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  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.
31

The effect of the AML1-ETO translocation on cell cycle tumor suppressor gene function

Ko, Rose Marie. January 2007 (has links) (PDF)
Thesis (Ph. D.)--University of Alabama at Birmingham, 2007. / Title from first page of PDF file (viewed Feb. 18, 2009). Includes bibliographical references.
32

Receptor desencadeador expresso nas células mielóides Tipo 1 (TREM-1) no diagnóstico e prognóstico na meningite bacteriana em crianças

Torres, Vitor Félix January 2015 (has links)
Base teórica: A meningite bacteriana é uma causa importante de morbidade e mortalidade na infância. Análise do líquido cefalorraquidiano (LCR) continua a ser a ferramenta de diagnóstico padrão ouro, porém novos biomarcadores para o diagnóstico e prognóstico ainda são necessários. Receptor Desencadeador Expresso nas Células Mielóides Tipo 1 (TREM-1) é um receptor transmembrana expresso em neutrófilos e monócitos, que desempenha um papel importante na modulação da resposta inflamatória. A sua fração solúvel (sTREM-1) também é aumentada na infecção, inflamação ou doenças imunológicas. Neste estudo nós avaliamos, prospectivamente, o valor do TREM-1 como um biomarcador de meningite bacteriana aguda em pacientes pediátricos e sua possível utilização como uma ferramenta de prognóstico neste cenário. Objetivos: O objetivo primário do presente estudo é caracterizar os níveis líquóricos solúveis de TREM-1 (sTREM-1) em pacientes admitidos por suspeita clínica de meningite. Analisamos também os níveis de sTREM-1 nos casos de meningite bacteriana e viral, além de medir a sensibilidade e especificidade deste biomarcador no LCR e estudar se esse biomarcador pode ser um fator associado ao prognóstico em meningite bacteriana aguda. Métodos: Sessenta e um pacientes pediátricos, de 0 a 10 anos foram avaliados quanto à meningite e foram prospectivamente incluídos neste estudo. Na admissão, após a suspeita clínica de meningite foram submetidos à análise do LCR para o diagnóstico e uma amostra do LCR inicial foi utilizado também para análise do sTREM-1. Os pacientes foram acompanhados durante a sua internação com o registro de seu tratamento e desfecho clínico para posterior análise dos dados. Resultados: Dentre os 61 pacientes, 38 (62%) foram negativos para a meningite, 7 (11%) pacientes foram diagnosticados com meningite viral e 16 (27%) pacientes foram diagnosticados com meningite bacteriana aguda e recebeu tratamento direcionado. Sexo (p = 0,15), presença de fatores de risco identificados (p = 0,17), presença de convulsões (p = 0,31), outras complicações clínicas (p = 0,11) e mortalidade (p = 0,66) não diferiram entre os grupos. Anormalidades sensoriais (p <0,0001) e presença de cefaléia (p = 0,003) foram mais prevalentes em pacientes com meningite. Como esperado, a contagem de leucócitos, glicose e proteína no LCR foram significativamente diferentes entre pacientes com meningite e pacientes sem meningite. As concentrações de sTREM-1 no LCR de pacientes com meningite bacteriana foi superior quando comparada com pacientes com meningite viral e com controles (1204,67 pg/ml, 39,34 pg/ml e 12,09 pg/ml, respectivamente; p <0,0001). Quando sTREM-1 foi usado como um determinante de diferenciação entre pacientes com ou sem meningite bacteriana, a análise da área sob a curva ROC foi de 0,95 (IC de 95% = 0,89-1,00; p <0,0001). A presença de fatores de risco para a meningite bacteriana (p = 0,04), anormalidades sensoriais (p <0,0001), contagem de leucócitos no LCR (p = 0,01), níveis de glicose no LCR (p = 0,002), níveis de proteína no LCR (p = 0,032) e os níveis de sTREM-1 no LCR (p = 0,004) foram associados com meningite bacteriana, incluindo os níveis sTREM-1 acima do ponto de corte estabelecido de 68,0 pg/ml (p <0,0001). A meningite bacteriana (p = 0,02) e os valores de sTREM-1 maior do que o ponto de corte (68,0 pg/ml) (p = 0,04) foram associados com sequelas neurológicas graves e morte neste grupo de pacientes. Conclusão: Avaliamos os níveis sTREM-1 de crianças com suspeita clínica de meningite. Os níveis de s-TREM-1 foram aumentados nos casos de meningite bacteriana e correlacionados com o prognóstico. Os nossos resultados sugerem que níveis elevados de sTREM-1 no LCR podem ser utilizados como um biomarcador para o diagnóstico de meningite bacteriana aguda em crianças e que pode ser útil na determinação do prognóstico do paciente nesse cenário. / Background: Bacterial meningitis is an important cause of morbidity and mortality in infancy. Cerebrospinal fluid (CSF) analysis remains the gold standard diagnostic tool, however new biomarkers for diagnosis and prognosis are still required. Triggering receptor expressed on myeloid cells-1 (TREM-1) is a transmembrane receptor expressed on neutrophils and monocytes that plays an important role on the immune response. Its soluble fraction (sTREM-1) is also increased in infection, inflammation or immune diseases. In this study we evaluate the value of sTREM-1 as a biomarker of acute bacterial meningitis in pediatric patients and its possible use as a prognostic tool prospectively. Methods: Sixty-one pediatric patients, from 0 to 10 years of age were evaluated for meningitis and were prospectively included in this study. At admission, following clinical hypothesis of meningitis patients were submitted to CSF analysis for diagnosis and a sample of initial CSF was also used for TREM-1 analysis. Patients were followed during hospitalization and clinical evaluation and treatment outcome were recorded for posterior analysis. Results: Thirty-eight (62%) out of 61 patients were negative for meningitis, 7 (11%) patients were diagnosed with viral meningitis and 16 (27%) patients were diagnosed with and received treatment for acute bacterial meningitis. Sex (p = 0.15), presence of identified risk factors (p = 0.17), presence of seizures (p = 0.31), other clinical complications (p = 0.11), and mortality (p = 0.66) did not differ among groups. Sensorial abnormalities (p<0.0001) and presence of headache (p= 0.003) were more prevalent in patients with meningitis. As expected, leukocyte count, glucose, and protein levels were significantly different between patients with meningitis and patients without meningitis. Concentrations of sTREM-1 in CSF from patients with bacterial meningitis was higher when compared to patients with viral meningitis and with controls (1204.67 pg/ml, 39.34 pg/ml and 12.09 pg/ml, respectively; p<0.0001). When sTREM-1 was used as a determinant to differentiate between patients with or without bacterial meningitis, the analysis of the area under the ROC curve (AUC) was 0.95 (95% CI=0.89-1.00; p<0.0001). Presence of risk factors for bacterial meningitis (p = 0.04), sensorial abnormalities (p<0.0001), CSF leukocyte count (p = 0.01), CSF glucose levels (p = 0.002), CSF protein levels (p = 0.032) and CSF sTREM-1 levels (p = 0.004) were all associated with bacterial meningitis, including sTREM-1 levels above the established cut-off point of 68.0 pg/ml (p<0.0001). Bacterial meningitis (p = 0.02) and values of sTREM-1 higher than the cut-off point (68.0 pg/ml) (p = 0.04) were associated with death and severe neurological disabilities in this patient cohort. Conclusion: We evaluated sTREM-1 levels in CSF of children with clinical hypothesis of meningitis. The sTREM-1 levels were increased in bacterial meningitis and correlated with prognosis. Our results suggest that CSF sTREM- 1 levels can be used as a biomarker for diagnosis of acute bacterial meningitis in children and it might be useful in determining patient’s prognosis in this scenario.
33

Do Serglycin Related Alterations of Thrombocytes and Myeloid Cells Affect Tumor Progression and Behavior

Hjelle, Kjersti Marie January 2015 (has links)
Investigation of tumor growth has traditionally been studied focusing only on the cancer cells. However, tumors consist of a complex tissue organization where heterotypic signaling occurs between different cell types. The cross-talk between tumor cells and other surrounding cell types may ultimately prove to be as important for the tumor cell behavior as the internal signaling cascades in the tumor cell itself.Myeloid cells, such as granulocytes and monocytes, and thrombocytes play an important role in the tumor tissue, as a tumor can be compared to a wound healing process without the normal regulation mechanisms. Platelets are thought to facilitate tumor cell extravasation by binding to the tumor cell and recruiting myeloid cells that secrete factors aiding tumor migration through the endothelial cells. Studying the content of granules and vesicles of the platelets and myeloid cells can provide important knowledge about how the tumor interactions are mediated and which key proteins that controls these processes.Serglycin is an intracellular proteoglycan that attaches chains of negatively charged glycosaminoglycans. It is thought to have a function in retaining and storing proteins in hematipoietic cells. In this project the impact of the loss of serglycin on platelets and myeloid cells was investigated, using a spontaneous insulinoma serglycin knockout mouse model. The results suggests that serglycin does not affect the amount of neutrophil granulocytes and monocytes in peripheral blood, nor does it seem to affect the amount of platelets sequestered to the tumor tissue. A co-staining for platelets and MMP9 positive granulocytes was also performed in order to assess if granulocyte-platelet interactions in the tumor were affected by loss of serglycin. Interactions between these cells were observed in both genotypes. Von Willebrand factor levels in the tumor tissue also remained unchanged upon loss of serglycin. However, preliminary experiments indicated that serglycin seems to play a role in the intracellular amounts of vimentin and VEGFB in undifferentiated primary bone marrow derived monocytes.
34

Receptor desencadeador expresso nas células mielóides Tipo 1 (TREM-1) no diagnóstico e prognóstico na meningite bacteriana em crianças

Torres, Vitor Félix January 2015 (has links)
Base teórica: A meningite bacteriana é uma causa importante de morbidade e mortalidade na infância. Análise do líquido cefalorraquidiano (LCR) continua a ser a ferramenta de diagnóstico padrão ouro, porém novos biomarcadores para o diagnóstico e prognóstico ainda são necessários. Receptor Desencadeador Expresso nas Células Mielóides Tipo 1 (TREM-1) é um receptor transmembrana expresso em neutrófilos e monócitos, que desempenha um papel importante na modulação da resposta inflamatória. A sua fração solúvel (sTREM-1) também é aumentada na infecção, inflamação ou doenças imunológicas. Neste estudo nós avaliamos, prospectivamente, o valor do TREM-1 como um biomarcador de meningite bacteriana aguda em pacientes pediátricos e sua possível utilização como uma ferramenta de prognóstico neste cenário. Objetivos: O objetivo primário do presente estudo é caracterizar os níveis líquóricos solúveis de TREM-1 (sTREM-1) em pacientes admitidos por suspeita clínica de meningite. Analisamos também os níveis de sTREM-1 nos casos de meningite bacteriana e viral, além de medir a sensibilidade e especificidade deste biomarcador no LCR e estudar se esse biomarcador pode ser um fator associado ao prognóstico em meningite bacteriana aguda. Métodos: Sessenta e um pacientes pediátricos, de 0 a 10 anos foram avaliados quanto à meningite e foram prospectivamente incluídos neste estudo. Na admissão, após a suspeita clínica de meningite foram submetidos à análise do LCR para o diagnóstico e uma amostra do LCR inicial foi utilizado também para análise do sTREM-1. Os pacientes foram acompanhados durante a sua internação com o registro de seu tratamento e desfecho clínico para posterior análise dos dados. Resultados: Dentre os 61 pacientes, 38 (62%) foram negativos para a meningite, 7 (11%) pacientes foram diagnosticados com meningite viral e 16 (27%) pacientes foram diagnosticados com meningite bacteriana aguda e recebeu tratamento direcionado. Sexo (p = 0,15), presença de fatores de risco identificados (p = 0,17), presença de convulsões (p = 0,31), outras complicações clínicas (p = 0,11) e mortalidade (p = 0,66) não diferiram entre os grupos. Anormalidades sensoriais (p <0,0001) e presença de cefaléia (p = 0,003) foram mais prevalentes em pacientes com meningite. Como esperado, a contagem de leucócitos, glicose e proteína no LCR foram significativamente diferentes entre pacientes com meningite e pacientes sem meningite. As concentrações de sTREM-1 no LCR de pacientes com meningite bacteriana foi superior quando comparada com pacientes com meningite viral e com controles (1204,67 pg/ml, 39,34 pg/ml e 12,09 pg/ml, respectivamente; p <0,0001). Quando sTREM-1 foi usado como um determinante de diferenciação entre pacientes com ou sem meningite bacteriana, a análise da área sob a curva ROC foi de 0,95 (IC de 95% = 0,89-1,00; p <0,0001). A presença de fatores de risco para a meningite bacteriana (p = 0,04), anormalidades sensoriais (p <0,0001), contagem de leucócitos no LCR (p = 0,01), níveis de glicose no LCR (p = 0,002), níveis de proteína no LCR (p = 0,032) e os níveis de sTREM-1 no LCR (p = 0,004) foram associados com meningite bacteriana, incluindo os níveis sTREM-1 acima do ponto de corte estabelecido de 68,0 pg/ml (p <0,0001). A meningite bacteriana (p = 0,02) e os valores de sTREM-1 maior do que o ponto de corte (68,0 pg/ml) (p = 0,04) foram associados com sequelas neurológicas graves e morte neste grupo de pacientes. Conclusão: Avaliamos os níveis sTREM-1 de crianças com suspeita clínica de meningite. Os níveis de s-TREM-1 foram aumentados nos casos de meningite bacteriana e correlacionados com o prognóstico. Os nossos resultados sugerem que níveis elevados de sTREM-1 no LCR podem ser utilizados como um biomarcador para o diagnóstico de meningite bacteriana aguda em crianças e que pode ser útil na determinação do prognóstico do paciente nesse cenário. / Background: Bacterial meningitis is an important cause of morbidity and mortality in infancy. Cerebrospinal fluid (CSF) analysis remains the gold standard diagnostic tool, however new biomarkers for diagnosis and prognosis are still required. Triggering receptor expressed on myeloid cells-1 (TREM-1) is a transmembrane receptor expressed on neutrophils and monocytes that plays an important role on the immune response. Its soluble fraction (sTREM-1) is also increased in infection, inflammation or immune diseases. In this study we evaluate the value of sTREM-1 as a biomarker of acute bacterial meningitis in pediatric patients and its possible use as a prognostic tool prospectively. Methods: Sixty-one pediatric patients, from 0 to 10 years of age were evaluated for meningitis and were prospectively included in this study. At admission, following clinical hypothesis of meningitis patients were submitted to CSF analysis for diagnosis and a sample of initial CSF was also used for TREM-1 analysis. Patients were followed during hospitalization and clinical evaluation and treatment outcome were recorded for posterior analysis. Results: Thirty-eight (62%) out of 61 patients were negative for meningitis, 7 (11%) patients were diagnosed with viral meningitis and 16 (27%) patients were diagnosed with and received treatment for acute bacterial meningitis. Sex (p = 0.15), presence of identified risk factors (p = 0.17), presence of seizures (p = 0.31), other clinical complications (p = 0.11), and mortality (p = 0.66) did not differ among groups. Sensorial abnormalities (p<0.0001) and presence of headache (p= 0.003) were more prevalent in patients with meningitis. As expected, leukocyte count, glucose, and protein levels were significantly different between patients with meningitis and patients without meningitis. Concentrations of sTREM-1 in CSF from patients with bacterial meningitis was higher when compared to patients with viral meningitis and with controls (1204.67 pg/ml, 39.34 pg/ml and 12.09 pg/ml, respectively; p<0.0001). When sTREM-1 was used as a determinant to differentiate between patients with or without bacterial meningitis, the analysis of the area under the ROC curve (AUC) was 0.95 (95% CI=0.89-1.00; p<0.0001). Presence of risk factors for bacterial meningitis (p = 0.04), sensorial abnormalities (p<0.0001), CSF leukocyte count (p = 0.01), CSF glucose levels (p = 0.002), CSF protein levels (p = 0.032) and CSF sTREM-1 levels (p = 0.004) were all associated with bacterial meningitis, including sTREM-1 levels above the established cut-off point of 68.0 pg/ml (p<0.0001). Bacterial meningitis (p = 0.02) and values of sTREM-1 higher than the cut-off point (68.0 pg/ml) (p = 0.04) were associated with death and severe neurological disabilities in this patient cohort. Conclusion: We evaluated sTREM-1 levels in CSF of children with clinical hypothesis of meningitis. The sTREM-1 levels were increased in bacterial meningitis and correlated with prognosis. Our results suggest that CSF sTREM- 1 levels can be used as a biomarker for diagnosis of acute bacterial meningitis in children and it might be useful in determining patient’s prognosis in this scenario.
35

Receptor desencadeador expresso nas células mielóides Tipo 1 (TREM-1) no diagnóstico e prognóstico na meningite bacteriana em crianças

Torres, Vitor Félix January 2015 (has links)
Base teórica: A meningite bacteriana é uma causa importante de morbidade e mortalidade na infância. Análise do líquido cefalorraquidiano (LCR) continua a ser a ferramenta de diagnóstico padrão ouro, porém novos biomarcadores para o diagnóstico e prognóstico ainda são necessários. Receptor Desencadeador Expresso nas Células Mielóides Tipo 1 (TREM-1) é um receptor transmembrana expresso em neutrófilos e monócitos, que desempenha um papel importante na modulação da resposta inflamatória. A sua fração solúvel (sTREM-1) também é aumentada na infecção, inflamação ou doenças imunológicas. Neste estudo nós avaliamos, prospectivamente, o valor do TREM-1 como um biomarcador de meningite bacteriana aguda em pacientes pediátricos e sua possível utilização como uma ferramenta de prognóstico neste cenário. Objetivos: O objetivo primário do presente estudo é caracterizar os níveis líquóricos solúveis de TREM-1 (sTREM-1) em pacientes admitidos por suspeita clínica de meningite. Analisamos também os níveis de sTREM-1 nos casos de meningite bacteriana e viral, além de medir a sensibilidade e especificidade deste biomarcador no LCR e estudar se esse biomarcador pode ser um fator associado ao prognóstico em meningite bacteriana aguda. Métodos: Sessenta e um pacientes pediátricos, de 0 a 10 anos foram avaliados quanto à meningite e foram prospectivamente incluídos neste estudo. Na admissão, após a suspeita clínica de meningite foram submetidos à análise do LCR para o diagnóstico e uma amostra do LCR inicial foi utilizado também para análise do sTREM-1. Os pacientes foram acompanhados durante a sua internação com o registro de seu tratamento e desfecho clínico para posterior análise dos dados. Resultados: Dentre os 61 pacientes, 38 (62%) foram negativos para a meningite, 7 (11%) pacientes foram diagnosticados com meningite viral e 16 (27%) pacientes foram diagnosticados com meningite bacteriana aguda e recebeu tratamento direcionado. Sexo (p = 0,15), presença de fatores de risco identificados (p = 0,17), presença de convulsões (p = 0,31), outras complicações clínicas (p = 0,11) e mortalidade (p = 0,66) não diferiram entre os grupos. Anormalidades sensoriais (p <0,0001) e presença de cefaléia (p = 0,003) foram mais prevalentes em pacientes com meningite. Como esperado, a contagem de leucócitos, glicose e proteína no LCR foram significativamente diferentes entre pacientes com meningite e pacientes sem meningite. As concentrações de sTREM-1 no LCR de pacientes com meningite bacteriana foi superior quando comparada com pacientes com meningite viral e com controles (1204,67 pg/ml, 39,34 pg/ml e 12,09 pg/ml, respectivamente; p <0,0001). Quando sTREM-1 foi usado como um determinante de diferenciação entre pacientes com ou sem meningite bacteriana, a análise da área sob a curva ROC foi de 0,95 (IC de 95% = 0,89-1,00; p <0,0001). A presença de fatores de risco para a meningite bacteriana (p = 0,04), anormalidades sensoriais (p <0,0001), contagem de leucócitos no LCR (p = 0,01), níveis de glicose no LCR (p = 0,002), níveis de proteína no LCR (p = 0,032) e os níveis de sTREM-1 no LCR (p = 0,004) foram associados com meningite bacteriana, incluindo os níveis sTREM-1 acima do ponto de corte estabelecido de 68,0 pg/ml (p <0,0001). A meningite bacteriana (p = 0,02) e os valores de sTREM-1 maior do que o ponto de corte (68,0 pg/ml) (p = 0,04) foram associados com sequelas neurológicas graves e morte neste grupo de pacientes. Conclusão: Avaliamos os níveis sTREM-1 de crianças com suspeita clínica de meningite. Os níveis de s-TREM-1 foram aumentados nos casos de meningite bacteriana e correlacionados com o prognóstico. Os nossos resultados sugerem que níveis elevados de sTREM-1 no LCR podem ser utilizados como um biomarcador para o diagnóstico de meningite bacteriana aguda em crianças e que pode ser útil na determinação do prognóstico do paciente nesse cenário. / Background: Bacterial meningitis is an important cause of morbidity and mortality in infancy. Cerebrospinal fluid (CSF) analysis remains the gold standard diagnostic tool, however new biomarkers for diagnosis and prognosis are still required. Triggering receptor expressed on myeloid cells-1 (TREM-1) is a transmembrane receptor expressed on neutrophils and monocytes that plays an important role on the immune response. Its soluble fraction (sTREM-1) is also increased in infection, inflammation or immune diseases. In this study we evaluate the value of sTREM-1 as a biomarker of acute bacterial meningitis in pediatric patients and its possible use as a prognostic tool prospectively. Methods: Sixty-one pediatric patients, from 0 to 10 years of age were evaluated for meningitis and were prospectively included in this study. At admission, following clinical hypothesis of meningitis patients were submitted to CSF analysis for diagnosis and a sample of initial CSF was also used for TREM-1 analysis. Patients were followed during hospitalization and clinical evaluation and treatment outcome were recorded for posterior analysis. Results: Thirty-eight (62%) out of 61 patients were negative for meningitis, 7 (11%) patients were diagnosed with viral meningitis and 16 (27%) patients were diagnosed with and received treatment for acute bacterial meningitis. Sex (p = 0.15), presence of identified risk factors (p = 0.17), presence of seizures (p = 0.31), other clinical complications (p = 0.11), and mortality (p = 0.66) did not differ among groups. Sensorial abnormalities (p<0.0001) and presence of headache (p= 0.003) were more prevalent in patients with meningitis. As expected, leukocyte count, glucose, and protein levels were significantly different between patients with meningitis and patients without meningitis. Concentrations of sTREM-1 in CSF from patients with bacterial meningitis was higher when compared to patients with viral meningitis and with controls (1204.67 pg/ml, 39.34 pg/ml and 12.09 pg/ml, respectively; p<0.0001). When sTREM-1 was used as a determinant to differentiate between patients with or without bacterial meningitis, the analysis of the area under the ROC curve (AUC) was 0.95 (95% CI=0.89-1.00; p<0.0001). Presence of risk factors for bacterial meningitis (p = 0.04), sensorial abnormalities (p<0.0001), CSF leukocyte count (p = 0.01), CSF glucose levels (p = 0.002), CSF protein levels (p = 0.032) and CSF sTREM-1 levels (p = 0.004) were all associated with bacterial meningitis, including sTREM-1 levels above the established cut-off point of 68.0 pg/ml (p<0.0001). Bacterial meningitis (p = 0.02) and values of sTREM-1 higher than the cut-off point (68.0 pg/ml) (p = 0.04) were associated with death and severe neurological disabilities in this patient cohort. Conclusion: We evaluated sTREM-1 levels in CSF of children with clinical hypothesis of meningitis. The sTREM-1 levels were increased in bacterial meningitis and correlated with prognosis. Our results suggest that CSF sTREM- 1 levels can be used as a biomarker for diagnosis of acute bacterial meningitis in children and it might be useful in determining patient’s prognosis in this scenario.
36

Rôle de LECT2 dans le microenvironnement immunitaire au cours de la cancérogènese hépatique / Role of LECT2 in the Immune Microenvironment During Liver Carcinogenesis

L'Hermitte, Antoine 25 October 2016 (has links)
Le carcinome hépatocellulaire (CHC) est la deuxième cause de mortalité par cancer dans le monde. Plusieurs études attestent du rôle du microenvironnement tumoral (MET) comme acteur fondamental de la carcinogenèse. A l’aide de modèles murins mimant un sous groupe de CHC fréquent, notre équipe avait identifié la molécule LECT2 comme un effecteur moléculaire important du MET dans le contrôle de l’agressivité tumorale.L'objectif de ma thèse a été d’adresser le rôle fonctionnel de LECT2 dans le microenvironnement immunitaire au cours du CHC.A l’aide de modèles murins, nous observons que l’absence de LECT2 entraine une accumulation importante de cellules myéloïdes dans le MET. Nous montrons que ces cellules myéloïdes sont immatures, arborent des capacités immunosuppressives puissantes vis-à-vis des lymphocytes T et ont un programme transcriptionnel permettant une action promotrice de tumeurs. De façon intéressante, l’accumulation de ces acteurs dans le microenvironnement est associée à l’émergence de nodules tumoraux indifférenciés exprimant des marqueurs de transition épithélio-mésenchymateuse/cellules progénitrices/métastases.D’un point de vue mécanistique, nous avons démontré une perte de différenciation plus importante des hépatocytes en absence de LECT2 dans des conditions d’activation de la signalisation β-caténine. Nous montrons également par des expériences de co-culture que les cellules myéloïdes infiltrant les tumeurs en absence de LECT2 ont une forte capacité à induire une perte de différenciation des hépatocytes.Enfin, nous avons analysé l'expression de LECT2 dans une vaste cohorte d’échantillons humains de CHC. Nous montrons que la diminution d’expression de LECT2 corrèle fortement avec 1)- la présence d’invasion vasculaire, 2)- la perte de différenciation des hépatocytes tumoraux et 3)- la présence d’infiltrats inflammatoires.L’ensemble de ces données démontre que LECT2 agit comme un régulateur essentiel dans la cancérogénèse hépatique à travers son action double sur les hépatocytes et sur la fonction des cellules myéloïdes infiltrant les tumeurs. Ainsi, ces travaux identifient LECT2 comme un biomarqueur potentiel ouvrant de nouvelles perspectives de traitement du CHC. / Hepatocellular carcinoma (HCC) is the second cause of cancer-rel ated death worldwide. Several studies highlighted the tumor microenvironment (TEM) as a key player in cancer from initiation to progression steps of tumorigenesis. Using relevant HCC mouse models, our team identified the chemokine-like LECT2 as a critical actor of liver TEM in the control of tumor aggressiveness.The aim of my thesis was to address functionally the role of LECT2 in the immune microenvironment during HCC.Using mouse models, we observed that the absence of LECT2 induces a significant accumulation of myeloid cells in the TEM. We showed that these myeloid cells were immature, harbored strong immunosuppressive capabilities on T cells and expressed a transcriptional program sustaining tumor progression. Interestingly, the accumulation of these actors in the microenvironment is associated with the emergence of poorly differentiated tumor nodules expressing epithelial-to-mesenchymal transition / progenitor / metastasis markers.Mechanistically, we demonstrated that LECT2-deficient hepatocytes in the context of β-catenin activation were able to perform EMT like WT hepatocytes do after TGF-β1 challenge. In co-culture experiments, we demonstrated that tumor-infiltrating myeloid cells in the absence of LECT2 have a strong ability to induce hepatocyte EMT.Finally, we analyzed the expression of LECT2 in a vast cohort of HCC liver samples and found that downregulation of LECT2 expression strongly correlates with 1) - the presence of vascular invasion, 2) – histological grade and 3) - the presence of inflammatory infiltrates.Altogether, our data demonstrate that LECT2 acts as a strong regulator of liver tumor aggressiveness through its dual action on hepatocytes and impact on the function of tumor infiltrating myeloid cells. This work identifies LECT2 as a new biomarker for HCC and pave the way to new therapeutic strategies.
37

Antibody-mediated initiation and lymphocyte-targeting therapies in CNS demyelinating disease

Torke, Sebastian 10 July 2019 (has links)
No description available.
38

Immunosenescence in Choroidal Neovascularization (CNV): Transcriptional Profiling of Naïve and CNV-Associated Retinal Myeloid Cells during Aging

Schlecht, Anja, Thien, Adrian, Wolf, Julian, Prinz, Gabriele, Agostini, Hansjürgen, Schlunck, Günther, Wieghofer, Peter, Boneva, Stefaniya, Lange, Clemens 02 February 2024 (has links)
Immunosenescence is considered a possible factor in the development of age-related macular degeneration and choroidal neovascularization (CNV). However, age-related changes of myeloid cells (MCs), such as microglia and macrophages, in the healthy retina or during CNV formation are illdefined. In this study, Cx3cr1-positive MCs were isolated by fluorescence-activated cell sorting from six-week (young) and two-year-old (old) Cx3cr1GFP/+ mice, both during physiological aging and laser-induced CNV development. High-throughput RNA-sequencing was performed to define the age-dependent transcriptional differences in MCs during physiological aging and CNV development, complemented by immunohistochemical characterization and the quantification of MCs, as well as CNV size measurements. These analyses revealed that myeloid cells change their transcriptional profile during both aging and CNV development. In the steady state, senescent MCs demonstrated an upregulation of factors contributing to cell proliferation and chemotaxis, such as Cxcl13 and Cxcl14, as well as the downregulation of microglial signature genes. During CNV formation, aged myeloid cells revealed a significant upregulation of angiogenic factors such as Arg1 and Lrg1 concomitant with significantly enlarged CNV and an increased accumulation of MCs in aged mice in comparison to young mice. Future studies need to clarify whether this observation is an epiphenomenon or a causal relationship to determine the role of immunosenescence in CNV formation.
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Rôle de l'autophagie dans la dissémination du VIH-1 par les cellules dendritiques dérivées des monocytes circulants

Tep, Tévy-Suzy 10 1900 (has links)
Les cellules myéloïdes incluant les monocytes, les macrophages et les cellules dendritiques (DCs, dendritic cells) contribuent à la pathogénèse de l’infection à VIH-1 en participant à la dissémination du virus, mais également en représentant des réservoirs viraux potentiels. Leurs fonctions sont exploitées par le VIH-1 afin d’assurer sa propagation à travers l’organisme. Notamment, une infection à VIH-1 est associée à une altération de la présentation antigénique et la perte de lymphocytes T CD4+ spécifiques à des antigènes. L’autophagie est un processus catabolique universel impliqué dans la régulation de la présentation antigénique subséquente à la neutralisation/destruction du pathogène. Des études récentes suggèrent que le VIH-1 altère le mécanisme d’autophagie afin d’assurer sa survie. Le premier volet de ce projet de maîtrise a visé la caractérisation des effets du VIH-1 sur l’autophagie dans les DCs dérivées de monocytes circulants (MDDC, monocyte-derived dendritic cells) et l’identification des stratégies thérapeutiques pour contrecarrer ces effets. Les objectifs spécifiques ont été de : (i) caractériser l’expression de marqueurs de maturation sur des MDDC exposées au VIH-1 in vitro, (ii) quantifier l’expression des protéines liées à la régulation positive (i.e., ATG5, LC3, p62) et négative (i.e., mTOR) de l’autophagie dans les MDDC exposées au VIH, (iii) déterminer le rôle de l’autophagie dans la trans infection du VIH-1 aux lymphocytes T CD4+ et (iv) explorer l’impact de l’autophagie sur la présentation antigénique par les MDDC infectées à VIH-1 in vitro. Nos résultats démontrent qu’une exposition des MDDC au VIH-1 in vitro altère dramatiquement leur maturation et leur habileté à induire la prolifération des cellules T autologues en réponse à Staphylococcus aureus et Cytomegalovirus (CMV) mais pas la réponse induite par Staphylococcal enterotoxin B (SEB). Nous démontrons que l’exposition des MDDC au VIH s’associe à une augmentation de l’expression de la protéine mTOR totale et de sa forme phosphorylée (phospho-mTOR) et de la protéine p62. Le traitement des MDDC à la rapamycine diminue l’expression de mTOR et réduit la capacité de trans infection du VIH-1 par les MDDC, sans toutefois restaurer leur potentiel immunogène. En effet, nous observons que la rapamycine réduit l’expression de CD83 par les MDDC et augmente l’expression de CCR7, indiquant ainsi que l’effet immunosuppresseur documenté de la rapamycine est associé à une défaillance de maturation des MDDC. Le second volet de ce projet de recherche s’est intéressé à la contribution des cellules myéloïdes à la persistance virale chez les sujets infectés par le VIH-1 sous thérapie antirétrovirale. Les objectifs spécifiques ont été : (i) d’évaluer la présence de différentes formes d’ADN viral dans les monocytes circulants de patients infectés par le VIH-1 et (ii) de mesurer l’intégration et la réplication virale dans des macrophages dérivés de monocytes (MDM) de patients infectés sous ART. Nos résultats indiquent que les monocytes portent des formes précoces de transcription virale inverse (ADN du VIH RU5) et que, malgré une charge virale plasmatique indétectable sous ART, les MDM supportent la réplication virale. Ces données très préliminaires apportent des évidences en faveur de la contribution des cellules myéloïdes à la persistance virale sous ART et représentent une ouverture pour un projet de recherche plus complexe dans le futur. En somme, nos résultats démontrent que le VIH-1 altère le potentiel immunogène des MDDC et que la rapamycine peut être employée pour limiter la trans infection des lymphocytes T CD4+ par les MDDC. Néanmoins, l’incapacité de la rapamycine à rétablir le potentiel immunogène des MDDC incite à identifier de nouvelles stratégies manipulant l’autophagie pour une restauration optimale de la compétence immunitaire chez les sujets infectés à VIH-1. Les cellules myéloïdes jouent un rôle primordial dans la dissémination et la persistance virale et doivent donc être ciblées par les stratégies actuelles d’éradication des réservoirs du VIH sous ART. / Myeloid cells including monocytes, macrophages and dendritic cells (DC) contribute to HIV-1 pathogenesis by participating in viral dissemination but also by representing potential viral reservoirs. Myeloid cells functions are exploited by HIV in order for the virus to spread throughout the organism. Notably, HIV-1 infection is associated with alterations in antigen presentation and the loss of pathogen-specific CD4+ T-cells. Autophagy is a universal catabolic process involved in the regulation of antigen presentation subsequent to pathogen neutralization/destruction. Recent studies suggest that HIV inhibits autophagy in DC so that it survives within the host. The goal of the main part of this master’s research project was to characterize the effects of the HIV exposure on the autophagy process in monocytes-derived DC (MDDC) and to identify therapeutic strategies to counteract these effects. The specific aims were to : (i) measure the expression of maturation markers on MDDC exposed to HIV-1 in vitro (ii) quantify the expression of proteins that positively (i.e., ATG5, LC3, p62) or negatively regulate autophagy (i.e., mTOR), (iii) determine autophagy role in HIV-1 trans infection to CD4+ lymphocytes T and (iv) explore the impact of autophagy on antigen presentation by in vitro HIV-infected MDDC. Our results demonstrated that exposure to HIV in vitro dramatically impaired MDDC maturation and their ability to induce proliferation of autologous CD4+ T-cells in response to Staphylococcus aureus and Cytomegalovirus (CMV) but not Staphylococcal enterotoxin B (SEB). Exposition of MDDC to HIV-1 was associated with an increase of mTOR, phosphomTOR and p62 expression. Treatment of MDDC with rapamycin decreased mTOR expression and altered MDDC trans infection ability although it failed to restore MDDC immunogenic potential. Indeed, rapamycin diminished CD83 expression on MDDC surface and increased CCR7 expression, indicating that the documented immunosuppressive property of this drug is associated with an impaired MDDC maturation. The second part of this master’s research project focused on the contribution of myeloid cells to HIV-1 reservoir persistence under ART. The objectives were to: (i) evaluate the presence of different forms of viral DNA in circulating monocytes from HIV-1 infected subjects and (ii) determine the viral integration and replication in monocytes-derived macrophages (MDM) from infected individuals receiving viral suppressive ART. Our results show that monocytes harbor early products from viral transcription (RU5 HIV-DNA) and that MDM support viral replication. Together, these very preliminary findings bring evidences that monocytes contribute to viral persistence under ART. Overall, our results indicate that HIV alters the immunogenic potential of DC and that rapamycin limits HIV trans-infection by DC. However, the fact that rapamycin fails to restore the immunogenic potential of DC stresses the need to identify additional strategies to manipulate the autophagy process for an optimal restoration of immune competence in HIV-infected subjects. Myeloid cells play a crucial role in HIV persistence and dissemination and thus must be aimed at when elaborating an antiviral therapy.
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Rôle des cellules myéloïdes immatures GR1+CD11b+ dans le rejet du mastocytome P815 / Role of GR1+CD11b+ myeloid immature cells on P815 mastocytoma rejection

Lanaya, Hanane 20 June 2008 (has links)
The failure of the immune system to provide efficient protection against tumour cells has been considered as a major issue in immunology. It is now well established that inadequate function of the host immune system is one of the main mechanisms by which tumours escape from immune control contributing to the limited success of cancer immunotherapy. Several cell populations have been described which display immunosuppressive properties and may impede tumor-specific immunity. Among them, GR1+CD11b+ immature myeloid suppressor cells and CD4+CD25+ regulatory T cells seem to play an important role. These cells accumulate in the spleens of tumour bearing mice and patients with cancer and contribute to immunosuppression by inhibiting the function of CD8+ T cells and/or by promoting tumour angiogenesis.<p><p>The aim of our work was to define the mechanisms by which a single dose of cyclophosphamide (CTX), a chemical agent commonly used in chemotherapy treatment, induces the rejection of established P815 mastocytoma. <p><p>Our data show that CTX treatment leads to the selective loss of GR1medCD11b+ splenic myeloid cell producing TGF-â, a cytokine which is known to suppress antitumoral response. Furthermore, injection of CTX causes a decrease in the number of naturally occurring regulatory T cells (CD4+CD25+Foxp3+) in the spleen and the tumor. Finally, CTX treatment induces the differentiation of GR1highCD11b+ splenic myeloid cells into mature GR1highCD11b+CD11c+ (possibly dendritic cells?) which express high levels of CD11c, MHC class II and CD86 molecules. Of note, these cells are mainly detected in tumour necrosis areas. <p><p>Collectively, these results suggest that CTX prevents suppressive mechanisms and induces a population of CD11c+ myeloid cells which may present tumor antigens and activate T lymphocytes, an hypothesis in line with the requirement for CD4+ cells in CTX-induced long term resistance. <p> / Doctorat en Sciences / info:eu-repo/semantics/nonPublished

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