Thesis (Ph. D.)--University of Texas at Austin, 2007. / Vita. Includes bibliographical references.

Thesis (M.S.)--Montana State University--Bozeman, 2006. / Typescript. Chairperson, Graduate Committee: Keith A. Hutchison. Includes bibliographical references (leaves 42-44).

Th. univ.--Méd.--Nancy 1, 1983. N°: 7 DU.

Th.--Méd.--Reims, 1981. N°: 61.

Th.--Méd.--Reims, 1981. N°: 83.

Studies of cognitive performance among persons with chronic fatigue syndrome (CFS) have yielded largely inconsistent results. The present study sought to contribute to findings in this area by examining intraindividual variability as well as level of performance in cognitive functioning. A battery of cognitive measures was administered to 14 CFS patients and 16 healthy individuals on 10 weekly occasions. Analyses comparing the two groups in terms of level of performance as defined by latency and accuracy scores revealed that the CFS patients were slower in their reaction speeds than healthy persons. Comparing the groups with respect to intraindividual variability (as measured by intraindividual standard deviations and coefficients of variation) revealed greater intraindividual variability within the CFS group, although the results varied by task and time frame used. Intraindividual variability was found to be fairly stable across time, and consistent across tasks on each testing occasion. The present findings support the proposition that intraindividual variability is a meaningful correlate of cognitive performance in CFS patients. / Graduate

Extensive efforts have shed light on the identity and biology of cancer stem cells, required and sufficient for the propagation of hematological malignancies and solid tumours. Much less is understood about the closely related issue as to the identity and properties of the normal stem and progenitor cells targeted by oncogenic lesions, and how the nature of the targeted cell might impact on the biology and clinical picture of the resulting cancer. To address this, we developed a mouse model allowing targeted inactivation of Ezh2 and Runx1 to different haematopoietic compartments. Inactivating mutations of EZH2 and RUNX1 frequently co-occur in haematological malignancies with markedly different phenotypes including myelodysplastic syndrome (MDS) and early thymic progenitor (ETP) leukaemia. Inactivation of Ezh2 and Runx1 in adult haematopoietic stem cells (HSCs) resulted in perturbed haematopoiesis leading to development of an MDS-like disease. Unexpectedly, this MDS phenotype could be fully reproduced when Ezh2 and Runx1 inactivation was targeted to multipotent progenitors (MPPs) using Flt3-Cre. Furthermore, the disease was transplantable by MPPs, but not more committed progenitor populations, demonstrating that MDS tumour propagating potential is not exclusive to intrinsically self-renewing HSCs. Targeting Ezh2 and Runx1 inactivation to early lympho-myeloid progenitors did not result in an MDS phenotype. These mice showed a marked expansion of ETPs within the thymus, combined with a block in thymocyte differentiation. These expanded ETPs displayed transcriptional features characteristic of ETP leukaemia, a treatment-resistant acute leukaemia subtype hypothesised to originate from ETPs. Combination of inactivation of Ezh2 and Runx1 in ETPs with the constitutively activating Flt3-ITD signalling mutation resulted in an aggressive lympho-myeloid acute leukaemia, which could be propagated by the expanded ETP population. These findings demonstrate the potential of lympho-myeloid progenitors such as ETPs to become leukaemia stem cells which propagate a disease retaining lympho-myeloid features. We used this novel ETP leukaemia model to explore therapeutic targeting of Ezh2-inactivated ETP leukaemias using inhibitors of the bromodomain and extra terminal (BET) proteins. Aberrant transcription resulting from epigenetic changes induced by Ezh2 loss could be reversed by BET inhibitors, and these compounds showed therapeutic efficacy against both mouse and human ETP leukaemias in vitro and in vivo.

Orientador: Maricilda Palandi de Mello / Tese (doutorado) - Universidade Estadual de Campinas, Instituto de Biologia / Made available in DSpace on 2018-08-25T05:17:39Z (GMT). No. of bitstreams: 1 Guaragna_MaraSanches_D.pdf: 3317402 bytes, checksum: 18a0edd0d0e225eed7d57b65d9bea76b (MD5) Previous issue date: 2014 / Resumo: A Síndrome Nefrótica (SN) é a principal doença renal na infância, sendo caracterizada por proteinuria, edema, hipoalbuminuria e hiperlipidemia. Usualmente é classificada de acordo com a idade em que se apresenta em Congênita (SNC), quando se manifesta intraútero ou durante os primeiros três meses de vida, Infantil durante o primeiro ano de vida, na Infância, entre o primeiro ano até os 12 anos de idade e Juvenil, entre os 12 e os 18 anos de idade, aproximadamente. De acordo com a resposta ao tratamento com corticoesteróides os pacientes podem ser divididos em córtico-resistentes (CR), córtico-sensíveis (CS) ou córtico-sensíveis com recidiva frequente (CS,RF). Uma disfunção na barreira de filtração glomerular leva às manifestações clínicas decorrentes da síndrome, tais como proteinúria maciça na urina. Mutações em diversos genes vêm sendo correlacionadas com a SN em crianças. No entanto, os genes mais estudados e responsáveis pela maioria dos casos são os genes NPHS1, NPHS2 e WT1. Os objetivos deste trabalho foram identificar e verificar a distribuição de mutações nestes três genes em uma casuística brasileira com SN ou proteinúria isolada e avaliar cada alteração identificada utilizando diversas predições in silico, com o intuito de se esclarecer suas respectivas funções biológicas. Para isto foi realizada a análise molecular de 150 crianças e adolescentes, sendo três não aparentados com SNC e os demais 147 com SN Infantil, SN na infância, SN juvenil e proteinúria isolada, dos quais 134 eram não aparentados. Além destes 150 pacientes, também foram analisados os materiais de biópsias renais fixadas em bloco de parafina de sete pacientes que já foram a óbito com SNC. Para verificar a segregação alélica nas famílias, para os casos nos quais foram identificadas alterações, a análise molecular dos pais foi realizada, quando possível. Um grupo controle de indivíduos saudáveis foi incluído para se avaliar a frequência de alterações não depositadas em bancos de dados. No estudo do gene NPHS1 para os casos com SNC identificamos mutações missense, frameshift e em região de splicing nos três pacientes encaminhados no período da tese e em um dos materiais proveniente de biópsia renal. Assim, um total de quatro pacientes com SNC apresentaram mutações que se correlacionam com o grave quadro clínico apresentado. Para os pacientes com SN infantil, SN infância/juvenil e proteinúria isolada, foram triados o gene NPHS2 e os éxons 8-9 do gene WT1. No estudo do gene NPHS2 foram identificadas duas alterações em heterozigose nos padrões de herança autossômica recessiva em 2,7% (4/147), todos CR, enquanto que apenas uma alteração em heterozigose simples foi identificada em 9,5% (14/147) em casos de SN com apresentação menos grave e tardia. Em três dos 14 pacientes com uma alteração no gene NPHS2, alterações no gene NPHS1 foram também identificadas, todas já descritas como polimorfismos frequentes na população em geral. Para o gene WT1, com herança autossômica dominante, foram identificadas mutações em heterozigose simples em 2,04% (3/147). A avaliação da frequência e distribuição de mutações nestes genes em crianças com SN é inédita no Brasil e traz um direcionamento para a análise molecular de grupos específicos das crianças com SN. Além disto, este trabalho contribui para o estabelecimento das bases moleculares da doença na população brasileira, o que tem uma repercussão importante na conduta dos pacientes, uma vez que, nos que apresentam mutações, pode-se considerar o transplante renal a partir de doador vivo, pois para estes considera-se um risco menor de recidiva de glomérulo esclerose focal e segmentar após transplante do que para pacientes sem mutações / Abstract: Nephrotic syndrome (NS) is the main kidney disease in children. It is characterized by proteinuria, edema, hypoalbuminemia and hyperlipidemia. Acccording to the age of the diagnosis, it is usually classified as Congenital (CNS) when it manifests in utero or during the first three months of life, Infantile when the event occurs during the first year of life, in Childhood when symptoms occur between one year and 12 years and Juvenile, with onset between 12 and 18 years old. NS is traditionally separated on the basis of the response to standard steroid treatment as steroid-resistant (SRNS), steroid-sensitive (SSNS) or steroid sensitive with frequent relapses. A dysfunction in the glomerular filtration barrier leads to the characteristic clinical manisfestations of the syndrome such as massive loss of essential proteins in the urine. Mutations in different genes have been associated with NS in children. However, the most studied genes are NPHS1, NPHS2 and WT1, which are responsible for the great majority of the cases. The aims of this study were to identify and verify mutation distributions in those three genes in a Brazilian cohort with NS or isolated proteinuria and to characterize each identified variation by using different in silico prediction programs in order to understand its biological functions. For that, we performed molecular analyses of 150 children and adolescents, being three unrelated children with CNS and the remaining 147 with Infantile, Childhood, Juvenile NS and isolated proteinuria, being 134 unrelated. Besides those 150 patients, paraffin-embebbed renal biopsies of seven patients who had died from CNS have been also analysed. To verify allelic segregation in the family, molecular analyses were also held, whenever possible, for parents of patients in whom mutations were identified. A healthy control group was included in the study to evaluate the frequency of alterations that were absent in the databanks. In the NPHS1 study for CNS cases, we identified missense, frameshift and splicing mutations in the three patients included during the thesis project and in the paraffin-embedded renal biopsy tissue of a patient who had died of CNS. Therefore a total of four CNS cases bore mutations that are associated with the disease. NPHS2 gene and exons 8-9 of WT1 were screened for the 147 patients with infantile NS, childhood/juvenile NS and isolated proteinuria. In the NPHS2 study, two heterozygous alterations compatible to an autossomal recessive inheritance have been identified in 2,7% (4/147), all of the cases were SRNS; whereas, only one heterozygous alteration was identified in 9,5% (14/147), such cases had a less severe and late onset form of NS. Three out of those 14 patients presented sequence variations also in NPHS1 gene, but they have been described as neutral polymorphisms. For the WT1 gene whose mutations present a dominant pattern of inheritance, heterozygous alterations have been identified in 2,04% (3/147). This is the first study focusing frequency evaluation and mutation distribution in Brazilian children with NS and provides a guidance to the molecular analysis of specific case groups of SN. Moreover, this work contributes to the establishment of the molecular bases of this disease in the Brazilian population, what reflects mainly in the conduction of patients, since those bearing mutations can be considered for receiving a kidney from a living donor, because for them it is considered a lower risk of recurrent focal segmental glomerulosclerosis after kidney transplant than for patients without mutations / Doutorado / Genetica Animal e Evolução / Doutora em Genética e Biologia Molecular

M.Tech.

Down syndrome (referenced in USA) or Down's syndrome throughout the world, the most common genetic birth defect is a chromosomal anomaly. It affects all races and economic levels equally throughout the world. It has only been over the past twenty years that significant advances in human genetics have compounded a move toward the future needs and potential of children and young adults with Down syndrome. Henceforth, individuals with Down syndrome can now be seen more within the confines of their neighboring schools, homes and communities.