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Doctoral Thesis
DOI
https://doi.org/10.11606/T.5.2020.tde-15032022-110724
Document
Author
Full name
Nelson Gaburo Junior
E-mail
Institute/School/College
Knowledge Area
Date of Defense
Published
São Paulo, 2019
Supervisor
Committee
Sabino, Ester Cerdeira (President)
Kulikowski, Leslie Domenici
Dinardo, Carla Luana
Montenegro, Marilia Moreira
Title in Portuguese
Estudo da expressão gênica em pacientes com doença de Chagas recebendo tratamento com Benznidazole: " a procura por um biomarcador de cura"
Keywords in Portuguese
Benznidazole
Biomarcadores
Doença de Chagas
Expressão gênica
Resposta terapêutica
Transcriptoma
Abstract in Portuguese
Mais de 100 anos após a doença de Chagas (DC) ter sido descrita pela primeira vez, em alguns países, como o Brasil, o benznidazole (BZN) é o único medicamento disponível para seu tratamento e, no entanto, não existe um bom marcador de cura. A descoberta de biomarcadores associados à resposta terapêutica do BZN é essencial. O objetivo deste estudo foi determinar se os perfis de expressão gênica de células sanguíneas periféricas poderiam distinguir os indivíduos com DC que respondem positivamente ao tratamento com BZN (Respondedores) daqueles que não respondem (NRespondedores). O critério de resposta terapêutica adotado foi a negativação sérica para T. cruzi por qPCR, avaliada em três momentos, final do tratamento 60 dias (T60), seis meses (T6M) e um ano (T12M) após o início do tratamento com BZN (T0). O perfil transcriptômico foi realizado por sequenciamento massivo (RNAseq) e avaliado utilizando amostras de RNA total de oito pacientes Respondedores e 17 NRespondedores, para amostras do T0, T60 e T12M. Dos 20802 genes codificantes observados, 1882 foram expressos de forma significativa e diferencial entre os grupos, em pelo menos um desses três momentos. Destes, 13 genes foram selecionados como candidatos a biomarcadores, para validação por RT-qPCR. O gene LTF provou ser um biomarcador tardio da resposta terapêutica do BZN, apresentando diferença significativa na expressão de amostras T12M (valor de P de 0,01). Os genes AZU1 e LCN2 demonstraram perfil de biomarcadores da resposta terapêutica ao BZN logo após o término do tratamento, bem como de forma tardia, uma vez que o gene AZU1 apresentou diferença significativa de expressão para as amostras T60 e T12M (valor de P de 0,05). Assim como o gene LCN2 para as amostras T60 (valor de P de 0,05), e T12M (valor de P de 0,01). Estes três genes têm plausibilidade biológica pois estão associados a resposta imune. Desta forma estes marcadores podem ser bons candidatos a validação em grandes estudos clínicos
Title in English
Gene expression study in Chagas disease patients receiving benznidazole treatment: the search for a biomarker of cure
Keywords in English
Benznidazole
Biomarkers, Transcriptome
Chagas disease
Gene expression
Therapeutic response
Abstract in English
More than 100 years after Chagas disease (CD) was first described, in some countries, such as Brazil, benznidazole (BZN) is the only drug available for its treatment, but there is no good biomarker of cure. Therefore, the discovery of biomarkers associated with BZN therapeutic response is essential. The aim of this study was to determine whether peripheral blood cell gene expression profiles could distinguish CD subjects who respond positively to BZN (Responders) and non-responders (NR) treatment. The criterion of therapeutic response adopted was serum negative for T. cruzi by qPCR, evaluated at three moments, end of treatment - 60 days (T60), six months (T6M) and one year (T12M) after the beginning of BZN treatment. (T0). The transcriptomic profile was performed by massive sequencing (RNAseq) and evaluated using total RNA samples from eight Responding and 17 NResponding patients for T0, T60 and T12M samples. Of the 20802 coding genes observed, 1882 were expressed significantly and differently between groups at least one of these three moments. Of these, 13 genes were selected as candidate biomarkers for validation by RT-qPCR. The LTF gene proved to be a late biomarker of BZN therapeutic response, showing significant difference in T12M sample expression (P value 0.01). The AZU1 and LCN2 genes demonstrated biomarkers profile of the therapeutic response to BZN soon after treatment completion, as well as late, since the AZU1 gene showed significant difference of expression for samples T60 and T12M (P value of 0 .05). As well as the LCN2 gene for samples T60 (P value 0.05), and T12M (P value 0.01). These three genes are biological plausible because they are all related to immune response. They are candidates for validation in large scale clinical trial studies
 
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Publishing Date
2022-03-15
 
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