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Objectives“Anti-science” accusations are common in medicine and public health, sometimes to discredit scientists who hold opposing views. However, there is no such thing as “one science”. Epistemology recognizes that any “science” is sociologically embedded, and therefore contextual and intersubjective. In this paper, we reflect on how “science” needs to adopt various perspectives to give a comprehensive and nuanced understanding of a phenomenon.Study designOpinion paper.MethodsBased on a targeted literature survey, we first clarify the known limits of traditional scientific methods and then reflect on how the scientific reporting about Covid-19 mRNA vaccines has evolved.ResultsThe first reports of the Covid-19 mRNA vaccines randomised controlled trial results showed impressive efficacy. Nevertheless, an abundant literature has since depicted a far more nuanced picture of the effectiveness and safety of those vaccines over the medium-term. We organise them around five themes: (i) differentiating between relative and absolute reduction; (ii) taking account of time in reporting effectiveness; (iii) taking account of all outcomes, including adverse effects; (iv) stratifying effectiveness and considering other decision criteria (efficiency, equity, and acceptance); (v) changing the outcome of concern and assessing vaccines’ effectiveness on mortality.ConclusionsScience offers a wide range of perspectives on a given study object. Only the process of deliberation amongst scientists and other stakeholders can result in accepted new knowledge useful to support decision-making. Unfortunately, by trying to reduce “science” to simple messages set in stone, scientists can become the worse enemies of science., SCOPUS: ar.j, info:eu-repo/semantics/published

Over the past years, progress made in next-generation sequencing technologies and bioinformatics have sparked a surge in association studies. Especially, genome-wide association studies (GWASs) have demonstrated their effectiveness in identifying disease associations with common genetic variants. Yet, rare variants can contribute to additional disease risk or trait heterogeneity. Because GWASs are underpowered for detecting association with such variants, numerous statistical methods have been recently proposed. Aggregation tests collapse multiple rare variants within a genetic region (e.g. gene, gene set, genomic loci) to test for association. An increasing number of studies using such methods successfully identified trait-associated rare variants and led to a better understanding of the underlying disease mechanism. In this review, we compare existing aggregation tests, their statistical features and scope of application, splitting them into the five classical classes: burden, adaptive burden, variance-component, omnibus and other. Finally, we describe some limitations of current aggregation tests, highlighting potential direction for further investigations., SCOPUS: re.j, info:eu-repo/semantics/published

The development of high-throughput next-generation sequencing technologies and large-scale genetic association studies produced numerous advances in the biostatistics field. Various aggregation tests, i.e. statistical methods that analyze associations of a trait with multiple markers within a genomic region, have produced a variety of novel discoveries. Notwithstanding their usefulness, there is no single test that fits all needs, each suffering from specific drawbacks. Selecting the right aggregation test, while considering an unknown underlying genetic model of the disease, remains an important challenge. Here we propose a new ensemble method, called Excalibur, based on an optimal combination of 36 aggregation tests created after an in-depth study of the limitations of each test and their impact on the quality of result. Our findings demonstrate the ability of our method to control type I error and illustrate that it offers the best average power across all scenarios. The proposed method allows for novel advances in Whole Exome/Genome sequencing association studies, able to handle a wide range of association models, providing researchers with an optimal aggregation analysis for the genetic regions of interest., SCOPUS: ar.j, info:eu-repo/semantics/published

Kashin-Beck disease (KBD) is a multifactorial endemic disease that only occurs in specific Asian areas. Mycotoxin contamination, especially from the Fusarium spp. has been considered as one of the environmental risk factors that could provoke chondrocyte and cartilage damage. This study aimed to investigate whether new mycotoxins could be identified in KBD-endemic regions as a potential KBD risk factor. This was investigated on 292 barley samples collected in Tibet during 2009-2016 and 19 wheat samples collected in Inner Mongolia in 2006, as control, from KBD-endemic and non-endemic areas. The LC-HRMS(/MS) data, obtained by a general mycotoxin extraction technic, were interpreted by both untargeted metabolomics and molecular networks, allowing us to identify a discriminating compound, enniatin B, a mycotoxin produced by some Fusarium spp. The presence of Fusarium spp. DNA was detected in KBD-endemic area barley samples. Further studies are required to investigate the role of this mycotoxin in KBD development in vivo., SCOPUS: ar.j, info:eu-repo/semantics/published

Although significant progress has been made in coaxial printing of vascularized tissue models, this technique has not yet been used to fabricate stimulus-responsive scaffolds capable of shape change over time. Here, we propose a new method of direct ink printing with a coaxial nozzle, coaxial 4D printing, enabling the manufacturing of thermoresponsive constructs embedded with a network of interconnected channels. In our approach, a poly(N-isopropylacrylamide) (PNIPAAm)-based thermoink is coaxially extruded into either core/sheath microfibers or microtubes. PNIPAAm renders a hydrogel temperature-sensitive and endows it with a shape-morphing property both at the micro- and macroscale. Specifically, the lumen diameter of the microtubes can be controlled by temperature by 30%. The macrostructural soft actuators can undergo programmed and reversible temperature-dependent shape changes due to the structural anisotropy of the hydrogel. The permeability tests demonstrate that the hydrogel can possess enough strength to maintain the hollow channels without breaking. In vitro tests confirm the biocompatibility of our material with EA.hy926 cells, paving the avenue for new perfusable soft robots, active implants, or vascularized tissue models. Finally, we combined microalgae Chlamydomonas reinhardtii with our hydrogels to fabricate materials having functions of both living microorganisms and stimuli-responsive polymers towards creating engineered living materials (ELMs) with a vein-like geometry., info:eu-repo/semantics/published

ObjectiveTo assess the contribution of interprofessional education (IPE) for pre-graduate students from eight study branches. These seminars had patient-partners and caregivers as co-facilitators for reflexive conversations, with educational goals of learning interprofessional communication and involving patients in decision-making.MethodsA pre/post seminar comparison with 2 questionnaires about the students’ professional identity, multidisciplinary collaboration and patients’ involvement, and the richness of stakeholders’ definitions.Results1142 students participated in the course (n = 740 after removing missing data). The results indicate that this type of education helps students feel more confident in their ability to communicate and collaborate (z = −10,204; p < 0,001), involves patients in their care plan (z = −7,996; p < 0,001) and fosters the competence and autonomy of the post-graduate students in their own professional field (z = −10,627; p < 0,001). It also enriches the definition of patients’ roles (n = 399; z = −17,276; p < 0,001).ConclusionIncluding patients-partners and caregivers in IPE enriches the professional identity and increases the self-efficacy of futures caregivers.Practice implicationsThis program exposed students to collaborative care practices, can reduce their resistance to this type of practice after graduation by making them more confident in using a structured team approach and recognising its benefits for both patients and caregivers., SCOPUS: ar.j, info:eu-repo/semantics/published

Introduction: Red blood cells (RBC) are one of the key elements of the microcirculation. Their ability to pass through capillaries and to deliver oxygen to cells is due to their large degree of deformability linked to the characteristics of the RBC membrane. Alterations in RBC deformability as a result of membrane damage, linked in part to increased synthesis of reactive oxygen species (ROS), can be observed in several diseases, such as sepsis, and may contribute to the altered microcirculation observed in these pathologies. Hyperbaric oxygen therapy (HBOT), with inhalation of 100 % oxygen, has been proposed in several acute or chronic pathologies, including carbon monoxide poisoning. Objective: We investigated the effects of HBOT on oxidative stress from ROS produced by myeloperoxidase (MPO) and on RBC deformability in patients with acute or chronic inflammation (n = 10), in patients with acute carbon monoxide poisoning (n = 10), and in healthy volunteers (n = 10). Methods: RBC deformability was evaluated before and after HBOT in the various populations using the ektacytometry technique (Laser-assisted Optical Rotational Red Cell Analyzer – LORRCA). Deformability was determined by the elongation index (EI) in relation to the shear stress (SS) over a range of 0.3 to 50 Pa. Oxidative stress was estimated through changes in proteins (chlorotyrosine and homocitrulline) induced by MPO activity measured by liquid chromatography-tandem mass spectrometry analysis. Results: Before HBOT, EI was significantly lower in patients with acute or chronic inflammation than in healthy volunteers and patients with acute carbon monoxide poisoning for the majority of SS values studied. After one session of HBOT, the EI was significantly higher than before HBOT for SS values of 1.93 Pa or higher in patients with acute or chronic inflammation. This effect remains constant after 10 sessions. There were no differences before and after HBOT in protein or amino acid oxidation due to ROS gener, SCOPUS: ar.j, info:eu-repo/semantics/published

Myeloperoxidase (MPO) has been reported in prostate tissue, and considering its pro-oxidant properties, this location might be linked to prostate pathology. The possibility that the glandular prostatic tissue might be the source of MPO and its potential inflammatory effects must be tested. Human prostate material was obtained from prostate biopsies and radical prostatectomies. Immunohistochemistry was performed using MPO-specific human antibody. In situ hybridization using MPO-specific probes and laser-assisted microdissection for quantitative real-time RT-PCR were performed to observe whether MPO is being produced in prostate tissue. Mass spectrometry on prostate biopsies was used to detect products of MPO activity in nucleic acids (DNA/RNA). MPO contribution to intracellular accumulation of ROS and interleukin-8 in prostatic epithelial cells was monitored in vitro. Immunohistochemistry confirmed cellular localization of MPO in epithelial cells of the prostate. The staining varied from light to high intensity. In situ hybridization did not address the presence of mRNA coding for MPO. No MPO-specific modifications on nucleic acids were detected. Mox-LDL was a major factor inducing ROS and cytokines production in prostatic epithelial cells. We did not demonstrate that MPO was synthetized by prostatic epithelial cells. However, in vitro experiments showed the ability of MPO to potentiate the ROS production and inflammation on prostate epithelial cells. Results do not allow us to demonstrate a role of MPO in prostate to date but further studies are mandatory to focus on the potential impact of MPO in the development of prostatic diseases., SCOPUS: ar.j, info:eu-repo/semantics/published

For many years epigenetics was defined by three pillars: DNA methylation, histone modifications, and ncRNA regulation. But recently, the development of next-generation sequencing and more sensitive mass spectrometry unveiled the presence of novel mRNA modifications. This new field of RNA epigenetics was then referred to as epitranscriptomics.During the golden age of epitranscriptomics, many new mRNA modifications were identified. Thanks to its abundance, m6A persists until now as the reference, with the discovery of complete enzymatic machinery (writers, readers, and erasers) as well as functions in physiology and pathology. However, the very existence of the other mRNA modifications remains under debate due to the high error rates in the sequencing technologies, the low specificity of new methods developed, and the poor reproducibility between the different epitranscriptomics studies. Thus, the aim of this thesis is to dive into the identification of new mRNA modifications through the prism of the writers and readers.In the first part of the thesis, by using the RNA biotin pull-down method, we uncovered promising readers from two mRNA modifications: FUBP3 for inosine and CSDE1 for m5U. Then, we further described the direct binding of FUBP3 to hyper-edited oligonucleotides.In the second part of the thesis, we developed and optimized new sequencing techniques, based on the TRMT2A writer to study the distribution of m5U in mRNA. Here, we provide the first transcriptome-wide list of around one thousand transcripts that are bound and m5U modified by TRMT2A. Moreover, we challenged the recently described Nanopore technology to map m5U at a single-nucleotide level. Using two different bioinformatic tools, we obtained a list of confident m5U peaks that need to be confirmed by primer extension.Lastly in the third part, we confirmed that CSDE1 acts as a reader of the m5U modification. We also showed that the depletion of TRMT2A induces changes in the transcriptome and proteo, Durant de nombreuses années, l’épigénétique était définie par trois piliers :la méthylation de l’ADN, les modifications d’histone et la régulation par ARN non codant. Récemment, le développement de nouvelles technologies de séquençage et de spectrométries de masse plus sensibles a dévoilé la présence de nouvelles modifications d’ARNm. Ce nouveau domaine de recherche lié à l’épigénétique des ARN est appelé épitranscriptomique. Durant l’âge d’or de l’épitranscriptomique, une dizaine de nouvelles modifications d’ARN a été identifiée. Grâce à son abondance, m6A reste jusqu’à ce jour la référence avec la découverte d’une machinerie enzymatique complète (writers, readers et erasers) ainsi que des fonctions en physiologie et pathologie. Cependant, l’existence même des autres modifications d’ARNm reste débattue à cause notamment du haut taux d’erreur des techniques de séquençage et de la faible spécificité des nouvelles méthodes développés. Donc, le but de cette thèse est de plonger dans le monde des nouvelles modifications d’ARNm par le biais des writers et readers.Dans cette première partie de thèse, en utilisant la méthode du biotin pull-down, nous avons identifié des readers prometteurs pour deux modifications d’ARNm :FUBP3 pour l’inosine et CSDE1 pour m5U. Ensuite, nous avons caractérisé davantage la liaison directe de FUBP3 à un oligonucléotide hyper-édité.Dans la deuxième partie, nous avons développé et optimisé de nouvelles techniques de séquençage basées sur le writer TRMT2A afin d’étudier la distribution de m5U dans les ARNm. Ici, nous présentons la première liste transcriptomique d’environ mille transcrits qui sont liés et modifié m5U par TRMT2A. De plus, nous avons testé la récente technologie du Nanopore afin de cartographier la position de m5U au nucléotide près. En utilisant deux outils bioinformatiques, nous avons obtenu une liste de piques m5U qui doivent être prochainement confirmés par la méthode du primer extension. Enfin, dans la troisième partie, nous, Doctorat en Sciences biomédicales et pharmaceutiques (Médecine), info:eu-repo/semantics/nonPublished

Introduction Globisporangium ultimum is an oomycetal pathogen causing damping-off on over 300 different plant hosts. Currently, as for many phytopathogens, its control relies in the use of chemicals with negative impact on health and ecosystems. Therefore, many biocontrol strategies are under investigation to reduce the use of fungicides. Results In this study, the soil bacterium Pseudomonas sp. NCIMB 10586 demonstrates a strong iron-repressed in vitro antagonism against G. ultimum MUCL 38045. This antagonism does not depend on the secretion of the broad-range antibiotic mupirocin or of the siderophore pyoverdine by the bacterial strain. The inhibitor molecule was identified as a novel non-ribosomal peptide synthetase (NRPS) siderophore named mupirochelin. Its putative structure bears similarities to other siderophores and bioactive compounds. The transcription of its gene cluster is affected by the biosynthesis of pyoverdine, the major known siderophore of the strain. Besides mupirochelin, we observed the production of a third and novel NRPS-independent siderophore (NIS), here termed triabactin. The iron-responsive transcriptional repression of the two newly identified siderophore gene clusters corroborates their role as iron scavengers. However, their respective contributions to the strain fitness are dissimilar. Bacterial growth in iron-deprived conditions is greatly supported by pyoverdine production and, to a lesser extent, by triabactin. On the contrary, mupirochelin does not contribute to the strain fitness under the studied conditions. Conclusion Altogether, we have demonstrated here that besides pyoverdine, Pseudomonas sp. NCIMB 10586 produces two newly identified siderophores, namely mupirochelin, a weak siderophore with strong antagonism activity against G. ultimum, and the potent siderophore triabactin., SCOPUS: ar.j, info:eu-repo/semantics/published

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L’enquête par questionnaire Be.hive menée en 2019 a révélé que la complexité était perçue différemment par les professionnels de la santé et les patients. Pour les patients, la douleur chronique est l’élément majoritairement cité parmi dix possibilités. Les professionnels quant à eux la citaient en avant dernier lieu. L’objectif est ici d’étudier les facteurs qui conduisent les patients à identifier la douleur chronique comme constitutive de la complexité qu’ils vivent., info:eu-repo/semantics/published

Human myeloperoxidase (MPO) utilizes hydrogen peroxide to oxidize organic compounds and as such plays an essential role in cell-component synthesis, in metabolic and elimination pathways, and in the front-line defence against pathogens. Moreover, MPO is increasingly being reported to play a role in inflammation. The enzymatic activity of MPO has also been shown to depend on its glycosylation. Mammalian MPO crystal structures deposited in the Protein Data Bank (PDB) present only a partial identification of their glycosylation. Here, a newly obtained crystal structure of MPO containing four disulfide-linked dimers and showing an elaborate collection of glycans is reported. These are compared with the glycans identified in proteomics studies and from 18 human MPO structures available in the PDB. The crystal structure also contains bound paroxetine, a blocker of serotonin reuptake that has previously been identified as an irreversible inhibitor of MPO, in the presence of thiocyanate, a physiological substrate of MPO., SCOPUS: ar.j, info:eu-repo/semantics/published

Inflammation and its resolution are the result of the balance between pro-inflammatory and pro-resolving factors, such as specialized pro-resolving mediators (SPMs). This balance is crucial for plaque evolution in atherosclerosis, a chronic inflammatory disease. Myeloperoxidase (MPO) has been related to oxidative stress and atherosclerosis, and MPO-oxidized low-density lipoproteins (Mox-LDLs) have specific characteristics and effects. They participate in foam cell formation and cause specific reactions when interacting with macrophages and endothelial cells. They also increase the production of intracellular reactive oxygen species (ROS) in macrophages and the resulting antioxidant response. Mox-LDLs also drive macrophage polarization. Mox-LDLs are known to be pro-inflammatory particles. However, in the presence of Mox-LDLs, endothelial cells produce resolvin D1 (RvD1), a SPM. SPMs are involved in the resolution of inflammation by stimulating efferocytosis and by reducing the adhesion and recruitment of neutrophils and monocytes. RvD1 also induces the synthesis of other SPMs. In vitro, Mox-LDLs have a dual effect by promoting RvD1 release and inducing a more anti-inflammatory phenotype macrophage, thereby having a mixed effect on inflammation. In this review, we discuss the interrelationship between MPO, Mox-LDLs, and resolvins, highlighting a new perception of the role of Mox-LDLs in atherosclerosis., SCOPUS: re.j, info:eu-repo/semantics/published

The cuticle of C. elegans is impermeable to chemicals, toxins, and pathogens. However, increased permeability is a desirable phenotype because it facilitates chemical uptake. Surface lipids contribute to the permeability barrier. Here, we identify the lipid transfer protein GMAP-1 as a critical element setting the permeability of the C. elegans cuticle. A gmap-1 deletion mutant increases cuticular permeability to sodium azide, levamisole, Hoechst, and DiI. Expressing GMAP-1 in the hypodermis or transiently in the adults is sufficient to rescue this gmap-1 permeability phenotype. GMAP-1 protein is secreted from the hypodermis to the aqueous fluid filling the space between collagen fibers of the cuticle. In vitro, GMAP-1 protein binds phosphatidylserine and phosphatidylcholine while in vivo, GMAP-1 sets the surface lipid composition and organization. Altogether, our results suggest GMAP-1 secreted by hypodermis shuttles lipids to the surface to form the permeability barrier of C. elegans., SCOPUS: ar.j, info:eu-repo/semantics/published

While coffee beans have been studied for many years, researchers are showing a growing interest in coffee leaves and by-products, but little information is currently available on coffee species other than Coffea arabica and Coffea canephora. The aim of this work was to perform a targeted and untargeted metabolomics study on Coffea arabica, Coffea canephora and Coffea anthonyi. The application of the recent high-resolution mass spectrometry-based metabolomics tools allowed us to gain a clear overview of the main differences among the coffee species. The results showed that the leaves and fruits of Coffea anthonyi had a different metabolite profile when compared to the two other species. In Coffea anthonyi, caffeine levels were found in lower concentrations while caffeoylquinic acid and mangiferin-related compounds were found in higher concentrations. A large number of specialized metabolites can be found in Coffea anthonyi tissues, making this species a valid candidate for innovative healthcare products made with coffee extracts., SCOPUS: ar.j, info:eu-repo/semantics/published

Although Erythrina senegalensis is a plant widely used in traditional medicine in sub-Saharan Africa, its biological properties have been poorly investigated to date. We first characterized by conventional reactions the composition of several stem bark extracts and evaluated in acellular and cellular assays their pro-or antioxidant properties supported by their high phenolic and flavonoid content, particularly with the methanolic extract. The pro-or antioxidant effects observed did not correlate with their IC50 concentrations against five cancer cell lines determined by MTT assay. Indeed, the CH2 Cl2 extract and its ethyl acetate (EtOAc) subfraction appeared more potent although they harbored lower pro-or antioxidant effects. Nevertheless, at equipotent concentration, both extracts induced ER-and mitochondria-derived vacuoles observed by fluorescent microscopy that further led to non-apoptotic cell death. LC coupled to high resolution MS investigations have been performed to identify chemical compounds of the extracts. These investigations highlighted the presence of compounds formerly isolated from E. senegalensis including senegalensein that could be retrieved only in the EtOAc subfraction but also thirteen other compounds, such as 16:3-Glc-stigmasterol and hexadecanoic acid, whose anticancer properties have been previously reported. Nineteen other compounds remain to be identified. In conclusion, E. senegalensis appeared rich in compounds with antioxidant and anticancer properties, supporting its use in traditional practice and its status as a species of interest for further investigations in anticancer drug research., SCOPUS: ar.j, info:eu-repo/semantics/published

An increasing number of clinical studies are reporting patterns of oligogenic inheritance in genetic diseases. Despite the advent of methods able to predict the pathogenicity of variant combinations, the underlying biological mechanisms remain unknown, since these models offer limited interpretability. To advance towards a better understanding of oligogenic disease aetiology, we developed a new interpretable predictive method based on a knowledge graph. This heterogenous network integrates curated oligogenic combinations together with multiple biological networks and biomedical ontologies. Our approach successfully captures association rules solely based on multi-hop relationships between genes. It combines them as a decision set model which can predict the pathogenicity of new gene pairs. These predictions come with explanations, obtained by querying the knowledge graph, which highlight relevant paths. The benchmarking of this model in a cross-validation setting achieves high accuracy and recalls independent gene pairs from recently published digenic combinations. The analysis of the rule-based paths highlights relevant contributors to the disease and shows the ability of this approach to generate knowledge-based hypotheses to investigate new disease mechanisms., info:eu-repo/semantics/published

Glandular epithelia, including the mammary and prostate glands, are generally composed by basal (BCs) and luminal cells (LCs) organised in a bilayered structure. Lineage tracing studies demonstrate that many glandular epithelia develop from multipotent basal stem cells (BSCs) that are replaced in adult life by distinct pools of unipotent basal and luminal stem cells. However, adult unipotent BSCs can reactivate multipotency under regenerative conditions and upon oncogene expression. Particularly, transplantation of mammary gland (MG) BCs alone that are unipotent in lineage tracing give rise to MG outgrowth composed of BCs and LCs, promoting the multipotent potential of BCs when transplanted without LCs. In contrast, when BCs are transplanted together with LCs, BCs maintain their unipotent basal fate, suggesting that LCs may actively restrict BCs multilineage differentiation potential in physiological conditions. The nature of this mechanism is unknown.During my thesis I studied the mechanisms involved in the activation of BSC multipotency in different conditions to identify whether a common multipotent program is activated in the different multipotent conditions, as well as, in different glandular epithelia. I first studied the activation of BSC multipotency upon LC ablation in multiple epithelia both in vivo in mice and in vitro in organoids. Performing bulk and single-cell RNA sequencing after LC ablation we identified that BSCs activate a hybrid basal and luminal cell differentiation program before giving rise to LCs—reminiscent of the genetic program that regulates multipotency during embryonic development. Also, using mammary gland derived organoids, we could demonstrate that the communication between LCs and BCs is essential to maintain BC unipotency. By predicting ligand–receptor pairs from single-cell data, we found that TNF—which is secreted by LCs—restricts BC multipotency under normal physiological conditions. By contrast, the Notch, Wnt and EGFR pathways, Doctorat en Sciences biomédicales et pharmaceutiques (Médecine), info:eu-repo/semantics/nonPublished

Misuse of prescription stimulants (PS) has been reported among students to enhance academic performance in Flanders (Belgium). However, PS misuse among students in the French-speaking community is unknown. The main purpose of the study was to estimate the prevalence of medical use and misuse of PS by university students in the French-speaking community (Belgium), and to investigate the reasons and sources associated with PS misuse., SCOPUS: ar.j, info:eu-repo/semantics/published

Background: In sepsis, neutrophil respiratory bursts participate in endothelium damage, the first step to multiple organ failure. In plasma two antioxidant selenoenzymes, which protect the endothelium, decrease: selenoprotein-P, and to a lesser extent glutathione peroxidase (GPX3). Sodium selenite (Na2SeO3) is a Se donor, but also an oxidant chemotherapy drug depending on its concentration. In a previous published study, Na2SeO3 continuous infusion in septic shock patients at a pharmacological dose of 4 mg1 Se/day on day-1, followed by a high nutritional dose of 1 mg Se/day during 9 days, showed no beneficial effect on weaning of catecholamine nor on survival. In this ancillary study, we report clinical and biological effects of such continuous infusion of Na2SeO3. Methods: This was a multicenter, placebo-controlled, double-blind study on 60 patients. Na2SeO3 or placebo in continuous infusion as described above. Evolution with time of plasma Se, selenoprotein-P, GPX3, Organ dysfunction (sequential organ failure assessment SOFA scores, including PaO2/FiO2, for respiratory failure, and plasma lactate) and quality of life at 6 months (by SF36 scores) were analyzed using two-way (time, treatment) non-parametric repeated-measures analysis of variance (Friedman test). Main Results: At baseline, plasma Se was about a quarter of reference values. From baseline to day-4 plasma Se, selenoprotein-P and GPX3 significantly increased by 3.9, 2.7 and 1.8 respectively in the Na2SeO3 group as compared with placebo and remained elevated by 2.3, 2.7 and 2.1 at day-14 respectively (p < 0.001). Na2SeO3 did not affect global and organ by organ SOFA Scores and plasma lactate concentration at day-1 and later up to day-14. The evolution of PaO2/FiO2 until day-14 was similar in the two groups. Quality of life in the surviving patients at 6 months was similar between the two groups. Conclusion: Continuous infusion of Na2SeO3 at 4 mg Se at day-1 seems to have neither beneficial nor toxic effec, SCOPUS: ar.j, info:eu-repo/semantics/published

We questioned whether EMT is required for metastasis, and we have analyzed metastasis formation in two distinct SCC models, different in terms of SCC ability to undergo EMT. We demonstrated that in spontaneous mouse model in which tumors presented a wide range of EMT (from well differentiated to fully EMT-like) presented high metastatic incidence: 49% (20/70) of mice presented LN metastasis and 28% (34/70) of mice presented lung metastases. Importantly, metastatic incidence was always associated with EMT-like tumors. However, in the second mouse model, that develops mostly well-differentiated tumors, the metastatic incidence was very low: 12% (5/42) of mice developed lung metastases and 10% (4/42) developed lymph node metastases. Importantly, the rare metastases were associated with tumors presenting some degree of EMT, supporting that EMT is needed for metastases arising from skin SCC.To understand whether EMT can occur at the intermediate step between primary tumor and distant metastasis, we analyzed blood from mice based on YFP reporter. We uncovered that most CTCs were EMT-like: 80% of CTCs were EpCAM-negative. This finding suggests that EpCAM marker, a gold standard used to detect CTCs, is not optimal as it doesn’t detect CTCs of EMT phenotype thus underestimating the real number of CTCs. Importantly, we noticed that the presence of CTCs was always associated with lung metastases and indeed can be used to predict prognosis of oncologic disease. Our immunofluorescent analysis of lung and lymph nodes showed that the majority of metastases were of differentiated phenotype. For the lung metastases, 71% (36/51) of them presented epithelial phenotype YFP+/K14+/Vim-, 14% (7/51) presented differentiated epithelial features but did not express K14 or Vimentin, 12% (6/51) presented an EMT hybrid epithelial phenotype YFP+/K14+/Vim+, whereas only 4% (2/51) were purely mesenchymal YFP+/K14-/Vim+. Histological analyses were confirmed by FACS analysis showing that lung metast, Doctorat en Sciences biomédicales et pharmaceutiques (Médecine), info:eu-repo/semantics/nonPublished

Governed through the World Trade Organization Agreement on Trade-Related Aspects of Intellectual Property Rights (TRIPS) since 1995, the current medical R&D system requires significant trade-offs between innovation and high monopoly prices for patented drugs that restrict patient access to medicines. Since its implementation, few amendments have been made to the original TRIPS agreement to allow low- and middle-income countries (LMICs) to facilitate access by generic manufacturers through flexible provisions, such as compulsory licensing and parallel import. Although a useful policy tool in theory, the routine use of TRIPS flexibilities in LMICs in the procurement of new essential medicines (EMs) is regarded as a ‘last resort’ due to strong political response in high-income countries (HICs) and new trade agreements’ restrictions. In this context, access-oriented biomedical Public-Private Partnerships (PPPs) have emerged. More recently, leading multilateral health organizations have recommended different types of intellectual property (IP) interventions, voluntary biomedical patent pools, as strategies to reduce prices and increase the diffusion of novel EMs in LMICs. Nevertheless, the recent Ebola and COVID-19 outbreaks highlight growing concerns regarding the use of TRIPS flexibilities and the limited success of voluntary mechanisms in promoting access to medicines in the Global South amidst health crises. This review aims at describing the state-of-the-art empirical research on IP-related options and voluntary mechanisms applied by emerging PPPs to guarantee timely and affordable access to EM in LMICs and reflect on both models as access paradigms. Some suggestions are put forward for future research paths on the basis of these analyses and in response to contemporary debates on waiving key IP rights on COVID-19 therapies, diagnostics, and vaccines., SCOPUS: re.j, info:eu-repo/semantics/published

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Oxidative modifications of HDLs and LDLs by myeloperoxidase (MPO) are regularly mentioned in the context of atherosclerosis. The enzyme adsorbs on protein moieties and locally produces oxidizing agents to modify specific residues on apolipoproteins A-1 and B-100. Oxidation of lipoproteins by MPO (Mox) leads to dysfunctional Mox-HDLs associated with cholesterol-efflux deficiency, and Mox-LDLs that are no more recognized by the LDL receptor and become proinflammatory. Several modification sites on apoA-1 and B-100 that are specific to MPO activity are described in the literature, which seem relevant in patients with cardiovascular risk. The most appropriate analytical method to assess these modifications is based on liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). It enables the oxidized forms of apoA-1and apoB-100 to be quantified in serum, in parallel to a quantification of these apolipoproteins. Current standard methods to quantify apolipoproteins are based on immunoassays that are well standardized with good analytical performances despite the cost and the heterogeneity of the commercialized kits. Mass spectrometry can provide simultaneous measurements of quantity and quality of apolipoproteins, while being antibody-independent and directly detecting peptides carrying modifications for Mox-HDLs and Mox-LDLs. Therefore, mass spectrometry is a potential and reliable alternative for apolipoprotein quantitation., SCOPUS: re.j, info:eu-repo/semantics/published

Significance: Sepsis is a health disaster. In sepsis, an initial, beneficial local immune response against infection evolves rapidly into a generalized, dysregulated response or a state of chaos, leading to multiple organ failure. Use of life-sustaining supportive therapies creates an unnatural condition, enabling the complex cascades of the sepsis response to develop in patients who would otherwise die. Multiple attempts to control sepsis at an early stage have been unsuccessful. Recent Advances: Major events in early sepsis include activation and binding of leukocytes and endothelial cells in the microcirculation, damage of the endothelial surface layer (ESL), and a decrease in the plasma concentration of the antioxidant enzyme, selenoprotein-P. These events induce an increase in intracellular redox potential and lymphocyte apoptosis, whereas apoptosis is delayed in monocytes and neutrophils. They also induce endothelial mitochondrial and cell damage. Critical Issues: Neutrophil production increases dramatically, and aggressive immature forms are released. Leukocyte cross talk with other leukocytes and with damaged endothelial cells amplifies the inflammatory response. The release of large quantities of reactive oxygen, halogen, and nitrogen species as a result of the leukocyte respiratory burst, endothelial mitochondrial damage, and ischemia/reperfusion processes, along with the marked decrease in selenoprotein-P concentrations, leads to peroxynitrite damage of the ESL, reducing flow and damaging the endothelial barrier. Future Directions: Endothelial barrier damage by activated leukocytes is a time-sensitive event in sepsis, occurring within hours and representing the first step toward organ failure and death. Reducing or stopping this event is necessary before irreversible damage occurs., SCOPUS: re.j, info:eu-repo/semantics/published

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Barrett syndrome is a squamo-columnar metaplasia increasing the risk of developing esophageal adenocarcinoma. Recently, we showed that esophageal cells can transdifferentiate into undifferentiated columnar cells in vivo. Here, we discuss about the potential of these cells to be a reservoir for intestinal metaplasia and/or esophageal adenocarcinoma., SCOPUS: ar.j, info:eu-repo/semantics/published

Une métaplasie se définit comme le remplacement d’un type cellulaire par un autre dans le même tissu. Les métaplasies cylindriques de l’œsophage sont caractérisées par le remplacement de l’épithélium squameux de l’œsophage par un épithélium cylindrique ressemblant à celui de l’estomac et/ou de l’intestin. La cellule à l’origine de ces métaplasies est cependant encore sujette à débat. Jusqu’à présent, des études ont montré que ces métaplasies seraient plutôt la conséquence d’une compétition entre l’épithélium cylindrique et l’épithélium squameux. Or, une étude récente a montré que la transdifférenciation de certains kératinocytes pouvait conduire à la formation de métaplasies in vivo, mais que les cellules de l’œsophage en étaient incapables. Ceci soulève donc la question de la plasticité des cellules de l’œsophage in vivo et de leur capacité à changer leur programme de différenciation.Afin d’étudier la plasticité des cellules de l’œsophage, nous avons combiné la transcriptomique, le suivi de cellules in situ et le séquençage d’ARN à l’échelle unicellulaire dans différents modèles de souris transgéniques. Nous avons démontré que le développement des métaplasies de l’œsophage est associé à la réactivation de la voie de signalisation Hedgehog dans les cellules épithéliales squameuses. Nous avons ensuite démontré que la réactivation de cette voie dans les cellules de l’œsophage induit une dédifférenciation associée à la réactivation d’un programme transcriptionnel et épigénétique similaire à celui de l’œsophage embryonnaire. De plus, une partie de ces cellules dédifférenciées sont capables d’activer un nouveau programme de différenciation menant à l’expression de marqueurs intestinaux. L’activation de ce nouveau programme dépend de l’expression du facteur de transcription Sox9. Notre travail a donc démontré que les kératinocytes de l’œsophage peuvent réaliser une conversion squamo-cylindrique complète in vivo et, ainsi, potentiellement participer à la formation de métap, Doctorat en Sciences biomédicales et pharmaceutiques (Médecine), info:eu-repo/semantics/nonPublished

Unlike those of coffee beans, the healthy properties of coffee leaves have been overlooked for a long time, even if they are consumed as a beverage by local communities of several African countries. Due to the presence of xanthines, diterpenes, xanthones, and several other polyphenol derivatives as main secondary metabolites, coffee leaves might be useful to prevent many daily disorders. At the same time, as for all bioactive molecules, careless use of coffee leaf infusions may be unsafe due to their adverse effects, such as the excessive stimulant effects on the central nervous system or their interactions with other concomitantly administered drugs. Moreover, the presence of some toxic diterpene derivatives requires careful analytical controls on manufactured products made with coffee leaves. Accordingly, knowledge about the properties of coffee leaves needs to be increased to know if they might be considered a good source for producing new supplements. The purpose of the present review is to highlight the biosynthesis, metabolism, and distribution of the 4 main classes of secondary metabolites present in coffee leaves, their main pharmacological and toxicological aspects, and their main roles in planta. Differences in coffee leaf chemical composition depending on the coffee species will also be carefully considered., SCOPUS: re.j, info:eu-repo/semantics/published

Malgré les progrès réalisées en matière de traitement et de diagnostic, le cancer du poumon demeure le plus répandu et le plus mortel dans le monde. La chimiothérapie conventionnelle, associant un composé de platine (cisplatine ou carboplatine) à un autre agent antinéoplasique est utilisée à quasiment tous les stades. Comme celle-ci est administrée par voie intraveineuse (IV), elle entraîne des effets secondaires systémiques importants dont certains sont dose- limitant (DLT) comme la néphrotoxicité pour le cisplatine ou la myélotoxicité pour le doublet carboplatine-paclitaxel. Par conséquent, ces agents sont administrés selon des cycles bien espacés pendant lesquels les tissus se rétablissent, et ce incluant la tumeur ;conduisant à une repopulation tumorale. En effet, une corrélation significative a été établie entre la concentration de platine dans les tumeurs pulmonaires et l’efficacité du traitement. Le but de ce travail était d’évaluer le potentiel de combiner une poudre sèche pour inhalation (CIS-DPI-50) avec le traitement de chimiothérapie IV, afin d’exposer la tumeur à l’agent cytotoxique de manière continue.La première partie de ce travail a permis de développer le CIS-DPI-50. Afin d’éviter qu’une haute concentration en cisplatine ne soit complètement solubilisée une fois dans les poumons, et afin d’assurer une exposition suffisante, il était essentiel de développer des formulations à libération contrôlée et à rétention pulmonaire suffisante. Ceci consistait en l’optimisation d’une formulation à base de microparticules lipidiques solides (CIS-DPI-TS) préalablement développée par Levet et al. Cette formulation a été reproduite afin d’évaluer son efficacité chez des souris greffées avec le modèle M109-HiFR (0.5 mg/kg, trois fois par cycle pendant deux cycles) et a démontré une survie similaire au CIS-IV (1.5 mg/kg, une fois par cycle pendant deux cycles). Cela a été effectué en (i) utilisant des excipients de grade pharmaceutique, reconnus comme sûrs (GRAS) (4, Doctorat en Sciences biomédicales et pharmaceutiques (Pharmacie), info:eu-repo/semantics/nonPublished

Immunoglobulins G (IgG) are proteins produced by the immune system of higher life forms that play a central role in the defense against microbial pathogens. IgG bind pathogens with the hypervariable Fab component and mediate a diversity of effector functions by binding to immune effector cells via their crystallizable (Fc) component. All IgG Fc carry a polymorphic N-glycan that regulates its binding properties and thereby its effector functions. The glycosylation profile of IgG Fc is modulated by physiological and pathological conditions, including infectious diseases and inflammatory disorders. Characterization of IgG Fc glycosylation profiles is a promising approach to understand the pathogenesis of diseases involving the immune system and to develop novel biomarkers of disease activity. Measuring the proportion of the different IgG Fc glycoforms remains an analytical challenge, that requires a sensitive and reproducible analytical approach.This chapter describes an optimized approach for the preparation and the analysis of Fc N-glycans from total serum or plasma IgG using magnetic beads, RapiFluor MS label©, and LC-MS., info:eu-repo/semantics/published

Early-onset myopathies are genetically heterogeneous mendelian diseases. We have performed solo or trio whole exome sequencing (WES) in a cohort of 24 individuals with genetically undiagnosed early-onset myopathies from 21 families. We have identified single nucleotide variant (SNV) or copy number variants (CNV) in known genes in 52% of the patients. We contributed to the expansion of the phenotypic spectrum for two genes (TTN, TRIP4). In particular, through international collaborative efforts, we described the severe end of the phenotypic spectrum of congenital titinopathy. Fifteen cases, with biallelic TTN truncating or canonical splice site mutations, presented with severe in utero features and/or severe weakness and respiratory compromise at birth, leading to termination of pregnancy, neonatal death or survival with long term respiratory support. The presence of multiple congenital limb contractures, congenital long bone fracture and/or complete absence of muscle groups can be diagnostic clues. All severely affected patients that survived until birth had at least one mutation predicted to result in the production of at least some near-normal-length titin, a finding that seems to be essential for human in utero survival.WES also allowed us to identify three novel candidate genes (JAG2, R. U.). Through Matchmaker Exchange, we assembled a cohort of 23 individuals with undiagnosed muscular dystrophy from 13 unrelated families with rare homozygous or compound heterozygous variants in JAG2. Individuals with JAG2 variants had a wide spectrum of phenotypes and disease severity but the muscle MRI findings appear to be the unifying feature that helps to identify these patients. Transcriptome analysis in the muscle of two affected individuals suggests satellite cell depletion, a finding that is also present in other muscular dystrophies linked to the Notch pathway like POGLUT1 or MEGF10 related muscular dystrophies. If the implication of our three novel candidate genes is, Doctorat en Sciences médicales (Médecine), info:eu-repo/semantics/nonPublished

Esophageal squamous cell carcinoma (eSCC) accounts for more than 85% cases of esophageal cancer worldwide and the 5-year survival rate associated with metastatic eSCC is poor. This low survival rate is the consequence of a complex mechanism of resistance to therapy and tumor relapse. To effectively reduce the mortality rate of this disease, we need to better understand the molecular mechanisms underlying the development of resistance to therapy and translate that knowledge into novel approaches for cancer treatment. The circadian clock orchestrates several physiological processes through the establishment and synchronization of circadian rhythms. Since cancer cells need to fuel rapid proliferation and increased metabolic demands, the escape from circadian rhythm is relevant in tumorigenesis. Although clock related genes may be globally repressed in human eSCC samples, PER2 expression still oscillates in some human eSCC cell lines. However, the consequences of this circadian rhythm are still unclear. In the present study, we confirm that PER2 oscillations still occur in human cancer cells in vitro in spite of a deregulated circadian clock gene expression. Profiling of eSCC cells by RNAseq reveals that when PER2 expression is low, several transcripts related to apoptosis are upregulated. Consistently, treating eSCC cells with cisplatin when PER2 expression is low enhances DNA damage and leads to a higher apoptosis rate. Interestingly, this process is conserved in a mouse model of chemically-induced eSCC ex vivo. These results therefore suggest that response to therapy might be enhanced in esophageal cancers using chronotherapy., This project has received funding from the European Union's Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 843107, SCOPUS: ar.j, info:eu-repo/semantics/published

Columnar metaplasia of the esophagus is the main risk factor for esophageal adenocarcinoma. There is a lack of evidence to demonstrate that esophageal progenitors can be the source of columnar metaplasia. In this study, using transgenic mouse models, lineage tracing, single-cell RNA sequencing, and transcriptomic and epigenetic profiling, we found that the activation of the Hedgehog pathway in esophageal cells modifies their differentiation status in vivo. This process involves an initial step of dedifferentiation into embryonic-like esophageal progenitors. Moreover, a subset of these cells undergoes full squamous-to-columnar conversion and expresses selected intestinal markers. These modifications of cell fate are associated with remodeling of the chromatin and the appearance of Sox9. Using a conditional knockout mouse, we show that Sox9 is required for columnar conversion but not for the step of dedifferentiation. These results provide insight into the mechanisms by which esophageal cells might initiate columnar metaplasia., SCOPUS: ar.j, info:eu-repo/semantics/published

L’overdose au paracétamol est l’une des intoxications médicamenteuses la plus fréquente au monde, caractérisée par une atteinte hépatique dont l’issue peut être fatale. Les études réalisées sur ce phénomène ont montré que la phase initiale de la toxicité est induite par le métabolite actif du paracétamol, le N-acétyl-p-benzoquinone imine (NAPQI). Ce dernier, en l’absence de quantité suffisante de glutathion, s’accumulent dans la cellule et finit par se lier à d’autres protéines, principalement mitochondriales, formant alors des adduits. Cette liaison va altérer la fonction primaire des protéines et conduire, en cas d’overdose sévère, à la mort des hépatocytes. La mort cellulaire s’accompagne alors de la libération de composants cellulaire dont le rôle sera d’alerter le système immunitaire des lésions tissulaires. Ces composants prennent alors le nom d’«alarmines» ou de « damage-associated molecular patterns » (DAMPs). La protéine HMGB1 (High Mobility Group Box 1) fait partie de cette catégorie.Au cours de cette thèse nous nous sommes intéressés de plus près à la protéine HMGB1, à son origine ainsi qu’à son rôle dans l’amplification et la propagation des lésions hépatiques initialement induites par l’overdose au paracétamol. Nos travaux se sont d’abord portés sur l’étude de la protéine HMGB1 dans un modèle murin d’hépatite au paracétamol. Nos expériences nous permettent, d’une part, de confirmer que la libération d’HMGB1 est liée à la sévérité des lésions hépatiques et d’autre part, de démontrer que l’amplification et la propagation de ces lésions, dans les phases précoces de l’intoxication au paracétamol, peuvent se produire indépendamment des cellules immunitaires. Sur base de ces résultats, nous avons émis l’hypothèse de l’existence d’un dialogue entre la protéine HMGB1 et les hépatocytes plutôt que du dialogue, généralement décrit dans la littérature, entre la protéine HMGB1 et les cellules du système immunitaire Nos travaux se sont donc poursuivis, in vitro, sur, Doctorat en Sciences biomédicales et pharmaceutiques (Médecine), info:eu-repo/semantics/nonPublished

Secondary metabolites are essential for plant survival and reproduction. Wild undomesticated and tropical plants are expected to harbor highly diverse metabolomes. We investigated the metabolomic diversity of two morphologically similar trees of tropical Africa, Erythrophleum suaveolens and E. ivorense, known for particular secondary metabolites named the cassaine-type diterpenoids. To assess how the metabolome varies between and within species, we sampled leaves from individuals of different geographic origins but grown from seeds in a common garden in Cameroon. Metabolites were analyzed using reversed phase LC-HRMS(/MS). Data were interpreted by untargeted metabolomics and molecular networks based on MS/MS data. Multivariate analyses enabled us to cluster samples based on species but also on geographic origins. We identified the structures of 28 cassaine-type diterpenoids among which 19 were new, 10 were largely specific to E. ivorense and five to E. suaveolens. Our results showed that the metabolome allows an unequivocal distinction of morphologically-close species, suggesting the potential of metabolite fingerprinting for these species. Plant geographic origin had a significant influence on relative concentrations of metabolites with variations up to eight (suaveolens) and 30 times (ivorense) between origins of the same species. This shows that the metabolome is strongly influenced by the geographical origin of plants (i.e. genetic factors)., SCOPUS: ar.j, info:eu-repo/semantics/published

The lacertus fibrosus (LF) is involved in various surgeries. However, the biomechanical contribution of the LF remains unclear. The aim of this study was to determine the role of the lacertus fibrosus on the elbow and forearm kinematics and on the biceps brachii muscle lever arms., SCOPUS: ar.j, info:eu-repo/semantics/published

People who survive a stroke are often left with long-term neurologic deficits that induce, among other impairments, balance disorders. While virtual reality (VR) is growing in popularity for postural control rehabilitation in post-stroke patients, studies on the effect of challenging virtual environments, simulating common daily situations on postural control in post-stroke patients, are scarce. This study is a first step to document the postural response of stroke patients to different challenging virtual environments. Five subacute stroke patients and fifteen age-matched healthy adults were included. All participants underwent posturographic tests in control conditions (open and closed eyes) and virtual environment without (one static condition) and with avatars (four dynamic conditions) using a head-mounted device for VR. In dynamic environments, we modulated the density of the virtual crowd (dense and light crowd) and the avoidance space with the avatars (near or far). Center of pressure velocity was collected by trial throughout randomized 30-s periods. Results showed that more challenging conditions (dynamic condition) induced greater postural disturbances in stroke patients than in healthy counterparts. Our study suggests that virtual reality environments should be adjusted in light of obtaining more or less challenging conditions., SCOPUS: ar.j, info:eu-repo/semantics/published

Cardiovascular diseases represent a major issue in terms of morbidity and mortality for dialysis patients. This morbidity is due to the accelerated atherosclerosis observed in these patients. Atherosclerosis is a chronic inflammatory disease characterized by key players such as monocytes, macrophages, or oxidized LDLs. Monocytes-macrophages are classified into subsets of polarized cells, with M1 and M2 macrophages considered, respectively, as pro- and anti-inflammatory. (1) Methods: The monocyte subsets and phenotypes were analyzed by flow cytometry. These data were completed by the quantification of plasma M-CSF, IL-8, CRP, Mox-LDLs, Apo-B, Apo-AI, chloro-tyrosine, and homocitrulline concentrations. The statistical differences and associations between two continuous variables were assessed using the Mann-Whitney U test and Spearman's correlation coefficient, respectively. (2) Results: Hemodialyzed patients showed a significant increase in their concentrations of CRP, M-CSF, and IL-8 (inflammation biomarkers), as well as chloro-tyrosine and homocitrulline (myeloperoxidase-associated oxidative stress biomarkers). Moreover, we observed a higher percentage of M2 monocytes in the plasma of hemodialysis patients as compared to the controls. (3) Conclusions: Our data suggest that oxidative stress and an inflammatory environment, which is amplified in hemodialysis patients, seems to favor an increase in the concentration of circulating M-CSF, therefore leading to an increase in M2 polarization among circulating monocytes., SCOPUS: ar.j, info:eu-repo/semantics/published

Les agents cytotoxiques et les thérapies moléculaires ciblées sont l’un des piliers du traitement des patients atteints de tumeurs génito-urinaires. Cependant, il existe de nombreuses situations médicales pour lesquelles l’on manque d’options thérapeutiques standards dans la pratique clinique. Ce travail de recherche clinique vise à identifier et comprendre de telles situations ainsi qu'à essayer d'améliorer les résultats cliniques de ces sous-groupes de patients. Afin d'atteindre cet objectif, différents projets cliniques ont été développés.La première partie de cette thèse est consacrée à l'évaluation de l'efficacité et de l'innocuité du cabozantinib, un puissant multi-inhibiteur de la tyrosine kinase approuvé dans le carcinome rénal avancé, ceci dans deux entités cliniques associes aux besoins médicaux non satisfaits :les patients avec un diagnostic de carcinome rénal pas à cellules claires métastatique et les patients avec un cancer du rein et métastases cérébrales.La deuxième partie de la thèse est consacrée au cancer de la vessie musculo invasif non métastatique pour lequel un traitement néoadjuvant et une résection chirurgicale sont recommandés. Nos projets évaluent les facteurs prédictifs potentiels de réponse à la chimiothérapie néoadjuvant standard à base de platine, l'efficacité et l'innocuité de l'ajout d'un agent immunothérapeutique à la chimiothérapie néoadjuvante ainsi que le rôle de l’ajout d’une chimiothérapie adjuvante chez les patients présentant une maladie résiduelle malgré une chimiothérapie néoadjuvante., Doctorat en Sciences médicales (Médecine), info:eu-repo/semantics/nonPublished