From a Biomarker to Targeting in a Proof-Of-Concept Trial

Background There is high medical need for safe long-term immunosuppression monotherapy in kidney transplantation. Selective targeting of post-transplant alloantigen-(re)activated effector-T cells by anti-TNF antibodies after global T cell depletion may allow safe drug minimization, however, it is unsolved what might be the best maintenance monotherapy. Methods In this open, prospective observational single-centre trial, 20 primary deceased donor kidney transplant recipients received 2x20 mg Alemtuzumab (d0/d1) followed by 5 mg/kg Infliximab (d2). For 14 days all patients received only tacrolimus, then they were allocated to either receive tacrolimus (TAC, n = 13) or sirolimus (SIR, n = 7) monotherapy, respectively. Protocol biopsies and extensive immune monitoring were performed and patients were followed-up for 60 months. Results TAC-monotherapy resulted in excellent graft survival (5yr 92%, 95%CI: 56.6–98.9) and function, normal histology, and no proteinuria. Immune monitoring revealed low intragraft inflammation (urinary IP-10) and hints for the development of operational tolerance signature in the TAC- but not SIR-group. Remarkably, the TAC-monotherapy was successful in all five presensitized (ELISPOT+) patients. However, recruitment into SIR-arm was stopped (after n = 7) because of high incidence of proteinuria and acute/chronic rejection in biopsies. No opportunistic infections occurred during follow-up. Conclusions In conclusion, our novel fast-track TAC- monotherapy protocol is likely to be safe and preliminary results indicated an excellent 5-year outcome, however, a full–scale study will be needed to confirm our findings. Trial Registration EudraCT Number: 2006-003110-1

Répertoire des lymphocytes T et biomarqueurs (approches statistiques)

En transplantation rénale, la recherche de marqueurs biologiques liés au devenir à long terme du greffon s oriente vers la prévention du rejet chronique et vers l identification de patients susceptibles de développer une tolérance spontanée de leur greffon, en l absence ou sous faible doses d immunosuppresseurs. L analyse globale du répertoire des lymphocytes T, basée sur l étude des distributions de longueurs des boucles CDR3 de la chaine beta du récepteur des lymphocytes T et sur les quantités de transcrits codant pour cette région, est un indicateur puissant de l état du système immunitaire des patients transplantés. Le développement de méthodes statistiques spécialement dédiées à l analyse des distributions de longueurs CDR3 constitue la majeure partie de ce travail et a permis de mettre en évidence les différences existant entre patients en rejet chronique et patient opérationnellement tolérant. Ces nouvelles méthodes ont aussi permis de révéler la grande hétérogénéité d une cohorte de deux cent patients stables depuis au moins cinq ans et sous immunosuppression. De nombreuses pistes restent encore à explorer, concernant l analyse des distributions de longueurs CDR3 et la validation des signatures du répertoire T, pour une prédiction efficace du devenir à long terme du greffon.In renal transplantation, biomarkers that predict long-term allograft outcome are dedicated towards prevention of chronic rejection or the identification of patients that could potentially develop a spontaneous tolerance versus their graft, without on low doses of immunosupressors. Global T cell repertoire analysis, based on the study of the length distributions of the T cell receptor CDR3 beta chain and of the quantities of transcripts coding for this region, is a powerful indicator of the state of the immune system of transplanted patients. The implementation of statistical methods specially dedicated to the analysis of CDR3 length distributions constitutes the major part of this work and allows putting in evidence the differences existing between patients with chronic rejection and operationally tolerant patients. These new methods also allowed showing the high heterogeneity of a cohort of two hundred patients with a stable graft function for at least five years and under immunosupression. Perspectives are given to this work in term of improving the statistical methods developed for the analysis of the CDR3 length distribution and for the validation of the T cell repertoire signatures in order to efficiently predict long-term allograft outcome.NANTES-BU Médecine pharmacie (441092101) / SudocSudocFranceF

How do Cancer Centers Communicate Clinical Trials Opportunities to Patients on Their Websites ?

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Promoting Engagement of Cancer Patients with a Biobank and Future Research Studies

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B.CaRe :un projet de recherche en co-création pour l’humanisation des soins en oncologie

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A contribution to the direct observation of transient phosphanylidene complexes [RP=W(CO)5] (R: Me, Ph) : a revisited approach to their electronic structure by UV-photoelectron spectroscopy

An original approach involving a coupling in the gas phase between flash vacuum thermolysis (FVT) and UV-photoelectron spectroscopy (UV-PES) allowed the transient terminal electrophilic phosphanylidene complex [MeP=W(CO)5] to be characterized; this is the first direct observation of this P–Me derivative. This approach also permitted the electronic structure of [PhP=W(CO)5] to be revisited and confirmed the results obtained with the methylated analogues. In contrast, [p-NC–C6H4P=W(CO)5] proved to be too reactive to be detected under our experimental conditions. These [RP=W(CO)5] phosphanylidene complexes (R: Me, Ph) were identified by their ionization potentials, which are real “fingerprints”. These experimental data, supported by density functional calculations, give an overall electronic cartography of these transient species. For generation in the gas phase of these phosphanylidene complexes, the thermal degradation of two kinds of precursors were investigated. The joint experimental/theoretical approach allowed us to conclude that phosphanorbornadiene complexes are more suitable precursors than phosphirane complexes

B.CaRe "Humanisation des soins oncologiques": Rapport de recherche intermédiaire

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How to Build Fully π-Conjugated Architectures with Thienylene and Phenylene Fragments

International audienceA series of small-sized model π-conjugated oligomers have been prepared from thienylene and phenylene or dimethylor dimethoxy-substituted phenylene units. Crystallographic data for the methoxylated compound show a quasi-planar conformation with a non-covalent S–O interaction. The resulting strong conjugation in the gas phase has also been highlighted by UV/photoelectron spectroscopy and theoretical calculations (DFT). Indeed, for these compounds there is a large energy gap ΔEπ arising from the interaction between the molecular orbitals of the isolated thienylene-phenylene species. This can be explained in terms of the energies of the two π orbitals of the dimethoxyphenylene unit, the shape of these molecular orbitals in a three-orbital interaction diagram and by the presence of the S···O interaction which re- Introduction π-Conjugated organic polymers have received much attention for several years because of the large variety of applications directly associated with the existence of an extended conjugated π-system along the polymer backbone. They have attracted much interest in the design of electronic and optoelectronic devices such as organic field-effect transistors (OFET), organic light-emitting diodes (OLED) or solar cells because of their remarkable electronic and electro- optical properties[1,2] which are easy to tune as a result of their molecular and supramolecular chemistry. Among the more notable examples, the regioregular poly(3-alkylthiophene) exhibits excellent chain planarity and extended conjugation lengths as a result of its head-to-tail regiochemistry,[ 3] leading to highly conjugated sheets with high field- [a] Hétérochimie Moléculaire et Macromoléculaire, UMR CNRS 5076, Ecole Nationale Supérieure de Chimie de Montpellier, 8, rue de l'Ecole Normale, 34296 Montpellier Cedex 05, France E-mail: [email protected] [b] Equipe de Chimie-Physique, IPREM-UMR CNRS 5254 Avenue de l'Université, B. P. 1155, 64013 Pau Cedex, France E-mail: [email protected] [c] Laboratoire des Agrégats Moléculaires et Matériaux Inorganiques, UMR CNRS 5072, Université Montpellier II, 2 Place Eugène Bataillon, 34095 Montpellier Cedex 5, France Supporting information for this article is available on the WWW under http://www.eurjoc.org or from the author. Eur. J. Org. Chem. 2007, 4019–4031 © 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 4019 duces the inter-ring angle between the two aromatic cycles. The nature of the sulfur–oxygen interaction, discussed from a theoretical point of view, is mainly electrostatic, the orbital contribution from the only correctly directed orbitals nO σ and σ*S–C being slightly stabilising. These results show extensive conjugation of the π system corroborated by a small HOMO– LUMO gap. These studies, carried out in the solid state and in the gas phase, show how important it is to combine thienylene and dialkoxyphenylene fragments to obtain oligomers with a strong electronic delocalisation. Thus, these compounds are of interest in the fields of electronic and optoelectronic devices

Sequential Targeting of CD52 and TNF Allows Early Minimization Therapy in Kidney Transplantation: From a Biomarker to Targeting in a Proof-Of-Concept Trial.

There is high medical need for safe long-term immunosuppression monotherapy in kidney transplantation. Selective targeting of post-transplant alloantigen-(re)activated effector-T cells by anti-TNF antibodies after global T cell depletion may allow safe drug minimization, however, it is unsolved what might be the best maintenance monotherapy.In this open, prospective observational single-centre trial, 20 primary deceased donor kidney transplant recipients received 2x20 mg Alemtuzumab (d0/d1) followed by 5 mg/kg Infliximab (d2). For 14 days all patients received only tacrolimus, then they were allocated to either receive tacrolimus (TAC, n = 13) or sirolimus (SIR, n = 7) monotherapy, respectively. Protocol biopsies and extensive immune monitoring were performed and patients were followed-up for 60 months.TAC-monotherapy resulted in excellent graft survival (5yr 92%, 95%CI: 56.6-98.9) and function, normal histology, and no proteinuria. Immune monitoring revealed low intragraft inflammation (urinary IP-10) and hints for the development of operational tolerance signature in the TAC- but not SIR-group. Remarkably, the TAC-monotherapy was successful in all five presensitized (ELISPOT+) patients. However, recruitment into SIR-arm was stopped (after n = 7) because of high incidence of proteinuria and acute/chronic rejection in biopsies. No opportunistic infections occurred during follow-up.In conclusion, our novel fast-track TAC-monotherapy protocol is likely to be safe and preliminary results indicated an excellent 5-year outcome, however, a full-scale study will be needed to confirm our findings.EudraCT Number: 2006-003110-18