Marine anticancer agents: An overview with a particular focus on their chemical classes

UID/Multi/04378/2019 IF/00700/2014 grant number 216Z167 grant RTA 2015-00010-C03-02 No. PBA/MB/16/01 PDOC/19/02/01The marine environment is a rich source of biologically active molecules for the treatment of human diseases, especially cancer. The adaptation to unique environmental conditions led marine organisms to evolve different pathways than their terrestrial counterparts, thus producing unique chemicals with a broad diversity and complexity. So far, more than 36,000 compounds have been isolated from marine micro- and macro-organisms including but not limited to fungi, bacteria, microalgae, macroalgae, sponges, corals, mollusks and tunicates, with hundreds of new marine natural products (MNPs) being discovered every year. Marine-based pharmaceuticals have started to impact modern pharmacology and different anti-cancer drugs derived from marine compounds have been approved for clinical use, such as: cytarabine, vidarabine, nelarabine (prodrug of ara-G), fludarabine phosphate (pro-drug of ara-A), trabectedin, eribulin mesylate, brentuximab vedotin, polatuzumab vedotin, enfortumab vedotin, belantamab mafodotin, plitidepsin, and lurbinectedin. This review focuses on the bioactive molecules derived from the marine environment with anticancer activity, discussing their families, origin, structural features and therapeutic use.publishersversionpublishe

The Boston criteria version 2.0 for cerebral amyloid angiopathy:a multicentre, retrospective, MRI–neuropathology diagnostic accuracy study

BACKGROUND: Cerebral amyloid angiopathy (CAA) is an age-related small vessel disease, characterised pathologically by progressive deposition of amyloid β in the cerebrovascular wall. The Boston criteria are used worldwide for the in-vivo diagnosis of CAA but have not been updated since 2010, before the emergence of additional MRI markers. We report an international collaborative study aiming to update and externally validate the Boston diagnostic criteria across the full spectrum of clinical CAA presentations. METHODS: In this multicentre, hospital-based, retrospective, MRI and neuropathology diagnostic accuracy study, we did a retrospective analysis of clinical, radiological, and histopathological data available to sites participating in the International CAA Association to formulate updated Boston criteria and establish their diagnostic accuracy across different populations and clinical presentations. Ten North American and European academic medical centres identified patients aged 50 years and older with potential CAA-related clinical presentations (ie, spontaneous intracerebral haemorrhage, cognitive impairment, or transient focal neurological episodes), available brain MRI, and histopathological assessment for CAA diagnosis. MRI scans were centrally rated at Massachusetts General Hospital (Boston, MA, USA) for haemorrhagic and non-haemorrhagic CAA markers, and brain tissue samples were rated by neuropathologists at the contributing sites. We derived the Boston criteria version 2.0 (v2.0) by selecting MRI features to optimise diagnostic specificity and sensitivity in a prespecified derivation cohort (Boston cases 1994-2012, n=159), then externally validated the criteria in a prespecified temporal validation cohort (Boston cases 2012-18, n=59) and a geographical validation cohort (non-Boston cases 2004-18; n=123), comparing accuracy of the new criteria to the currently used modified Boston criteria with histopathological assessment of CAA as the diagnostic standard. We also assessed performance of the v2.0 criteria in patients across all cohorts who had the diagnostic gold standard of brain autopsy. FINDINGS: The study protocol was finalised on Jan 15, 2017, patient identification was completed on Dec 31, 2018, and imaging analyses were completed on Sept 30, 2019. Of 401 potentially eligible patients presenting to Massachusetts General Hospital, 218 were eligible to be included in the analysis; of 160 patient datasets from other centres, 123 were included. Using the derivation cohort, we derived provisional criteria for probable CAA requiring the presence of at least two strictly lobar haemorrhagic lesions (ie, intracerebral haemorrhages, cerebral microbleeds, or foci of cortical superficial siderosis) or at least one strictly lobar haemorrhagic lesion and at least one white matter characteristic (ie, severe visible perivascular spaces in centrum semiovale or white matter hyperintensities in a multispot pattern). The sensitivity and specificity of these criteria were 74·8% (95% CI 65·4-82·7) and 84·6% (71·9-93·1) in the derivation cohort, 92·5% (79·6-98·4) and 89·5% (66·9-98·7) in the temporal validation cohort, 80·2% (70·8-87·6) and 81·5% (61·9-93·7) in the geographical validation cohort, and 74·5% (65·4-82·4) and 95·0% (83·1-99·4) in all patients who had autopsy as the diagnostic standard. The area under the receiver operating characteristic curve (AUC) was 0·797 (0·732-0·861) in the derivation cohort, 0·910 (0·828-0·992) in the temporal validation cohort, 0·808 (0·724-0·893) in the geographical validation cohort, and 0·848 (0·794-0·901) in patients who had autopsy as the diagnostic standard. The v2.0 Boston criteria for probable CAA had superior accuracy to the current Boston criteria (sensitivity 64·5% [54·9-73·4]; specificity 95·0% [83·1-99·4]; AUC 0·798 [0·741-0854]; p=0·0005 for comparison of AUC) across all individuals who had autopsy as the diagnostic standard. INTERPRETATION: The Boston criteria v2.0 incorporate emerging MRI markers of CAA to enhance sensitivity without compromising their specificity in our cohorts of patients aged 50 years and older presenting with spontaneous intracerebral haemorrhage, cognitive impairment, or transient focal neurological episodes. Future studies will be needed to determine generalisability of the v.2.0 criteria across the full range of patients and clinical presentations. FUNDING: US National Institutes of Health (R01 AG26484)

Research of new anticancer compounds from marine origin : isolation, structural determination and synthesis

Ce manuscrit traite des travaux menés pendant 3 ans sur l’étude chimique et biologique de métabolites secondaires issus d’invertébrés marins. L’étude chimique porte sur l’extraction, l’isolement et la caractérisation structurale de produits naturels marins ainsi que, pour certains, leur synthèse chimique. L’étude biologique permet d’évaluer les activités biologiques des différents composés ainsi que leur mode d’action et d’établir les relations structure-activité qui peuvent en découler. L’étude chimique de l’éponge Leuconia sp. nous a tout d’abord permis d’isoler 9 composés dont un nouveau : l’acide makaluvique D. Parmi les 8 autres composés déjà recensés, 7 sont des pyrroloiminoquinones : les makaluvamines D, G, H, J, K et P et la damirone A. Le dernier métabolite isolé de cette éponge est la 3,7-diméthylguanine. De nombreuses études préalables ont déjà permis d’observer diverses activités biologiques intéressantes. En effet, les makaluvamines sont des composés anticancéreux, antipaludéens et antioxydants. Ces études ont permis d’établir plusieurs relations structure-activité : i) l’importance de la présence d’une charge positive, ii) l’importance de la substitution par un 4 éthylphénol et iii) l’importance de la conjugaison dans le tricycle central. En revanche, les acides makaluviques ne semblent pas révéler d’activités intéressantes. De nouveaux tests biologiques seront réalisés dans un futur proche pour confirmer ou non ces hypothèses. Par ailleurs, l’étude de l’éponge Clathria rugosa nous a permis d’isoler un nouveau composé de la famille des peroxyacarnoates : l’acide peroxyacarnoïque E. Une activité anticancéreuse très intéressante a été observée pour ce métabolite contenant un endoperoxyde. En effet, ce composé présente des activités cytotoxiques. De plus, des études plus ciblées ont permis de mettre en avant le mécanisme d’action de ce nouveau métabolite. Il cible les voies de mort cellulaire et en particulier des voies de nécrose régulée telles que la nécroptose ou la ferroptose. De plus, une étude cellulaire a permis de mettre en cause une perturbation au niveau de la chaîne respiratoire mitochondriale et un dysfonctionnement de la phosphorylation oxydative. La synthèse convergente de ce composé a également été réalisée mais n’a pas encore abouti. Cependant, des voies d’optimisation sont proposées. La finalisation de cette synthèse permettrait d’évaluer plus en détail le mode d’action de l’acide peroxyacarnoïque E et de le comparer aux médicaments commercialisés actuellement.This manuscript deals with the work carried out during 3 years on the chemical and biological studies of secondary metabolites from marine invertebrates. On the one hand, the chemical study addresses the extraction, the isolation, and the structural elucidation of marine natural products as well as, if necessary, their chemical synthesis. On the other hand, the biological study allows us to characterize the biological activities of these compounds and their mode of action, and to establish some structure-activity relationships that may result from.First, the chemical study of the sponge Leuconia sp. has allowed us to isolate 9 compounds, including a new one: the makaluvic acid D. Among the 8 known metabolites, 7 are pyrroloiminoquinones: the makaluvamines D, G, H, J, K and P and the damirone A. The last isolated metabolite is the 3,7 dimethylguanine. Several significant biological activities have already been discovered thanks to numerous prior studies. Indeed, the makaluvamines were proved to be antitumor, antimalarial and antioxidant compounds. These studies have also evidenced several structure-activity relationships: i) the importance of the presence of a positive charge, ii) the importance of the 4 ethylphenol inclusion and iii) the importance of the conjugation within the tricyclic core. However, the makaluvic acids do not seem to unveil any significant bioactivity. Some new biological tests will be carried out in the future to confirm or reject these hypotheses.Then, the study of the sponge Clathria rugosa has allowed us to isolate a new compound from the peroxyacarnoate family: the peroxyacarnoic acid E. This endoperoxide-containing metabolite has shown a significant antitumor activity. Indeed, this compound displayed strong cytotoxic activities. Moreover, several more targeted studies have allowed us to highlight the action mechanism of this new metabolite. It targets cell death pathways and specifically regulated necrosis pathways such as necroptosis or ferroptosis. In addition, a cellular study has revealed a disruption of the mitochondrial respiratory chain and an oxidative phosphorylation dysfunction. The convergent synthesis of this compound has also been carried out but has not been resulted in success yet, but some pathways are suggested to address this issue. The completion of this synthesis would allow us to evaluate more accurately the mode of action of the peroxyacarnoic acid E and to compare it to the currently marketed drugs

Disturbance modelling of plant community dynamics in managed grasslands

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Des certificats médicaux : loi, déontologie et pratique

Le nombre croissant de réglementations applicables à bien des domaines de la pratique médicale et leur complexité grandissante renforcent l?importance du droit médical en tant que discipline propre particulière des sciences juridiques. De plus en plus, les médecins de toutes spécialités sont requis pour se porter garants par attestations adéquates de l?état de santé, de l?aptitude ou de la situation de maladie de leurs patients. Ces derniers en retirent des avantages que leur octroie la société. Soucieux de l?intérêt de leur patient, les praticiens sont parfois tentés d?agir en fonction de leur propre subjectivité ; ceci peut leur valoir des sanctions pénales ou disciplinaires et induit un déni de confi ance de la part de ceux qui exercent une autorité. La méfi ance initiale qui a bâti le système de l?attestation s?étend à ceux-là même dont on attendait la collaboration. Comment sortir de cette ronde infernale, stérilisante, dénaturant l?acte médical ? En attendant que des hommes de bonne volonté se penchent sur le système pour le réformer, il reste aux rédacteurs de certifi cats à déjouer les pièges qui leur sont tendus. La prétention du présent ouvrage est de proposer des modèles de certificat que le praticien peut remplir au gré des circonstances. Il est conçu comme un vade-mecum aidant le praticien dans sa démarche de certifi cation en lui proposant des choix motivés. C?est la raison pour laquelle chaque modèle est encadré de sa justification et des pièges auxquels il expose le certificateur

Het medisch attest : Wetgeving, deontologie en Praktijk

Het juridische luik wint in een groot deel van de geneeskunde aan belang door het steeds groeiende aantal richtlijnen die ook steeds ingewikkelder worden. Meer en meer wordt van artsen verwacht dat ze zorg dragen voor het afleveren van de juiste attesten inzake de gezondheid, de geschiktheid of de ziektetoestand van hun patiënten. Een deel van deze patiënten haalt hier dan ook bepaalde voordelen uit, voorzien door de gemeenschap. In het belang van hun patiënt kunnen artsen soms geneigd zijn subjectief te handelen: wat hen zowel strafrechterlijke als tuchtrech- terlijke sancties kan opleveren. Bovendien wordt het vertrouwen van de overheid in de artsen hierdoor beschaamd. Het wantrouwen dat ooit aan de basis lag van het systeem van certificaten, breidde zich uit tot diegenen van wie men medewerking verwachtte. Hoe te ontsnappen uit deze cirkel die het beoefenen van de geneeskunst overschaduwt? In afwachting dat enkelen zich te goeder trouw buigen over de hervorming van het bestaande systeem, blijft het de taak van wie attesten uitschrijft om mogelijke valkuilen te vermijden. Het doel van dit boek is u te laten kennis maken met de verschillende attesten die u kan uitschrijven naargelang de specifieke noden en omstandigheden. Dit boek wil een vademecum zijn dat artsen bij de opmaak van de attesten begeleidt aan de hand van een uitgebreide reeks voorbeelden. Bij elk model krijgt u verantwoording waarom dit gebruikt wordt en wordt aandacht gegeven aan de mogelijke addertjes onder het gras

Evolving Reservoirs for Meta Reinforcement Learning

Animals often demonstrate a remarkable ability to adapt to their environments during their lifetime. They do so partly due to the evolution of morphological and neural structures. These structures capture features of environments shared between generations to bias and speed up lifetime learning. In this work, we propose a computational model for studying a mechanism that can enable such a process. We adopt a computational framework based on meta reinforcement learning as a model of the interplay between evolution and development. At the evolutionary scale, we evolve reservoirs, a family of recurrent neural networks that differ from conventional networks in that one optimizes not the weight values but hyperparameters of the architecture: the later control macro-level properties, such as memory and dynamics. At the developmental scale, we employ these evolved reservoirs to facilitate the learning of a behavioral policy through Reinforcement Learning (RL). Within an RL agent, a reservoir encodes the environment state before providing it to an action policy. We evaluate our approach on several 2D and 3D simulated environments. Our results show that the evolution of reservoirs can improve the learning of diverse challenging tasks. We study in particular three hypotheses: the use of an architecture combining reservoirs and reinforcement learning could enable (1) solving tasks with partial observability, (2) generating oscillatory dynamics that facilitate the learning of locomotion tasks, and (3) facilitating the generalization of learned behaviors to new tasks unknown during the evolution phase

Observation d'attracteurs d'onde d'inertie-gravité dans un bassin axi-symétrique

International audienceInternal waves are ubiquitous in the ocean and play an essential role in the transport of energy and mixing. Their peculiar reflection enables the concentration of energy on a limit cycle. With wave beams viewed as rays, this reflection on an inclined slope shrinks its width and generically brings closer two initially different trajectories eventually reaching a limit cycle called an attractor. Following previous studies, a ray-tracing algorithm is used to track the convergence of wave beams onto such a structure in a 3D axisymmetric domain. This information is used to design experiments using a truncated conical shaped tank in order to form an inertia-gravity waves attractor in a 3D axisymmetric geometry. By increasing the amplitude of the forcing, an evolution of the attractor characteristics can be observed. The occurrence of waves at frequencies lower than the forcing frequency ω 0 suggests triadic resonant instability in a rotating or in a stratified case. Experiments performed in a stratification-only or a rotation-only case indicate two distinct behaviors. The existence of easily excited standing waves, resonant modes of the tank, at frequencies lower than the forcing one enables sharp triadic resonance instability for internal gravity waves, which is not possible for inertial waves. The effect of the symmetry axis is also investigated by adding a cylinder of sufficient diameter at the center of the domain for the wave to reflect on and thereby avoid the interaction on the singularity. Without it, the large amplitude of the waves on the axis triggers nonlinear effects and mixing, denying the access to the wave turbulence regime

Kinase-Based Screening of Marine Natural Extracts Leads to the Identification of a Cytotoxic High Molecular Weight Metabolite from the Mediterranean Sponge Crambe tailliezi

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