Tesis sobre el tema "Recherche de biomarqueurs"
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Lemesle, Gilles. "Recherche de biomarqueurs pronostiques dans l'insuffisance cardiaque". Thesis, Lille 2, 2015. http://www.theses.fr/2015LIL2S028/document.
Texto completoRisk stratification of patients with systolic chronic heart failure (HF) is critical to better identify those who may benefit the most from invasive therapeutic strategies such as cardiac transplantation. In spite of recent advances, risk stratification of HF patients needs to be further improved. Indeed, there remains variability in the prognosis with some patients who are categorized at low risk but experience early mortality; and conversely, patients categorized as severe but have an unexpectedly prolonged survival. Proteomics has been used to provide prognostic information in various diseases.Aim – Our aim was to investigate the potential value of plasma proteomic profiling for risk stratification in HF and to find new circulating biomarkers that are associated with early cardiovascular mortality of chronic HF patients.Methods and results – For that purpose, we first designed 2 populations: a discovery and a validation population. Both populations issued from the INsuffisance CArdiaque (INCA) cohort, which is constituted of all consecutive patients referred in our institution for extensive prognostic evaluation of systolic chronic HF (LVEF <45%) between November 1998 and May 2010. For the discovery phase (case/control population), we selected 198 patients included between November 1998 and December 2005: 99 patients who died from cardiovascular cause within 3 years after the initial evaluation (cases) were individually matched for age, sex, and HF etiology with 99 patients who were still alive at 3 years (controls). For the validation phase, we evaluated a cohort of 344 consecutive patients included between January 2006 and May 2010. Study populations were carefully phenotyped. Cardiovascular death included cardiovascular-related death, urgent transplantations defined as United Network for Organ Sharing status 1 and urgent assist device implantation. A proteomic profiling using surface enhanced laser desorption ionization - time of flight - mass spectrometry was then performed in the case/control discovery population on plasma samples collected at inclusion. Plasma samples were depleted for major proteins and randomly analyzed in duplicate using CM10 (Weak Cation Exchanger) and H50 (Reverse Phase) proteinchip arrays. Forty two ion m/z peaks were found differentially abundant between cases and controls in the discovery population and were used to develop proteomic scores predicting cardiovascular death using 3 statistical regression methods: support vector machine, sparse partial least square discriminant analysis and lasso logistic regression. The proteomic scores were then tested in the validation population and score levels were significantly higher in patients who subsequently died within 3 years with the 3 methods. Proteomic scores remained significantly associated with cardiovascular mortality after adjustment on confounders. Furthermore, use of the proteomic scores allowed a significant improvement in discrimination of HF patients as determined by integrated discrimination improvement and net reclassification improvement indexes on top of “classic” prognostic evaluation. The next step was the purification and identification of the proteins related to the different m/z peaks (n=13) that were found significantly differentially abundant in both populations. We have currently identified several peaks as apolipoproteins: 14511 CM10-BM (ApoA1), 29024 CM10-BM (ApoA1), 3267 H50-BM (ApoC1), 6416 H50-BM (ApoC1), 6616 H50-BM (ApoC1), 6825 H50-BM (ApoC1), 8764 H50-BM (ApoC3), 9421 H50-BM (ApoC3). This has led to the quantification of these apolipoproteins in the INCA population using mass reaction monitoring technique.Conclusion – Proteomic analysis of plasma proteins may help to improve risk prediction of early mortality in HF patients.Perspectives – Further investigations are ongoing in order to determine the impact of the different apolipoproteins tested in risk stratification of chronic HF patients
Acosta, Martin Adelina Elena. "Recherche de biomarqueurs de l'anévrysme de l'aorte abdominale". Phd thesis, Université du Droit et de la Santé - Lille II, 2009. http://tel.archives-ouvertes.fr/tel-00447240.
Texto completoRobert, Rémy. "Recherche de biomarqueurs pour l'imagerie moléculaire de l'athérosclérose". Bordeaux 2, 2006. http://www.theses.fr/2006BOR21324.
Texto completoThis thesis is divided in two parts. Its aim is the development of human monoclonal antibodies of cardiovascular interest. The first part involves the production, the purification and the biochemical analysis of human antibody fragments directed against the αIIbβ3 integrin. The second part described the in vivo selection by phage display of human scFvs targeting atherosclerotic lesions. We have screened in vivo the atherosclerotic plaques of this model with two different combinatorial libraries of human antibodies. Our strategy is based on a substractive screening with normal and atherosclerotic protein-coated filters, allowing the detection of scFvs after one round of in vivo biopanning. This substractive aproach has permitted us to isolate two scFvs specific to atherosclerotic proteins. The development of such antibodies could be useful : (1) in diagnosis for the early detection of atherosclerotic lesions by MRI, (2) in gene therapy, to improve the molecular targeting
Szacherski, Pascal. "Reconstruction de profils protéiques pour la recherche de biomarqueurs". Phd thesis, Université Sciences et Technologies - Bordeaux I, 2012. http://tel.archives-ouvertes.fr/tel-00788410.
Texto completoNegroni, Luc. "Analyse phosphoprotéomique pour la recherche de biomarqueurs : développements et applications". Phd thesis, Université Sciences et Technologies - Bordeaux I, 2013. http://tel.archives-ouvertes.fr/tel-00965662.
Texto completoBen, Ameur Siala Randa. "Recherche de biomarqueurs précoces de diagnostic de la néphropathie diabétique". Thesis, Montpellier 2, 2011. http://www.theses.fr/2011MON20004.
Texto completoDiabetic nephropathy (DN) is one of the most serious complications of diabetes. It affects about 30% of diabetic patients. Microalbuminuria is currently the main available marker for DN risk, but has inadequate specificity and precocity. Several published studies intended to research new biomarkers (BM) of DN by proteomic approaches. We have shown1 that, if several candidate BM were claimed, there was no consensus about their nature and that a number of studies could not identify BM earlier than albumin because of the study design. Thus, we have selected an original cohort of type 1 diabetic patients considered at risk of developing DN, on the basis of urinary albumin excretion after an exercice test. A control cohort was also enrolled. Using 2D gel electrophoresis we compared the urinary proteomes of patients from both cohorts. Then, candidate BM were identified by mass spectrometry. Functional analysis of these proteins showed that some are involved in the coagulation cascade and in mechanisms of endothelial dysfunction. The diagnostic potential of these proteins was validated by Western blotti ng. The nature and physiological function of candidate biomarkers allowed to better understand the molecular pathogenic mechanisms of DN. Results from this part of the work are shown in the form of an article2. Preliminary studies to assess the diagnostic potential research of specific urinary proteins (nephrin and different isoforms of adiponectin) are also presented.1 Ben Ameur R. et al Proteomic approaches for discovering biomarkers of diabetic nephropathy. Nephrol Dial Transplant 25, 2866-752 Ben Ameur R. et al Identification of early candidate biomarkers for diabetic nephropathy by urine proteomic analysis. To be submitted
Collignon, Olivier. "Recherche statistique de biomarqueurs du cancer et de l'allergie à l'arachide". Phd thesis, Nancy 1, 2009. http://tel.archives-ouvertes.fr/tel-00430177.
Texto completoLe, Faouder Julie. "Recherche de biomarqueurs tissulaires de la cancerogenèse hépatique par imagerie Maldi". Paris 7, 2012. http://www.theses.fr/2012PA077002.
Texto completoHepatocellular carcinoma (HCC) represents the sixth most common cancer in the world, and the third most frequent oncological cause of death. Over 80% of HCC develop from cirrhosis, mainly related to viral etiology. The prognosis of HCC is mostly poor, because of its late detection at an advanced stage. Thus, new effective biomarkers are needed. MALDI imaging mass spectrometry (MALDI IMS) allows differential distribution visualization of potential markers within tissue. The aim of the present project was to investigate, using MALDI IMS, the proteome of HCC and to compare it with peritumoral cirrhosis so as to characterize new biomarkers of HCC. We found a set of proteins/peptides with a differential intensity level that most accurately delineated cancer from adjacent cirrhotic tissue. We generated a classification model enabling correct classification of most spectra present in cirrhosis or tumor areas from the independent validation group. The most discriminating marker (m/z 8,565) increased in HCC was characterized as the monomeric ubiquitin and further validated by immunohistochemistry. Marker m/z 2,753 was a peptidic fragment of albumin and was overexpressed in HCC while m/z 3,195, identified as a fragment of the alpha chain of hemoglobin, was specifically more intense in cirrhosis. This work provides complementary tools that could be useful in the early diagnosis of HCC. Identified biomarkers will gain further insights in the role of proteasome in the liver cancerogenesis. MALDI IMS and identification developed methods will be useful for other projects
Hinsinger, Geoffrey. "Recherche de biomarqueurs biologiques de sclérose en plaques par protéomique quantitative". Thesis, Montpellier, 2016. http://www.theses.fr/2016MONTT027.
Texto completoDiscovery, confirmation and verification of candidate biomarkers for multiple sclerosis diagnosis and prognosis in cerebrospinal fluid.Multiple sclerosis (MS) is an inflammatory disease of the central nervous system. Most often the disease initiates by a first demyelinating event called clinically isolated syndrome (CIS), followed by remission periods and relapses occurring at irregular intervals. Clinical symptoms and MRI are used for diagnosis, but clinicians lack tools to predict the rate of disease progression. This study aims at identifying biomarkers that predict the delay of conversion to MS after a CIS. We compared the cerebrospinal fluid (CSF) proteome from MS patients and symptomatic controls and the CSF from CIS patients with rapid conversion to MS (<1 year) and CIS patients with slow conversion to MS (>2 years). For the discovery step, human CSF samples (n=40) depleted of the 20 major plasma proteins were digested using a modified filter-assisted sample preparation (FASP) and analysed by high-resolution mass spectrometry using isobaric mass tag labelling or label-free quantification procedures. Proteins upregulated in CSF from MS patients included two proteins involved in tissue remodeling, namely chitinase-3-like protein-1 (CHI3L1) and chitinase-3-like protein-2 (CHI3L2). Their increased level in CSF of MS patients was confirmed by ELISA in a new cohort comprising CIS and MS patients (n=123) at different disease stages. Moreover, CHI3L1 levels in CSF and serum from CIS patients discriminated patients with rapid conversion to MS (< one year) from those with slower conversion.We also implemented a PRM method (peptide selection, dilution optimization of heavy isotope labeled non-purified peptides, reproducibility evaluation and method validation) to qualify a larger set of candidate biomarkers (226 peptides corresponding to 87 proteins) in a cohort different from the one used for the discovery step (n=60), including CSF from controls and MS patients at different disease stages. Finally, to further verify the 11 candidate biomarkers that passed this qualification step, we monitored 16 peptides in a new PRM assay, using shorter gradient and high-purity heavy isotope labeled peptides. This new PRM analysis was performed on a larger cohort (n=189) that included CSF of patients with other inflammatory and non-inflammatory neurological disorders in addition to control and MS patients. These analyses identified seven robust candidate biomarkers, which might help to discriminate patients suffering from MS or other neurological disorders
Bodet, Pierre-Edouard. "Recherche de biomarqueurs glucidiques de mucopolysaccharidoses et étude de la physiopathologie". Thesis, Université Paris-Saclay (ComUE), 2016. http://www.theses.fr/2016SACLE001/document.
Texto completoThe identification of biomarkers remains one of the main challenges for analytical sciences and a major stake for clinical research. Glycosaminoglycans (GAGs) have been identified as potential biomarkers of mucopolysaccharidoses (MPS) belonging to rare genetic diseases with often a deadly issue. These pathologies are due to a deficiency in one of the enzymes responsible for GAGs catabolism. This enzymatic defect results in the accumulation of partially catabolized GAGs in organism and leads to neurodegeneration for the most severe forms of the disease. GAGs are complex polyanionic polysaccharides involved in numerous physiological processes in mammals. Their study remains a challenging task because of their high structural heterogeneity and their low biodisponibility, besides the lack of dedicated analytical tools. Our aim was to detect and quantify these compounds in biologic fluids such as urine and cerebrospinal fluid, and to elucidate their structures by mass spectrometry. This study focused on heparan sulfate (HS) oligosaccharides, as potential biomarkers of MPS featured by neurological manifestations (MPS I, IIIB and IIIC), and possibly responsible of lesions in the central nervous system. An experimental strategy allowing the extraction of HS oligosaccharides from biological fluids was implemented, thereby the structures of urinary heparan sulfate oligosaccharides were deciphered, leading to possible biomarkers candidates of MPS IIIB and IIIC. These compounds could be useful for diagnostic and patient follow-up that are currently lacking for the monitoring of therapeutic assays. In vitro exposition of different cerebral cell types to HS oligosaccharides was carried out to establish the relation between the structure of oligosaccharides and neuropathological effects. These studies highlighted several cellular processes that could be involved in neurodegeneration and constitute new therapeutic targets
Kowalczewska, Malgorzata. "Recherche de biomarqueurs de la maladie de Whipple par une approche protéomique". Aix-Marseille 2, 2007. http://www.theses.fr/2007AIX20683.
Texto completoBoudon, Sabrina. "Recherche de biomarqueurs plasmatiques pour prédire la qualité de la viande bovine". Thesis, Université Clermont Auvergne (2017-2020), 2020. http://www.theses.fr/2020CLFAC004.
Texto completoA challenge for the ruminant sector is to predict and manage the phenotypic traits related to meat production and quality especially tenderness, a priority of the beef industry. Meat quality is a complex phenotype that can be evaluated only after slaughtering and meat ageing. Previous research efforts have investigated the potential of muscle-derived markers to assess meat quality from biopsy or on carcass samples. However, recent studies have reported relationship sometimes inverse between protein abundance and tenderness depending on the muscle type or animal considered. Thus, the identification of “generic” and low-invasive biomarkers is an issue for the beef sector. In this context, the objective of my PhD thesis was to discover plasma candidate biomarkers to predict and manage beef tenderness. To meet this objective, my research included two complementary approaches: (i) a molecular data aggregation from publicly available data combined with bioinformatics (in silico approach) to reconstruct the secretome associated withtenderness; (ii) a proteomic analysis (Shotgun LC-MS/MS) to identify plasma and muscle candidates (Longissimus et Rectus abdominis muscles) from contrasted tenderness groups of PGI Fleur d’Aubrac heifers. Extreme groups of tenderness were established based on three evaluation methods: Warner Bratzler Shear Force, sensory analysis, and according to a synthetic index which combines the previous two evaluation systems. Thanks to the combination of the two approaches, I can propose for the first time an atlas of 107 plasma candidate proteins to assess the tenderness in cattle, of which 32 are included in tenderness QTL. I could also complete the list of muscle candidates reported in the scientific literature. While published data report mainly data on male bovines (steers, bull calves), my PhD work allows to propose for the first time a list of plasma and novel muscle candidates for heifer tenderness. My results also contribute to improve knowledge on tenderness determinism, notably through the involvement of extracellular vesicles (micro-vesicular (EVs), macro-vesicular (exosomes)), and the primary cilia. This knowledge will help to design phenotypic tools for “tenderness potential” prediction, in living animal and to add value to high-quality beef sector
Lanzini, Justine. "Recherche de biomarqueurs et études lipidomiques à travers diverses applications en santé". Thesis, Sorbonne Paris Cité, 2016. http://www.theses.fr/2016USPCB126.
Texto completoBiomarker was defined as "a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacological responses to therapeutic intervention". The scientific interest in biomarkers is more and more important. They allow, in particular, to better understand pathogenic processes and to diagnose, even to predict pathologies. "Omics" studies, such as lipidomics, play an essential role in the new biomarkers discovery. Lipidomics consist in exploring biological samples lipidome and in detecting pathogenic impact on this latter. Lipids are a large and important metabolite family found in all living cells. Their quantity is estimated to more than 100,000 species in mammals. They are involved, in particular, in the energy storage and the signal transduction. My PhD thesis involved carrying out lipidomics approaches with LC-MS through various health applications such as severe combined immunodeficiency associated with alopecia syndrome, infantile nystagmus syndrome and renal graft rejection. For this purpose, multivariate and univariate statistical analyses were carried out in order to detect potential lipid biomarkers
Li-Thiao-Té, Sébastien. "Traitement du signal et images LC/MS pour la recherche de biomarqueurs". Phd thesis, Cachan, Ecole normale supérieure, 2009. https://theses.hal.science/tel-00466961/fr/.
Texto completoLiquid chromatography mass spectrometry is a promising technique in analytical chemistry for the discovery of protein biomarkers. This thesis deals with correcting distortions such as LC/MS image alignment and intensity standardization. We then apply a contrario detection, and study the limit of detection of the proposed algorithm
Li-Thiao-Té, Sébastien. "Traitement du signal et images LC/MS pour la recherche de biomarqueurs". Phd thesis, École normale supérieure de Cachan - ENS Cachan, 2009. http://tel.archives-ouvertes.fr/tel-00466961.
Texto completoKossorotoff, Manoëlle. "Approche physiopathologique et recherche de biomarqueurs associés aux complications neurovasculaires chez l'enfant drépanocytaire". Thesis, Paris 5, 2014. http://www.theses.fr/2014PA05P624/document.
Texto completoCerbrovascular involvement is frequent in children with sickle-cell disease (SCD). It is severe in terms of morbidity (handicap) and mortality. Accelerated intracranial arterial blood flow velocity measured by transcranial doppler (TCD) is predictive for stroke occurrence and leads to therapeutic modifications. In SCD children, ischemic stroke results from stenotic cerebral vasculopathy associated with hypercoagulability, and cell activation. We prospectively addressed associations between biological markers and TCD velocity in 108 children with sickle-cell anemia (HbSS or HbSβ°) and looked for predictive factors for vascular peripheral or cerebral events. We performed extensive work-up of endothelial function, coagulation activation, cell activation, and arterial wall mechanics. Cerebral vasculopathy was defined using TCD velocity (continuous data) rather than the classical category classification. The main result is the demonstration of the role of hematopoietic stem cell CD34+ for the prediction of clinical vascular event occurrence. We also demonstrated an imbalanced coagulation profile in SCD children with recurrent cephalalgia or migraine. This finding supports the hypothesis that recurrent cephalalgia, especially migraine, could be a symptom of ultra-transient ischemic cerebrovascular events in SCD children. Therefore, this symptom may also indicate increased cerebrovascular ischemic risk. We demonstrated that the ratio cerebral hemorrhagic risk / cerebral ischemic risk in SCD children remains stable, despite the routine use of strategies aiming at reducing ischemic stroke risk. The concurrent observation of intracranial arterial stenotic lesions and aneurysm suggests common pathophyiological mechanisms. Improving pathophysiological understanding of cerebrovascular complications and demonstrating predictive risk factors for clinical events may help clinicians to improve early diagnosis of SCD-associated cerebral vasculopathy, to better understand stroke mechanism in this population, and probably to improve neurological outcome with earlier and more adapted management
Fertin, Marie. "Recherche de biomarqueurs circulants du remodelage ventriculaire gauche en post-infarctus du myocarde". Thesis, Lille 2, 2012. http://www.theses.fr/2012LIL2S025.
Texto completoLeft ventricular (LV) remodelling after myocardial infarction (MI) indicates a high risk of heart failure and death but remains difficult to predict in clinical practice. Biomarkers may help to refine risk stratification. The main purpose was to find circulating biomarkers of LV remodelling after MI, using two strategies : candidate protein approach and differential proteomic approach, working on a population with a clearly defined phenotype, the REVE-2 study, a prospective multicenter study including 246 patients with a first anterior Q-wave MI. Blood samples were obtained at hospital discharge, at 1 month, 3 months and 1 year. An echocardiography was performed at the same time except for the 1st month to assess LVR.By candidate protein approach, we confirmed that B-type natriuretic peptide (BNP) was a powerful predictor of LV remodelling after MI. Additional biomarkers, such as matrix metalloproteinase-8 (MMP-8), MMP-9, hepatocyte growth factor (HGF), C-reactive protein (CRP) and cardiac troponin I were found to be associated with LV remodelling, highlighting several pathways implicated in pathophysiology of LV remodelling. We have also shown that biomarkers in association (BNP and cardiac troponin I, BNP and MMP-8, BNP and MMP-9) could improve risk stratification in post-MI by selecting groups of patients at higher risk.As the ideal biomarker was still not identified, we applied a differential proteomic approach, with no a priori hypothesis, in order to characterize proteomic signature of LV remodelling. The use of a protein enrichment kit, consisting of a library of combinatorial hexapeptide ligands, compressed the protein concentration range of plasma and serum, through the simultaneous onestep dilution of high-abundance and concentration of lowabundance proteins. Protein enrichment kit prior to two-dimensional (2D) electrophoresis or SELDI TOF MS (surface-enhanced laser desorption–ionization time of flight) analysis enabled the detection of proteins that were not detected in native blood sample and the accessibility to proteolytic fragments obtained from major proteins. Clusterin (apolipoprotein J) was identified as a potential biomarker of LV remodelling by 2D-DIfferential Gel Electrophoresis (2D-DIGE). Clusterin was quantified by Western blot and ELISA and was found to be positively associated with LV remodelling. However, this association was not found with all LV remodelling parameters nor at each time during the year following MI, requiring further analysis. Differential proteomic approach by SELDI TOF MS selected 26 m/z peaks, as potential biomarkers of LV remodelling. Of them, 12 were identified by mass spectrometry. The 2777 m/z peak was identified directly from the ProteinChip array as being the N-terminal peptide (24–48 aa) generated from albumin by pepsin cleavage. Other peaks were identified after purification using chromatographic columns or liquid-phase isoelectric focusing : most of them were found to be proteolytic fragments of proteins like fibrinogen, C3, C4 and C1q complement. Identifications have now to be validated with specific techniques, usually by immmunoprecipitation and Western blot analysis.Finding new biomarkers of LV remodelling could help refine risk stratification and identify patients in whom more aggressive therapy and/or more frequent follow-up could be needed
Maizi, Magali. "Le protéome urinaire : caractérisation et intérêt pour la recherche de biomarqueurs de pathologies". Thesis, Grenoble, 2014. http://www.theses.fr/2014GRENV075/document.
Texto completoBladder cancer is the 4th type of cancer causing man death in Europe. In most cases, primary tumors can be easily removed by resection but in 60% of the cases, the tumors regrowth in more aggressive forms. Therefore, it is essential to detect early recurrence of bladder cancer. To date, the gold standard for the diagnosis of bladder cancer is cystoscopy. It allows the examination of the inside of the bladder using an optical system which is inserted in the urethra. This method is sensitive and specific but extremely uncomfortable and invasive for the patient. Therefore, it is crucial to find new diagnosis and monitoring methods for bladder tumour more comfortable for the patient, in a cost efficient way. The search for clinically useful protein biomarkers in the urine is a major alternative for the diagnosis, the prognostic and the therapeutic treatment of patients with urea-genital pathologies. In the specific case of the bladder cancer, the bladder contains the cells left by the tumour, and subsequently urine becomes the ideal fluid for biomarker investigation as a “proximal fluid”. In the last few years, the search for protein biomarkers has benefited of significant progress in the field of mass spectrometry and bio-chemistry, allowing the detection of a wide variety of proteins in a large dynamic range of concentrations. In addition, new approaches of quantitative proteomic, such as the “Accurate Mass and Time (AMT) tags” approach, coupled with the “label free” quantification, allows the comparison of proteomes from distinct physiological state by measuring protein abundances. During this thesis, we developed an experimental protocol covering the whole process of discovering new biomarkers associated to bladder cancer in urines, i.e., from the collection and preparation of urine samples, to the evaluation of the best fractioning method to define the urinary proteome using quantitative approaches and dedicated statistical methodologies. This work enables the population of a database containing 2014 urinary proteins. Abundance variations were measured for more than the half through a cohort of 98 healthy and bladder cancer patients. A final list of 97 biomarker candidates has been established. This list holds a significant number of exosomal proteins that are potentially secreted by the tumour
Leduc, Antoine. "Recherche, chez la vache laitière, de biomarqueurs du déficit énergétique dans le lait". Electronic Thesis or Diss., Rennes, Agrocampus Ouest, 2022. http://www.theses.fr/2022NSARB364.
Texto completoDairy cows are very susceptible to negative energy balance, which occurs when their energy needs exceed their intake. Negative energy balance affects milk production as well as the animal health. Its early detection is thus essential and feed restriction experiments are conducted to it. The objective of this thesis was to identify milk molecules affected by feed restrictions of different intensity to propose a panel of non-invasive biomarkers of negative energy balance, usable in dairy farming. The study of milk contents, metabolites, major proteins, as well as proteome and miRNome, allowed the identification of variable molecules reflecting the adaptation of the mammary metabolism to the energy stress. Variations induced by these restrictions were a factor of their intensity and some of the identified variableswere verified on other animals, during the physiological negative energy balance in early lactation. The integrative study of all these data led to 25 candidate biomarkers among which some were selected for their potential to be monitored by a tool commonly used in breeding: the mid infrared spectrometry. Equations will be developed to evaluate the concentrations of glutamate, uric acid and isocitrate via these spectra and will be used with those already existing to evaluate the lactose content and the fatty acids concentrations, to constitute a panel of biomarkers of the negative energy balance. Validation of this tool will have to be done but, if its reliability is confirmed, it will allow a better monitoring of the energy balance in dairy cows and will help to improve their health, their welfare, and their productivity
Fragnoud, Romain. "Recherche de marqueurs pronostiques des formes sévères de dengue". Thesis, Lyon, École normale supérieure, 2013. http://www.theses.fr/2013ENSL0807.
Texto completoDengue is a endemic viral disease in tropical countries. If its classical form (CF) is benign, its severe form (SF) leads however to serious complications. Currently, the prognosis of severe dengue is unreliable. Differential proteomic studies on acute CF and FS plasma specimens were performed in order to identify early markers of progression to severe forms.The non-structural protein 1 (NS1) is a viral protein associated with pathogenicity. A method using SELDI-TOF/MS (Surface Enhanced Laser Desorption Ionization-Time of Flight/Mass Spectrometry) coupled to anti-NS1 monoclonal antibodies was developed in order to profile the proteins interacting with NS1 in plasma. Whereas NS1 protein was specifically detected in acute dengue plasma specimens, no NS1 ligand was identified. This method however allowed for sample serotyping.Plasma proteins of SF and CF patients were analyzed differentially using ICPL (Isotope Coded Protein Labeling). Three markers potentially related to disease severity were identified and validated by ELISA.As cellular partners are involved in virus biosynthesis, the viroproteome associated to each disease was characterized by LC-MS/MS. A method of dengue virus purification was first developed on an in vitro model. This method was then applied to pools of acute plasma of either CF or SF patients. We identified viral proteins as well as host proteins potentially associated with the viral particles. A footprint involving specific canonical pathways were subsequently identified in SF patients. Finally, a set of proteins found differentially expressed was validate by ELISA.Beyond identification of tools allowing assessment of dengue severity prognosis, these results give clues on the complex mechanisms underlying the transition from the CF to the SF
Jegou, Maëva. "Recherche de biomarqueurs sanguins de la plasticité lipidique chez le porc et le poulet". Thesis, Rennes, Agrocampus Ouest, 2016. http://www.theses.fr/2016NSARB247/document.
Texto completoMeat production at a lower cost requires robust and efficient animals able to adapt to different rearing conditions. This requires assessing animal’s abilities to store and restore its energy reserves. The objective of the current thesis was to identify potential blood markers of body composition. Two monogastric species were studied, pig and chicken. For each species, animals of two genetic lines (divergent selection on Residual Feed Intake in pigs and abdominal fat proportion in chicken) received two diets contrasted in energy sources (high vegetable oils and fibers vs. rich in starch) but isoproteic and isoenergetic. Plasma parameters and the blood transcriptome were studied in response to those diets.Plasma metabolites and hormones were affected by the diet in pigs whereas those parameters were affected by the diet and the genetic lines in chickens. Metabolome analysis, associated with targeted measurement of metabolites and hormones concentrations, shows that the combination of several blood parameters explained between 37 and 75% of the variability of body fat in pig or chicken. For both species, the blood transcriptome was more affected by the line than by the diet. Pigs and chickens fed a diet rich in lipids and fibers, overexpressed the gene encoding the hepatic form of a mitochondrial enzyme: CPT1A. In summary, this work supports the potential use of blood transcriptome to study variations of phenotypes in a dynamic way throughout the life of the animal and to highlight biomarkers for future selection process
Longuespée, Rémi. "Histologie moléculaire : développements et applications pour la recherche de biomarqueurs du cancer de l’ovaire". Thesis, Lille 1, 2012. http://www.theses.fr/2012LIL10045/document.
Texto completoEpithelial ovarian Cancers (EOC) are amongst the most deadly gynecological neoplastic afflictions in western countries. As this time, there is no method for the efficient screening of the disease in its early steps of development. The topics of this PhD are based on two objectives related to biomarkers research of EOC. The first one was the development of analytical methods for MALDI Mass Spectrometry for global biomarkers screenings in different types EOC. An extraction procedure for high molecular mass proteins on tissue sections has been designed in order to push back the limits of sensitivity of the method. Then, multivariate analyses allowed us to compare spectral informations contained in histological regions of different natures. All these developments conducted to the histopathological validation of a biomarker of immunosupression associated to ovarian cancer, namely the C-terminal fragment of PA28 (Reg-Alpha). Another issue, the determination of EOC origin, has also been studied. The second goal of this PhD has been the exploration of the relative implication of the different members of proproteine convertases (PCs) in EOC, which are keys enzymes involved in the maturation of many molecular actors of tumoral progression. To do so, SKOV-3 cell lines have been knocked-down for different PCs to study the functional redundancy of these enzymes. It has then been possible to determine, in cellulo and in vivo, that PACE4 is particularly influent on ovarian cancer progression
Ben, Bahria-Sediki Islem. "Recherche de biomarqueurs pronostiques dans le cancer de la vessie dans la population Tunisienne". Thesis, Paris, EPHE, 2016. http://www.theses.fr/2016EPHE3032/document.
Texto completoBladder cancer is the first most common urogenital cancer in men in Tunisia, with a high recurrence rate. Patients with muscle-invasive disease develop metastasis. The need for expensive continuous surveillance. In this thesis we try to search some candidate biomarkers. Their use for cancer staging and personalization of therapy at the time of diagnosis in order to identify a better treatment could improve patient care. The aim of this first part of our study was to investigate the clinical significance of three immune cell-related transcription factors, T-bet, GATA-3 and Bcl-6 in Tunisian patients with bladder cancer. We found that T-bet level was significantly higher in invasive carcinoma with high- grade. However, T-bet is predictive of response to BCG. On the contrary, the expression of GATA-3 and Bcl-6 was significantly higher in non-invasive carcinoma with low grade. We furthermore studied the effect of activation of soluble FasL and TRAIL molecule in bladder cancer. We demonstrate that the mean serum level of sFasL was higher in patients than in normal donors. sFasL was only higher than in sera of healthy donors where patients had superficial stage and low- and medium-grade cancer. sTRAIL was significantly lower in sera from patients with invasive and high-grade bladder carcinoma than in controls. Finally, we demonstrate that p-Akt levels in patients with invasive carcinoma and high-grade bladder cancer were significantly elevated compared to patients with non-invasive and low grade bladder cancer. Altogether, our results suggest that Akt activation can provide useful prognostic information
Beynel, Lysianne. "Dépression et Stimulation Magnétique Transcrânienne : à la Recherche de biomarqueurs (Oculométrie et Excitabilité Corticale)". Thesis, Université Grenoble Alpes (ComUE), 2015. http://www.theses.fr/2015GREAS043/document.
Texto completoThe aim of this doctoral thesis was to develop biomarkers for mood disorders (unipolar major depression and bipolar disorders). Considering mood disorders' etiology (Dorso lateral prefrontal cortex hypometabolism and GABA/glutamate neurotransmission deficits), we decided to study two biomarkers: saccadic performance and cortical excitability. Our results showed that saccadic performance (notably Antisaccades) allows (i) discriminating bipolar patients from healthy subjects, (ii) ascertaining patients' mood improvement, and (iii) evaluating the short-term neuromodulation induced by repetitive transcranial magnetic stimulation.Regarding cortical excitability measurements, our results did not reveal any differences neither between patients and healthy subjects, nor between Responders and non Responders to a treatment (Ketamine injection or rTMS). We suggested that the null results could be explained by the lack of control of State-Dependency. This assumption was tested and validated through the manipulation of the subjects' cognitive and emotional states.A second aim of this doctoral thesis was to study the efficacy of rTMS, a non pharmacological therapeutic alternative, as a treatment for mood disorders. Meta-analyses showed that anti depressant effect of rTMS seems to be significant but still moderate. In our experiment, mood improvement did not differ between active and sham rTMS. Basic methodological reasons such as stimulation parameters could explain this lack of efficacy. Overall, one could wonder about the validity of the theoretical postulate of rTMS, drawn upon motor cortex reactivity. This postulate inferred that both cortical reactivity of motor cortex and DLPFC are similar. Using TMS-EEG coupling, we studied the reactivity of these cortices, to TMS pulses, which revealed that motor cortex and DLPFC reactivities should not be assimilated. This result calls into question the relevance of the rTMS theoretical postulate. Coupling TMS and EEG should allow a better understanding of the impact of rTMS neuromodulatory effect over the targeted area, and thus to a better adaption of the stimulation parameters, which could lead to an improvement of rTMS efficacy as a treatment for mood disorders
Bechade, Guillaume. "Advances in mass spectrometry based proteomics : recherche de biomarqueurs et caractérisation de complexes covalents". Strasbourg, 2009. https://publication-theses.unistra.fr/public/theses_doctorat/2009/BECHADE_Guillaume_2009.pdf.
Texto completoThe hype surronding mass spectrometry based proteomics has hidden crucial points such as the quality and the validation of the results. Great difficulties remain to identify and get a maximal sequence coverage of all proteins contained in a sample. Collected information is currently clearly incomplete and uncertain. Progress is still needed in separation techniques, in mass spectrometry and in bioinformatics for the acquisition and the validation of proteomics data. In this context, this thesis hinges on two thematics : ‣ The development of methodologies to improve proteomic analysis. A study of the repeatability of nanoLC-MS/MS analyses of complex biological samples lead to the development of original solutions to improve the number and the quality of proteins identifications. These innovations have been applied to (1) the discovery of new biomakers for leukemia with ambiguous diagnosis ; (2) the identification of interaction partners for transcription factors implied in liver tumor suppression. ‣ The development of approches to characterize covalent complexes involving cystein-cystein linkage. Measurements of intact proteins by LC-MS with high mass resolution and analysis of bridged peptides by nanoLC-MS/MS were especially optimized to study intracellular redox mechanisms. This thesis highlights a cleverer and a more reliable application of mass spectrometry, and univocally shows the relevance of proteomic approaches for clinical discovery, functionnal analysis and enzymatic mechanisms study
Bourderioux, Matthieu. "Approches protéomiques pour l’analyse des exosomes de liquides biologiques pour la recherche de biomarqueurs". Thesis, Sorbonne Paris Cité, 2015. http://www.theses.fr/2015USPCB102/document.
Texto completoA biomarker is a molecule (or a cluster of molecule) which will reflect the occurrence of a pathological state, giving us the ability to detect a disease, to predict its severity or to assess drug efficiency. Biological fluids are the golden standards for biomarker research in human as they are routinely collected for patients’ follow-up and are less invasive than biopsies. During my PhD, I focused on exosomes that can be found in these biological fluids. Exosomes are nanovesicles with a diameter ranging between 30 and 100 nanometers. Exosomes are secreted by all cell types and harbor cytoplasmic and membranous proteins specific of their cells of origins. One of the major interest of exosomes enriched from biological fluids is that they represent a valuable source of biomarkers. They can be considered as a « liquid biopsy ». Their analysis could complete classical diagnosis and follow-up tools. In this project, we applied high resolution, high throughput proteomic techniques for exosomes analysis. We firstly focused on protein profiles in urinary exosomes in the context of two urinary tract diseases: cystinuria and kidney cancer. Cystinuria is an inherited autosomal recessive disease that is characterized by the formation of cystine stones in the kidneys. To date, there are no markers to predict the evolution toward end stage renal disease. We developed a method to prepare exosomes in order to reproducibly analyze their protein profiles. We applied this method to eight cystinuria patients and compared their profiles to those of ten healthy subjects. A panel of 38 differentially expressed proteins in patients were found and validated by western blots. We also applied this method to patients with clear cell renal cell carcinoma, for which invasive biopsies are necessary for clear diagnosis. We analyzed urinary exosomes form eight patients before and after nephrectomy. We were able to highlight 25 overexpressed proteins in patients’ exosomes. Eventually, the last part of my thesis was dedicated to the analysis of exosomes enriched from bronchoalveolar lavage fluid collected in cystic fibrosis patients, a disease that affects mostly the lungs. Bronchoalveolar lavage fluid exosomes analysis could give a new insight on the mechanisms of this disease. We compared protein profiles in exosomes from four cystic fibrosis patients and six asthmatic patients. The whole point of this work is to show that proteomic analysis of exosomes isolated from biological fluids could become a golden standard for the discovery of diagnosis or prognosis biomarkers
Kessal, Karima. "Explorations physiopathologiques de la maladie de l’œil sec à travers la recherche de biomarqueurs". Electronic Thesis or Diss., Sorbonne université, 2023. http://www.theses.fr/2023SORUS735.
Texto completoDry eye disease (DED) or keratoconjunctivitis sicca (KCS) is a multifactorial pathology of the anterior segment of the eye affecting the ocular surface (OS). This thesis work aimed to decipher and explore the cellular and molecular mechanisms underlying the initiation and progression of the disease, which could lead to the identification of candidate biomarkers. This was undertaken through targeted or untargeted molecular omics approaches, using human samples of patient OS and experimental models of MOS. This research program was structured into 3 main parts. Firstly, omics approaches and pre-analytical considerations of OS from human samples. Then, clinical phenotyping with specific imaging for precise classification of patients. Finally, the identification of candidate biomarkers for dry eye. This multimodal approach ensured the application of a rational methodology for the dissection of molecular networks from rare samples such as conjunctival imprints or Schrimer strips. The identified molecular effectors highlight the role of epithelial cells in OS homeostasis through the cross-talk between oxidative stress and inflammation, mediated by the IFNs and TNF-alpha pathways, among others. In addition, clinical phenotyping through anatomical characteristics through precision or cellular imaging of the OS has made it possible to provide new thinking to reconsider the refined classification of patients into subgroups
Ernoult, Emilie. "Recherche de biomarqueurs de la neurotoxicité des traitements anticancéreux à base d'oxaliplatine: approche protéomique quantitative". Phd thesis, Université d'Angers, 2011. http://tel.archives-ouvertes.fr/tel-00668340.
Texto completoIbrahim, Marianne. "Recherche de biomarqueurs d'exposition et d'effet à des cancérigènes de l'environnement par spectrométrie de masse". Phd thesis, Université de Strasbourg, 2013. http://tel.archives-ouvertes.fr/tel-01018695.
Texto completoLe, Rhun Émilie. "Recherche de biomarqueurs protéiques dans le but de réaliser une classification moléculaire des gliomes : étude GLIOMIC". Thesis, Lille 2, 2017. http://www.theses.fr/2017LIL2S005/document.
Texto completoThe annual incidence of gliomas is estimated at 6.6 per 100,000. Suvival varies profoundly by type of glioma, with 5-year survival rates of 48% for World Health Organization (WHO) grade II diffuse astrocytoma, 28% for WHO grade III anaplastic astrocytomas, 80% for WHO grade II oligodendroglioma, 52% for WHO grade III anaplastic oligodendroglioma and 5% for WHO grade IV glioblastoma, the most frequent primary malignant brain tumor. A better understanding of the molecular pathogenesis and the biology of these tumors is required to design better therapies which can ultimately improve the prognosis of patients. The WHO 2016 classification of central nervous system tumors has for the first time integrated molecular data with the histopathological data, in order to improve the classification of the different subgroups of central nervous system tumors and to allow to derive more specific therapeutic strategies for each of the different subgroups.In the present work, we aimed at evaluating the value of a proteomic approach using matrix-assisted laser desorption/ionization (MALDI) mass spectrometry coupled with microproteomic analysis in gliomas through the GLIOMIC clinical study (NCT02473484), we aimed at obtaining a molecular classification of glioblastomas by integrating clinical data to the ones obtained by such technologies. The feasibility of this approach was first demonstrated in a cohort of anaplastic gliomas. In this first analysis, we showed that although proteomic analysis confirmed the heterogeneity of brain tumors already observed with the histological analysis, the two approaches may lead to different and complementary information. Three different groups of proteins of interest were identified: one involved in neoplasia, one related to glioma with inflammation, and one involved neurogenesis. Then, analyses of glioblastomas confirmed the three proteomic patterns of interest already observed in the anaplastic gliomas, which represents new information as compared to histopathological analysis alone. These results have to be confirmed in a larger cohort of patients.We conclude that MALDI mass spectrometry coupled with microproteomic analysis may provide new diagnostic information and may aid in the identification of new biomarkers. The integration of these proteomic biomarkers into the clinical data, histopathological data and data from molecular biology may improve the knowledge on gliomas, their classification and development of new targeted therapies
Hemadou, Audrey. "A la recherche d’anticorps humains et de nouveaux biomarqueurs pour le ciblage de la plaque d’athérome". Thesis, Bordeaux, 2017. http://www.theses.fr/2017BORD0806/document.
Texto completoThis thesis is based on the selection of human antibodies and identification of newbiomarkers to develop a diagnosis and a therapy of atherosclerosis. The part one treats, first,the selection of human antibodies in a pathophysiological context in an animal model ofatherosclerosis. To access not only to a large panel of targets but also proteins in their nativeconformation and influenced by their microenvironment, an in vivo selection was performed.In a second time, an innovative high throughput flow cytometry screening was implemented.Contrary to the use of ELISA screening which needs to have an identified target, the flowcytometry doesn’t have this limitation and uses a lower quantity of proteins than ELISAassays. By this screening, two thousand clones were selected. Characterization and specificitytests of these antibodies have yielded to the discovery of galectin 3 has a new biomarker. Thisprotein is implicated in macrophage activation, binding of oxLDL by macrophages to formfoam cells. The second part is about a second screening approach of the antibodies issuingfrom the in vivo selection by using Next Generation Sequencing methods (PacificBiosciences). The results of this primary study allowed for highlighingt two points: (1) thefeasibility to obtain long reads >1000bp identified as scFv after analysis by IMGT/HighVQUEST(international database of immunglobulins) and (2) the feasibility to identify hits ofclones preferentially enriched during the in vivo selection. In conclusion and perspectives,these two complementary methods give the opportunity to obtain human antibodies for (1) thecoupling to nanoparticles for diagnosis by MRI of atheroma plaque and (2) serve as ligandsfor in situ delivery of drugs
Pulcrano-Nicolas, Anne-Sophie. "Recherche de biomarqueurs circulants de la survenue du vasospasme chez des patients souffrant d'hémorragie sous-arachnoïdienne". Thesis, Sorbonne université, 2019. http://www.theses.fr/2019SORUS312.
Texto completoSubarachnoid hemorrhage (SAH) morbidity and mortality are not solely due to the aneurism rupture but also to the delayed neurological ischemic disorders (DNI) that could happen. Among these, vasospasm is a severe complication occurring between the 4th and 12th day after the bleeding for one third of the SAH patients. To date, there exists no predictive marker of its happening, which force physician to give any SAH patient a preventive treatment against its occurrence not exempt of severe side effects. VASOGENE cohort was built up to search by omic approaches biomarkers of vasospasm occurrence to identify at risk patients. The thesis' aim is to identify circulating biomarkers of vasospasm occurrence post SAH. Two groups of patients were present in this cohort: aSAH patients developing (VSP+) or not (VSP-) a vasospasm. A first study comparing whole blood microRNA between VSP+ and VSP- enabled us to identify has-miR-3177-3p and LHDA as good candidate biomarkers. A second work was performed on transcriptomic data comparing mRNA levels between VSP+ and VSP-. We identified another candidate gene that is currently submitted
Gilabert, Marine. "Recherche de biomarqueurs pronostiques et prédictifs de la réponse thérapeutique des tumeurs pancréatiques : "le projet pacaomics"". Thesis, Aix-Marseille, 2014. http://www.theses.fr/2014AIXM5012/document.
Texto completoWe developed an efficient strategy in which PDAC samples from 17 consecutive patients were collected by Endoscopic Ultrasound-Guided Fine-Needle Aspiration (EUS-FNA) or surgery and preserved, by an original approach, as breathing tumors by xenografting and as a primary culture of epithelial cells. Transcriptomic analysis was performed from breathing tumors by an Affymetrix approach. We observed a significant heterogeneity in the RNA expression profile of tumors. However, the bioinformatic analysis of this data was able to discriminate between patients with long- and short-term survival corresponding to patients carrying poorly-differentiated PDAC tumors respectively. We identified 942 genes with statically different expression. Among these genes, 439 were under-expressed and 505 genes over-expressed (fold change ≥2) in short survivors. Primary culture of cells allowed us to analyze their relative sensitivity to anticancer drugs in vitro by a "Chemogram", by similarity with the antibiogram for microorganisms, establishing an individual profile of drug sensitivity. As expected, the response was patient-dependent. Interestingly, we also found that the transcriptome analysis predict the sensitivity of cells to the five anticancer drugs the most frequently used to treating patients with PDAC. In conclusion, using this approach, we found that the transcriptomic analysis could predict the sensitivity to anticancer drugs and the clinical outcome of patients with PDAC
Audran, Emilie. "Recherche de biomarqueurs des cellules propagatrices de glioblastome : étude de la signalisation calcique et du protéome membranaire". Phd thesis, Université de Strasbourg, 2012. http://tel.archives-ouvertes.fr/tel-00767650.
Texto completoGueguen, Claire. "Caractérisation des cellules dendritiques de type 2 : Application à la recherche de biomarqueurs de l’immunothérapie spécifique allergénique". Thesis, Paris 11, 2015. http://www.theses.fr/2015PA114806.
Texto completoAllergy or type I hypersensitivity is an inappropriate response of the immune system to a foreign substance in the body, called "allergen". Allergen immunotherapy (AIT) is currently the only treatment on the market that can handle the etiology of allergic disease versus symptomatic treatments that temporarily reduce allergic manifestations. Its action is to reduce the sensitivity of the body against allergens.The aim of this thesis was to define biomarkers of clinical efficacy of AIT. The research strategy is based on the following hypothesis: dendritic cells (DCs) are involved in the success of immunotherapy. In particular, we assume that the treatment induces a decrease in DCs type 2 (DC2), which induce type 2 helper T cells, and an increase of regulatory DCs (DCreg), which induce regulatory T cells.First, we defined optimal culture conditions inducing the polarization of in vitro immature monocyte-derived DCs (MoDCs) toward a DC2 pattern. After screening several biological and pharmaceutical agents, we selected a cocktail of six molecules with some of them are pro-allergenic molecules. The phenotype of those DC2 cells and the CD4+ T cell polarization induced after coculture were characterized extensively in comparison with type 1 DC (DC1) and DCreg.In a second part, we compared the transcriptomes and the proteomes of MoDCs polarized into DC1, DC2 and DCreg by using cDNA microarrays together with label-free mass spectrometry. The differential expression of the most relevant markers was confirmed at the transcriptional and protein level. In the third part, markers were also followed in the peripheral blood from allergic patients enrolled in a randomized, double-blind, placebo-controlled AIT study. The expression of three DC2 markers was down-regulated and of three DCreg markers was up-regulated in patients who responded to the treatment and correlated with clinical efficacy. These markers could be used as follow-up read-outs of AIT efficacy in order of to discriminate responders from nonresponders
El, Ayed Mohamed. "Applications de l’imagerie par spectrométrie de masse MALDI à la recherche de biomarqueurs du cancer de l’ovaire". Thesis, Lille 1, 2010. http://www.theses.fr/2010LIL10064/document.
Texto completoAt the proteomics’ time, mass spectrometry has become a powerful tool for research and identification of biomolecules. Over the past decade, a new application, MALDI imaging was grafted to the existing methods for the detection of biomolecules such as peptides, proteins and lipids in tissues. Applied to biomarkers research in ovarian cancer, this technique allowed us to identify several proteins expressed in cancer using differential analysis system based on statistical tools such as principal component analysis (PCA). Among the biomarkers identified, we found a fragment of the 11S immunoproteasome. The location of this fragment in cancer tissue has been validated by IHC; it is present in epithelial cells with a change of localization between cancer and Benin, from the nucleus to the cytoplasm. A list of specific tissue markers for ovarian cancer has been obtained, most of them corresponding to a protein associated with cell proliferation, involved in modulating immune response, signaling at the cytoskeleton, the tumor progression and conversion of epithelial cells with mesenchymal cells. A cross validation was performed by a specific new approach TAG MASS, by Western Blot and PCR (using SKOV3 ovarian cancer cells). The second point is the study of the presence of the protein Reg alpha in the fluids. Subsequently, with the discovery of a large number of biomarkers identified by MS corresponding to proteins cleaved, a hypothesis of a viral etiology has been proposed for further work. Were able to identify oncovirales proteins of herpes viridae family as HHV6, HHV4 and EBV. Finally, we managed to develop new quantification techniques using mass spectrometry technique based on the ELISA and PCR
Sulpice, Laurent. "Rôle du microenvironnement dans la progression du cholangiocarcinome intrahépatique : mécanismes moléculaires impliqués et recherche de biomarqueurs pronostiques". Thesis, Rennes 1, 2014. http://www.theses.fr/2014REN1B001/document.
Texto completoThe aim of this study was to specifically determine through a translational approach combining basic and clinical research, the role of the microenvironment in the tumor progression of intrahepatic cholangiocarcinoma (ICC). By gene expression profiling, we identified a signature that significantly discriminate the tumor stroma from non-tumor fibrous tissue, and the functional analysis of differentially expressed genes showed an enrichment in genes of the extracellular matrix , the cell cycle, the TGFb pathway and stem cell markers. Tissue microarray analysis using an independent cohort of ICC patients validated at a protein level the increased expression of selected candidate genes. Statistical analysis between basic and clinical data demonstrated that the stromal expression of Osteopontin was an independent prognostic marker for overall and disease-free survival. We also demonstrated that the preoperative serum level of Osteopontin was significantly higher in ICC patients than in healthy subjects. Our results identified the best diagnostic threshold to 57,8 ng/ml, associated with a sensitivity and specificity reaching to 80 and 100%, respectively. Moreover, we showed that level expression of stem cell markers such as EpCAM and CD44 in tumor stroma as well as in the fibrous non tumor liver tissue was correlated with recurrence, suggesting the pivotal role of cancer stem cells in ICC prognosis. In conclusion, our study confirmed the major involvement of the microenvironment in the progression of CCIH, allowed to identify two new prognostic tumor biomarkers, and highlighted new pathways for targeted therapeutics
Bolze, Pierre-Adrien. "Recherche de biomarqueurs prédictifs de l’évolution et de la réponse au traitement dans les maladies trophoblastiques gestationnelles". Thesis, Lyon, 2019. http://www.theses.fr/2019LYSEN016.
Texto completoHydatidiform moles are a pretumoral placental proliferation which can turn into a tumorrequiring chemotherapy. In order to reduce mortality and propose an optimal therapeuticmanagement, the aim of this thesis is to identify genes which are predictive of postmolartumor transformation and chemoresistance.Concerning the prediction of transformation, the expression analysis of candidate-geneson molar tissue shows a relocalization of Syncytin-1 at the syncytiotrophoblast apicalborder in moles followed by malignant transformation, without modification oftranscription of its receptors and two other retroviral placental envelopes. A wholetranscriptomeapproach using 3 different microarrays-based methods did not identify anydifferentially expressed gene according to the post molar evolution. This may reflect thatinter-individual variability and the different criteria used for tumor diagnosis impede theidentification of robust biomarkers.Concerning the prediction of chemoresistance, a broad-spectrum transcriptomicapproach on choriocarcinoma tumor tissue identifies a down regulation of HLA-G in case of monochemoresistance, confirmed at the protein level by immunohistochemistry.Pathway analysis of the differentially expressed genes suggests thatmonochemoresistance is associated with impaired T-cell differentiation, whereaspolychemoresistance is associated with impaired proliferation of blood cells.Ultimately, the evidence of trophoblastic ubiquitous expression of the PD-L1 immunecheckpoint led us to the evaluation of the efficacy of PD-L1 blockade in chemoresistantpatients. The encouraging results of this trial and the possibility of stratifying patientswith HLA-G and Syncytin-1 markers encourages the assessment of PD-L1 blockadecombined with monochemotherapy as a first line treatment for trophoblastic tumors
Zimmer, Aline. "Caractérisation immunologique et protéomique des cellules dendritiques tolérogènes humaines. Application à la recherche de biomarqueurs de l’immunothérapie spécifique allergénique". Thesis, Paris 11, 2011. http://www.theses.fr/2011PA114818/document.
Texto completoThe aim of this thesis is to define biomarkers of allergen-specific immunotherapy (SIT).These biomarkers can be predictive of a clinical response or could be efficacy biomarkersable to discriminate responders versus non responder patients. The research strategy is based on the following hypothesis: if immunotherapy works, effector DCs are decreased where as regulatory DCs are increased locally or in the peripheral blood.First, we screened several biological or pharmacological agents to identify effector orregulatory DCs polarization agents. Four distinct molecules lead to the generation of eitherDC1, DC17 or regulatory DCs. In particular, proteases from Aspergillus Oryzae were clearinducer of tolerogenic DCs. The phenotype of those cells and the CD4+ T cell polarization induced after coculture were characterized extensively.In a second part, two proteomic approaches were used to compare the whole cell proteome of generated DCs. Most pertinent markers of polarization were validated in several cellular models. Markers were also followed in a randomized, double blind, placebo controlled clinical trial testing the efficacy of grass pollen tablets. Two markers were up regulated in patients who responded to the treatment pointing to a potential role of these proteins as early efficacy biomarkers. These markers are of crucial interest in the follow up of patients after SIT and could also be used in other diseases like autoimmune diseases or transplantation
Muller, Leslie. "Développements de méthodes de préparation d’échantillons pour l’analyse protéomique quantitative : application à la recherche de biomarqueurs de pathologies". Thesis, Strasbourg, 2017. http://www.theses.fr/2017STRAF067/document.
Texto completoLabel-free quantitative proteomics strategies are very attractive for diseases biomarkers researches. These approaches require the full control and the repeatability of the analytical workflow. In particular, the sample preparation has to be repeatable enough to ensure the quality and reliability of the results. Objectives of this work were to optimize and develop analytical methods for quantitative proteomics, with a special focus on the sample preparation step. Thus, an innovative, easy and fast protocol allowing the analysis of high sample numbers with high repeatability was developed and further optimized: the “Tube-Gel” protocol. Besides,sample preparations adapted to a variety of biological matrices were developed for the search of biomarkers. The developed methods and their application allowed the identification of potential biomarkers for a variety of diseases: glioblastoma, diffuse large B-cell lymphomas and renal transplants failures
Michalak, Zuzanna. "Altération de la barrière hémato-encéphalique et autoimmunité dans l'épilepsie : rôle des Immunoglobulines G et recherche de biomarqueurs". Thesis, Montpellier 1, 2012. http://www.theses.fr/2012MON13502/document.
Texto completoEpilepsy is a chronic neurologic disorder characterized by recurrent unprovoked seizures. Seizures are generated by an imbalance in the functioning of neurotransmitters and ion channels that control excitability. Epileptogenesis is mostly associated with neuronal loss, gliosis, and inflammation more or less important. A third of patients become drug refractory. Recently, several teams have shown an association between drug-resistant focal epilepsy and disruption of the blood-brain barrier (BBB). In addition, a possible role of the immune system and an autoimmune nature in epilepsy has been suggested. In this thesis, in the tissue of patients with drug-resistant temporal lobe epilepsy (TLE), leakage of immunoglobulin G (IgG) into the parenchyma and IgG accumulation in neurons with attendant signs of neurodegeneration was observed. In addition, the high affinity IgG receptor, FcγRI was expressed on microglia/macrophage shaped cells. The expression of the low affinity IgG receptor, FcγRIII and the inhibitory IgG receptor, FcγRII was decreased. In the same tissue the complement proteins C3c and C5b9 were present on astrocyte/ microglia and macrophage/ microglia shaped cells respectively. Then, we evaluated whether the mouse model of focal epilepsy induced by intra-amygdala microinjection of kainic acid reproduced a pathophysiology of TLE associated with BBB impairment. ZO-1, the main tight junction protein presented discontinuous staining indicating that BBB was affected. Both IgG and albumin extravasations from blood vessels were noted and its parenchymal accumulation was concomitant with seizure occurrence. Another hypothesis of IgG presence in epilepsy incriminates an auto-immune cause. Protein microarray technology was used for identification in pooled plasma samples, of antigens that bind plasma antibody from TLE patients. 19 potential autoantibodies were identified as potential diagnostic biomarkers. Together, these observations suggest that IgG leakage is associated with neuronal impairment, leading to immunological changes in epileptic focus involved in the pathogenesis of TLE. A better interpretation of the profiles of these autoantibodies could offer new therapeutic and diagnostic perspectives
Bou, Samra Elias. "Recherche et caractérisation de biomarqueurs pronostiques dans les leucémies myélomonocytaires chroniques et aiguës myéloïdes par exploration des transcriptomes". Thesis, Montpellier 2, 2012. http://www.theses.fr/2012MON20057/document.
Texto completoA challenge of transcriptomics is to explore the full repertoire of normal and abnormal transcripts. Gene expression profiling analyses based on microarray technology are widely used in cancer research since many years. Meanwhile, new methods based on high-throughput sequencing methods offers henceforth the possibility to undergo accurate and sensitive analyses necessary for studying normal and cancer cells. Despite the method, the characterization of all coding and non-coding transcripts is a real biological challenge in identifying novel diagnostic and prognostic markers, and for the proper care of patients. In the present work, I had the opportunity to address two different aspects of biology, both convergent toward the identification of aberrantly expressed transcripts in myeloid leukemia. The first aspect was to provide a selection of molecular biomarkers for the characterization of chronic myelomonocytic leukemia (CMML). We developed a gene expression-based prognostic score which identified two clinically distinct groups of patients. We then completed our study with a phenotypic characterization by flow cytometry of aberrant subpopulations constituting the myeloid and granulocytic lineages. A part of this work has been extended to acute myeloid leukemia (AML) patients with normal karyotype. The other aspect was to participate in the implementation of an integrated computational approach in order to characterize novel non annotated RNAs, more likely non-coding. We quantified and characterized the proportion of these transcripts in intergenic regions by exploring Digital Gene Expression (DGE) data. We checked their expression in normal and cancer tissues by crossing with RNA-Seq data, and their conservation and expression in other species
Marie, Caroline. "Recherche de nouveaux biomarqueurs d'exposition aux hydrocarbures aromatiques polycycliques à travers l'étude des lésions de l'ADN chez l'homme". Phd thesis, Grenoble 1, 2007. http://www.theses.fr/2007GRE10178.
Texto completoMarie, Caroline. "Recherche de nouveaux biomarqueurs d'exposition aux hydrocarbures aromatiques polycycliques à travers l'étude des lésions de l'ADN chez l'homme". Phd thesis, Université Joseph Fourier (Grenoble), 2007. http://tel.archives-ouvertes.fr/tel-00196858.
Texto completoBednarek, Nathalie. "Mmp-2, -9, timp-1, -2 : recherche de biomarqueurs de lésions cérébrales chez l'enfant prématuré et à terme". Paris 7, 2008. http://www.theses.fr/2008PA077103.
Texto completoThe perinal brain injuries are a major cause of death or handicap. We hypothezise that the MMP-2, -9, and the TIMP- 1 and 2 could be early markers of these cerebral lesions. The cortical profile of MMP-2, -9, TIMP-1 and -2 was studied during embryonic life to adulthood. The plasmatic neonatal profiles were studied according to the gestational age, gender and neonatal pathologies. They were also studied in animal models of perinatal brain injuries. MMP-2, TIMP-1 are largely expressed during embryonic life and TIMP-2 more likely in early post-natal period. MMP-9 is quasi undetectable whatever the moment. Gender does not influence the expression of MMP-2, -9 and their inhibitors in the new-born as well as in the mouse. In ischemic encephalopathy, MMP-9 and TIMP- 1 are specifically raised in new-born plasma but also in mice brain and plasma. In PWMD new-born, no gelatinase or inhibitor elevation was seen, but in mouse cortex and plasma, an exclusive and transitory raise of TIMP-1 is obvious. This preliminary study brings arguments to explore MMP-9 and TIMP-1 as severity and prognosis markers in hypoxic-ischemic encephalopathy
Abtroun, Hamlaoui Belmouloud Lilia. "Une problématique de découverte de signatures de biomarqueurs". Thesis, Montpellier 2, 2011. http://www.theses.fr/2011MON20205.
Texto completoIn the framework of current intricate questions to be solved by the pharmaceutical industry, this manuscript examines the generation of biomarker signatures through an approach that combines association rules extraction and Formal Concept Analysis. It led to the development of a methodology which was validated by six research industrial projects. While there is no single optimal method to handle biomarkers datasets, this logical methodology relies on a global datamining scenario made up of four different methods. Each method utilizes different processes. This architecture qualifies global approach that helps to optimize a response to different biomarker signatures discovery problems. The six applications presented in this manuscript demonstrate the interest of an early consideration of the quality criteria are expressed by the experts in the field. The interactivity is supported throughout the process of discovery and produces unexpected results for the expert. The methodology helps the systematic stratification of individuals, which constitutes the first step towards personalized medicine
Parfait, Sébastien. "Classification de spectres et recherche de biomarqueurs en spectroscopie par résonance magnétique nucléaire du proton dans les tumeurs prostatiques". Phd thesis, Université de Bourgogne, 2010. http://tel.archives-ouvertes.fr/tel-00596568.
Texto completoZimmer, Aline. "Caractérisation immunologique et protéomique des cellules dendritiques tolérogènes humaines. Application à la recherche de biomarqueurs de l'immunothérapie spécifique allergénique". Phd thesis, Université Paris Sud - Paris XI, 2011. http://tel.archives-ouvertes.fr/tel-00736730.
Texto completoGrzych, Guillaume. "Étude du profil métabolomique des patients atteints de stéatose hépatique non alcoolique (NASH) : recherche d’hypothèses physiopathologiques et de biomarqueurs". Thesis, Lille 2, 2020. http://www.theses.fr/2020LIL2S026.
Texto completoNAFLD (Non-Alcoholic Fatty Liver Disease), a major public health issue, is considered thehepatic manifestation of the metabolic syndrome. NAFLD is characterized by liver injury dueto an accumulation of triglycerides in the liver which, when associated with inflammation, canprogress to steatohepatitis (NASH Non-Alcoholic Steato Hepatitis). The molecular mechanismsunderlying the pathogenesis, and particularly the transition from steatosis to NASH, are still poorly understood. A better understanding of the pathophysiology of NASH is necessary to identify potential therapeutic targets and non-invasive markers for the diagnosis and monitoring of the pathology. In this context, metabolomic approaches are promising.Metabolomics is the comprehensive analysis of metabolites in a biological medium, and it complements other "omics" techniques for the study of dynamic biological processes. The objective of this work is to use the metabolomics approach to highlight a particular profile in NASH patients in order to understand the pathophysiology and identify potential biomarkers.For this, we have used two metabolomic approaches: 1/ the targeted approach, on plasma,focusing on two classes of metabolites, amino acids and bile acids, 2/ the non-targeted approach on human plasma and livers (results are pending).In the literature, bile acids (B A) are studied as pathophysiological actors and potential biomarkers in the context of NASH. However, interpretation of many cohort studies is complicated by the close association of NASH with type 2 diabetes (T2D), insulin resistance(IR) and obesity, which are also associated with variations in BA. We therefore sought tounderstand the complex relationship between NASH and BA concentrations, as a function ofT2D status, considering IR and obesity as confounding parameters. Through analysis of BAprofiles in two cohorts (ABOS n=219, RESOLVE n=58) of well-characterized obese patients (histological analysis of liver biopsies, clinical-biological status, well-powered statistically), weshow that plasma BA concentrations are higher in NASH vs. non-NASH patients in both T2Dand non-T2D patients. These increases are dependent on the degree of IR, suggesting that NASH causes AB alterations only in the presence of advanced IR and independently of diabetes status.In the literature, plasma levels of branched-chain AA (BCAA) are associated with obesity, IR,and severity of liver damage in NAFLD. In addition, plasma BCAA concentrations differ between genders, which display different susceptibilities to development of cardiometabolicdisease. We evaluated the association between plasma BCAA concentrations and the severity stages of NAFLD, independent of gender, IR and obesity. In the RESOLVE cohort, 112 obese patients were divided into four groups based on NAFLD severity and matched for gender, BMI,IR, and HbA1c. As expected, a modest positive correlation was observed between BCAAconcentrations and NAFLD severity, as well as a major impact of gender on BCAAconcentrations. Subgroup analysis revealed that while plasma BCAA concentrations increased with the severity of NAFLD in females, they tended to decrease in males, suggesting an impact of gender on the metabolic component of NAFLD. Analysis of other AA in the cohort reveals plasma AA alterations involved in the methionine cycle (serine, cysteine, ...), whose molecular mechanisms are being explored in mouse models. The use of metabolomics has allowed us to better characterize the complex interactions of NASH with IR and sex on BA and AA
Clément, Thomas. "Recherche de liens entre expression d'ARN non codants et physiopathologies articulaires, utilisation des microARN comme biomarqueurs du phénotype chondrocytaire". Thesis, Université de Lorraine, 2014. http://www.theses.fr/2014LORR0113/document.
Texto completoOsteoarthritis (OA) is the most frequent joint disease and its prevalence still grows with the increase in lifespan. OA is characterized by articular cartilage degeneration, together with synovitis and abnormal subchondral bone remodeling, leading to progressive loss of mobility and pain. Chondrocyte is the unique cell type in cartilage which accounts for the synthesis of extracellular matrix (ECM) components (collagens, proteoglycans). During OA, chondrocyte phenotype is altered and the balance between ECM synthesis and degradation is impaired towards cartilage degradation. To date no treatment can efficiently reduce OA progression so that the search for reliable biomarkers and potential therapeutic targets is very active, particularly since the discovery of microRNAs. miRNAs are estimated to regulate 50% of cellular genes. They contribute to major cellular processes such as cell differentiation, apoptosis or tumorigenesis. Therefore, miRNAs are interesting putative biomarkers. During this PhD thesis, we studied the contribution of miARNs to the control of chondrocyte phenotype. Using a model of chondrocyte differentiated phenotype loss induced by extensive subculturing or IL-1β challenge we studied changes in miRNAs profile with microarrays. We determined a panel of 43 varying miRNA including the miR-23~27b~24-1 cluster and miR-29b. The differential production of miRNAs from this cluster has been investigated, but we didn’t succeed in identifying the underlying mechanisms. However, we identified miR-29b as a negative post-transcriptional regulator of Col-IIa1 during differentiated phenotype loss and OA. Finally, as equilibrium between extracellular levels of inorganic phosphate and pyrophosphate (ePi/ePPi) was previously shown in the laboratory to be crucial for the maintenance of a differentiated chondrocyte phenotype, we studied the regulation of the genes encoding the 4 proteins regulating this balance (ANK, PC1, Pit-1 and TNAP). From in silico analysis, we selected a panel of 4 miRNAs: let7e, miR-9, miR-188 and miR-219. Using reporter assays, we showed that miR-9 was a negative regulator of PC-1, Pit-1 and TNAP, according or not to bioinformatics prediction