Bioengineering, MESH : Materials Testing, Biomaterials, 03 medical and health sciences, MESH : Biocompatible Materials, PEG ratio, medicine, Humans, MESH: Particle Size, Fourier transform infrared spectroscopy, Particle Size, MESH : Embolization, Therapeutic, 030304 developmental biology, MESH: Surface Properties, Chromatography, MESH: Humans, MESH : Humans, Silane, MESH: Embolization, Therapeutic, chemistry, MESH: Polyethylene Glycols, Ceramics and Composites, PEGylation
Abstract

International audience; In this study, microspheres designed for embolization, defined as GF2000-Trisacryl MS (GF-MS) and DEAE-Trisacryl MS (DEAE-MS), were originally PEGylated using (3-amino propyl) triethoxy silane as coupling agent. Indomethacin was loaded into both PEGylated and non-PEGylated DEAE-MS, displaying ion-exchange ability, through a batch process with a respective capacity of 1.2 and 0.25 g/g. The morphology of naked and PEGylated MS was evaluated by scanning electron microscopy (SEM). Both micosphere resins surface looked like orange skin, although DEAE-MS showed a slightly rougher surface due to the copolymerization process. PEGylated microspheres have a most likely swelling surface owing to the presence of PEG hydrophilic chains. The mean diameters were of about 66 and 60 microm for GF-MS and DEAE-MS, respectively. Data obtained for PEGylated MS by Fourier Transform Infrared spectroscopy (FTIR) confirmed that microspheres were successfully PEGylated. Finally, complement activation in vitro was performed to evaluate the activating capacity of different microspheres. Both PEGylated GF-MS and DEAE-MS activated the complement system of about 33% less than their corresponding naked microspheres, while loading PEGylated DEAE-MS with indomethacin almost suppressed complement activation. This inhibiting role implies that PEGylation as well as loading the microspheres with anti-inflammatory drug has a compact effect on the interaction of microspheres with blood proteins.

Published
2006

45. [Complementary treatments of chronic viral hepatitis C]

Author

Thierry, Thevenot, Vincent, Di Martino, Françoise, Lunel-Fabiani, Claire, Vanlemmens, Marie-Claude, Becker, Jean-Pierre, Bronowicki, Solange, Bresson-Hadni, Jean-Philippe, Miguet, Service d'Hépato-Gastro-Entérologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Agents pathogènes et inflammation - UFC (EA 4266) (API), Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Service d'Hépato-gastro-entérologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), and WHO Collaborating Center on Prevention and Treatment of Human Echinococcosis

Subjects
MESH: Antiviral Agents, MESH: Interferon Alfa-2a, MESH: Anemia, MESH: Interferon Alfa-2b, Neutropenia, MESH: Neutropenia, Interferon alpha-2, Antiviral Agents, Antioxidants, Polyethylene Glycols, MESH: Ribavirin, Ribavirin, Humans, MESH: Erythropoietin, Erythropoietin, MESH: Thrombocytopenia, MESH: Humans, MESH: Antioxidants, Interferon-alpha, Anemia, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Hepatitis C, Chronic, Thrombocytopenia, Antidepressive Agents, Recombinant Proteins, MESH: Hepatitis C, Chronic, MESH: Polyethylene Glycols, MESH: Antidepressive Agents
Abstract

International audience; Pegylated interferon and ribavirin combination therapy represent the standard-of-care treatment for chronic hepatitis C, that allows to cure more than half of the patients. However, the success of this bitherapy is in balance with numerous side effects, especially hematologic and psychiatric. This review is focused on complementary treatments (erythropoietin, G-CSF, vitamin E, glutathion, ursodeoxycholic acid and antidepressants) likely to bring a benefit in maintaining adequate interferon and ribavirin dosages and in improving quality of life. This analysis has been performed by using the Medline(R) data base and with data from laboratories which commercialized these molecules. Erythropoietin, G-CSF and antidepressants are the best tools to optimize the bitherapy in its dose and its duration while privileging the quality of life of HCV-infected patients.

Published
2006

46. Pluronic F68 block polymer, a very potent suppressor of carcinogenesis in the colon of rats and mice

Author

Ginette Peiffer, Géraldine Parnaud, Denis E. Corpet, Sylviane Taché, Xénobiotiques, Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA), Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Institut National de la Recherche Agronomique - INRA (FRANCE), National Cancer Institute (USA), and Ecole Nationale Vétérinaire de Toulouse - ENVT (FRANCE)

Subjects
Male, Cancer Research, Pathology, potency, Colorectal cancer, efficacy, medicine.disease_cause, Polyethylene Glycols, chemistry.chemical_compound, 0302 clinical medicine, chemoprevention, MESH: Animals, Anticarcinogen, Cancer, 0303 health sciences, cancer prevention, MESH: Drug Screening Assays, Antitumor, Pluronic, 3. Good health, MESH: Precancerous Conditions, Oncology, colon cancer, laxative, 030220 oncology & carcinogenesis, Colonic Neoplasms, Female, aberrant crypt foci, poloxamer, colon-cancer, Aberrant crypt foci, medicine.medical_specialty, Colon-cancer, mice, chemoprevention, aberrant-crypt-foci, MESH: Rats, Colon, Ratón, Short Communication, polymer, block copolymer, [SDV.CAN]Life Sciences [q-bio]/Cancer, Chemoprevention, Excipients, 03 medical and health sciences, polyetylene glycol, PEG ratio, medicine, Animals, MESH: Colon, MESH: Mice, 030304 developmental biology, ACF, MESH: Excipients, Colorectal Cancer, MESH: Colonic Neoplasms, Azoxymethane, business.industry, MESH: Rats, Inbred F344, technology, industry, and agriculture, medicine.disease, MESH: Poloxamer, PEG, Rats, Inbred F344, MESH: Male, rats, pluronic, rat, chemistry, MESH: Polyethylene Glycols, Cancer research, Aberrant-crypt-foci, Rat, Drug Screening Assays, Antitumor, business, Carcinogenesis, Precancerous Conditions, MESH: Female
Abstract

Polyethylene-glycol (PEG) is a strong inhibitor of colon cancer in rats, and the most potent suppressor of aberrant crypt foci. 9 PEG-like block copolymers were tested in rodents, after an azoxymethane injection. Dietary pluronic F68 led to a 98.6% reduction in the number of aberrant crypt foci in a first rat study (P< 0.0001). Next 3 studies confirmed this pluronic efficacy in rats and mice. This non-toxic laxative seems roughly 5 times more potent than PEG for chemoprevention. © 2001 Cancer Research Campaign http://www.bjcancer.com

Published
2001

47. Cytostatic effect of polyethylene glycol on human colonic adenocarcinoma cells

Author

Laurence Gamet-Payrastre, Géraldine Parnaud, Denis E. Corpet, ProdInra, Migration, Xénobiotiques, Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA), Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire de Toulouse (ENVT), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées

Subjects
Cancer Research, MESH: Flow Cytometry, Apoptosis, Sodium Chloride, Polyethylene Glycols, chemistry.chemical_compound, MESH: Osmolar Concentration, Tumor Cells, Cultured, Sorbitol, Osmotic pressure, MESH: Cell Size, colorectal, intestinal, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, cancer prevention, cytostatique, MESH: G0 Phase, Cell Differentiation, DNA, Neoplasm, Flow Cytometry, CANCER, HT29, 3. Good health, Oncology, Biochemistry, CaCo2, polyethylene glycol, Colonic Neoplasms, MESH: Cell Division, MESH: Caco-2 Cells, Cell Division, MESH: Cell Differentiation, MESH: Cell Nucleus, MESH: Sodium Chloride, PRESSION OSMOTIQUE, mechanism, MESH: DNA, Neoplasm, [SDV.CAN]Life Sciences [q-bio]/Cancer, Antineoplastic Agents, macromolecular substances, Polyethylene glycol, Adenocarcinoma, Biology, MESH: G1 Phase, Resting Phase, Cell Cycle, Osmotic Pressure, anit-cancer, PEG ratio, Humans, AGENT CHEMOPREVENTIF, MESH: Tumor Cells, Cultured, Lactic Acid, Cell Size, MESH: Colonic Neoplasms, Cell Nucleus, MESH: Humans, colon, Osmotic concentration, Cell growth, MESH: Apoptosis, MESH: Adenocarcinoma, Cell Membrane, Osmolar Concentration, G1 Phase, technology, industry, and agriculture, MESH: Osmotic Pressure, PEG, Molecular biology, Culture Media, rats, MESH: Polyethylene Glycols, chemistry, Caco-2, Cell culture, Cancer cell, MESH: Culture Media, cells, MESH: Antineoplastic Agents, MESH: Lactic Acid, MESH: Sorbitol, Caco-2 Cells, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, MESH: Cell Membrane
Abstract

International audience; Polyethylene glycol (PEG 8000) is a potent cancer chemopreventive agent. This osmotic laxative polymer markedly suppresses colon cancer in rats. To explain the mechanism, we have tested the in vitro effect of PEG on four human cell lines. Two poorly differentiated adenocarcinoma lines (HT29 and COLO205), a fetal mucosa line (FHC) and a differentiated line (post-confluent Caco-2) were incubated with various PEG concentrations for 2-5 days. Results show that PEG markedly and dose-dependently inhibited HT29 and COLO205 cell growth. This cytostatic effect was associated with a blocking of the cell cycle in G0/G1 phase. In addition, PEG decreased the viability of HT29 and COLO205 adenocarcinoma cells. In contrast, post-confluent intestinal-like Caco-2 cells and normal FHC cells were, respectively, not or little affected by PEG. Moreover, the lactate concentration increased twofold in the medium of PEG-treated HT29 cells compared with untreated cells. Microscopic observations showed that PEG induced cell shrinking, membrane blebbing and the condensation of nuclear chromatin. However, because no DNA ladder and no annexin staining were detected, we presume that PEG did not induce apoptosis. PEG increased the osmotic pressure of the culture medium. Hyperosmotic media with added NaCl or sorbitol also inhibited HT29 cell growth, and increased lactate release. These results suggest that PEG may be selectively cytostatic for proliferating cancer cells. This growth inhibition may be due to the high osmotic pressure induced by PEG in vitro. Because the osmotic pressure is high in feces of PEG-fed rats, it may explain the suppression of colon carcinogenesis by PEG.

Published
2001

48. Oligonucleotide hybridisations on glass supports: a novel linker for oligonucleotide synthesis and hybridisation properties of oligonucleotides synthesised in situ

Author

Uwe Maskos, Edwin M. Southern, Department of Biochemistry [Oxford], University of Oxford [Oxford], U.M. was supported by the Maximilianeum, Munich, Germany, the Studienstiftung des deutschen Volkes, the Bayerische Begabtenforderung, and the Deutscher Akademischer Austauschdienst., and We would like to thank Dr H. Blöcker for suggesting the 'trityl-on' assay to us and also for valuable comments on the manuscript.

Subjects
Molecular Sequence Data, Oligonucleotides, Sequence (biology), 02 engineering and technology, Biology, Oligonucleotide synthesis, MESH: Base Sequence, MESH: Chromatography, Chemical synthesis, Polyethylene Glycols, MESH: Nucleic Acid Hybridization, 03 medical and health sciences, chemistry.chemical_compound, Nucleic acid thermodynamics, [SCCO]Cognitive science, MESH: Oligonucleotides, Genetics, MESH: Silanes, 030304 developmental biology, 0303 health sciences, Chromatography, Silanes, MESH: Molecular Sequence Data, Base Sequence, Oligonucleotide, Nucleic Acid Hybridization, 021001 nanoscience & nanotechnology, Combinatorial chemistry, Silane, MESH: Glass, chemistry, Biochemistry, MESH: Polyethylene Glycols, Glass, 0210 nano-technology, Linker
Abstract

International audience; A novel linker for the synthesis of oligonucleotides on a glass support is described. Oligonucleotides synthesised on the support remain tethered to the support after ammonia treatment and are shown to take part in sequence specific hybridisation reactions. These hybridizations were carried out with oligonucleotides synthesised on 'ballotini' solid sphere glass beads and microscope slides. The linker has a hexaethylene glycol spacer, bound to the glass via a glycidoxypropyl silane, terminating in a primary hydroxyl group that serves as starting point for automated or manual oligonucleotide synthesis.

Published
1992

49. Spheroplast Fusion as a Mode of Genetic Recombination in Mycobacteria

Author

Nalin Rastogi, Hugo L. David, Elie Rafidinarivo, Tuberculose et Mycobactéries, Institut Pasteur [Paris], Centre de Recherche de Biochimie et de Génétique Cellulaire (CRBGC), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Institut Pasteur [Paris] (IP), Université Toulouse III - Paul Sabatier (UT3), and Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Genetic Markers, Mutant, Mutagenesis (molecular biology technique), Spheroplasts, MESH: Microscopy, Electron, Biology, MESH: Genetic Markers, MESH: Mycolic Acids, Microbiology, Genetic recombination, Mycobacterium aurum, Mycobacterium, Polyethylene Glycols, 03 medical and health sciences, MESH: Mycobacterium, MESH: Spheroplasts, MESH: Diploidy, 030304 developmental biology, Recombination, Genetic, Genetics, 0303 health sciences, 030306 microbiology, Spheroplast, biology.organism_classification, Carotenoids, Diploidy, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Microscopy, Electron, Mycolic Acids, Biochemistry, MESH: Polyethylene Glycols, Genetic marker, MESH: Carotenoids, MESH: Recombination, Genetic, Recombination
Abstract

International audience; Spheroplasts were prepared from two carotenoid pigment mutants of Mycobacterium aurum named NgR9 and A11, which were obtained by the chemical mutagenesis of the wild type strain A+ with N-methyl-N'-nitro-N-nitrosoguanidine. The carotenoid pigments and the alpha- and beta-mycolic acids were taken as genetic markers and the recombinants were selected on the basis of their colour on Löwenstein-Jensen medium. Spheroplasts of the two mutants were mixed in a 1:1 ratio and were treated with 40% (w/v) polyethylene glycol 6000 for 5 min at 37 degrees C. The frequency of NgR9 X A11 recombination in optimal conditions was about 2.5 X 10(-3). The recombinants selected on the basis of their carotenoid pigment profile were also tested for their alpha- and beta-mycolic acids as a second genetic marker. The results were further confirmed by electron microscopy. The optimal conditions for spheroplast fusion as a mode of genetic recombination in M. aurum are described.

Published
1983

50. Lactotransferrin receptor of mouse small-intestinal brush border. Binding characteristics of membrane-bound and triton X-100-solubilized forms

Author

Wei-Li Hu, G. Sawatzki, Joël Mazurier, Jean Montreuil, Geneviève Spik, Unité de Glycobiologie Structurale et Fonctionnelle UMR 8576 (UGSF), Université de Lille-Institut National de la Recherche Agronomique (INRA)-Centre National de la Recherche Scientifique (CNRS), Unité de Glycobiologie Structurale et Fonctionnelle - UMR 8576 (UGSF), Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Recherche Agronomique (INRA), Université de Lille-Centre National de la Recherche Scientifique (CNRS), and Institut National de la Recherche Agronomique (INRA)-Université de Lille-Centre National de la Recherche Scientifique (CNRS)

Subjects
MESH: Microvilli, MESH: Intestine, Small, Plasma protein binding, Lactoglobulins, Biochemistry, Polyethylene Glycols, chemistry.chemical_compound, Mice, Intestine, Small, MESH: Animals, Receptor, MESH: Receptors, Cell Surface, 0303 health sciences, Microvilli, 030302 biochemistry & molecular biology, Serum Albumin, Bovine, Ligand (biochemistry), Lactotransferrin, MESH: Lactoglobulins, Research Article, Protein Binding, Brush border, Cations, Divalent, Octoxynol, Receptors, Cell Surface, MESH: Binding, Competitive, Biology, Binding, Competitive, 03 medical and health sciences, Receptors, Transferrin, MESH: Octoxynol, MESH: Cations, Divalent, Animals, MESH: Protein Binding, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Receptors, Transferrin, Binding site, Molecular Biology, MESH: Mice, 030304 developmental biology, Binding Sites, Cell Biology, Molecular biology, MESH: Lactoferrin, Lactoferrin, Membrane protein, chemistry, MESH: Binding Sites, MESH: Polyethylene Glycols, Triton X-100, MESH: Muramidase, Muramidase, MESH: Serum Albumin, Bovine
Abstract

International audience; A specific lactotransferrin receptor was identified in the mouse small-intestinal brush-border membrane and the binding features were investigated in homologous and heterologous systems. The receptor was found to be specific for lactotransferrins isolated from milk of various species, but the affinity was higher toward the homologous ligand (Ka = 3.5 x 10(6) M-1 compared with 2.6 x 10(6) M-1 for both human and bovine lactotransferrins). However, the number of binding sites (n) was the same for the three lactotransferrins, namely 0.53 x 10(12)/micrograms of membrane protein. The binding of mouse lactotransferrin to its receptor was found to be pH-dependent, with an optimal binding at pH 5.5, and seemed unlikely to be carbohydrate-mediated. The receptor was demonstrated to be devoid of any affinity for human and mouse serotransferrins or for a 'serotransferrin-like' protein isolated from mouse milk. The receptor was solubilized with 1% Triton X-100 with good yield. The solubilized receptor was found to retain lactotransferrin-binding activity and sensitivity to pH.

Published
1988

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