Дисертації з теми "Pronostic biomarker"
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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.
Повний текст джерелаThe 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
Ozenne, Brice. "Modélisation statistique pour la prédiction du pronostic de patients atteints d’un Accident Vasculaire Cérébral." Thesis, Lyon 1, 2015. http://www.theses.fr/2015LYO10169/document.
Повний текст джерелаStroke is a serious disease that needs emergency health care. Due to potential side effects, the patients must fulfil very restrictive criteria for eligibility to the curative treatment. These criteria limit drastically the accessibility to treatment : currently, an estimated 10% of stroke patients are treated. The purpose of this work was to develop a statistical framework for stroke predictive models. We deal with assessing predictive models in a low-prevalence context, building predictive models for spatial data, making volumic predictions depending on the treatement option, and performing image segmentation in presence of image artefacts. Tools developed in this thesis have been collected in an R package named MRIaggr
Vereecken, Pierre. "Contribution to the study of diagnosis and prognosis of cutaneous melanoma: is Galectin-3 a relevant biomarker ?" Doctoral thesis, Universite Libre de Bruxelles, 2008. http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/210417.
Повний текст джерелаLe mélanome, véritable problème de santé publique qui est susceptible d’atteindre 1 individu sur 75 dans nos contrées, reste un tumeur mal comprise avec des évolutions parfois incertaines, et des traitements dont l’efficacité est limitée. Le diagnostic histologique du mélanome lui-même peut parfois représenter une difficulté pour le clinicien et l’expert pathologiste ou dermatopathologiste. La couleur (hyperpigmentation d’un lésion pigmentée), dont l’évaluation d’ailleurs reste subjective à défaut de standardisation, ne peut à elle seule signer la malignité d’une lésion pigmentée. Globalement l’évolution d’un patient est prédite par l’indice de Breslow qui traduit en mm l’épaisseur de la tumeur. Si cet indice dépasse 1mm, le risque métastatique augmente, justifiant la réalisation de bilans extensifs de suivi. Ceci dit, certains mélanomes épais peuvent ne pas présenter de caractéristiques d’aggressivité, alors que des mélanomes fins sont parfois mortels. L’identification de marqueurs moléculaires est donc impérative, tant pour développer des stratégies thérapeutiques ciblées, que pour affiner le diagnostic et le pronostic d’un patient.
Après avoir mis en évidence par immunohistochimie une expression de Gal-3 par les mélanocytes, nous avons démontré une surexpression de cette protéine par les mélanocytes tumoraux. Nous avons démontré également sur des lésions primitives qu’à l’aggressivité mesurée selon l’indice de Breslow correspondait une diminution de cette surexpression. Cette observation a pu être confirmée par un modèle de greffe orthotopique chez la souris nude.
Nous nous somme intéressés par la suite à la détection de la protéine dans le sérum, et nous avons constaté, un taux élevé de Gal-3 dans le sérum de patients en stade métastatique avancé, ce taux élevé pouvant s’expliquer tant par la charge tumorale que par la présence d’une inflammation, d’ailleurs bien connue chez le patient cancéreux en stade avancé. Le rôle antiapoptotique de la Gal-3 nous a alors amené à préciser la valeur prédictive et pronostique de cette protéine. L’hypothèse d’une potentielle action bénéfique sur la réponse immunitaire des patients atteints de mélanome qui ont été vaccinés a été rejetée. La Gal-3 sérique s’est révélée comme facteur de mauvais pronostic chez les patients métastatiques, et une analyse multivariée avec la définition d’une valeur « cut-off » de 10 ng/ml a permis de montrer une valeur pronostique indépendante, supérieure à la S100B et à la CRP.
Doctorat en Sciences médicales
info:eu-repo/semantics/nonPublished
Raposo, Nicolas. "Apport des nouveaux biomarqueurs sur la physiopathologie, le diagnostic et le pronostic de l'angiopathie amyloïde cérébrale." Thesis, Toulouse 3, 2019. http://www.theses.fr/2019TOU30340.
Повний текст джерелаSporadic cerebral amyloid angiopathy (CAA) is a common cerebral small vessel disease with growing interest among clinicians and researchers. CAA occurs frequently in elderly subjects and is a major and increasing cause of intracerebral hemorrhage and dementia. Over the last several years, important advances have been made in this research field, with the development of new biomarkers for the disease, thanks to advances in structural, functional and molecular neuroimaging. Anti-amyloid therapies are currently in development and clinical trial assessing anticoagulant strategy in these patients are ongoing, raising the perspective of future treatments. Hence, evaluating these new biomarkers of CAA seems particularly important. The main objective of this PhD thesis was to get insights into novel neuroimaging biomarkers and their potential clinical applications in patients with CAA. We conducted 6 clinical research studies exploring new hemorrhagic (cortical superficial siderosis, convexity subarachnoid hemorrhage) and non-hemorrhagic (enlarged perivascular spaces, amyloid PET, brain network connectivity) markers of the disease. Biomarkers are evaluated as diagnostic tools and their clinical relevance, as prognostic markers are investigated
M'Rabet, Manel. "Identification d'un nouveau biomarqueur, facteur pronostic et cible dans le cancer du sein triple négatif & développement préclinique d'une thérapie ciblée sur l'utilisation d'anticorps monoclonaux conjugués." Thesis, Aix-Marseille, 2017. http://www.theses.fr/2017AIXM0204.
Повний текст джерелаNectin-4 has been identified as a breast and ovarian biomarker at CRCM. Nectin-4 is a celladhesion molecule belonging to the immunoglobulin superfamily and is involved in ectodermaldevelopment in human. Nectin-4 has been recently identified as the epithelial receptor for themeasles virus. Together, this work has been rewarded by Inserm in 2012 (Prix del’Innovation). During my thesis, I have characterized nectin-4 as new prognosis biomarker andtherapeutic target in 63% of triple-negatif breast cancer (TNBC) . TNBCs represent 20% ofbreast cancer and are associated with poor prognosis as there is no exisiting targeted therapy.These results open the possibility for Antibody Drug Conjugate (ADC)-based targetedtreatment of primary and advanced TNBCs similar to trastuzumab-emtansine for HER2-positive breast cancers. We selected and validated a monoclonal antibody against nectin-4ectodomain and developed an ADC conjugated to monomethyl auristatin-E (MMAE). Weassessed the therapeutic efficiency of this ADC in vitro and in vivo in localised and metastaticTNBC Patient derived Xenografts (PDXs). In vivo, this ADC induced rapid, complete anddurable responses on nectin-4-positive xenograft TNBC samples including primary tumours,metastatic lesions, and local relapses. This antibody has been humanized, patented and iscurrently under clinical development by a pharmaceutical company testing toxicity and efficacyin cynomolgus monkeys
Jiao, Yunlong. "Pronostic moléculaire basé sur l'ordre des gènes et découverte de biomarqueurs guidé par des réseaux pour le cancer du sein." Thesis, Paris Sciences et Lettres (ComUE), 2017. http://www.theses.fr/2017PSLEM027/document.
Повний текст джерелаBreast cancer is the second most common cancer worldwide and the leading cause of women's death from cancer. Improving cancer prognosis has been one of the problems of primary interest towards better clinical management and treatment decision making for cancer patients. With the rapid advancement of genomic profiling technologies in the past decades, easy availability of a substantial amount of genomic data for medical research has been motivating the currently popular trend of using computational tools, especially machine learning in the era of data science, to discover molecular biomarkers regarding prognosis improvement. This thesis is conceived following two lines of approaches intended to address two major challenges arising in genomic data analysis for breast cancer prognosis from a methodological standpoint of machine learning: rank-based approaches for improved molecular prognosis and network-guided approaches for enhanced biomarker discovery. Furthermore, the methodologies developed and investigated in this thesis, pertaining respectively to learning with rank data and learning on graphs, have a significant contribution to several branches of machine learning, concerning applications across but not limited to cancer biology and social choice theory
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.
Повний текст джерелаIt 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
Nguyen, Thanh Nhan. "Deeper insights into the deleterious roles of ZNF217 in tumorigenesis and the identification of a novel and functional interplay between ZNF217 and ERalpha in breast cancer." Thesis, Lyon 1, 2013. http://www.theses.fr/2013LYO10331.
Повний текст джерелаZNF217 is a candidate oncogene encoding for a Krüppel-like transcription factor. This study aims at exploring deeper insights on deleterious roles of ZNF217 and the prognostic significance of ZNF217 expression in breast cancers. We found that: (i) high levels of ZNF217 expression (at both mRNA and protein levels) are associated with poor prognosis in breast cancer patients, more particularly in ER+/Luminal/Luminal A breast cancers; (ii) ZNF217 induces epithelial-mesenchymal transition (EMT) in human mammary epithelial cells via the TGF-beta-activated Smad signaling pathway; (iii) in vitro ZNF217 stimulates several aggressive phenotypes in breast cancer cells, including anchorage-independent growth, cell migration and invasion; (iv) ZNF217 stimulates tumor growth and promotes the development of metastases in vivo; (v) ZNF217 binds with ERalpha and enhances 17beta- estradiol (E2)-induced ERalpha transactivation by increasing the recruitment of ERalpha to estrogen-responsive elements (EREs); (vi) ZNF217 increases mammosphere formation in ER– or ER+ breast cancer cell lines; (vii) ZNF217 confers resistance to endocrine therapy (tamoxifen) in ER+ breast cancer cells, and (viii) high levels of ZNF217 expression are associated with shorter relapse-free survival (RFS) in breast cancer patients treated with endocrine therapy only. Our findings suggest that ZNF217 expression represents a novel and powerful prognostic biomarker in ER+/Luminal/Luminal A breast cancers, allowing the re-stratification of these “good prognosis” breast cancers, which are currently not further classified by any other biomarkers available. In conclusion, ZNF217 could be a potential therapeutic target for a personalized treatment strategy in patients overexpressing ZNF217, in particular in ER+/ZNF217+ patients
Le, Bescont Aurore. "Etude des expressions hors-contexte de gènes tissus-spécifiques dans le cancer du poumon." Thesis, Grenoble, 2013. http://www.theses.fr/2013GRENV068/document.
Повний текст джерелаEach human cell contains a genome carrying all the genetic information necessary for the constitution of the whole organism. However, differentiated cells express only a restricted repertoire of genes. The control of gene expressions is fundamental for the establishment and maintenance of cell identity. The first level of gene expression regulation, the transcriptional control, is based on the integrity of the gene sequence but also on its accessibility, itself dependent on a set of epigenetic mechanisms that control chromatin dynamics. In a pathological context, genetic and epigenetic alterations can lead to gene deregulations and altered cellular functions. During the bronchial carcinogenesis, lung cancer cells acquire a capacity of uncontrolled proliferation and an increased resistance to cell death. These phenotypic characteristics, favoring tumor growth, result from abnormalities that accumulate in the genome of cancer cells. These are somatic genetic alterations, from point mutations to large-scale chromosomal rearrangements, but also a global disruption of the epigenetic landscape – both leading to an identity crisis and to gene deregulations. While the phenomenon of aberrant gene repression (including repression of tumor suppressor genes) has been extensively studied, ectopic activation of normally silent genes remains poorly understood. Our hypothesis is that the “out of context” expression of tissue-specific genes not only could be involved in carcinogenesis, but could also be of high interest as tumor biomarkers or novel therapeutic targets. In this work, we focused on the prolactin-encoding PRL gene, normally mainly expressed in the pituitary gland and absent from non-tumor lung. We detected an ectopic PRL gene activation in 10% of lung tumors, mainly neuroendocrine tumors. We observed that PRL expression is associated with aggressive tumors and a poor prognosis for patients. We also found that the expression of PRL is associated with an increased resistance of lung cancer cells to a genotoxic stress. Unexpectedly, our data suggest that the oncogenic action of PRL expression is not based on the conventional mechanisms of prolactin action, and we did not confirm the initial hypothesis of a secretion by lung cancer cells of the prolactin hormone, and its action in an autocrine/paracrine loop within the tumor through the activation of the prolactin receptor. Indeed, the receptor is absent in lung cancer cells and the transcribed PRL mRNA is missing its first exons, possibly leading to the production of a truncated prolactin protein, without a functional signal peptide, therefore unable to follow the classical secretion pathway and retained inside the cancer cell. Although the detailed mechanisms of prolactin action in lung cancer remain to be deciphered, our study suggests that the ectopic expression of PRL could be used as a new therapeutic target in the treatment of aggressive lung tumors. This work, also including additional results on three testis-specific genes aberrantly expressed in lung tumors (BRDT, SOX30 and SPATA22) highlights the interest of studying ectopic gene expressions in tumor cells, which can provide new diagnosis and prognosis tools for clinicians as well as new targeted approaches that could be used in addition to conventional lung cancer therapies, which are presently insufficient to limit the high mortality due to lung neoplasms
Dubois, Christelle. "Confirmation de biomarqueurs pour le pronostic du sepsis et développement de tests rapides High plasma level of S100A8/S100A9 and S100A12 at admission indicates a higher risk of death in septic shock patients Top-down and bottom-up proteomics of circulating S100A8/S100A9 complexes in plasma of septic shock patients." Thesis, Université Paris-Saclay (ComUE), 2019. http://www.theses.fr/2019SACLS521.
Повний текст джерелаSepsis is the 3rd leading cause of death in Western countries, with a mortality rate between 20 and 50% depending on the severity. The 'prediction' of the patient's clinical outcome is essential to establish the most appropriate treatment. Some inflammation or infection markers protein (CRP, procalcitonin) are cited for clinical follow-up of patients but lack specificity for sepsis. On the other hand, "omics" studies have generated lists of potential biomarkers of sepsis prognosis. However, none have yet been validated and/or confirmed based on the severity of the sepsis and the patient's fate. This requires access not only to fully characterized patient cohorts but also to robust and validated quantitative methods. Mass spectrometry provides a high level of specificity and high multiplex capacity and that would allow to confirm the interest of one or more of these proteins for sepsis prognosis. Immunological assays provide, in addition to sensitivity and specificity, a simple and rapid routine clinical implementation. First, a list of biomarkers identified with patient cohorts was established from the literature. Then, methods to quantify these candidate biomarkers were developed. On the one hand, we have been interested in quantifying calgranulins in plasma by developing ELISAs and mass spectrometry methods using bottom-up and top-down approaches. On the other hand, two multiplex quantification methods by mass spectrometry with and without immunopurification step according to protein concentrations have been developed to verify the relevance of the list of potential biomarkers. All these methods were applied to a cohort of 49 patients with septic shock
Rozenblum, Laura. "Nouveaux biomarqueurs d'imagerie pour la prise en charge des lymphomes primitifs du système nerveux central : études en TEP-IRM au 18F-FDG et à la 18F-FLUDARABINE." Electronic Thesis or Diss., Sorbonne université, 2024. https://accesdistant.sorbonne-universite.fr/login?url=https://theses-intra.sorbonne-universite.fr/2024SORUS150.pdf.
Повний текст джерелаPrimary central nervous system lymphoma (PCNSL) is a malignancy with a dismal prognosis, increasingly prevalent, especially among elderly and immunocompetent patients. The therapeutic approach for PCNSL relies on evaluating established prognostic indicators: patient age and performance status. However, there is a growing need to enhance current therapeutic strategies, which are centered on high-dose methotrexate-based induction polychemotherapy, potentially followed by maintenance treatment. This has encouraged interest in identifying new biomarkers. This thesis positions itself within this research and innovation framework in PCNSL, supported by the LOC network (Lymphome Oculo-Cerebraux) in France, aiming to improve prognostic stratification and therapeutic monitoring for these patients. Currently, cerebral magnetic resonance imaging (MRI) is the gold standard for PCNSL follow-up. However, recent studies have highlighted its limitations, notably the high percentage of patients relapsing rapidly despite a complete response on end-of-treatment evaluation. Our research investigates the potential of positron emission tomography (PET) with 18F-fluorodeoxyglucose (FDG) combined with MRI as an innovative tool in the management of PCNSL patients. The study is structured around three main axes: firstly, exploring PET-MRI FDG as a prognostic biomarker for end-of-induction treatment response; secondly, its utility as a tool for early evaluation of the chemotherapy response; and finally, exploiting artificial intelligence methods to refine the pathophysiological understanding through advanced radiomic analyses, and to develop a predictive deep-learning model scalable for broad application. This work relied on the the longitudinal prospective data from the Localyse cohort, an ancillary study of the phase III multicentric BLOCAGE-01 trial, investigating the utility of maintenance chemotherapy in aged, immunocompetent patients. The results of this doctoral research identified two novel prognostic biomarkers in FDG-PET for PCNSL and demonstrated the potential superiority of interim PET over interim MRI in assessing the therapeutic response post two chemotherapy cycles. Incorporating the latest advances in radiomic analysis and deep learning, this thesis contributes to the development of robust and innovative tools in AI applied to neuro-oncology. Lastly, it examines the potential of 18F-Fludarabine, a radiotracer specifically targeting B lymphocytes, which could offer new perspectives in the future management of PCNSL patients. In conclusion, our work facilitates the development of new tools for managing PCNSL patients, paving the way for treatment strategies guided by PET findings
Samimi, Mahtab. "Marqueurs pronostiques dans une cohorte historico-prospective de carcinomes de Merkel." Thesis, Tours, 2016. http://www.theses.fr/2016TOUR3801.
Повний текст джерелаMerkel Cell Carcinoma is a rare and aggressive neuroendocrine skin cancer. The Merkel cell polymavirus has been identified as the main etiological agent of such cancer. We aimed to identify viral and cellular markers relevant as prognostic and theranostic tools in patients with Merkel Cell Carcinoma. Using serological immunoassays, we observed that patients with high levels of serum antibodies against the MCPyV major capsid protein at baseline had better outcomes, whereas antibodies directed against the MCPyV oncoproteins reflected the tumor burden and course of disease. We also demonstrated that Merkel Cell Carcinoma tumors displayed a heterogeneous expression of receptors to somatostatin, which could constitute a theranostic tool for the use of targeted therapies using somatostatin analogs. Finally, current studies focus on the assessment of cellular immunity in Merkel Cell Carcinoma patients. Our results indicate that the blood neutrophil-to-lymphocyte ratio is an independent marker of mortality in Merkel Cell Carcinoma patients
Fragnoud, Romain. "Recherche de marqueurs pronostiques des formes sévères de dengue." Thesis, Lyon, École normale supérieure, 2013. http://www.theses.fr/2013ENSL0807.
Повний текст джерелаDengue 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
Masson, Lecomte Alexandra. "Polymorphismes des gènes associés à l’inflammation et microenvironnement tumoral lymphocytaire CD8+ : valeur pronostique dans les carcinomes urothéliaux de la vessie." Thesis, Paris Est, 2017. http://www.theses.fr/2017PESC0073/document.
Повний текст джерелаThe aim of this study was to explore prognostic value for bladder cancer of germline polymorphisms in inflammatory genes and tumor CD8+ lymphocytic microenvironment. For constitutional markers, two approaches were conducted jointly: one genome-based using specific GWAS statistical methods, the other gene-based focusing on PDL1, an inflammatory gene implicated in immune checkpoints. At the genome level, using both standard and innovative statistical methods (multi marker methods Bayesian Lasso and Bayes A) we demonstrated that variants (SNPs) in TNIP1, CD5 and JAK3 were associated with the risk of recurrence of non-muscle invasive bladder cancer (NMIBC) while SNPs in MASP1, AIRE and CD3 were associated with risk of progression. Meanwhile, association between PDL1 and prognosis of NMIBC and muscle invasive BC (MIBC) was explored using classical SNPS by SNP investigations and a gene based approach. We identified a very strong association between PDL1 variants and MIBC prognosis in a large prospective cohort but failed replicating those results in the TCGA consortium series.In non-muscle invasive bladder cancer, we developed and evaluated a standardized counting approach of CD8+ cells, T-cytotoxic lymphocytes implicated in tumor cells death. Morphometric analysis after double immuno-staining of tumor cells and digitalization allowed separate estimation of CD8+ cells in the tumor and stroma compartment and estimation of spatial intra tumoral heterogeneity. We demonstrated that this heterogeneity compromised CD8+ estimation on Tissue Micro Arrays, which sample the tumors in a restrictive manner. Keeping those limitations in mind, we identified an association between CD8+ inflammatory infiltrate and both NMIBC stage and T1 tumours risk of recurrence. In the future, germline variation in inflammatory genes and evaluation of tumor inflammatory infiltrate could be integrated for better prediction of bladder cancer prognosis
Spehner, Laurie. "Caractérisation des réponses immunitaires périphériques des cancers épithéliaux exprimant les papillomavirus humains." Thesis, Bourgogne Franche-Comté, 2019. http://www.theses.fr/2019UBFCE011.
Повний текст джерелаThe increased incidence and the lack of therapeutic resources for non-operable forms of HPV+ cancer patients constitutes a major challenge. High immunosurveillance in HPV-associated tumors and the presence of viral antigens associated with oncogenesis of these cancers should focus on the development of immunotherapy strategies such as anti-tumor vaccination and adoptive transfer of TILs. These technological advances encourage a better understanding of immune responses in these pathologies and aim to develop strategies combining immunotherapies for the treatment of all HPV-related cancers. We first looked for tumor antigens associated with the prognosis of patients with anal canal cancer. The patients were treated with a combination of chemotherapy whose therapeutic benefit was demonstrated by our team. Monitoring specific T-immune responses in the peripheral blood of these patients has shown that telomerase is a tumor antigen associated with SCCA; and moreover that the presence of Telomerase-specific LT Th1 is a predictor of progression-free survival at 12 months. Our data also highlighted the influence of M-MDSC on the T-specific immune responses of our antigens as well as on the survival of patients with SCCA. As a result, M-MDSCs are a prognostic factor in the response to treatment of patients with metastatic SCCA treated with chemotherapy. The second work of this thesis validated the feasibility of isolating TILs from biopsy samples from patients with HPV-associated cancer. The specific T immune responses of HPV16 oncoproteins are correlated in 50 and 60% of cases between peripheral blood and tumor. The final objective of this thesis work demonstrated the immunogenicity of the SALL4 protein, a transcription factor associated with pluripotency and self-renewal of embryonic stem cells. We have generated anti-SALL4 CD4 Th1 response analysis technology to monitor immune responses in patients with digestive adenocarcinoma. Our work has also shown a low frequency of SALL4-specific T responses in the peripheral blood of patients with SCCA. These results suggest that the presence of specific SALL4 responses in the peripheral blood of SCCA patients could be subject to immunomonitoring resulting in a decrease in the frequency of CD4 LT SALL4+. It would be interesting to analyze the presence of specific LT of this antigen in the early forms of HPV-related cancers
Gourvest, Morgane. "Etude des longs ARNs non codants dans les leucémies aiguës myéloïdes : relevance clinique et caractérisation fonctionnelle." Thesis, Toulouse 3, 2020. http://www.theses.fr/2020TOU30117.
Повний текст джерелаLong noncoding RNAs (lncRNAs) are defined as transcripts longer than 200 nucleotides without protein-coding potential. Long considered as useless, their recent study has demonstrated that lncRNAs have important roles in gene expression regulation. Cumulative evidence points toward the implication for lncRNAs deregulation in tumorigenesis. In this study, we sought to evaluate specific lncRNAs expression profiles among cytogenetically normal AML patients (CN-AML), their involvement in this pathology being barely referenced. The RNA sequencing that we performed on forty CN-AML patients allowed us to highlight a minimal set of 12 differentially expressed lncRNAs in AML patients bearing the mutation in the Nucleophosmin gene (NPM1). These results were confirmed by RT-qPCR (Fluidigm) on a validation set of 134 CN-AML patients. Among these, we identified one putative biomarker, the lncRNA XLOC_109948, whose low expression indicates a good prognosis, especially for NPM1-mutated patients. Consistently, the downregulation of XLOC_109948 using GapmeRs in a NPM1-mutated AML cell line enhances apoptosis of these cells treated with aracytine, suggesting the role of XLOC_109948 in drug sensitivity. We also functionally characterized another lncRNA of the NPM1 signature, that we named LONA (lncRNA overexpressed in NPM1-mutated AML patients). On one hand, we observed that the mutation of NPM1 leads to a nuclear delocalization of LONA lncRNA, which consequently modulates its cellular functions. Loss and gain of functions strategies allowed us to show that LONA seems to have oncogenic effects in a NPM1 mutated AML context, where it is implicated in vitro in myeloid differentiation and in vivo cellular growth processes by regulating the expression of master genes such as THSB1, ASB2, and MAFB. At the contrary, the deregulation of LONA lncRNA in a NPM1 wild type AML context leads to opposite and tumor suppressor effects, suggesting a different regulation depending on the mutational status of NPM1. On the other hand, the LONA’s genomic locus is located on chromosome 6, within a cluster of histone coding genes. In NPM1 mutated AML patients, we observed that the expression of LONA inversely correlates with the expression of some neighboring histones genes. Consistently, the downregulation of LONA lncRNA by using GapmeRs in a NPM1 mutated AML cell line leads to the upregulation of some proximal histones genes of the cluster. By RNA immunoprecipitation, we showed that LONA interacts with the Polycomb Repressive Complex 2 (PRC2), suggesting its contribution to epigenetic regulation of histone genes transcription and chromatin remodeling. More preliminary, we also think that LONA could regulate the maturation step of histone messengers by sequestrating, as a molecular sponge, the snRNA U7, a small regulatory RNA implicated in the maturation of histone messengers 3’ ends. Altogether, these data suggest that lncRNAs could be considered as strong prognostic biomarkers and emerged as key players in the pathogenesis of Acute Myeloid Leukemia
Toffart, Anne-Claire. "Déterminants de la prise en charge et du pronostic des cancers broncho-pulmonaires hospitalisés." Thesis, Grenoble, 2014. http://www.theses.fr/2014GRENS030/document.
Повний текст джерелаIn patients with advanced lung cancer non-eligible for curative treatment, the goal of care is not healing but improving symptoms and survival. The prognosis is related to patient and tumor characteristics, response to chemotherapy and its overall management decided jointly with the medical team, the patient and his family. It is therefore necessary to assess early these prognostic factors to optimize the risk-benefit ratio of treatment undertaken.As part of this work, ethical, clinical and laboratory determinants of management and prognosis of locally advanced or metastatic lung cancer patients were investigated. In the first part, the prognosis' determinants of patients treated with chemotherapy (« Pharmacogenoscan-poumon » study) were studied: association between the level of expression of protein biomarkers and tumor response to chemotherapy and assessment of interest of tumor response according to RECIST criteria. We have, in the second part, analyzed the factors influencing the management and prognosis of lung cancer patients developing organ failure. Three situations were described: patients at the time of the development of this organ failure, lung cancer patients admitted to intensive care units, the overall population and only those carrying an oncogenic mutation
Lemesle, Gilles. "Recherche de biomarqueurs pronostiques dans l'insuffisance cardiaque." Thesis, Lille 2, 2015. http://www.theses.fr/2015LIL2S028/document.
Повний текст джерелаRisk 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
Seronde, Marie-France. "Facteurs diagnostiques et pronostiques dans l'insuffisance cardiaque aiguë." Thesis, Besançon, 2013. http://www.theses.fr/2013BESA3009/document.
Повний текст джерелаHeart failure (HF) is highly prevalent disease, and prevalence increases with age. HF is generally discovered on presentation of an acute episode of decompensation (or insufficiency). Acute decompensated heart failure (ADHF) is very frequent in elderly subjects and is difficult to diagnose when the patient is admitted with acute dyspnoea. The advent of plasma biomarkers, such as BNP or NT-proBNP represents a major advancement in the diagnostic of ADHF. ADHF leads to high rates of re-admission and mortality. The objectives of this doctoral thesis were: (1) to describe the epidemiology of ADHF in France in a one-day observational study of admissions for ADHF in 170 French hospitals; (2) to evaluate the prognostic and diagnostic value of natriuretic peptides (NPs) in ADHF; (3) to describe the extent of post-transcriptional modifications in these NPs in ADHF; and (4) to search for new biomarkers.The comparison of the prognostic and diagnostic properties of NPs showed that the 4 commercially available NPs (namely BNP, NT-proBNP, proBNP and MR-proANP) overall have very similar prognostic and diagnostic abilities. However, proBNP and BNP seem to be more useful for diagnosis, while MR-proANP appears to be better for the association with 5-year mortality.Amongthe post-transcriptional modifications of BNP, we studied the impact of glycosylation of pro¬BNP. Threonin 71 0-glycosylation prevents cleavage of proBNP into BNP and NT-proBNP, resulting in the release of proBNP from the cell without being cleaved. Conversely, non-glycosylated proBNP is cleaved into BNP and NT-proBNP by corin or furin. We showed that non-glycosylation of proBNP and activation of furin are two important mechanisms in the acceleration of production of NPs during ADHF. We also showed that production of NT-proBNP was more closely linked to the rate of glycosylation of proBNP than to the production of BNP. Thus, our results strongly suggest that NT-proBNP should be used in future studies exploring the concept of "biomarker-guided therapy" in ADHF.To investigate new biomarkers, we explored plasma concentrations of 5 microRNAs (miR-l/-21/-23/-126/-423-5p), in patients with acute dyspnoea. None of these microRNAs were shown to have any diagnostic value. Conversely, miR-423-5p appears to be a prognostic marker for re-admission at 1 year. Secondly, we investigated the consequences of cardiac congestion on the liver. The hepatic markers studied were alkaline phosphatise and transaminases. Markers of cholestasis were associated with hepatic congestive while markers of cellular necrosis (transaminases) were related to arterial hypertension and low cardiac output. An increase in transaminases was associated with various criteria of excess mortality in the short term
Akodad, Mariama. "Marqueurs pronostiques biologiques et morphologiques du TAVI à l’ère de l’évolution des pratiques." Thesis, Montpellier, 2019. http://www.theses.fr/2019MONTT061.
Повний текст джерелаManagement of aortic stenosis was revolutionized by the advent of transcatheter aortic valve replacement (TAVI). This technique, initially targeting patients at high surgical risk, was extended to lower risk patients regarding to improved outcomes and was accompanied, over the years, by a simplification at each step of the procedure. However, the careful selection of patients upstream of the procedure remains the key to success. Clinical and echographic factors are not sufficient to allow an accurate assessment of their risk profile. Thus, biomarkers and aortic valve calcifications evaluation may improve risk profile stratification. The objective of this thesis was to evaluate the prognostic value of troponin and aortic valve calcium score in patients undergoing TAVI in the era of TAVI simplificationThe first chapter of this thesis confirmed the prognostic value of pre- and post-procedure troponin (myocardial injury) in patients undergoing TAVI and of calcium score with previous generation prosthesis.The second chapter highlighted the impact of predilatation on this post-procedure troponin elevation with a potential prognostic impact
Piton, Nicolas. "Optimisation de la prise en charge diagnostique, pronostique et théranostique des carcinomes broncho-pulmonaires humains : des techniques d’imagerie in vivo à la biologie moléculaire. Ligation -dependent RT-PCR : a new specific and low-cost technique to detect ALK, ROS and RET rearrangements in lung adenocarcinoma A new assay for detection of theranostic gene translocations and MET exon 14 skipping in thoracic oncology. One-year perspective routine LD-RT-PCR in 413 newly diagnosed lung tumors STK11 mutations are associated with lower PDL1 expression in lung adenocarcinoma BRAF V600E mutation is not always present as expected ! A case report of lung and thyroid carcinomas A novel method for in vivo imaging of solitary lung nodules using navigational bronchoscopy and confocal laser microendoscopy." Thesis, Normandie, 2019. http://www.theses.fr/2019NORMR119.
Повний текст джерелаLung cancer is a serious and frequent condition for which the management strategies have been dramatically modified in recent years, from a diagnostic, prognostic and “theranostic” perspective, most notably with the introduction of “targeted therapies”. The latter have demonstrated dramatic improvement in both quality of life and survival rates of eligible patients, yet consequently highlight new complications in diagnosis, treatment options or technical considerations which can be attributed to the growing number of molecular alterations to be detected from limited tissue samples frequently encountered in thoracic oncology. This work combines 5 different research papers from 2 different angles: prognostic and “theranostic” molecular markers of lung cancer, as well as in vivo diagnostic procedures of lung cancer. The first angle encompasses 4 articles. The first two evaluate a new molecular technique, LD-RT-PCR, to detect gene translocation in lung cancer. The third article explores the association between STK11 mutations in lung cancer and the expression of PDL1. Finally, the fourth article is a case report illustrating the importance of a morphological approach to lung cancer. The second angle compares in vivo imaging techniques by endoscopy using confocal laser microendoscopy alongside a conventional microscopic approach
Deye, Nicolas. "Cardiac Arrest-Induced Brain Injury : Diagnostic And Prognostic Values of Circulating Biomarkers." Thesis, Sorbonne Paris Cité, 2018. http://www.theses.fr/2018USPCC150.
Повний текст джерелаOutcome of cardiac arrest (CA) remains dramatic. To quickly diagnose the cause of CA and establish a reliable outcome prediction (prognostication) as early as possible could help to guide initial treatments. It could avoid futile treatments in patients with low chance of survival or of good neurological recovery, or conversely allow treatment optimization in patients expected to have a high likelihood of good neurological outcome. Usefulness of biomarkers to guide clinicians in finding the CA diagnosis and helping prognostication is debated. Biomarkers are considered as not sensitive and accurate enough, especially within the first hours after return of spontaneous circulation (ROSC). Their use is only recommended in prognostication for Neuron Specific Enolase (NSE) as a second line tool and after the third day from CA. Our first study confirmed that biomarkers “specific” of brain injury (S100B protein: S100 and moreover NSE) cannot sufficiently discriminate the neurological cause of CA on ICU admission. If early coronary angiogram is the standard for diagnosing a probable cardiac cause of CA, biomarkers cannot replace brain computed-tomography (CT) in CA from a neurological cause. The second study evaluated, during the 1st day after ROSC, the link between biomarkers (S100 and NSE) and 2 surrogates of brain oedema recently proposed as outcome predictors: echography of the optic nerve sheath diameter (ONSD), and grey to white matter attenuation ratio (GWR) on brain CT-scan. Even though we cannot conclude on a definitive relationship between these parameters, ONSD enlargement at day 1 was associated with specific brain damage after CA, such as brain oedema and mostly axonal injuries, as reflected by increases in NSE (on admission and at day 1) and low GWR measurements. Whereas NSE, GWR and ONSD at day 1 were correlated, S100, which is more specific of glial injuries, did not reach significance. NSE and S100 on admission, at days 1 and 2 after ROSC, as well as ONSD at day 1, were associated with survival at hospital discharge. The third study evaluated the prognostic value of several biomarkers in the early phase after CA (NSE and S100 being sampled at median 220 min after ROSC). S100, blinded to physicians, was the biomarker with the best accuracy after ICU admission to correctly predict unfavourable outcome at hospital discharge and at 3 months after CA, compared with all other biomarkers such as lactate, pH, creatinine, and especially NSE. S100 variations during the first day after admission refined prognostication. Initial S100 was an early independent predictive factor associated with unfavourable outcome at hospital discharge, with the no-flow duration, initial lactate value, initial non-shockable rhythm, and the presence of clinical seizure. According to guidelines, prognostication theoretically needs to be delayed and multimodal, biomarkers alone not being recommended especially in the early phase after CA. Biomarkers cannot seem to be an alternative option compared to imaging to precisely diagnose the CA cause. By contrast, some biomarkers, such as S100 after admission, could easily and specifically discriminate CA patients with certainty of unfavourable outcome. Associated with other predictive tools (clinical or using imaging), biomarkers could interestingly be incorporated in early decisional algorithms to optimally guide initial therapies. This correct patient classification could help to avoid unuseful treatments versus to maximize aggressive therapies. The choice of recommended servo-controlled targeted temperature management devices, very efficient but invasive and expensive, or the indication -or not- of a cardio-circulatory assist device implementation should be guided in the early stage after ROSC using this simple strategy of patient selection
Elaldi, Roxane. "Carcinomes épidermoïdes cutanés : caractérisation du micro-environnement immunitaire tumoral et identification de biomarqueurs moléculaires pronostiques." Electronic Thesis or Diss., Université Côte d'Azur, 2023. https://intranet-theses.unice.fr/2023COAZ6054.
Повний текст джерелаCutaneous squamous cell carcinomas (cSCC) are the second most common skin tumors after basal cell carcinomas. Most are treated surgically, and their prognosis is good. However, some "high-risk" tumors, particularly those on the face and neck, frequently relapse within 2 years of surgery. These relapses, sometimes inoperable, have a poor prognosis, and the identification of patients with "high-risk" tumors is universally is a major challenge in managing these cancers and including these patients in clinical trials. Additionally, cSCC show an overall response rate of 50% to anti-PD1 immunotherapies, and several immunosuppression mechanisms characterizing these inflammatory tumors have been identified by our laboratory, emphasizing the impact of the immune microenvironment in their carcinogenesis and progressionMy work hypothesis was that the spatial and integrative characterization of immune cells of the tumor microenvironment, together with a comparison of immunological profiles of tumors with different prognoses, would provide a better understanding of the complexity of these tumors.To answer this question, I worked with formalin fixed paraffin embedded tissue sections (FFPE) from primary and recurrent tumors of patients belonging to a cohort I set up in collaboration with the Centre de Ressources Biologiques of the Centre Antoine Lacassagne (Nice), and an imaging mass cytometry (IMC) approach.First, I created a cohort of 160 patients who underwent surgery for 217 face and neck cSCC at the Centre Antoine Lacassagne. I compared the performance of the four currently most widely used classifications system to identify patients with "high-risk" cSCC. I did not find a significantly superior classification in terms of discrimination for identifying patients with recurrence, and the highest positive predictive value found was 30% (Elaldi et al, J Clin Med, 2023). These results confirmed the need to refine the selection of "high-risk" patients by identifying a new prognostic marker that takes into account the spatial organization of the tumor microenvironment of these tumors.I therefore set up and validated a panel of 39 markers enabling the characterization of the microenvironment of human cSCC on a single FFPE tissue section by IMC (Elaldi et al, Front Immunol, 2021). Then, using the previously described clinico-histological database, I set up an exploratory cohort of primary and recurrent tumors in patients who had or had not relapsed within 2 years following the surgery. I then characterized the healthy peri-lesional skin and tumors of this cohort with the previously developed IMC 39-marker panel. I identified immunological patterns that distinguish these two types of tumors, notably a macrophage subpopulation characteristic of healthy skin and enriched in tumors with a good prognosis (Elaldi et al, in preparation).My thesis work is improving our understanding of the immune mechanisms at work in the fight against cSCC relapse. In the short term, the analysis of a validation cohort will validate the prognostic value of the macrophage population we described in order to improve the selection of "high-risk" patients and their management
Beaudoux, Olivia. "Caractérisation anatomo-clinique et moléculaire du mélanome primitif muqueux Prognostic factors and incidence of primary mucosal melanoma: a population-based study in France Massively invasive orbital melanoma: Uveal or conjunctival origin? “Response to imatinib of a patient with double-mutant KIT metastatic penile melanoma." Thesis, Reims, 2020. http://www.theses.fr/2020REIMM201.
Повний текст джерелаPrimary mucosal melanoma (M) (MM) is a rare and serious malignant tumor, including oral and nasopharyngeal, vulvovaginal, conjunctival, anorectal and penile (PM) M. The oncogenes involved are largely unknown. Unresectable and metastatic cases are not very sensitive to current treatments, targeted therapies and immunotherapies. In order to better characterize these orphan cancers, we have: (1) studied, on the basis of incident cases in Champagne-Ardenne between 2004 and 2014 (n = 39): the annual incidence (0.18 / 100,000) and the incidence ratio between MM / cutaneous M (1/50), the relative frequency of different mucosal sites, the diagnosis (late at 77%), the median survival (24 months) and the 5-year specific survival (32%); (2) reported the first case of response to imatinib and long-term survival of a patient with KIT-mutated metastatic PM and discussed the possible mechanisms of this exceptional response; (3) reported a case of GNA11 mutated massively invasive orbital M, and discussed its origin, conjunctival or uveal; (4) carried out a systematic review of the literature (n = 88), in order to establish the frequency of the KIT (13.5%), BRAF (12.9%) and NRAS (12.1%) variants, and triple negative (64.2%), to discuss the mutated genes in more than 5% of cases (including MTOR, TSC1, ATRX, POM121 and DISP3), and, in less than 5% of cases if there was an impact clinic (including POLE); (5) studied, using a panel of 275 genes, on 29 PMM, the mutational frequency of KIT (31%), BRAF (24%), NRAS (14%), TP53 (14%), SF3B1 (10%), NF1 (45%), PIK3CA and KRAS (both at 7%). Our studies indicated that a dedicated NGS custom panel should be useful for clinical practice
Leroy, Mélanie. "Contribution des bases de données de soin courant à l’amélioration du diagnostic et du pronostic de la maladie d’Alzheimer et des dégénérescences lobaires frontotemporales." Electronic Thesis or Diss., Université de Lille (2018-2021), 2021. http://www.theses.fr/2021LILUS026.
Повний текст джерелаBiomarkers, whether cerebrospinal fluid (CSF), magnetic resonance imaging (MRI), or positional emission tomography (PET), have acquired a prominent place in the diagnostic process of a cognitive disorder. They are an integral part of the diagnostic criteria for Alzheimer's disease (AD) and its main differential diagnosis, frontotemporal dementia (FTD). In 2021, however, histological analysis, where pathological changes are observed directly on tissues, often remains the only method allowing a diagnosis of certainty.In 1992, the Lille Memory Resource and Research Center (CMRR) set up a network of memory consultations in the Nord Pas-de-Calais region. In addition to standardizing care, it has set up a database that now includes over 120,000 patients. Based on this large active file, our work consisted in studying the clinical and biochemical characteristics of AD and FTD patients on different scales (rare but perfectly characterized cases of clinicopathological correlations, monocentric cohorts of patients having undergone lumbar puncture, regional or international cohorts).Our first study focused on the correlations between the biochemical profile of cerebrospinal fluid (CSF) and post-mortem findings. We were able to show that amyloid and tau biomarkers are less sensitive to the corresponding pathologies when these are not yet fully developed in the cortex, leading to incomplete detection of patients with AD-related neuropathological changes.We subsequently focused on AD patients with pathological tau and pTau biomarkers in the CSF, pathological Aβ42/Aβ40 ratio, but normal Aβ42 levels. We showed that the cognitive, morphological, and functional profile of patients with AD and normal Aβ42 does not differ from those with pathological Aβ42.In the setting of FTD, CSF biomarkers are used to rule out a possible diagnosis of AD. Nevertheless, if this is the case, a whole spectrum of pathology remains possible as FTD is so heterogeneous. There are currently few established phenotype-pathology correlations, which, at the dawn of the development of a targeted treatment, may represent a loss of chance for these patients. We wished to constitute a multicentric cohort of patients with confirmed post-mortem FTD, in order to improve clinicopathological correlations. This preliminary work demonstrates the complexity of the FTD spectrum, with many phenotypic and histological overlaps.In addition to this study of gold standard FTD patients, we wished to consider the entire FTD active file of the Nord Pas-de-Calais memory consultation network. Although this disease is rare, the pooling of data within the network allowed us to reach a large number of patients. This work allowed us to demonstrate that FTD differs from AD, both in terms of initial characteristics, speed of progression and treatment. Despite the use of the latest clinical criteria, these pathologies remain under-diagnosed and should no longer be considered as limited to young subjects.Although each memory center, individually, is in a position to contribute to the advancement of science and to help better understand neurodegenerative diseases, it seems obvious at this time that the pooling of health data is indispensable. Within the framework of the European Human Brain Project, we have worked on the implementation of a federated data analysis tool. The Medical Informatics Platform allows complex analyses to be carried out from geographically distant databases, thus avoiding transfers and the risk of health data leaks between research centers.Data from routine care is abundant and contains a lot of information. It is up to us to make the most of it to advance our understanding of neurocognitive diseases, a challenge for the years to come
Ternes, Nils. "Identification de biomarqueurs prédictifs de la survie et de l'effet du traitement dans un contexte de données de grande dimension." Thesis, Université Paris-Saclay (ComUE), 2016. http://www.theses.fr/2016SACLS278/document.
Повний текст джерелаWith the recent revolution in genomics and in stratified medicine, the development of molecular signatures is becoming more and more important for predicting the prognosis (prognostic biomarkers) and the treatment effect (predictive biomarkers) of each patient. However, the large quantity of information has rendered false positives more and more frequent in biomedical research. The high-dimensional space (i.e. number of biomarkers ≫ sample size) leads to several statistical challenges such as the identifiability of the models, the instability of the selected coefficients or the multiple testing issue.The aim of this thesis was to propose and evaluate statistical methods for the identification of these biomarkers and the individual predicted survival probability for new patients, in the context of the Cox regression model. For variable selection in a high-dimensional setting, the lasso penalty is commonly used. In the prognostic setting, an empirical extension of the lasso penalty has been proposed to be more stringent on the estimation of the tuning parameter λ in order to select less false positives. In the predictive setting, focus has been given to the biomarker-by-treatment interactions in the setting of a randomized clinical trial. Twelve approaches have been proposed for selecting these interactions such as lasso (standard, adaptive, grouped or ridge+lasso), boosting, dimension reduction of the main effects and a model incorporating arm-specific biomarker effects. Finally, several strategies were studied to obtain an individual survival prediction with a corresponding confidence interval for a future patient from a penalized regression model, while limiting the potential overfit.The performance of the approaches was evaluated through simulation studies combining null and alternative scenarios. The methods were also illustrated in several data sets containing gene expression data in breast cancer
Thuny, Franck. "Approche translationnelle de la recherche sur la prise en charge des endocardites infectieuses." Thesis, Aix-Marseille 2, 2011. http://www.theses.fr/2011AIX20707/document.
Повний текст джерелаInfective endocarditis is a serious disease affecting around 2000 patients in France and 17000 in the United-States. Despite therapeutic progress, in-hospital mortality remains high, around 20%. This is mainly the consequence of a too late diagnosis and insufficiencies in the risk stratification. In fact, novel perspectives on the management of endocarditis are emerging and offer a hope for decreasing the rate of residual deaths by accelerating the process of diagnosis and risk stratification, a reduction of delays of instauration of antimicrobial therapy, the rapid transfer of high-risk patients to specialised medio-surgical centres, the development of new surgical modalities, and close long-term follow-up.Since many years, we have developed, in our institution, a research program based on a close collaboration between the researchers of the UMR 6236-CNRS and the physicians and the surgeons of the Cardiology and Cardiac Surgery Departments. This thesis reports the results of this translational research on the management of endocarditis. We have demonstrated that the standardization of the diagnostic process and of the surgical indications reduces infective endocarditis-related mortality in infective endocarditis. To improve the management, innovations such as the use of new biomarkers represent a critical new approach for this disease. From a transcriptional based approach, we have identified several new genes strongly involved in the pathophysiology of infective endocarditis. Thus, our works shows that the matrix metalloproteinase-9, S100A11 and aquaporin-9 would be potential new biomarkers for the diagnosis and the prediction of complications during infective endocarditis
Perrotti, Andréa. "Impact pronostique des biomarqueurs en chirurgie cardiaque." Thesis, Bourgogne Franche-Comté, 2017. http://www.theses.fr/2017UBFCE003.
Повний текст джерелаA biomarker is a biological parameter absent or expressed at a basal Ievel in physiological situation, and present or overexpressed in the event ofalteration of the corresponding tissue function. The dosage ofsome biomarkers makes it possible to follow or even anticipate the occurrence of a postoperative complication, and allows a rapid and adapted management ofthis complication. Patients with heart surgery are exposed to several types of complications. The most important are residual myocardial ischemia and perioperative infarction, respiratory complications, renal insufficiency and sternal wound infections. Each c these complications increases post-operative morbidity and mortality. The determination of the cardiac TROPONINE I has shown its interest in the detection ofresidual myocardial ischemia and the diagnosis ofperioperative infarction. We tested the cardiac Troponin I ratio at 12 h / cardiac Troponin I at 6 h in the detection ofpost-operative residual myocardial ischemia. We have demonstrated that a ratio oftroponin Hl2 / H6> 1.3 makes it possible to detect the lesions of the grafts after coronary bypass surgery. Their early detection makes it possible to prevent the pejorative evolution of the grafts. NEUTROPHIL GELATINASE-ASSOCIATED LIPOCALIN (NGAL), is a marker ofrenal failure never tested in patients with chronic renal failure in preoperative cardiac surgery. We have demonstrated that plasma NGAL is a robust marker for the development of acute renal failure in postoperative cardiac surgery in patients with pre-operative renal failure. An NGAL level at the 6th hour above 155ng / ml is an independent risk factor for the occurrence of postoperative acute renal failure. ENDOCAN is a marker ofpulmonary involvement, which has never been tested in cardiac surgery. We propose to: 1) Determine the kinetics ofEndocan in the inflammatory context of the CEC, 2) Assess the Iink between the decrease in circulating endocan and the risk ofprogress towards respiratory failure ofseptic origin or Inflammatory, 3) Compare endocan kinetics with other markers of inflammation and infection: Protein C Reactive (CRP) and procalcitonin (PCT), and 4) Assess the prognostic value of the rate of inflammation, Endocan in the occurrence ofpostoperative respiratory deaths. We conducted a pilot study that found that 6 hours after the procedure, patients with postoperative pulmonary infection had significantly higher levels ofEndocan than patients without pulmonary infection. This pilot study showed a potential interest in designing a specific study, which was submitted for publication. We performed a prospective study, which included 155 patients. The results confirm the results of the pilot study, namely that the preoperative and 6-hour Endocan is predictive ofpostoperative pulmonary involvement
Cléry-Melin, Galichon Marie-Laure. "Étude des fonctions neurocognitives dans la dépression : caractérisation de déficits motivationnels et cognitifs, évaluation de leur valeur pronostique Why don't you try harder? An investigation of effort production in major depression Neural mechanisms underlying motivation of mental versus physical effort Psychomotor retardation is a scar of past depressive episodes, revealed by simple cognitive tests Are cognitive deficits in major depressive disorder progressive? A simple attention test in the acute phase of a major depressive episode is predictive of later functional remission Progress in elucidating biomarkers of antidepressant pharmacological treatment response: a systematic review and meta-analysis of the last 15 years Stability of the diagnosis of seasonal affective disorder in a long-term prospective study." Thesis, Sorbonne Paris Cité, 2018. http://www.theses.fr/2018USPCB218.
Повний текст джерелаHese deficits coexist in the acute phase of a depressive episode and interfere with decision-making and goal-directed behaviors, and the associated feeling of effort. They appear to persist in periods of clinical remission, decreasing the quality of the therapeutic and functional response and lately worsening the prognosis of the disorder. The aim of this work is to identify objectively measurable neurocognitive markers in clinical practice, and to study their association with the prognosis of a depressive episode, in order to better predict remission and potentially to optimize therapeutic prescribing strategies for patients accordingly. The impairment of neurocognitive processes related to reward constitutes a first vulnerability marker for major depressive disorder (MDD): in a study assessing the production of motor effort in order to obtain a reward, depressed patients had a deficit in production of effort, unlike healthy subjects. Such deficit in incentive motivation - a process underpinned by the activation of ventral cortico-striatal circuits in healthy subjects - may constitute a specific dimension of MDD. It participates in the decision-making and action processes impairments and is associated with – and possibly a consequence of- more specifically cognitive deficits. In a study assessing several cognitive functions in a large cohort of depressed patients, the persistence of psychomotor retardation after 6 to 8 weeks of treatment - in patients considered as being in clinical remission - was positively and independently correlated with the number of past depressive episodes, thus constituting a marker of "cumulative" marker of past depressive episodes. Finally, in a literature review on the progressive evolution of cognitive deficits in MDD, we discussed the existence of a “neurotoxic” effect of the lifetime accumulation of depressive episodes on neurocognitive deficits and its consequences on disease prognosis (increased risk of incomplete functional/clinical remission, relapses, evolution towards dementia). One of the main interest in identifying clinical and cognitive markers of vulnerability is to highlight their capacity to predict the course of a depressive episode-or disorder. In a study based on a cohort of more than 500 depressed patients, a measurement of attention (d2 attention test) was able to significantly and independently predict the subsequent course towards complete remission (clinical and functional) and to constitute a trait -marker of depression, easy to use in clinical practice. Other cognitive markers (such as executive functions) have shown high predictive values for therapeutic response, comparable to those provided by imaging or electrophysiology markers, according to the results of a recent meta-analysis, that emphasizes the interest of using them in patient’s follow-up. Finally, in order to better assess the prognosis of depressive disorder, we have shown that Seasonal Affective Disorder (SAD) diagnosis criteria - which nevertheless represents a specific depressive disorder with well-known physiopathology substrates (construction validity) - had a low predictive validity, prompting to consider this disorder as a temporary expression of a mood disorder, rather than a specific disorder. The identification of clinical tools measuring motivational and cognitive deficits in clinical routine and predicting the course of a depressive episode or disorder represents a major challenge in the improvement of personalized therapeutic management and the long-term prognosis in depressed patients
Moulton, Eric. "Methodological Considerations and Clinical Relevance of Diffusion Tensor Imaging in Acute Stroke Prognosis." Thesis, Sorbonne université, 2019. http://www.theses.fr/2019SORUS249.
Повний текст джерелаPredicting motor, language, and global outcome after ischemic stroke is a major research concern. While initial impairment, age, and lesion volume have proven indicators of future outcome, the preservation of major white matter structures also play a role in these outcome domains. Diffusion tensor imaging (DTI) is sensitive to acute ischemic damage and can evaluate the integrity of important white matter bundles. Using a large cohort of patients who underwent a DTI protocol at 24 hours post-stroke and a clinical evaluation 3 months afterwards, the current thesis sought to (1) investigate spatial normalization strategies to optimally analyze imaging data, (2) establish which DTI parameter best predicts global outcome, and (3) determine if DTI can provide independent biomarkers of motor and language outcome. The major findings of the current thesis were: (1) fiber orientation distribution (FOD)-based spatial normalization performed similarly to scalar normalization for acute stroke data but yielded stronger anatomo-clinical correlations in subacute-chronic stroke patients, (2) axial diffusivity (AD) in the corona radiata highly contributes to the prediction of autonomy in patients, and (3) the AD of the corticospinal tract and arcuate fasciculus are independent markers of motor and aphasia outcome, respectively. These results support the use of AD for quantifying early brain damage in important white matter structures, such as the corona radiata, corticospinal tract, and arcuate fasciculus. These markers could be used for patient information, as surrogates of neuroprotective therapies at the hyperacute stage, or as stratification means for rehabilitative therapies