Dissertations / Theses on the topic 'Analyse radiostéréométrique – Dissertation universitaire'
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Khalifé, Marc. "Contribution à l’étude de l’alignement postural global : Analyse du corps entier avec abaques normatifs par la stéréoradiographie et la barycentremétrie." Electronic Thesis or Diss., Paris, HESAM, 2023. http://www.theses.fr/2023HESAE100.
Adult spinal deformities are common pathologies, but their surgical treatment is associated with a high rate of mechanical complications. The aims of this article-based thesis were to identify new anatomical parameters associated with postural alignment, and to redefine reference values for alignment parameters used in clinical practice using stereoradiography and barycentremetry. A cohort of 879 healthy subjects with bi-planar whole-body radiographs was set up. The aim will then be to apply these findings to a population of patients undergoing surgery for adult spinal deformity, and to assess their impact on mechanical complications.The first study showed a correlation between the angle of the upper ribs and the thoracic spine, and between the lower ribs and the lumbar spine. Greater thoracic kyphosis was associated with a greater anteroposterior diameter of the rib cage, and less penetration of the spine, resulting in greater rib cage volume. More interestingly, with regard to global alignment, a compensatory increase in pelvic tilt was found in association with an increase in ribcage width in the sagittal plane.The second study showed a significant correlation between femoral neck version angle and pelvic tilt. This relationship was non-linear, as neck version was comparable in the low and medium pelvic tilt groups, while the group with the highest pelvic tilt had a significantly greater femoral neck version. The findings of this study may suggest that implant orientation in hip replacement surgery should be adapted to the patient's pelvic tilt. Moreover, an association was previously demonstrated between increased femoral version and the risk of hip osteoarthritis and ischiofemoral impingement.Many alignment parameters (pelvic tilt, TPA, SFA, SSA) are physiologically correlated with age, and with pelvic incidence (PI) due to their anatomical definitions. The third study proposes formulas for estimating these four parameters as a function of age and PI. The overall cohort was divided into five groups according to PI, making it possible to provide reference values for all alignment parameters for each group. This study also found that thoracic kyphosis and cervical curvature were not significantly correlated with PI. These results enable a more precise study of postural alignment, taking into account individual patient specificities, for a more patient-specific correction and thus bring a reduction in the risk of postoperative mechanical complications in adult spinal deformity surgery.The barycentremetric study showed that a higher lumbar lordosis was associated with a posterior translation of the body's center of mass above the apex of the thoracic kyphosis. Center of mass analysis also validated the role of the lower limbs in postural alignment. Greater hip extension, pelvic tilt and knee flexion were associated with a posterior translation of the whole-body center of mass. The strong correlation of ODHA with the different centers of mass makes it a good surrogate parameter for estimating the body's line of gravity. A significant association was found between postural alignment and the distance between the spine and the body envelope at the level of lumbar lordosis: a greater distance was associated with pelvic retroversion, as well as an increase in cervical lordosis
Cuffaro, Bernardo. "Analyse fonctionnelle de bactéries du microbiote intestinal humain et évaluation de leurs propriétés bénéfiques contre l’obésité et l’inflammation intestinale." Thesis, Lille 2, 2021. http://www.theses.fr/2021LIL2S007.
Alterations in the gut microbiota composition are suggested to play a role in the development of chronic diseases, including obesity and inflammatory bowel disease (IBD). This dysbiosis leads to the disruption of several key biological processes known to regulate the host physiology, notably the gut barrier integrity and the immune responses leading to a pro-inflammatory state. There is also an alteration in the production of Short Chain Fatty Acids (SCFA), key bacterial metabolites that regulate host metabolism by stimulating the secretion of endocrine peptides. Microbiota-targeting interventions therefore represent interesting tools in the management of chronic diseases. The knowledge on the composition and functions of the gut microbiota has extended the range of microorganisms with potential health benefits. These microorganisms are likely to be fully adapted to the gastrointestinal tract environment and to have important interactions with the host and for these reasons they are being evaluated as next generation probiotics (NGPs). We selected dominant bacteria from the gut microbiota and we checked their robustness to environmental conditions such as oxygen-tolerance and their capacity to survive to gastric stress and observed a strain-dependent capacity. We further characterized their potential beneficial activities using different in vitro models. Most of them were able to induce the release of SCFA in the culture supernatants, mainly acetate and to a lower extend propionate or butyrate. Among the screened strains, a majority was able to restore the gut barrier in an in vitro gut epithelial (Caco-2) barrier model and several strains exhibited an anti-inflammatory potential after human immune cells (PBMC) stimulation and/or were good inducers of GLP-1 after STC-1 endocrine cell line stimulation. Interestingly some ofthem combined several properties. We then evaluated in vivo the most promising strains in different murine models of diet-induced obesity and colitis. We identified three strains exhibited promising abilities against obesity. We also showed a strain-dependent effect of Parabacteroides distasonis strains against colitis and selected three effective strains. These studies provide us better insights on the functionality of commensal bacteria and crucial clues to select next-generation probiotics able to target inflammatory chronic diseases such as obesity and related disorders or IBD
Cuvelliez, Marie. "Analyse des réseaux moléculaires impliqués dans le remodelage ventriculaire gauche post-infarctus du myocarde et dans l’insuffisance cardiaque." Thesis, Lille 2, 2019. http://www.theses.fr/2019LIL2S027.
Nowadays, cardiovascular diseases remain a main public health issue in developed countries.Following a myocardial infarction (MI), at least 30% of patients developed a left ventricularremodeling (LVR), that can lead to heart failure (HF) and to death. The aims of this project were tostudy the mechanisms involved in LVR post-MI and HF and to identify new biomarkers allowing theprediction of a deleterious evolution after MI and early death of HF patients by systems biology andstatistical approaches.First, we built a molecular network based on experimental data obtained in the plasma of post-MI patients of the REVE-2 study at 4 time-points (baseline, 1 month, 3 months and 1 year). An activemodule analysis, extracted at each time-point between patients with LVR and patients without LVR,and a betweenness centrality analysis allowed the selection of 6 molecules potentially involved inLVR : 2 transcription factors, EP300 and ESR1, and 4 microRNAs, miR-335-5p, miR-26b-5p, miR-375 and miR-17-5p. We showed that ESR1 mRNA was significantly increased at 2 months post-MI inthe LV a model of post-MI rats, miR-26b-5p was significantly decreased at 7 days post-MI and miR-335-5p had a trend to increase at 7 days post-MI.Secondly, we built a molecular network using the experimental data obtained by SOMAscanassay, in the plasma of patients diagnosed for systolic HF from the INCA study and followed during 3years. A topological and betweenness centrality analysis allowed the study of the mechanismsinvolved in HF. In parallel, a penalised regression analysis, performed in collaboration with the Bililleplatform, allowed the selection of 6 proteins (C3, MAPKAPK5, Cathepsin S, MMP-1, MMP-7 andFAM107B) that allowed the prediction of early death of HF patients. The quantification of C3, MMP-1 and MMP-7 by conventional assays (ELISA, Luminex) in a subset of the INCA population gaveconsisting results with the SOMAscan assay, but not for cathepsin S
Loisel, François. "Analyse cinématique et biomécanique de la main et du poignet par modélisation personnalisée. Effet de lésions et d’instrumentations." Electronic Thesis or Diss., Paris, HESAM, 2023. http://www.theses.fr/2023HESAE097.
The architecture of the hand and wrist is a complex set of articulations enabling the efficient execution of all the gestures of daily life.Precision of movement and transmission of effector forces require optimal joint congruence and bone cohesion ensured by an organized ligament system.Any trauma resulting in articular step off (fracture) or loss of bone cohesion (ligament rupture) is likely to produce pathological kinematics within these joints. The result is pain, decrease range of motion and impaired overall function. Knowledge of the pathophysiological mechanisms leading to these disorders is essential on several levels: firstly, in a diagnostic context, to be able to identify and treat any injury, even a partial one. Secondly, to improve overall knowledge of the physiological and pathological kinematics of the hand and wrist. And lastly, as part of an innovation drive to propose new solutions (implants) to unresolved problems.The design of customized geometric and biomechanical models in the general context of the study of human joints provides answers to these types of questions. In preliminary work, linked to my Master's research and Stan Durand's thesis, biomechanical tests were carried out on anatomical parts to analyze the effect of a specific implant on the kinematic behavior of the wrist, and to design a method for personalized modeling of the hand and wrist using low-dose biplane X-rays.Following on from this project, this thesis has several objectives.The first objective is to validate our method of personalized hand and wrist modeling in living subjects, by comparing it with the reference technique of TDM segmentation.Secondly, we will apply this method to create a corridor of physiological displacement of certain carpal bones of interest (scaphoid, lunate, triquetrum), between two reference positions (wrist in neutral position or closed fist) among a population of volunteers free of ligament lesions. This corridor of normality is useful for comparing physiological and pathological displacements in clinical practice.Indeed, the third objective is to compare carpal kinematic data from patients with infra-radiological ligament lesions with this corridor of normality. The aim is to assess the diagnostic capabilities of the customized model. By analyzing pre- and post-operative data, a feasibility study will also investigate the field of objective follow-up of surgical restoration by suture or ligament re-anchoring.The aim of such a study is therefore to use geometric, kinematic and biomechanical models of the hand and wrist to assess normal and pathological kinematics (diagnosis), and to analyze current surgical implants in order to propose areas for improvement
Jourdain, Marie-Laure. "Analyse phénotypique et fonctionnelle des ostéoclastes et de leurs précurseurs dans la maladie osseuse liée à la mucoviscidose Inflammation and CFTR-related bone remodeling in patients in cystic fibrosis CFTR-deficient pigs display alterations of bone microarchitecture and composition at birth Overexpression of RANKL in osteoblasts: a possible mechanism of susceptibility to bone disease in cystic fibrosis." Thesis, Reims, 2019. http://www.theses.fr/2019REIMO201.
The increasing life expectancy of patients with cystic fibrosis (CF) is associated with extra-pulmonary complications which prevalence increases with age, such as bone disease or diabetes, that impact the quality of life of CF patients. The bone deficit related to cystic fibrosis is still incompletely characterized and the understanding of the impact of CFTR (Cystic Fibrosis Transmembrane conductance Regulator) defect on bone physiology is essential to propose new therapeutic strategies. The most common mutation of CFTR, (F508del) in osteoblasts is associated with a high RANK-L/OPG ratio that may stimulate osteoclastogenesis. The aim of this work was to study the impact of CFTR defective activity on osteoclast precursors and their differentiation as well as the functional activity of CF osteoclasts. We have demonstrated that there is an overexpression of the RANK and M-CSF receptors on the surface of osteoclastic precursors derived from patients carrying the CFTR G551D mutation. Furthermore, we have revealed that the osteoclasts phenotype is strongly impacted by the F508del mutation as well as the S1P pathway, a prominent mediator for the circulation of osteoclastic precursors between blood and bone compartments. All of these data and the demonstration of a disturbed resorptive osteoclasts profile when CFTR activity is deficient suggest that there is a dysregulation of resorption and more widely of bone remodeling in CF patients
Georgel, Anne-France. "Analyse des réponses anti-bactériennes et anti-virales respiratoires induites par les agonistes des récepteurs de l’immunité innée." Thesis, Lille 2, 2018. http://www.theses.fr/2018LIL2S053.
Viral and bacterial infections remain a burden for health care systems. The current therapeutic approaches by antibiotic have shown their effectiveness but also their limit especially in cases of multidrug-resistant microorganisms or in the treatment of patients with aggravating pathologies. Stimulation of innate immunity could be a complementary therapeutic approach to current treatments. Indeed, the activation of the innate immune system induces local production of antimicrobial molecules and the recruitment of effector cells involved in controlling infection.The Toll-like Receptors (TLRs) are innate sensors that trigger signaling cascades and promotes the archetypal pro-inflammatory responses involved in antimicrobial defense. TLR5 recognizes flagellin, the structural protein of bacterial flagella. TLR5 is expressed on the surface of macrophages, dendritic cells and epithelial cells.In the first part of the work, we assessed the ability of flagellin to control the replication of influenza A virus H3N2. We first showed that intranasal or systemic administration of flagellin activated transcription of anti-viral genes in lung tissue. Administration of flagellin reduced viral replication in the lung of mice infected with H3N2 IAV. This effect is also observed in Il22-/- and Ifnar-/- mice suggesting a mechanism independent of type I interferon and interleukin 22 signaling. Finally, we also showed that the combination of flagellin with oseltamivir (neuraminidase inhibitor) was more efficacious than standalone treatments.The second part of this work is the ASTRAL clinical study, which assesses the ability of blood mononuclear cells to respond to different TLR agonists in patients with acute lobar pneumonia. This study started in October 2017 and plans to include 38 patients. The objective is to observe the response after TLR agonist stimulation by transcriptional analysis and cytokine assays. The first results (analysis of 7 patients) show that blood mononuclear cells can be activated by TLR agonists in the context of pneumonia
Lespagnol, Elodie. "Impact du diabète de type 1 sur la vasoréactivité et la variabilité de la fréquence cardiaque au repos et en réponse à l’exercice aigu." Thesis, Lille 2, 2020. http://www.theses.fr/2020LIL2S003.
Despite intensive insulin treatment and advanced techniques of glucose self-monitoring, hyperglycemia and hypoglycemia are frequent complications in type 1 diabetes. Chronic hyperglycemia may contribute to early alterations in endothelial function and in cardiac autonomic activity. The literature about endothelial dysfunction is very large and sometimes contradictory but suggests that endothelial dysfunction can be evidenced during exercise. The underlying mechanisms of the altered vasoreactivity to exercise remain to be explored but may involve a decrease in the bioavailability of the main vasodilating molecule: nitric oxide (NO). In addition, chronic hyperglycemia but also acute hyper or hypoglycemic excursions may alter cardiac autonomic activity, even in patients with still uncomplicated type 1 diabetes. This manifests by a decrease in heart rate variability and in one of its components, the parasympathetic tone. Although regular exercise is recognized in non-diabetic populations to improve heart rate variability, the challenge for people with T1D may lie in the occurrence of exercise-induced hypoglycemic episodes, with a possible negative impact on parasympathetic tone. The objectives of this PhD were : 1) a systematic analysis of the literature throughout a meta-analysis, to study the presence or not of endothelial dysfunction in persons with type 1 diabetes compared to persons without diabetes, 2) investigating some molecular mechanisms underlying exercise-induced impairment in muscle vasoreactivity and finally, 3) studying the impact of a multi-day sustained cycling exercise on cardiac autonomic activity in athletes with type 1 diabetes, while considering glycemic excursions. The results show that 1) people with type 1 diabetes, albeit still free from overt micro- and macrovascular complications, have indeed an early endothelial dysfunction but also an alteration in the vascular smooth muscles function. The endothelial dysfunction was evidenced in response to various stimuli (exercise, occlusion-reperfusion, pharmacological substances or heat). Nevertheless, standardisation of methods would make the results less heterogeneous and help in the follow-up of endothelial dysfunction. 2) Alteration in muscle vasoreactivity to maximal exercise might be the consequence of a decrease in the availability of L-Arginine, the exclusive substrate of enzymatic NO synthesis. In addition, a decrease in the major circulating antioxidant, uric acid, is possibly involved, while vitamins, total free thiols and erythrocyte enzymatic antioxidant defences appear normal. 3) amateur athletes with type 1 diabetes show an increase in the time spent in hyperglycemia, but not hypoglycemia, in response to the unusual multi-day moderate-to-intense exercise, with possible deleterious impact on their nocturnal parasympathetic cardiac tone. In view of all these results, it appears therefore crucial to find non-pharmacological alternatives in an attempt to improve early endothelial and cardiac autonomic activity disorders
Vuillod, Bruno. "Stratégie de modélisation multi-fidélité via une approche système incluant des métamodèles basés sur les entités NURBS." Electronic Thesis or Diss., Paris, HESAM, 2024. http://www.theses.fr/2024HESAE003.
The more complex the problem, the greater the amount of computational resources needed to simulate it. On the other hand, the need for accuracy in the results of a system will not be the same depending on its design phase and the domain studied. The goal of this thesis is to propose a fast, low-cost multi-fidelity modeling strategy. To meet this need, a hybrid modeling approach is developed that combines Model-Based System Engineering (MBSE) and a metamodel based on Non-Uniform Rational Basis-Spline (NURBS) hypersurfaces. More specifically, the scientific challenge of this work is to develop a metamodel based on NURBS entities to simulate the behavior of highly nonlinear systems that require high fidelity modeling but are capable of providing results in real time to be compatible with the MBSE approach. In this context, the NURBS entity-based metamodel is obtained as a solution to an optimization problem solved with a gradient algorithm. In addition, a smoothing term is included in the problem formulation, not only to reduce the influence of any spurious nonlinearities in the training database, but also to limit the phenomenon of overfitting. The technical and scientific challenge of this work is to couple the general MBSE approach with the NURBS-based metamodel
Houzé, de l'Aulnoit Agathe. "Acquisition du rythme cardiaque fœtal et analyse de données pour la recherche de facteurs prédictifs de l’acidose fœtale." Thesis, Lille, 2019. http://www.theses.fr/2019LIL2S007.
Visual analysis of the fetal heart rate FHR is a good method for screening for fetal hypoxia but is not sufficiently specific. The visual morphological analysis of the FHR during labor is subject to inter- and intra-observer variability – particularly when the FHR is abnormal. Underestimating the severity of an FHR leads to undue risk-taking for the fetus with an increase in morbidity and mortality and overvaluation leads to unnecessary obstetric intervention with an increased rate of caesarean section. This last point also induces a French public health problem.FHR automated analysis reduces inter and intra-individual variability and accesses other calculated parameters aimed at increasing the diagnostic value. The FHR morphological analysis parameters (baseline, number of accelerations, number and typing of decelerations, long-term variability (LTV)) were described as well as others such as the decelerations surfaces, short-term variability (STV) and frequency analyzes. Nevertheless, when attempting to analyze the FHR automatically, the main problem is computation of the baseline against which all the other parameters are determined.Automatic analysis provides information on parameters that cannot be derived in a visual analysis and that are likely to improve screening for fetal acidosis during labor.The main objective of the thesis is to establish a predictive model of fetal acidosis from a FHR automated analysis. The secondary objective is to determine the relevance of the classical basic parameters (CNGOF 2007) (baseline, variability, accelerations, decelerations) and that of other parameters inaccessible to the eye (indices of short-term variability, surfaces of decelerations, frequency analysis ...). Later, we want to identify decision criteria that will help in the obstetric care management.We propose to validate FHR automated analysis during labor through a case-control study; cases were FHR recordings of neonatal acidosis (arterial cord pH less than or equal to 7.15) and controls, FHR recordings of neonatal without acidosis (arterial cord pH upper than or equal to 7.25). This is a monocentric study at the maternity hospital of Saint Vincent de Paul Hospital, GHICL - Lille, on our « Well Born » database (digital archiving of RCF plots since 2011), with a sufficient number of cases on this only center. Since 2011, the Saint Vincent de Paul hospital (GHICL) has had about 70 cases per year of neonatal acidosis (pHa less than or equal to 7.10) (3.41%). The R software will be used for statistical analysis
Poissenot, arrigoni Corentin. "Identification inverse du comportement thermomécanique à partir des champs cinématiques et thermique mesurés dans la zone de cisaillement primaire en rabotage : application à l'Inconel 718." Electronic Thesis or Diss., Paris, HESAM, 2023. http://www.theses.fr/2023HESAE089.
The shaping process through machining involves severe thermomechanical loading, potentially leading to deformations and local changes in the properties of the machined material. These undesired consequences of cutting are quite common in nickel-based alloys, as this material family exhibits good mechanical properties at high temperatures. Currently, simulation tools could potentially predict the consequences of machining on the integrity of the finished piece; however, no test or methodology allows for the complete determination of material behavior laws with gradients and thermomechanical kinetics representative of those induced by a machining operation. In the overall perspective of strengthening confidence in machining process simulations, the objective of this thesis is to develop an innovative methodology for the inverse identification of thermomechanical behavior and damage laws of nickel-based alloy materials under machining conditions.To achieve this, in a first step, preparatory work for the deployment of measurements through infrared thermography is proposed. An innovative method for calibration insensitive to integration times for sensors cooled in indium antimonide has been developed. Additionally, to convert radiometric temperatures of the observed scene into absolute temperatures, a method for the direct measurement of emissivity based on the use of a multispectral camera has been developed. Subsequently, an image processing method has been developed, allowing for obtaining comprehensive thermal information about the cut for low and high magnification objectives. Finally, a study of measurement errors induced by thermography, based on a radiometric model, has been proposed.In a second step, an extensively instrumented planing experiment allowing the observation of kinematic and thermal fields has been designed. A triaxial dynamometric plate enables the acquisition of cutting forces, and an optical system, based on wavelength separation, allows simultaneous observation of the cut through visible and infrared cameras through a single lens. An analysis of images from the visible camera using digital image correlation provides access to kinematic fields, and a specific treatment of images from the infrared camera provides a mapping of the thermal field during cutting. With the collected data, an analysis of the characteristics of the primary shear zone could be conducted, including an estimation of the dimensions of the deformed material zone and the temperatures reached.In a third step, a numerical model simulating the thermomechanical field induced by an orthogonal cutting operation has been developed. To optimize computation time, a sensitivity study of mesh size and the number of cores allocated to the calculation has been conducted. Finally, a sensitivity study of input parameters for the simulation has highlighted the most influential parameters on the thermomechanical field.Ultimately, leveraging experimental and simulated kinematic and thermal behaviors within the primary shear zone induced by cutting, an inverse identification algorithm has been developed. This algorithm aims to determine the constants of the Johnson-Cook plasticity and damage behavior laws (the chosen thermomechanical behavior model for this study) of the machined material under cutting conditions. The algorithm also incorporates indicators of the discrepancy between experimental and simulated results for each measured quantity, providing a confidence indicator for the identified material constants.In conclusion, through precise instrumentation, the kinematic and thermal fields applied to the workpiece during planing have been observed and quantified. These experimental data have subsequently fueled an inverse identification algorithm, enabling the determination of material constants for Johnson-Cook behavior and damage laws under cutting conditions
Touat, Mahdi. "Mécanismes et implications thérapeutiques de l'hypermutation dans les gliomes Mechanisms and Therapeutic Implications of Hypermutation in Gliomas Mismatch Repair Deficiency in High-Grade Meningioma: A Rare but Recurrent Event Associated With Dramatic Immune Activation and Clinical Response to PD-1 Blockade Buparlisib in Patients With Recurrent Glioblastoma Harboring Phosphatidylinositol 3-Kinase Pathway Activation: An Open-Label, Multicenter, Multi-Arm, Phase II Trial Hyman DM. BRAF Inhibition in BRAFV600-Mutant Gliomas: Results From the VE-BASKET Study Glioblastoma Targeted Therapy: Updated Approaches From Recent Biology Successful Targeting of an ATG7-RAF1 Gene Fusion in Anaplastic Pleomorphic Xanthoastrocytoma With Leptomeningeal Dissemination Ivosidenib in IDH1-Mutated Advanced Glioma." Thesis, université Paris-Saclay, 2020. http://www.theses.fr/2020UPASL071.
High tumor mutational burden (hypermutation) is observed in some gliomas; however, the mechanisms by which hypermutation develops and whether it predicts chemotherapy or immunotherapy response are poorly understood. Mechanistically, an association between hypermutation and mutations in the DNA mismatch-repair (MMR) genes has been reported in gliomas, but most MMR mutations observed in this context were not functionally characterized, and their role in causing hypermutation remains unclear. Furthermore, whether hypermutation enhances tumor immunogenicity and renders gliomas responsive to immune checkpoint blockade (e.g. PD-1 blockade) is not known. Here, we comprehensively analyze the clinical and molecular determinants of mutational burden and signatures in 10,294 gliomas, including 558 (5.4%) hypermutated tumors. We delineate two main pathways to hypermutation: a de novo pathway associated with constitutional defects in DNA polymerase and MMR genes, and a more common, post-treatment pathway, associated with acquired resistance driven by MMR defects in chemotherapy-sensitive gliomas recurring after temozolomide. Experimentally, the mutational signature of post-treatment hypermutated gliomas (COSMIC signature 11) was recapitulated by temozolomide-induced damage in MMR-deficient cells. While MMR deficiency was associated with acquired temozolomide resistance in glioma models, clinical and experimental evidence suggest that MMR-deficient cells retain sensitivity to the chloroethylating nitrosourea lomustine. MMR-deficient gliomas exhibited unique features including the lack of prominent T-cell infiltrates, extensive intratumoral heterogeneity, poor survival and low response rate to PD-1 blockade. Moreover, while microsatellite instability in MMR-deficient gliomas was not detected by bulk analyses, single-cell whole-genome sequencing of post-treatment hypermutated glioma cells demonstrated microsatellite mutations. Collectively, these results support a model where differences in the mutation landscape and antigen clonality of MMR-deficient gliomas relative to other MMR-deficient cancers may explain the lack of both immune recognition and response to PD-1 blockade in gliomas. Our data suggest a change in practice whereby tumor re-sequencing at relapse to identify progression and hypermutation could inform prognosis and guide therapeutic management
Casolla, Barbara. "Pronostic vasculaire au long cours des patients après une hémorragie intracérébrale." Thesis, Lille 2, 2019. http://www.theses.fr/2019LIL2S026.
Background: Spontaneous (non-traumatic) intracerebral hemorrhage (ICH) is the mostdramatic type of stroke being responsible for the majority of mortality and stroke related disability. Survivors are at high risk of major vascular events, nevertheless, data on long-term prognosis after ICH are scarce. The main objective was to study long term cerebral and extra-cerebral vascular prognosis after ICH.Methods: We included patients from the PITCH (Prognosis of Intra Cerebral Haemorrhage) cohort which is a prospective and observational study that included consecutive adults admitted at the Lille University Hospital for spontaneous ICH between 2004 and 2009. We aimed to determine (i) cumulative incidence of major ischemic and hemorrhagic vascular events and their clinical and radiological predictors;(ii) the prevalence of cortical superficial siderosis (cSS) and its associated factors; (iii) the impact of cerebral microbleeds on ICH recurrence.Results: We showed that ICH survivors are at high risk of major cerebral and extracerebralvascular events. Ischemic risk overwhelmed the hemorrhagic one on long term,particularly in deep index ICH. Concerning recurrent ICH, we found that in our cohort,one out of five patients had cSS on baseline MRI and its presence was a strong predictorof recurrent ICH, suggesting the implication of underlying cerebral amyloid angiopathy.Global burden of microbleeds was also associated with higher rate of ICH recurrence.Conclusion: These findings have immediate clinical relevance and suggest that ICH survivors should benefit of a long-term and multidisciplinary follow-up. These results may also provide additional information on the risk of major ischemic and hemorrhagicevents after ICH and on radiological predictors of recurrence risk
Kasdi, Ahmed Reda. "Prise en charge néonatale du syndrome de coarctation selon une stratégie en 1 temps ou en 2 temps : revue systématique de la littérature et méta-analyse." Thesis, Lille 2, 2019. http://www.theses.fr/2019LIL2S039.
INTRODUCTION:Neonatal management of aortic coarctation when associated to a ventricularseptal defect is still under debate. Mainly, two strategies are possible. Thefirst one, known as a one-stage full repair, allows to achieve a completerepair of the coarctation and closure of the ventricular septal defect bysternotomy and under cardio-pulmonary bypass in the neonatal period. Thesecond strategy, known as a staged repair, addresses only the coarctationin the neonatal period by thoracotomy, with a concomitant pulmonaryartery banding if required, and then subsequently closes the ventricularseptal defect, if still required, by sternotomy and under cardiopulmonarybypass.METHODS:The aim of this literature review was to systematically synthetize evidenceon practices between January 1980 and December 2018 in the neonatalpopulation (age < 30 days). A quantitative approach by meta-analysisallowed to compare mortality between both surgical strategies to figure outwhich one yields better outcome. Methodology described by PRISMA group(Preferred Reporting Items for Systematic Reviews and Meta-Analyses) wasfollowed to synthetize the evidence drawn from observational studies andthe Joanna Briggs Institute Critical Appraisal Tools were used to assessinternal validity (risk of bias) of included studies.5RESULTS:Literature review found different practices without real consensus, oftensubjective relying on local habits and expertise throughout the differentscreened centers.Statistical analysis did not allow to identify the superiority of a strategy overthe other in terms of mortality, even when considering different surgicaleras. An insignificant trend favoring the staged repair was however noticedeven though this was less obvious on the most recent surgical eras.Nonetheless, the one stage full repair strategy proved to be safe, comparingwith the staged strategy, when applied.Recoarctation rates of both strategies are exposed without being compareddue to the diversity in hypoplastic arch repair techniques described andfollow-up periods reported. Finally, a management algorithm is suggested.CONCLUSION:A case-adapted management considering the anatomy and situation of theventricular septal defect and aortic arch is to be favored in order to betteraddress this same association of lesions although presenting under multiplesettings.Instead of continuing to compare between the two management strategies,future investigations should pay more attention on how to best predict thefate of some ventricular septal defects, if ignored, and of some proximalhypoplastic aortic arches, if addressed by thoracotomy, when the decisionis made to treat only the aortic coarctation in the neonatal period
Pellay, François-Xavier. "Méthodes d'estimation statistique de la qualité et méta-analyse de données transcriptomiques pour la recherche biomédicale." Thesis, Lille 1, 2008. http://www.theses.fr/2008LIL10058/document.
To understand the biological phenomena taking place in a cell under physiological or pathological conditions, it is essential to know the genes that it expresses Measuring genetic expression can be done with DNA chlp technology on which are set out thousands of probes that can measure the relative abundance of the genes expressed in the cell. The microarrays called pangenomic are supposed to cover all existing proteincoding genes, that is to say currently around thirty-thousand for human beings. The measure, analysis and interpretation of such data poses a number of problems and the analytlcal methods used will determine the reliability and accuracy of information obtained with the microarrays technology. The aim of thls thesis is to define methods to control measures, improve the analysis and deepen interpretation of microarrays to optimize their utilization in order to apply these methods in the transcriptome analysis of juvenile myelomocytic leukemia patients, to improve the diagnostic and understand the biological mechanisms behind this rare disease. We thereby developed and validated through several independent studies, a quality control program for microarrays, ace.map QC, a software that improves biological Interpretations of microarrays data based on genes ontologies and a visualization tool for global analysis of signaling pathways. Finally, combining the different approaches described, we have developed a method to obtain reliable biological signatures for diagnostic purposes
Hamade, Hussein. "Analyse des mécanismes moléculaires et cellulaires conduisant à une inflammation dans l'intestin et une progression tumorale induits par la perte de la sous-unité d'intégrine Alpha6 chez la souris." Thesis, Strasbourg, 2014. http://www.theses.fr/2014STRAJ062/document.
We generated a new mouse model, α6ΔIEC, in which the genetic ablation of α6 integrin from intestinal epithelial cells triggered the development of spontaneous colitis and colorectal cancer. My main goal was to define the mechanisms by which inflamed lesions degenerate into infiltrating adenocarcinomas. Loss of α6 integrin in this model resulted in epithelial barrier damage, enhanced permeability, altered mucus layers, abnormal bacterial segregation, chronic inflammation and tumor development.In order to define the sequence of events and the mechanisms involved at each stage of the disease, from inflamed to tumor lesions, I developed an inducible mouse model, α6ΔIECTAM, in which α6 integrin ablation was induced by tamoxifen treatment. This line recapitulates all aspects of inflammation observed in the α6ΔIEC model, as early as two weeks after tamoxifen treatment. In particular, I tried to define the respective contribution of infection by bacteria and mechanical stress during disease progression
Bruno, Céline. "Etude des mécanismes de transmission de dérégulations épigénétiques : analyse de la transmission spermatique chez l'homme." Thesis, Bourgogne Franche-Comté, 2018. http://www.theses.fr/2018UBFCI002/document.
The notion that environmental exposure can be memorized and promote epimutation (defined as defects on DNA methylation) raises the question of possible epigenetic transgenerational transmission in humans. To address whether an epimutation could be transmitted in humans, we pursued two axes. First, the evaluation of intergenerational transmission in the family of a Silver-Russell patient has shown, for the first time, the efficiency of epigenetic reprogramming in humans, specifically on imprinted regions. Indeed, no imprinted defect on causal H19/IGF2 locus was detected in the patient’s spermatozoa or in the DNA of his daughter. The second axis was to assess the presence of sperm epimutations 1/ from fathers of children diagnosed with imprinted syndromes and 2/ from men presenting testicular seminoma. Pyrosequencing analyses on imprinted genes did not reveal any alteration of sperm DNA methylation, though we confirmed an association between oligozoospermia and sperm imprinting defects.The next step will be to identify the mechanisms involved in the origin of the sperm epimutation. The main hypotheses converge to small non-coding RNAs or certain DNA regions which escape to controls setting up (at least partially) at the time of epigenetic reprogramming
Nguyen, Phuc Dam. "Etude phytochimique de plantes de la médecine traditionnelle du Vietnam et du Laos. Evaluation biologique dans le domaine de la santé." Thesis, Reims, 2015. http://www.theses.fr/2015REIMP204/document.
The objective of this work is to contribute to the improvement of phytochemical and biological knowledge of medicinal plants, in order to enhance and promote their uses in traditional medicine in Vietnam. In this thesis, we carried out a phytochemical study on three plants: Cleome chelidonii (Cleomaceae) Dolichandrone spathacea (Bignoniaceae) and Flacourtia rukam (Salicaceae). 90 compounds were isolated and their structures were determinated using the spectroscopic techniques of 1D & 2D NMR and by the ESI-MS mass spectrometry, spectral data UV, IR, measurement of optical rotation and CD, and by comparison with the literature data. Among them, 29 are new molecules. The isolated compounds may be classified into many groups: flavonoids, iridoids, saponins, megastigmanes, phenolic glycosides, alkaloids...The antiradical activity of the flavonoids of C. Chelidonii was evaluated by the DPPH test, and the antimicrobial activity were examinated on all extracts and compounds of D. spathacea and F. rukam. Among the tested compounds, the new flavonoid CF-3 has a significant anti-radical activity (IC50 = 17.74 µM) and the new phenolic glucoside FRP-4 has the most significant antibacterial activity against three Gram-positive bacteria (MIC = 31.2 µg / ml) and two gram-negative bacteria (MIC = 125 µg /ml)
Billaud, Amandine. "Analyse moléculaire, enjeux et limites des thérapies ciblées en oncologie : extension des sensibilités aux anti-PARP dans les cancers ovariens par caractérisation de variants non annotés et nouveaux mécanismes de résistance dans les cancers bronchiques. Caractérisation moléculaire de l’EGFR dans les cancers bronchiques non à petites cellules : étude prospective comparative des technologies NGS et automate Idylla Somatic mRNA analysis of BRCA1 splice variants provides a direct theranostic impact on PARP inhibitors." Thesis, Angers, 2020. http://www.theses.fr/2020ANGE0003.
Despite significant clinical benefit from the consideration of molecular context, targeted therapies are still challenging. First part of this work focused on tyrosine kinase inhibitors targeting EGFR in non small cell lung cancers. Thus, improvement of biomarkers detection methods was completed by in vitro characterization of an unreported mechanism of acquired resistance. Briefly, pulmonary cells were exposed to a mutagen agent and a selection pressure was applied with EGFR inhibitors allowing the detection of TBK1 signature. Finally, synergic effect of that co-inhibition was highlighted. Now essentials in gynaecological cancers management, PARP inhibitors represent the second part of that work. Those targeted therapies are based on synthetic lethality. Consequently, BRCA1/2 pathogenic mutations are required for their administration, illustrating the issue of variants of uncertain significance. Toward their functional characterization necessity, a transcriptional analysis of splicing variant was first conducted on mRNA extracted from FFPE samples. Then, to evaluate functional signification of all types of variants, genomic edition was developed. Editing efficiencies of the unknown variant and a silent control one were compared in a haploid model where those genes are essentials. Functional signification of BRCA1/2 variants, and thereby mutations from all essential tumor suppressor genes in our model, can be evaluated in three weeks which is compatible with clinical management
Deltreil, Guillaume. "Matrices emplois expositions biomécaniques et troubles musculosquelettiques : comment modéliser au mieux les contraintes physiques par matrice dans la prédictivité des troubles musculosquelettiques." Electronic Thesis or Diss., Angers, 2023. https://dune.univ-angers.fr/documents/dune17781.
Musculoskeletal disorders (MSDs) represent a major occupational health issue. The growth in the number of workers affected by these pathologies is a marker of the worsening of working conditions. Job-exposure matrices area tool for assessing the impact on the relationship between these conditions and these disorders. The objective of this thesis was to study, from a lifetime perspective,musculoskeletal disorders based on data from job-exposure matrices and using statistical tools.The CONSTANCES job-exposure matrix was used as a source of exposure across this work. It is based on the cohort of the same name and gathers personal and work-related data concerning the general population. Through the development of a tool, it was possible to select a logistic regression model linking the interaction between the duration of exposure and the level of exposure with the appearance of the pathology within the framework of the study of knee pain. It was showed that the level of exposure was the most strongly impacting factor (1.34-2.81) on the onset of disorders, although the duration also increased (0.83-1.10) the risks. Secondly, it was possible to found that this same model should also be selected for the study of low back pain and severe hand pain, with similar results. Finally, using a machine learning tool, it was possible to adapt our model within the framework of the study of the imbalance data. Tor the carpal tunnel surgery, the impact of the duration (1.29) was more important than in the other studies but it is the level of intensity (1.31) which remained the most determining.In conclusion, the job-exposure matrices made it possible to obtain an assessment of the impact of different factors on the occurrence of several disorders, even in a context of data imbalance, although many more studies are needed before it can be applied by practitioners
Jané, Palli Pau. "Quantification des affinités PBM/PDZ et de leurs sites modulateurs par des approches expérimentales et informatiques à haut débit." Electronic Thesis or Diss., Strasbourg, 2020. http://www.theses.fr/2020STRAJ051.
This thesis focuses on PDZ domains, a family of globular domains that bind to conserved PDZ-Binding Motifs (called henceforth PBMs) generally situated at the extreme C-terminus of their partner proteins. Domain-motif networks are often modulated by reversible post-translational modifications (PTMs). We used synthetized PBMs to reproduce different conditions, such as a wild-type, acetylation or phosphorylation, addition of extra exosites or residue mimication of PTM in the literature. These peptides were used for interaction studies using the holdup assay, an assay originally developed in our laboratory. We evaluated the impact of diverse modifications of the PBM/PDZ interactions, which led to a global change of the PDZ-binding capability. These results provided quantitative information on the biological effects that such modifications may have in the context of full-length proteins
Alassane, Seydou. "Modification du pigment maculaire lors du vieillissement oculaire : analyse à partir de l'étude de population Montrachet." Thesis, Bourgogne Franche-Comté, 2018. http://www.theses.fr/2018UBFCI007/document.
Given the limits of the literature on the environmental nutritional impact in ocular aging witch is partially due to the lack of data in general population notably in French elderly, first, we were interested in the relationships of diet, plasma xanthophylls and macular pigment optical density as well as its spatial distribution and second of plasma fatty acids and dry eye disease signs in the 1153 Montrachet study participants.Firstly, we reported the high consumption of squash, the high plasma lutein and zeaxanthin levels and also the high plasma lutein level, the high macular pigment optical density level in nonsmokers subjects. In addition, the macular pigment values we provided in the study could be used as reference in population based study. Our results are very consistent with those found in other epidemiological studies even though our population is on average older. Secondly, we have shown that dry eye disease signs are more frequent in elderly subjects with low plasma polyunsaturated and saturated fatty acids level. Thus, our results provide new elements in the involvement of fatty acids in the process of dry eye disease.Finally, this work enriches the literature on macular pigment, its density, as well as its spatial distribution and its determinants as well as the determinants of dry eye disease. However, given the transversal nature of our studies, these results make only possible to formulate hypotheses that will be confirmed with longitudinal studies and could reinforce the interest of interventions based xanthophylls carotenoids supplementation in elderly
Adam, Clément. "Impact de l’acétoacétate sur la biologie des macrophages humains : analyse phénotypique et métabolique The roles of CSF s on the functional polarization of tumor‐associated macrophages." Thesis, Angers, 2019. http://www.theses.fr/2019ANGE0049.
In case of inflammation or injury, macrophages must adapt and function in a hostile environment, such as an acidic environment. Indeed, excessive production and local accumulation of lactic acid, is a characteristic of inflammatory process and tissue damage. Currently, the metabolic adaptation of human monocytes and macrophages to acidosis and the nature of the factors that enable them to acquire a repair profile are poorly understood. In this study, we show that monocytes differentiated in vitro into macrophages in the presence of the acetoacetate, aketone body produced by the liver, show an increase in oxidative phosphorylation associated with the acquisition of a pronounced repair profile. In addition, ketone bodies and acetoacetate accelerate the rate of healing in an in vivo healing model. From a mechanistic point of view, monocytes differentiated into lactic acidosis accumulate depolarized mitochondria and show signs of mitophagy as well as a significant reduction in nutrient absorption making their survival dependent on autophagy. Interestingly, acetoacetate prevents the consequences of acid stress (maintaining integrity and mitochondrial function), allowing cells to survive without resorting to autophagy. Acetoacetate therefore appears as a unique metabolite to improve the tolerance of cells and tissues to damage induced by acidosis and a local factor promoting the generation of macrophages with a repair profile
Pham, Hong-Ngoc. "Synthesis of enantiopure 3,4-dihydro-2H-1,4-benzoxazine analogues for potential biological applications." Electronic Thesis or Diss., Université de Lorraine, 2020. http://www.theses.fr/2020LORR0186.
This work describes the syntheis and conformational analysis of enantiopure 1,4-benzoxazine-based pseudodipeptides and pseudotripeptides. Enantiomers of ethyl 2,3-dibromopropionate and ethyl 3,4-dihydro-2H-1,4-benzoxazine-2-carboxylate are obtained by two strategies (i) via enantioselective synthesis and (ii) via preparative HPLC enantioseparation of racemate on multigram scale. Because of the racemization process during the enantioselective synthesis, preparative HPLC enantioseparation on racemates are successfully applied to afford enantiomers with high enantiomeric purities (ee ≥ 99.5%). Both enantiomers of the 1,4-benzoxazine compound are used to design new 1,4-benzoxazine-based pseudopeptides via peptide coupling reactions on C- and N-terminal extremities. Their conformational behaviour in solution and solid states are investigated by spectroscopic (IR, NMR) and X-Ray diffraction analyses. The results indicate (i) a predominant C5 pseudocycle involving a lone pair of electrons of oxygen in 1,4-benzoxazine ring with NH group from C-extremity elongation and (ii) a slight influence of the absolute configuration at C2 position of 1,4-benzoxazine scaffold and the side chains of amino acids
Guyot, Pauline. "Modélisation et analyse du signal électrocardiographique pour l'étude du système cardio-respiratoire. Application au syndrome d'apnées du sommeil." Electronic Thesis or Diss., Université de Lorraine, 2019. http://www.theses.fr/2019LORR0134.
The heart is at the center of the cardiorespiratory system and the electrocardiogram is one of the most standard medical exam to monitor it along with echocardiography. Electrocardiogram analysis is complex due to the various cardiac pathologies and the emergence of new measurement technologies allows the acquisition of longer but also noisier signals taken in a daily life context. Noise and the huge amount of processed data impose the development of more accurate and robust analytical methods. This thesis aims at developing a new modeling method of cardiac waves using a dictionary composed of skew normal distribution. It fully characterizes each wave (P, Q, R, S and T) through a small number of parameters. This modeling also permits the precise computation of the different classical intervals used in electrocardiography but also the classification of each beat to provide an accelerated reading of long signals and a diagnostic assistance. Finally, those analytical tools are used on two different subjects: the creation of an electrocardiogram simulator as part of the Hopital Virtuel de Lorraine project ; and the detection of sleep apnea syndrom on electrocardiogram signals and more particularly the Cheyne-Stokes respiration, a nocturnal respiratory pathology still not understood, primarily impacting patients with severe heart failure. The method is based on the extraction of signals correlated to respiration from the electrocardiogram signal and allows to graduate different levels of the Cheyne-Stokes respiration
Lacas, Benjamin. "Apport clinique des méta-analyses dans les cancers ORL localement avancés." Thesis, université Paris-Saclay, 2020. http://www.theses.fr/2020UPASS054.
Radiotherapy and chemotherapy are both recommended treatments for locally advanced head and neck cancers. During conventional radiotherapy, 70 Grays are given in 35 fractions over 7 weeks (called « conventional fractionation »). Chemotherapy may be given before (induction), at the same time (concomitant) or after (adjuvant) locoregional treatment (surgery and/or radiotherapy). Many randomized clinical trials studied the efficacy of altered fractionated radiotherapy and others studied the addition of chemotherapy to locoregional treatment. Individual patient data meta-analysis consists in the collection of the databases of the trials, the check and the analysis, together. It allows to perform advanced analyses like variation of the treatment effect over trials’ or patient’s characteristics. The objectives of the present work were:1/ The first update of the MARCH meta-analysis, which included 34 trials (from 1979 to 2010) and 11,969 patients in order to study the efficacy of altered fractionated radiotherapy compared to conventional fractionation. A toxicity analysis has also been performed. A secondary question was the efficacy of altered fractionation alone compared to conventional fractionation plus concomitant chemotherapy.2/ The second update of the MACH-NC meta-analysis, which included 105 trials (1965-2010) and 19,511 patients in order to study the efficacy of the addition of chemotherapy compared to locoregional treatment. A secondary question was the efficacy of the addition of concomitant chemotherapy compared to the addition of induction chemotherapy
Pruneau, Ludovic. "Analyse du transcriptome d'Ehrlichia ruminantium agent causal de la cowdriose : mise en évidence des gènes impliqués dans la virulence et les mécanismes d'atténuation et application à l'élaboration d'un vaccin recombinant." Thesis, Antilles-Guyane, 2012. http://www.theses.fr/2012AGUY0562/document.
Transcriptomic study of gardel and senegal both virulent and attenuated e. ruminantium strains was conducted during my phd. an analysis of transcriptome at different stages of development has been first conducted for virulent gardel strain. at reticulate body stage (intracellular form non-infectious), over-expression of genes coding for proteins involved in metabolism, transport and exchange of nutrients and resistance to oxidative stress was observed. at this stage of development, e. ruminantium seems to activate mechanisms for its survival and development within the host cell. at elementary body stage, dksa the gene encoding for a transcription factor was over-expressed. this gene has been shown to be involved in the regulation of virulence factors. it seems, therefore, at the elementary body stage, e. ruminantium induces its virulence factors. secondly, we compare the transcriptome of elementary body between virulent and attenuated strains. our results showed an important membrane modification of attenuated and virulent strains. for attenuated strains, we observed an over-expression of genes involved in membrane biogenesis and a diminution of expression of map multigenic family. it seems that map proteins subvert the protective immune response. hypothetical membrane proteins are over-expressed in both virulent and attenuated strains. some over-expressed proteins in attenuated strains seem to be good vaccine candidates and willstudied
Mboup, Bassirou. "Validation de biomarqueurs prédictifs de la réponse au traitement : extension des courbes de prédictivités à un critère de jugement censuré On Evaluating How Well a Biomarker Can Predicttreatment Response With Survival Data Insights for Quantifying the Long-Term Benefit of Immunotherapy Using Quantile Regression." Thesis, université Paris-Saclay, 2020. http://www.theses.fr/2020UPASR011.
It is common in oncology to want to determine whether or not only a subgroup of patients will benefit from a treatment. This is one of the paradigms of personalized or stratified medicine. Predictive biomarkers are often used to select these patients and most of these biomarkers are continuous. For example genomic signatures such as Oncotype-Dx. A methodology for evaluating a biomarker with binary response has been proposed in the literature. The objective of this thesis is in first work to extend this methodology with right-censored data and to determine at different prediction horizons the optimal threshold of the biomarker beyond which treatment will be attributed or avoided. A model whose estimates of these parameters are based on inverse censored probability weights is proposed to provide consistent estimators. An extension of the predictiveness curves will be carried out. In a second work, a test of the calibration hypothesis with right-censored data has been proposed. This test will be valid beyond the 60% censoring rate contrary to those already existing in the literature and will allow us to study the influence of a bad calibration on the determination of the threshold. A third work focuses on the determination of the threshold of a new prognostic biomarker for ovarian cancer in order to classify patients at high or low risk of relapse. Finally, a fourth work consists in illustrating the relevance of the censored quantile regression for quantifying the long term benefit of immunotherapy in a reconstructed data set from a single randomized trial. The proposed methodology can be readilty employed for individual patients data meta-analysis to summarize evidence of immunotherapy as quantified by the upper quantile of the survival distribution
Pagliaro, Sarah Beatriz De Oliveira. "Transcriptional control induced by bcr-abl and its role in leukemic stem cell heterogeneity. Single-Cell Transcriptome in Chronic Myeloid Leukemia: Pseudotime Analysis Reveals Evidence of Embryonic and Transitional Stem Cell States Single Cell Transcriptome in Chronic Myeloid Leukemia (CML): Pseudotime Analysis Reveals a Rare Population with Embryonic Stem Cell Features and Druggable Intricated Transitional Stem Cell States A novel neuronal organoid model mimicking glioblastoma (GBM) features from induced pluripotent stem cells (iPSC) Experimental and integrative analyses identify an ETS1 network downstream of BCR-ABL in chronic myeloid leukemia (CML)." Thesis, université Paris-Saclay, 2020. http://www.theses.fr/2020UPASQ032.
Chronic myeloid leukemia is a clonal hematopoietic malignancy, characterized by the acquisition of the t (9;22) translocation leading to Ph1 chromosome and its counterpart BCR-ABL oncogene, in a very primitive hematopoietic stem cell. CML is a model of targeted therapies as the proof of concept of the feasibility of targeting the tyrosine kinase (TK) activity BCR-ABL using TK inhibitors (TKI) has been shown to lead to major responses and remissions. However, the current problems encountered in these therapies are primitive leukemic stem cells resistance and their persistence which is thought to be related to the heterogeneity of the stem cells at diagnosis leading to clonal selection of cells resisting to TKI therapies. I have applied the technology of single cell transcriptome analysis to CML cells using a panel of genes involved in different pathways combined with trajectory inference analysis to the gene expression pattern. The results showed a transitional stem cell states including embryonic genes identified in CML cells at diagnosis which could contribute to LSC resistance and persistence. Furthermore, the oncoprotein Bcr-Abl is the constitutively active tyrosine kinase produced by the chimeric BCR-ABL gene in chronic myeloid leukemia (CML). The transcriptional targets of Bcr-Abl in leukemic cells have not been extensively studied. A transcriptome experiment using the hematopoietic UT7 cell line expressing BCR-ABL, has identified the overexpression of eukaryotic elongation factor kinase 2 (eEF2K) which plays a major role in the survival of cells upon nutrient deprivation. Overall, the data suggest that overexpression of eEF2K in CML is associated with an increased sensitivity to nutrient-deprivation
Legeay, Marc. "Étude de la régulation anti-sens par l’analyse différentielle de données transcriptomiques dans le domaine végétal." Thesis, Angers, 2017. http://www.theses.fr/2017ANGE0021/document.
A challenging task in bioinformatics is to decipher cell regulation mechanisms. The objective of this thesis is to study gene networks from apple data with the particularity to integrate anti-sense transcription data. Anti-sense transcripts are mostly non coding RNAs and their different roles in the cell are still not well known. In our study, to explore the role of anti-sense transcripts, we first propose a differential functional analysis that highlights the interest of integrating anti-sense data into a transcriptomic analysis. Then, regarding gene networks, we propose to focus on inference of a core network and we introduce a new differential analysis method that allows to compare a sense network with a sense and anti-sense network. We thus introduce the notion of AS-impacted genes, that allows to identify genes that are highly co-expressed with anti-sense transcripts. We analysed apple data related to ripening of fruits stored in cold storage; biological interpretation of the results of our differential analysisprovides some promising leads to a more targeted experimental study of genes or pathways, which role could be underestimated without integration of anti-sense data
Desrues, Mathilde. "Surveillance opérationnelle de mouvements gravitaires par séries temporelles d'images." Thesis, Strasbourg, 2021. http://www.theses.fr/2021STRAH002.
Understanding the dynamics and the behavior of gravitational slope movements is essential to anticipate catastrophic failures and thus to protect lives and infrastructures. Several geodetic techniques already bring some information on the displacement / deformation fields of the unstable slopes. These techniques allow the analysis of the geometrical properties of the moving masses and of the mechanical behavior of the slopes. By combining time series of passive terrestrial imagery and these classical techniques, the amount of collected information is densified and spatially distributed. Digital passive sensors are increasingly used for the detection and the monitoring of gravitational motion. They provide both qualitative information, such as the detection of surface changes, and a quantitative characterization, such as the quantification of the soil displacement by correlation techniques. Our approach consists in analyzing time series of terrestrial images from either a single fixed camera or pair-wise cameras, the latter to obtain redundant and additional information. The time series are processed to detect the areas in which the Kinematic behavior is homogeneous. The slope properties, such as the sliding volume and the thickness of the moving mass, are part of the analysis results to obtain an overview which is as complete as possible. This work is presented around the analysis of four landslides located in the French Alps. It is part of a CIFRE/ANRT agreement between the SAGE Society - Société Alpine de Géotechnique (Gières, France) and the IPGS - Institut de Physique du Globe de Strasbourg / CNRS UMR 7516 (Strasbourg, France)
Martz, Pierre. "Effet de l’obésité sur la récupération fonctionnelle de la marche après prothèses totales de hanche et de genou : analyse biomécanique et clinique." Thesis, Bourgogne Franche-Comté, 2018. http://www.theses.fr/2018UBFCI009/document.
Introduction : Body Mass Index (BMI) impact on gait recovery after total hip and total knee arthroplasty (THA and TKA) remains misunderstood. Few studies have analyzed the influence of BMI on the recovery of hip and knee range of motion (ROM) during gait or walking speed after THA and TKA. Our objective was to assess this impact preoperatively and post-operatively using both 3D gait analysis and clinical assessment. Our hypothesis was that obesity (BMI> 30kg /m2) would be a negative factor in the recovery of gait parameters.Material and methods: After conducting a systematic review of the literature on functional recovery after total prostheses of the lower limb (THA and TKA) to ensure the originality of this work and its relevance we conducted 2 independent prospective studies: including 76 THA in hip osteoarthritis patients on the one hand and 79 TKA in knee osteoarthritis patients on the other hand. All patients had a quantified gait analysis of preoperatively and postoperatively (at 6 months for THA and 1 year for TKA). A control group of matched healthy people followed the same protocol. The gait speed, ROM hip and knee, as well as functional and quality of life scores were evaluated, for all parameters the gain was calculated. Patients were divided into 2 groups in each cohort: non-obese patients (G1): BMI <30kg/m2 and obese patients (G2): BMI≥30kg/m2. Paired t-tests were used to evaluate the pre- and post-operative differences between G1 and G2, then the differences in gain between G1 and G2. Finally, a uni- and multivariate linear regression sought associations between BMI, gait speed, and ROM.Results: In both cohorts: preoperatively, gait speed and ROM were significantly lower in obese patients. Postoperatively, walking speed and ROM were significantly lower for all patients undergoing TKA or THA compared with the control group. Preoperatively obese patients were more symptomatic. A significant difference was found between G1 and G2 regarding pain improvement in favor of the obese (on the gain of WOMAC pain for TKA and analogic pain scale for THA). For all other parameters the gains were not different between G1 and G2. Uni- and multivariate regression showed no significant relationship between gait speed, ROM and BMI.Conclusion: BMI has no direct negative effect on recovery of walking parameters after THA or TKA. Indeed despite a higher preoperative symptomatology obese patients show a comparable improvement in terms of gain to non-obese patients clinically and biomechanically. However, postoperative gait parameters after THA or TKA remain significantly lower than those of controls, regardless of the BMI of patients without full clinical or biomechanical recovery. Though, obesity appears to have a similar effect on the gait parameters recovery after THA or TKA
Pauchard, Laure-Anne. "Analyse et modulation de la réponse inflammatoire au cours de l'agression pulmonaire liée à l'infection bactérienne et à la ventilation mécanique." Thesis, Dijon, 2015. http://www.theses.fr/2015DIJOMU05/document.
Despite major advances since decades in the management of ventilated patients, ventilator-associated pneumonia (VAP) continues to complicate the course of approximately 28% of the patients receiving mechanical ventilation (MV). Among patients hospitalized in intensive care units, the risk of pneumonia is 3- to 10- fold increased in MV patients. However, MV is often the only way to care for critically ill patients with respiratory failure. It has now been clearly demonstrated that MV, in particular adverse ventilatory strategies could activate lung cells, thus leading to a proinflammatory response, even in the absence of pathogen. This is the biotrauma paradigm, which accounts, at least in part, for the ventilator induced lung injury (VILI). In one way, MV primes airway cells to respond massively to a second proinflammatory insult, through the subsequent release of large amounts of cytokines (as interleukin (IL)‐ 8), thus leading to additional lung injury, particularly through the recruitment of neutrophils attracted by the massive release of IL-8. Accordingly, innate immunity plays an important role in the developement of VILI. The involvement of Toll-like receptors has been suggested by several experimental studies. Ventilation in the prone position (PP) has been described to have beneficial effects on patients under MV, especially in those with lobar involvement. Our team focused particularly on the TLR2, which interacts with Gram-positive bacteria, and we have previously demonstrated in vitro that cyclic stretch of human pulmonary cells resulted in TLR2 overexpression and enhanced TLR2 reactivity to Gram-positive cell wall components. We confirmed these datas in an in vivo model of ventilated rabbits which immune response had been stimulated with Pam3CSK4. In a first project, we assessed the impact of the PP on unilateral pneumonia to Enterobacter aerogenes in rabbits subjected to MV. Our results shows that the prone position could be protective if the host is subjected to MV and unilateral bacterial pneumonia. To ensure the relevance of our hypothesis on TLR2 in our animal model of VAP, we conducted experiments using live bacteria specifically recognized by TLR2 (Methicilin resist. aureus). We demonstrate that mild-‐stretch MV impaired lung bacterial clearance, hastened tissue injury and promoted a systemic inflammatory response. Both pulmonary and peripheral blood TLR2 overexpression could account for such an impact. The third project assessed the impact of a statins therapy in the context of MRSA VAP, treated with linezolid, in our model of ventilated rabbits. Our results suggest that statin exposure prior to pneumonia provides an anti-‐inflammatory effect within the lung and the systemic compartment of rabbits with MRSA VAP. Although LNZ enhances pulmonary bacterial clearance, dampening the host systemic inflammatory response with statin could impede defense against MRSA in this compartment. It could be subsequent to enhanced antibacterial defences and improvements in lung mechanics, thereby blunting overwhelming inflammation. In the last project, in collaboration with the University of Geneva, we assessed whether mitochondrial alarmins are released during VILI and can generate lung inflammation. Our results confirmed the hypothesis made and showed indeed that alarmins are released during during cyclic stretch of human epithelial cells, as well as in BAL fluids from rabbits ventilated with an injurious ventilatory regimen. These alarmins stimulate lung cells to produce bioactive IL-‐1, and are likely to represent the proximal endogenous mediators of VILI and ARDS, released by injured pulmonary cells
Deguettes, Quentin. "Conception, caractérisation et évaluation de formes galéniques à libération prolongée pour l’administration parentérale d’une protéine naturelle destinée à stimuler l’ovulation chez la vache Controlled delivery of follicle-stimulating hormone in cattle." Thesis, université Paris-Saclay, 2020. http://www.theses.fr/2020UPASQ016.
Stimulation of ovulation in cows (superovulation) is necessary for cattle farms to optimize the cost/production balance. For this purpose, treatments requiring a large number of injections over several days of a natural protein have been available for many years. The development of a system that is easy to handle, guaranteeing the stability of the protein, and ensuring its sustained-release would greatly benefit for the user (breeder and/or veterinarian) and the animal. In this work, we have, firstly, set up methods for the characterization of the protein in solution (quantity and integrity) in order to assay and monitor the release of the active form. Secondly, we have developed and evaluated in vitro the potential of in situ forming implants and in situ gelling hydrogels. Thirdly, formulations selected on the in vitro results were tested in vivo in the female rat. The single subcutaneous injection of some drug delivery systems containing the protein resulted in ovarian stimulation similar to or better than the multi-injection protocol. Finally, the study of the physico-chemical properties of the formulations injected into the female rat has allowed us to understand the results obtained
Heckler, Géraud. "Étude de l'effet d'un stress oxydant sur l'activité spliceosomale et sur les RNP à boîtes C/D et H/ACA." Thesis, Université de Lorraine, 2019. http://www.theses.fr/2019LORR0351.
During pre-RNA maturation process, alternative splicing (AS) selectively includes or excludes specific intronic or exonic sequences. This process leads from a given pre-RNA, to different isoforms. Some recent studies estimate that 95% of human genes are alternatively spliced. Then, it is not surprising that stress-induced modifications of splicing profils participate to the establishment of the cell response to stress or to the development of pathologies. Our global transcriptomic analysis has revealed significant splicing variations in response to an oxidative stress (500μM H2O2). That is why we were interested in such stress effects on the spliceosome, responsible for the dynamic catalysis of splicing. The functional spliceosome is composed by different ribonucleoproteins (RNPs), each being composed of a Uridine-rich small nuclear RNA (U snRNA) associated with specific proteins to form the mature UsnRNPs. To be functional, each UsnRNP should be maturated following different steps including the chemical modification of its RNA component. These post-transcriptional modifications are induced by another type of RNPs which are particularly enriched within nuclear Cajal bodies and are named scaRNPs (for small Cajal Bodies RNPs). Our results obtained by fluorescence microscopy techniques show that oxidative stress changes Cajal bodies structure by inducing the nucleoplasmic redistribution of its main structural and functional component, the coilin protein. Interestingly, we highlighted that coilin redistribution is accompanied with changes of the localization of others Cajal Body components: (i) factors involved in the formation of post-transcriptional modifications in UsnRNAs, (ii) factors involved in scaRNPs retention, (iii) UsnRNPs components. Oxidative stress also seems to induce the exclusion of SMN protein from the nucleus, knowing that it plays a central role in UsnRNP nuclear re-import during their maturation. This study has generated a large amount of fluorescence microscopy data, so that I have developed different bio-image analysis protocols in order to optimize the extraction and the processing of these data. In parallel, RNA-Immunoprecipitation (RIP) experiments coupled with high-throughput sequencing have revealed (i) a significant increase of U4, U5 and U6 snRNP fraction suggesting a potential effect of oxidative stress on the U4/U6-U5 tri-snRNP, (ii) oxidative stress-induced variations of the 2’-O-methylation level directly in mature U snRNPs
Bayar, Mohamed Amine. "Randomized Clinical Trials in Oncology with Rare Diseases or Rare Biomarker-based Subtypes." Thesis, Université Paris-Saclay (ComUE), 2019. http://www.theses.fr/2019SACLS441.
Large sample sizes are required in randomized trials designed to meet typical one-sided α-level of 0.025 and at least 80% power. This may be unachievable in a reasonable time frame even with international collaborations. It is either because the medical condition is rare, or because the trial focuses on an uncommon subset of patients with a rare molecular subtype where the treatment tested is deemed relevant. We simulated a series of two-arm superiority trials over a long research horizon (15 years). Within the series of trials, the treatment selected after each trial becomes the control treatment of the next one. Different disease severities, accrual rates, and hypotheses of how treatments improve over time were considered. We showed that compared with two larger trials with the typical one-sided α-level of 0.025, performing a series of small trials with relaxed α-levels leads on average to larger survival benefits over a long research horizon, but also to higher risk of selecting a worse treatment at the end of the research period. We then extended this framework with more 'flexible' designs including interim analyses for futility and/or efficacy, and three-arm adaptive designs with treatment selection at interim. We showed that including an interim analysis with a futility rule is associated with an additional survival gain and a better risk control as compared to series with no interim analysis. Including an interim analysis for efficacy yields almost no additional gain. Series based on three-arm trials are associated with a systematic improvement of the survival gain and the risk control as compared to series of two-arm trials. In the third part of the thesis, we examined the issue of randomized trials evaluating a treatment algorithm instead of a single drugs' efficacy. The treatment in the experimental group depends on the mutation, unlike the control group. We evaluated two methods based on the Cox frailty model to estimate the treatment effect in each mutation: Maximum Integrated Partial Likellihood (MIPL) using package coxme and Maximum H-Likelihood (MHL) using package frailtyHL. MIPL method performs slightly better. In presence of a heterogeneous treatment effect, the two methods underestimate the treatment effect in mutations where the treatment effect is large, and overestimates the treatment effect in mutations where the treatment effect is small
Alari, Anna. "Variations temporelles et géographiques des méningites à pneumocoque et effet du vaccin conjugué en France." Thesis, Université Paris-Saclay (ComUE), 2018. http://www.theses.fr/2018SACLV070/document.
Streptococcus pneumoniae is a Gram-positive commensal bacterium of the oropharyngeal flora usually colonizing human’s rhino pharynx, of which almost 100 serotypes are known. Infants and young children constitute its main reservoir. Pneumococcus may cause serious infections, such as meningitis, bacteremia and pneumonia, or less serious but more common such as sinusitis and acute otitis media (AOM). Two conjugate pneumococcal vaccines have been introduced in France: PCV7 (covering 7 serotypes) in 2003 and PCV13 (covering 6 additional serotypes) in 2010. The overall objective of this thesis is to assess the impact of vaccination policy on invasive pneumococcal diseases in France, by focusing on temporal and geographical trends of the most serious of them: pneumococcal meningitis (PM). An initial study of PMs temporal dynamics over the 2011-2014 period assessed the impact of conjugate vaccines’ introduction. Statistical modeling techniques were used for time series analysis. The results confirm the effects found in literature: a reduction of vaccine serotypes PMs but at the same time an increase of PMs, due to non-vaccine serotypes (effect of “serotype replacement”). Therefore, the first benefit of vaccine introduction at population scale has been observed no less than 11 years after PCV7 introduction, and then principally after PCV13 was introduced in 2010, with a 25% decrease in PMs in 2014. The geographic component was then implemented to analyze the role of vaccine coverage in annual PM variability between geographic units over the 2001-2016 period. Results confirm the effectiveness of both vaccine compositions on vaccine serotypes PMs and suggest homogeneity of this effect among geographic units. Conversely the serotype replacement has been confirmed only after the first vaccine composition was introduced and presents a variable and heterogeneous geographical repartition. Variability in vaccine coverage among geographic units doesn’t explain the differences in PMs, which could suggest the role of others factors such as demographic density. Finally, a dynamic modeling capable of taking into consideration fundamental aspects of pneumococcus transmission and infection mechanisms not integrated in static modeling has been proposed in order to predict the impacts of different vaccination strategies for 65+ adults and therefore assess their cost-utility ratios