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Pauwels E.,Ghent University | Claeys D.,Ghent University | Claeys D.,Federal Agency for Medicines and Health Products | Martins J.C.,Ghent University | And 4 more authors.
RSC Advances | Year: 2013

Structural analysis of modified DNA with NMR is becoming ever more difficult with increasingly complex compounds under scrutiny for use in medical diagnosis, therapeutics, material science and chemical synthesis. To facilitate this process, we developed a molecular modeling approach to predict proton chemical shifts in sufficient agreement with experimental NMR measurements to guide structure elucidation. It relies on a QM/MM partitioning scheme and first principle calculations to predict the spatial structure and calculate corresponding proton chemical shifts. It is shown that molecular dynamics simulations that take into account solvent and temperature effects properly are of utmost importance to sample the conformational space sufficiently. The proposed computational procedure is applicable to modified oligonucleotides and DNA, attaining a mean error for the proton chemical shifts of less than 0.2 ppm. Here, it is applied on the Drew-Dickerson d(CGCGAATTCGCG)2 dodecamer as a benchmark system and the mispair-aligned N3T-ethyl-N 3T cross-linked d(CGAAAT*TTTCG)2 undecamer, illustrating its use as computational tool to assist in structure elucidation. For the proton chemical shifts in the cross-linked system our methodology yields a strikingly superior description, surpassing the predictive power of (semi-)empirical methods. In addition, our methodology is the only one available to make an accurate prediction for the protons in the actual cross-link. To the best of our knowledge, this is the first computational study that attempts to determine the chemical shifts of oligonucleotides of this size and at this level of complexity. This journal is © 2013 The Royal Society of Chemistry. Source

Baldo A.,University of Liege | Mathy A.,University of Liege | Tabart J.,University of Liege | Camponova P.,University of Liege | And 5 more authors.
British Journal of Dermatology | Year: 2010

Background Microsporum canis is a pathogenic dermatophyte that causes a superficial cutaneous mycosis, mainly in cats and humans. Proteolytic enzymes, including subtilisins, have been postulated to be key factors involved in adherence and invasion of the stratum corneum and keratinized epidermal structures. Objectives To evaluate the importance of Sub3 as a M. canis virulence factor using a SUB3 RNA-silenced strain. Materials and methods The stability of a previously constructed RNA-silenced strain IHEM 22957 was tested in three different ways. The involvement of Sub3 in the adherence process was evaluated using a new ex vivo adherence model of M. canis arthroconidia to feline epidermis. In order to investigate the contribution of Sub3 in epidermal invasion, the pathogenicity of the SUB3 silenced strain was compared with that of the control strain in a guinea pig model of experimental M. canis dermatophytosis. Results The silenced strain was shown to be stable after four in vitro transfers and after the in vivo experimental infection. This strain has dramatic loss of adherence capacity to feline corneocytes when compared with the parental strain. In contrast, no significant differences were observed at any time during the infection between the control strain and the SUB3 silenced strain, indicating that Sub3 secretion is not required for invasion of epidermal structures. Conclusions RNA interference is a useful tool to evaluate pathogenic mechanisms of M. canis. For the first time, a role in pathogenicity could be attributed to a protease of a dermatophyte, namely Sub3 from M. canis, which is required for adherence to but not for invasion of the epidermis. © 2010 British Association of Dermatologists. Source

Weise M.,Bundesinstitut For Arzneimittel Und Medizinprodukte | Bielsky M.-C.,Medicines and Healthcare Products Regulatory Agency | De Smet K.,Federal Agency for Medicines and Health Products | Ehmann F.,European Medicines Agency | And 16 more authors.
Blood | Year: 2012

Biosimilar medicinal products (biosimilars) have become a reality in the European Union and will soon be available in the United States. Despite an established legal pathway for biosimilars in the European Union since 2005 and increasing and detailed regulatory guidance on data requirements for their development and licensing, many clinicians, particularly oncologists, are reluctant to consider biosimilars as a treatment option for their patients. Major concerns voiced about biosimilars relate to their pharmaceutical quality, safety (especially immunogenicity), efficacy (particularly in extrapolated indications), and interchangeability with the originator product. In this article, the members and experts of the Working Party on Similar Biologic Medicinal Products of the European Medicines Agency (EMA) address these issues. A clear understanding of the scientific principles of the biosimilar concept and access to unbiased information on licensed biosimilars are important for physicians to make informed and appropriate treatment choices for their patients. This will become even more important with the advent of biosimilar monoclonal antibodies. The issues also highlight the need for improved communication between physicians, learned societies, and regulators. © 2012 by The American Society of Hematology. Source

Mastelic B.,University of Geneva | Garcon N.,Glaxosmithkline | Del Giudice G.,Novartis | Golding H.,U.S. Food and Drug Administration | And 3 more authors.
Biologicals | Year: 2013

Vaccination represents one of the greatest public health triumphs; in part due to the effect of adjuvants that have been included in vaccine preparations to boost the immune responses through different mechanisms. Although a variety of novel adjuvants have been under development, only a limited number have been approved by regulatory authorities for human vaccines. This report reflects the conclusions of a group of scientists from academia, regulatory agencies and industry who attended a conference on the current state of the art in the adjuvant field. Held at the U.S. Pharmacopeial Convention (USP) in Rockville, Maryland, USA, from 18 to 19 April 2013 and organized by the International Association for Biologicals (IABS), the conference focused particularly on the future development of effective adjuvants and adjuvanted vaccines and on overcoming major hurdles, such as safety and immunogenicity assessment, as well as regulatory scrutiny. More information on the conference output can be found on the IABS website, http://www.iabs.org/. © 2013. Source

Hinsenkamp M.,Brussels University | Muylle L.,University of Antwerp | Muylle L.,Federal Agency for Medicines and Health Products | Eastlund T.,University of New Mexico | And 3 more authors.
International Orthopaedics | Year: 2012

Purpose: The use of bone and connective tissue allografts has grown rapidly and surpassed the use of autografts in many countries. Being of human origin, bone and tendon allografts carry the risk of disease transmission and complications have been reported. As part of the Project NOTIFY led by the World Health Organisation, an effort to improve recognition, reporting, tracking and investigation of adverse outcomes of allografts was initiated, achieving a comprehensive review of associated disease transmission and failures. Those involving the use of musculoskeletal allografts are reported here. A major objective is to involve orthopaedic surgeons in the improvement of the safe use of the musculoskeletal allografts. Methods: We reviewed the medical literature, requested reports from surgeons in selected professional organisations and informally surveyed tissue bank organisations and selected tissue bank professionals to discover reported and unreported cases of adverse outcomes. We analysed each case to decide the likelihood that the complication was truly allograft related. Results: The efficiency of the procedures involved in bone banking and bone and tendon allograft has improved significantly during the last three decades. The evolution of the incidence of reported adverse reactions and events reflects positively on the safety of transplanted tissues. Cases of bacterial and viral transmission by bone and tendon allografts occurred mainly with those that contained viable cells, were not processed to remove cells, or were not disinfected or sterilised. We documented cases of transmission of human immunodeficiency virus (HIV), hepatitis C virus (HCV), human T-lymphotropic virus (HTLV), unspecified hepatitis, tuberculosis and other bacteria. Reporting of these adverse outcomes has led to corrective actions and has significantly improved the safety of allograft use. However, it is probable that not all cases have been reported and investigated. Conclusions: Considering the high quality standards achieved in many countries, the best approach for further improvement in the safety of allografts is through a systematic reporting of all serious adverse reactions and events in the context of a global biovigilance programme. © 2011 Springer-Verlag. Source

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