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Biological studies of the haemopoietic system in essential thrombocythaemiaHarrison, Claire Nicola January 1999 (has links)
No description available.
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Etude de mutations rares du récepteur de la TPO, MPL, dans les thrombocytoses sporadiques et héréditaires / Study of rare mutations of the TPO receptor, MPL, in sporadic and hereditary thrombocytosisFavale, Fabrizia 29 September 2016 (has links)
Les thrombocytoses correspondent à une élévation du taux de plaquettes au-delà de 450x109/L et sont soit réactionnelles dans la plupart des cas, soit primitives quand il existe une altération génétique sur la voie de la production plaquettaire. Dans ce dernier cas il est habituel de distinguer les thrombocytoses sporadiques des thrombocytoses familiales, qui partagent néanmoins un mécanisme physiopathologique commun à l’image de la mutation MPLS505N résultant en une activation constitutive du récepteur. En effet les thrombocytémies essentielles (TE), les plus fréquentes, présentent une mutation activatrice dans 85% des cas soit de JAK2, de CALR ou MPL. Les thrombocytoses héréditaires quant à elles peuvent être la conséquence de mutations de MPL, de JAK2 ou de la TPO. Nous avons étudié dans un premier temps la mutation MPLP106L décrite chez une famille saoudienne mais dont le mécanisme physiopathologique aboutissant à la thrombocytose était mal compris. En effet les sujets homozygotes présentent une thrombocytose importante et de manière paradoxale un taux de TPO élevé. Nous avons pu montrer qu’il s’agit d’un récepteur fonctionnel sans autonomie de croissance mais qu’il existe un défaut de trafic cellulaire, MPL restant bloqué dans le réticulum endoplasmique et étant adressé faiblement à la membrane. Néanmoins l’expression membranaire de MPL est moins diminuée à la surface des cellules immatures par rapport aux cellules matures expliquant un découplage entre la fonction de prolifération (mégacaryocytes) et de clearance de la TPO (plaquettes). Nous avons également étudié les TE triples négatives pouvant correspondre potentiellement à des mutations de MPL liées à un défaut de trafic cellulaire comme pour MPLP106L. Grâce à un séquençage à haut débit de l’exome entier, nous avons pu mettre en évidence de nouvelles mutations récurrentes comme MPLS204P ou Y591N qui sont des mutations faiblement activatrices ne donnant pas de croissance autonome mais n’altérant pas le trafic cellulaire et nécessitant la présence éventuellement d’autres mutations pour déclencher une thrombocytose. / Thrombocytosis is defined as a platelet count exceeding 450x109/L and generally either is a reactive process or is caused by genetic alteration on the way of platelet production. In the latter case sporadic thrombocytosis are usually distinguished from familial thrombocytosis, the boundaries between these two cases becoming less sharp since the mutation first described in familial thrombocytosis (MPLS505N) is also found in sporadic cases. Essential thrombocythemia (ET), the most frequent, sporadic thrombocytosis have an activating mutation in 85% of cases in either JAK2, MPL or CALR genes. Hereditary thrombocytosis may be the result of mutations of MPL, JAK2 or TPO. We studied initially MPLP106L already described in a Saudi family in which the pathophysiologic mechanism leading to thrombocytosis was misunderstood. Indeed homozygous patients exhibit significant thrombocytosis and paradoxically high TPO plasma level. We have shown that MPLP106L is a functional receptor without spontaneous growth but with a trafficking defect and a low cell surface expression. Nevertheless membrane expression of MPL is less reduced on immature cell surface compared to mature cells, explaining an uncoupling between proliferation (megakaryocyte precursors) and TPO clearance (platelets) functions. We also studied triple negative ET, to find potentially MPL mutations linked to a trafficking defect like MPLP106L. Thanks to Whole Exome Sequencing we were able to decipher new MPL mutations as MPLS204P or Y591N, which are weakly activating mutations without autonomous growth and the absence of trafficking defect and requiring the presence of other mutations in most cases to trigger thrombocytosis.
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Thrombocytosis Following Pancreatectomy with Islet Autotransplantation in Children: Cincinnati Children's Hospital ExperienceGurria, Juan P. 21 September 2018 (has links)
No description available.
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Prognosis, Prediction and Risk Assessment in the Prevention and Treatment of Non-Small Cell Lung CancerSandelin, Martin January 2015 (has links)
Background: Lung cancer causes more deaths than any other cancer. Smoking causes roughly 90% of lung cancer cases. Concurrent chemoradiation therapy is the standard of care for stage IIIb patients with performance status (PS) 0-1. A less toxic approach is warranted for less fit patients. To optimize care, the understanding of common clinical variables such as haematological responses to inflammation could be much improved. Adherence to guidelines for proper clinical work-up is vital to ensure patients’ optimal care, especially for predictive assays. Screening of high-risk patients is now being implemented internationally. Chronic pulmonary obstructive disease (COPD) patients, a group at high risk to develop lung cancer, could be of interest for screening. Methods: Patient cohorts collected nationally and regionally by manual search in patient records or automated search in electronic patient records and national registries were analysed in relation to overall survival, comorbidities, medication, treatment, smoking status, biomarkers and adherence to guidelines. Standard statistics were applied to adjust for confounding factors. Results: Induction chemotherapy results in longer overall survival than radiotherapy alone (15.6 and 11.6 months respectively). The overall survival for patients with combined anaemia, leucocytosis and thrombocytosis at diagnosis is half of what could be anticipated if blood samples are normal (8.0 and 16.0 months respectively). Fifty percent of patients were overlooked in the routine work-up with EGFR analysis. Less than 40% of the patients received EGFR-tyrosine kinase inhibitors in first-line therapy. The frequency of EGFR mutation was 9.9%. COPD patients with asthma and medicating with inhaled corticosteroids, specific serotonin reuptake inhibitors (SSRI) or beta-blockers have a significantly decreased risk of lung cancer. Conclusions: Patients unfit to receive chemoradiation therapy should be considered for induction chemotherapy sequentially to radiotherapy. A patient that presents with pathological blood samples is likely to have poor prognosis and diagnostic work-up should be thorough to optimize outcome. Inadequate adherence to the national guidelines regarding treatment and EGFR analysis was shown. COPD patients medicating with ICS, beta-blockers or SSRI and with a concurrent asthma diagnosis have a decreased risk of lung cancer.
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Prognostic Factors in Non-Small Cell Lung Cancer (NSCLC)Holgersson, Georg January 2017 (has links)
Background: Non-small cell lung cancer (NSCLC) is the cancer disease with the highest mortality globally. About 75% of NSCLC patients are diagnosed in an advanced stage where surgical treatment is not possible. For patients with locally advanced disease without distant metastases, the treatment of choice is curatively intended radiotherapy. However, this treatment has considerable side effects and many patients relapse. To individualize the treatment strategy for these patients, it is essential to have as much prognostic information as possible. The aim of this thesis was to investigate the prognostic significance of histology and pre-treatment hematopoietic blood parameters. Material and Methods: Data were collected retrospectively for NSCLC patients treated between 1990 and 2000 with curatively intended radiotherapy. The data were obtained by manually searching patient records from all radiation oncology departments in Sweden. The prognostic significance of histology, and pre-treatment levels of hemoglobin (Hgb), white blood cells (WBC) and platelets (Plt) were analyzed in relation to overall survival using univariate and multivariate statistical methods. These prognostic factors were further analyzed in a chemoradiation patient cohort and in a cohort of patients with recurrent NSCLC treated with palliative docetaxel, or the insulin-like growth factor 1 receptor (IGF-1R) modulator AXL1717. Results: In the cohort of NSCLC patients treated between 1990 and 2000, squamous cell carcinoma (SCC) histology and pre-treatment anemia (Hgb <110 g/L), leukocytosis (WBC > 9.0 x109/L), and thrombocytosis (Plt >350 x109/L) were independent prognostic factors for shorter overall survival. However, in the chemoradiation cohort only thrombocytosis retained independent prognostic significance in a multivariate analysis. In the cohort of patients with recurrent disease treated with palliative systemic therapy, only leukocytosis was significantly associated with worse survival. Conclusions: Routine pre-treatment hematopoietic blood parameters—together with other prognostic factors such as disease stage and performance status—can provide decision-making support when individualizing treatment of NSCLC. The prognostic role of histology is unclear and further research is warranted to determine its significance.
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Role of MicroRNAs and Their Downstream Targets in Zebrafish ThrombopoiesisAl Qaryoute, Ayah 05 1900 (has links)
Previous studies have shown that human platelets and megakaryocytes carry microRNAs suggesting their role in platelet function and megakaryocyte development, respectively. However, there is limited information on microRNAs' role in zebrafish thrombopoiesis. Zebrafish thrombocytes could be used as a model to study their role in megakaryocyte maturation and platelet function because thrombocytes have both megakaryocyte features and platelet properties. In our laboratory, I identified 15 microRNAs in thrombocytes using single-cell RNA sequencing. Knockdown of three microRNAs, mir-7148, let-7b, and mir-223, by the piggyback method in zebrafish led to an increase in the percentage of thrombocytes. Functional thrombocyte analysis using plate tilt assay showed no modulatory effect of the three microRNAs on thrombocyte aggregation/agglutination. I then verified these findings in zebrafish larvae after the knockdown of the above microRNAs followed by an arterial laser thrombosis assay. I concluded mir-7148, let-7b, and mir-223 are repressors for thrombocyte production. Furthermore, I explored let-7b downstream genes in thrombocytes detected by RNA-seq analysis and chose 14 targets based on their role in cell differentiation (rorca, tgif1, rfx1a, deaf1, zbtb18, mafba, cebpa, spi1a, spi1b, fhl3b, ikzf1, irf5, irf8, and lbx1b) that are transcriptional regulators. The qRT-PCR analysis of expression levels the above genes following let-7b knockdown showed significant changes in the expression of 13 targets. I then studied the effect of the 14 targets on thrombocytes production and identified 5 genes (irf5, tgif1, irf8, cebpa, and rorca) that showed thrombocytosis and one gene ikzf1 that showed thrombocytopenia. Furthermore, I tested whether mir-223 regulates any of the above 13 transcription factors after mir-223 knockdown using qRT-PCR. Six of the 13 genes showed similar gene expression as observed with let-7b knockdown and 7 genes showed opposing results. Thus, our results suggested a possible regulatory network in common with both let-7b and mir-223. I also identified that tgif1, cebpa, ikzf1, irf5, irf8, and ikzf1 play a role in thrombopoiesis. Since the ikzf1 gene showed a opposite expression profiles following let-7b and mir-223 knockdowns (decreased and increased expression, respectively) and knockdown of ikzf1 resulted in thrombocytopenia I confirmed a definitive role for ikzf1 using an ikzf1 mutant obtained from the Zebrafish International Resource Center (ZIRC). The arterial laser thrombosis assay of ikzf1 mutant progeny confirmed our piggyback hybrid knockdown results. Taken together, these studies shed light on understanding the role and the regulatory effects of zebrafish microRNA on thrombopoiesis and identified novel downstream target transcription factors for let-7b and mir-223.
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Approche génomique des syndromes myéloprolifératifs et des lymphomes B-diffus à grandes cellules en rechute / Genomic approach of myeloproliferative neoplasms and relapsed large B-cell lymphomaBroséus, Julien 12 September 2016 (has links)
L’outil génomique a considérablement modifié notre connaissance des hémopathies malignes, que ce soit sur le plan physiopathologique, diagnostique, pronostique ou thérapeutique. Dans la première partie de ce travail, nous avons travaillé sur une grande cohorte d’anémies réfractaires sidéroblastiques avec thrombocytose (ARS-T). Nous avons démontré qu’il s’agissait d’une entité indépendante, avec une présentation moléculaire particulière associant (i) des mutations de SF3B1 dans plus de 85% des cas, expliquant son versant myélodysplasique et (ii) des anomalies de JAK2 dans plus de 50% des cas, expliquant son versant prolifératif. La perspective de cette première partie est d’identifier la ou les mutation(s) responsables du caractère myéloprolifératif dans les ARS-T JAK2WT. Les lymphomes B-diffus à grandes cellules (LBDGC) représentent les lymphomes malins non-Hodgkiniens les plus fréquents chez l’adulte. Dans la deuxième partie de ce travail, nous avons réalisé l’analyse par SNP-array d’une série homogène d’échantillons issus de la cohorte CORAL, une étude prospective internationale portant sur les LBDGC en rechute. Notre objectif était d’identifier les anomalies de nombre de copies (ANC) associées à chacun des deux types de rechutes, précoces ou tardives. Les rechutes précoces sont associées à une forte proportion d’anomalies affectant les régulateurs du cycle cellulaire, de l’apoptose et de la transcription. Les rechutes tardives sont associées à des anomalies affectant les régulateurs de l’immunité et de la prolifération cellulaire. Cette étude permet de mieux comprendre les déterminants de la rechute dans les LBDGC et ouvre de nouvelles perspectives thérapeutiques / Genomics provided new insights in our knowledge of pathophysiology, diagnostic approach, prognosis and therapeutic perspectives in hematological malignancies. In the first part of this work, we studied a large cohort of Refractory Anemia with Ring sideroblasts and marked Thrombocytosis (RARS-T). We demonstrated that RARS-T can be considered as an independent entity, with a specific molecular pattern, associating : (i) SF3B1 mutations in more than 85% of cases, accounting for its myelodysplastic aspect and (ii) JAK2 mutations, accounting for its myeloproliferative aspect in more than 50% of cases. Future prospects of the first part of this work is to identify (the) mutation(s) responsible for the myeloproliferative part of JAK2WT RARS-T. Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma in adults. In the second part of this work, we performed SNP-array analysis of a homogeneous series of samples from the CORAL cohort, an international prognostic study on relapsed DLBCLs. Our purpose was to identify Copy Number Variations (CNV) associated ER or LR. ER DLBCLs are associated with high rates of CNVs affecting regulators of cell cycle, apoptosis and transcription. In LR DLBCLs, CNVs are related to immune response and cell proliferation. This study provides new insights into the genetic aberrations in relapsed DLBCLs and open up new therapeutic perspectives
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