DMTs and Covid-19 severity in MS: a pooled analysis from Italy and France

We evaluated the effect of DMTs on Covid-19 severity in patients with MS, with a pooled-analysis of two large cohorts from Italy and France. The association of baseline characteristics and DMTs with Covid-19 severity was assessed by multivariate ordinal-logistic models and pooled by a fixed-effect meta-analysis. 1066 patients with MS from Italy and 721 from France were included. In the multivariate model, anti-CD20 therapies were significantly associated (OR = 2.05, 95%CI = 1.39–3.02, p < 0.001) with Covid-19 severity, whereas interferon indicated a decreased risk (OR = 0.42, 95%CI = 0.18–0.99, p = 0.047). This pooled-analysis confirms an increased risk of severe Covid-19 in patients on anti-CD20 therapies and supports the protective role of interferon

Métabolites d'éponges marines de la famille de la famille de la palau'amine (isolement et synthèse biomimétique)

Ce manuscrit porte sur l'isolement des métabolites secondaires d'une éponge marine appartenant au genre Axinella, sur la chimiotaxonomie des familles Axinellidae, Agelasidae, Halichondriidae, Dictyonellidae et sur la synthèse biomimétique de P-2-AIs dimériques. L'étude chimique de l'éponge Axinella sp., récoltée au Liban, a conduit à l'isolement de 17 produits dont trois nouveaux composés : la slagénine D, le stylissazole G et la tribromostyloguanidine. Une étude approfondie de la tribromostyloguanidine par RMN et modélisation moléculaire a permis de confirmer sa configuration relative. Les familles d'éponges marines phylogénétiquement liées ont été étudiées d'un point de vue chimiotaxonomique afin d'établir des liens de parenté par la recherche de marqueurs biochimiques potentiels. Le processus de dimérisation de l' oroïdine a été exploré et a abouti à la première synthèse biomimétique de congénères des nagélamides. Ces synthèses illustrent l'hypothèse de biogenèse du laboratoire désignant l'oroïdine comme précurseur commun aux dimères de la famille des P-2-AIs. Une seconde approche biomimétique de la palau'amine repose sur la méthodologie, développée au laboratoire, d'addition oxydante de guanidine sur un pseudopeptide pyrrole-proline. La voie d'accès au bispseudopeptide a été optimisée en 7 étapes avec un rendement global de 30%. La stratégie d'addition de guanidine a été explorée et a abouti à la synthèse d'intermédiaires avancés de la palau'amine présentant les cycles A, C, D, E et F. La réaction observée est proposée comme cascade biogenétique des congénères de la palau'amine. Ce travail de recherches a permis d'approfondir nos connaissances sur la famille des P-2-AIs par une combinaison d'extraction d'éponges et de synthèse biomimétique conduisant à une approche biomimétique originale de la palau'amine, du nagélamide D et de leurs congénères.The work described in this manuscript deals with the isolation of marine secondary metabolites from a sponge belonging to the genus Axinella, together with the chemotaxonomy of the families Axinellidae, Agelasidae, Halichondriidae, Dictyonellidae and with the biomimetic syntheses of Pyrrole-2-Aminoimidazole (P-2-AIs) dimers. The chemical study of the selected sponge Axinella sp. collected in Lebanon led to the isolation of 17 P-2-AIs, including 3 new compounds : slagenine D, stylissazole G and tribromostyloguanidine. An NMR study of tribromostyloguanidine confims its proposed relative configuration. These families of marine sponges have been investigated using a chemotaxonomy approach in search of biomolecular tags to help differentiate species. The process of biomimetic dimerization of oroïdin was explored, leading to the first biomimetic synthesis of nagelamides congeners. These syntheses illustrate our biogenetic hypothesis that identifies oroïdin as a common precursor of P-2-AIs dimers. Another biomimetic approach of palau'amine relies on oxidative methodology of guanidine addition on a pyrrole-proline pseudopeptide. The pathway of the pyrrole-proline bispseudopeptide was shortened down to 7 steps and improved with an overall 30% yield. The strategy of oxidative addition of guanidine was carried out, leading to the formation of advanced precursors of palau'amine bearing the A, C, D, E and F cycles. The reaction cascade observed during this investigation is though to be biomimetic. This research work allowed us to deepen our knowledge on the biogenesis of the P-2-AIs family of sponge metabolites by selectively combining extraction and synthetic studies, thus leading to an original biomimetic approach to the biosynthesis of palau'amine, nagelamides and congeners.ORSAY-PARIS 11-BU Sciences (914712101) / SudocSudocFranceF

Unprecedented Biomimetic Homodimerization of Oroidin and Clathrodin Marine Metabolites in the Presence of HMPA or Phosphonate Salt Tweezers

The first biomimetic homodimerization of oroidin and clathrodin was effected in the presence HMPA and diphosphonate salts, strong guanidinium and amide chelating agents. The intermolecular associations probably interfere with the entropically and kinetically favored intramolecular cyclizations. Use of oroidin·¹/₂HCl salt or clathrodin·¹/₂HCl was indicative in the presence of the ambident nucleophilic and electrophilic tautomers of the 2-aminoimidazolic oroidin and clathrodin precursors. Surprisingly, the homodimerization of oroidin led to the nagelamide D skeleton, while the homodimerization of clathrodin gave the benzene para-symmetrical structure <b>19</b>. The common process was rationalized from tautomeric precursors <b>I</b> and <b>III</b>

Concise synthesis of Didebromohamacanthin A and Demethylaplysinopsine: Addition of Ethylenediamine and Guanidine Derivatives to the Pyrrole-Amino Acid Diketopiperazines in Oxidative Conditions

Oxidative nucleophilic addition of ethylenediamine and guanidine derivatives to pyrrole-amino acid diketopiperazines was shown to provide substituted 5,6-dihydro-2­(1<i>H</i>)-piperazinones, quinoxalinones, and 2-aminoimidazolones. On the basis of this methodology, a concise approach to natural products didebromohamacanthin A and demethylaplysinopsine has been demonstrated

Uma experiência de tradução do conto “Marcha Fúnebre” de Machado de Assis para o japonês

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Reporter Ligand NMR Screening Method for 2‑Oxoglutarate Oxygenase Inhibitors

The human 2-oxoglutarate (2OG) dependent oxygenases belong to a family of structurally related enzymes that play important roles in many biological processes. We report that competition-based NMR methods, using 2OG as a reporter ligand, can be used for quantitative and site-specific screening of ligand binding to 2OG oxygenases. The method was demonstrated using hypoxia inducible factor hydroxylases and histone demethylases, and <i>K</i>_D values were determined for inhibitors that compete with 2OG at the metal center. This technique is also useful as a screening or validation tool for inhibitor discovery, as exemplified by work with protein-directed dynamic combinatorial chemistry

Management of Pathogenic CDH1 Variant Carriers Within the FREGAT Network

International audienceObjective: To describe the management of pathogenic CDH1 variant carriers (pCDH1vc) within the FREGAT (FRench Eso-GAsTric tumor) network. Primary objective focused on clinical outcomes and pathological findings, Secondary objective was to identify risk factor predicting postoperative morbidity (POM).Background: Prophylactic total gastrectomy (PTG) remains the recommended option for gastric cancer risk management in pCDH1vc with, however, endoscopic surveillance as an alternative.Methods: A retrospective observational multicenter study was carried out between 2003 and 2021. Data were reported as median (interquartile range) or as counts (proportion). Usual tests were used for univariate analysis. Risk factors of overall and severe POM (ie, Clavien-Dindo grade 3 or more) were identified with a binary logistic regression.Results: A total of 99 patients including 14 index cases were reported from 11 centers. Median survival among index cases was 12.0 (7.6-16.4) months with most of them having peritoneal carcinomatosis at diagnosis (71.4%). Among the remaining 85 patients, 77 underwent a PTG [median age=34.6 (23.7-46.2), American Society of Anesthesiologists score 1: 75%] mostly via a minimally invasive approach (51.9%). POM rate was 37.7% including 20.8% of severe POM, with age 40 years and above and low-volume centers as predictors ( P =0.030 and 0.038). After PTG, the cancer rate on specimen was 54.5% (n=42, all pT1a) of which 59.5% had no cancer detected on preoperative endoscopy (n=25).Conclusions: Among pCDH1vc, index cases carry a dismal prognosis. The risk of cancer among patients undergoing PTG remained high and unpredictable and has to be balanced with the morbidity and functional consequence of PTG

Plant Growth Regulator Daminozide Is a Selective Inhibitor of Human KDM2/7 Histone Demethylases

The JmjC oxygenases catalyze the <i>N</i>-demethylation of <i>N</i>^ε-methyl lysine residues in histones and are current therapeutic targets. A set of human 2-oxoglutarate analogues were screened using a unified assay platform for JmjC demethylases and related oxygenases. Results led to the finding that daminozide (<i>N-</i>(dimethylamino)­succinamic acid, 160 Da), a plant growth regulator, selectively inhibits the KDM2/7 JmjC subfamily. Kinetic and crystallographic studies reveal that daminozide chelates the active site metal via its hydrazide carbonyl and dimethylamino groups