Thesis (M.D.)--Boston University

Thesis (M.S.)--Oregon State University, 2008. / Printout. Includes bibliographical references (leaves 89-99). Also available on the World Wide Web.

Submitted by Valquíria Barbieri (kikibarbi@hotmail.com) on 2017-08-30T21:44:32Z No. of bitstreams: 1 DISS_2014_Beluci Bianca Nunes de Siqueira.pdf: 720939 bytes, checksum: f785c41d77a555cc4b6a978ad9366ed8 (MD5) / Approved for entry into archive by Jordan (jordanbiblio@gmail.com) on 2017-09-01T14:03:51Z (GMT) No. of bitstreams: 1 DISS_2014_Beluci Bianca Nunes de Siqueira.pdf: 720939 bytes, checksum: f785c41d77a555cc4b6a978ad9366ed8 (MD5) / Made available in DSpace on 2017-09-01T14:03:51Z (GMT). No. of bitstreams: 1 DISS_2014_Beluci Bianca Nunes de Siqueira.pdf: 720939 bytes, checksum: f785c41d77a555cc4b6a978ad9366ed8 (MD5) Previous issue date: 2014-07-11 / CAPES / Esta pesquisa tem como proposta compreender a experiência de adoecimento de adultos jovens por uma condição crônica: a Leucemia Mielóide Aguda. Ressaltamos nesse estudo a dimensão social, pois essa nova condição é tratada com prognóstico ruim, mutilante, fatal; sendo comparada/associada a desordens físicas, mentais e sociais, além disso, a sociedade deprecia as pessoas adoecidas pelo câncerestigmatizando- as. Trata-se de uma pesquisa qualitativa baseado em pressupostos da fenomenologia de Alfred Schutz. As informações foram obtidas mediante entrevistas semiestruturadas realizada com quatro jovens, na faixa etária de 20 a 28 anos, em fase de manutenção no tratamento em uma unidade de referência oncológica no período de novembro de 2013 até janeiro de 2014, no estado de Mato Groso. Após as entrevistas foi realizada a descrição dos sujeitos entrevistados, e em seguida o agrupamento dos temas principais nas experiências dos adoecidos. Os resultados abrangem: o processo de descoberta do adoecimento por leucemia, em que destacase o diagnóstico realizado com rapidez sendo esse o diferencial entre a vida e a morte; o conceito, sendo a leucemia atribuída a uma doença fatal, contagiosa, silenciosa e invisível; noções causais relacionado a uma doença com causas pluralísticas de acordo com o seu contexto, como hereditariedade, agentes externos e momento marcante negativamente em sua vida; os impactos e as estratégias cotidianas de enfrentamento relatados com maior importância estavam ligados com a aparência corporal, morte vivenciada de amigos e prenúncios da própria morte e o apoio social recebidos tanto pelo apoio informal quanto formal para a realização do tratamento;e as motivações dos sujeitos para as suas ações. A pesquisa demonstrou a complexidade do adoecimento crônico, como o adoecimento marca a vida cotidiana dos sujeitos e como são realizadas as estratégias de enfrentamento na tentativa de integrar a condição crônica ao novo ritmo da vida, resignificando sua experiência com a leucemia. Além disso, possibilita a refletir sobre as práticas de atenção e de gestão oncológica. / This research aims at understanding the experience of illness in young adults with a chronic condition: the Acute Myeloid Leukemia. This study emphasize the social dimension, because this new condition is treated bad, mutilating, fatal prognosis; being compared / associated with physical, mental, and social disorders, moreover, detracts society people with cancer have fallen ill-branding them. This is a qualitative research based on assumptions of phenomenology of Alfred Schutz. Data were obtained through semi-structured interviews conducted with four youths, aged 20-28 years in the maintenance phase of treatment in an oncology referral from November 2013 until January 2014, the state of Mato Groso. After the interviews were performed description of the interviewees, and then grouping the main themes in the experiences of the diseased. The results include: the process of discovery of illness from leukemia, where the highlight is the diagnosis made quickly that being the difference between life and death; the concept, and the leukemia attributed to a fatal, contagious, silent and invisible disease; causal notions related to a disease with pluralistic causes according to its context, such as heredity, external agents and negatively striking moment in your life; impacts and everyday coping strategies reported most importance were linked with body appearance, experienced death of friends and harbingers of death itself and the social support received by both the informal and formal support for the completion of the treatment, and the motivations of the subjects for their actions. Research has demonstrated the complexity of chronic illness, such as illness marks the daily lives of the subjects and how the coping strategies in an attempt to integrate the new chronic condition pace of life are held, redefining his experience with leukemia. Furthermore, it allows to reflect on care practices and oncological management.

Orientadores: José Andrés Yunes, Nilson Ivo Tonin Zanchin / Tese (doutorado) - Universidade Estadual de Campinas, Instituto de Biologia / Made available in DSpace on 2018-08-24T06:00:33Z (GMT). No. of bitstreams: 1 Silveira_AndreBortolini_D.pdf: 16883235 bytes, checksum: e0759c48520d471791a5272349e1a837 (MD5) Previous issue date: 2013 / Resumo: A via PI3K está frequentemente hiperativada em células primárias de leucemia linfoide aguda T (LLA-T) pediátrica, característica previamente associada à resistência a glucocorticoides. Pacientes cujas células leucêmicas apresentam mutações em PTEN, o principal regulador negativo de PI3K, podem apresentar maior risco de falha na terapia de indução e recaída. Neste estudo, uma assinatura baseada em expressão gênica foi utilizada para acessar o nível de ativação da via PI3K em amostras diagnósticas de LLA-T. Nós identificamos Myc como um importante integrador da atividade de sinalização por PI3K e observamos que maior atividade da via está associada à resistência a glucocorticoides e pior prognóstico. O inibidor de PI3K AS605240 mostrou atividade antileucêmica e forte sinergismo com glucocorticoides tanto in vitro como em um modelo xenográfico de LLA-T em camundongos NOD/SCID. Em contraste, a inibição de PI3K resultou em antagonismo com metotrexato e daunorrubicina, drogas que atuam preferencialmente em células em divisão. Esta interação antagonística, no entanto, pôde ser revertida pelo uso de um esquema temporal específico de administração das drogas. Nossos dados indicam os potenciais benefícios e limitações para a incorporação de inibidores de PI3K na terapia da LLA-T / Abstract: The PI3K pathway is frequently hyperactivated in primary T-cell acute lymphoblastic leukemia (T-ALL) cells. Activation of the PI3K pathway has been suggested as one mechanism of glucocorticoid resistance in T-ALL, and patients harboring mutations in the PI3K negative regulator PTEN may be at increased risk of induction failure and relapse. In this study, a PI3K gene expression signature was used as readout of PI3K activity in diagnostic T-ALL samples. We identified Myc as an important downstream integrator of PI3K pathway activity in T-ALL and found that higher PI3K activity is associated with glucocorticoid resistance and worse clinical outcome. The PI3K inhibitor AS605240 showed anti-leukemic activity and strong synergism with glucocorticoids both in vitro and in a NOD/SCID xenograft model of T-ALL. In contrast, PI3K inhibition showed antagonism with methotrexate and daunorubicin, drugs that preferentially target dividing cells. This antagonistic interaction, however, could be circumvented by the use of correct drug scheduling schemes. Our data indicate the potential benefits and difficulties for the incorporation of PI3K inhibitors in T-ALL therapy. OBSERVAÇÃOArquivo pdf com capa, página de rosto, folha de assinatura da banca examinadora, resumo e abstract foi editado segundo informação CCPG/002/2013 / Doutorado / Genetica Animal e Evolução / Doutor em Genetica e Biologia Molecular

Patients with acute promyelocytic leukemia (APL) often present with potentially lifethreatening hemorrhagic diathesis. The underlying pathomechanisms of APLassociated coagulopathy are complex. However, two pathways considered to be APLspecific had been identified: 1) annexin A2 (ANXA2)-associated hyperfibrinolysis and 2) podoplanin (PDPN)-mediated platelet activation and aggregation. In contrast, since disseminated intravascular coagulation (DIC) is far less frequent in patients with non- APL acute myeloid leukemia (AML), the pathophysiology of AML-associated hemorrhagic disorders is not well understood. Furthermore, the potential threat of coagulopathy in non- APL AML patients may be underestimated. Herein, we report a patient with non-APL AML presenting with severe coagulopathy with hyperfibrinolysis. Since his clinical course resembled a prototypical APL-associated hemorrhagic disorder, we hypothesized pathophysiological similarities. Performing multiparametric flow cytometry (MFC) and immunofluorescence imaging (IF) studies, we found the patient’s bone-marrow mononuclear cells (BM-MNC) to express ANXA2 - a biomarker previously thought to be APL-specific. In addition, whole-exome sequencing (WES) on sorted BM-MNC (leukemiaassociated immunophenotype (LAIP)1: ANXAlo, LAIP2: ANXAhi) demonstrated high intratumor heterogeneity. Since ANXA2 regulation is not well understood, further research to determine the coagulopathy-initiating events in AML and APL is indicated. Moreover, ANXA2 and PDPN MFC assessment as a tool to determine the risk of life-threatening DIC in AML and APL patients should be evaluated.

No description available.

Background: Acute promyelocytic leukemia (APL) is considered a hematologic emergency due to high risk of bleeding and fatal hemorrhages being a major cause of death. Despite lower death rates reported from clinical trials, patient registry data suggest an early death rate of 20%, especially for elderly and frail patients. Therefore, reliable diagnosis is required as treatment with differentiation-inducing agents leads to cure in the majority of patients. However, diagnosis commonly relies on cytomorphology and genetic confirmation of the pathognomonic t(15;17). Yet, the latter is more time consuming and in some regions unavailable. - Methods: In recent years, deep learning (DL) has been evaluated for medical image recognition showing outstanding capabilities in analyzing large amounts of image data and provides reliable classification results. We developed a multi-stage DL platform that automatically reads images of bone marrow smears, accurately segments cells, and subsequently predicts APL using image data only. We retrospectively identified 51 APL patients from previous multicenter trials and compared them to 1048 non-APL acute myeloid leukemia (AML) patients and 236 healthy bone marrow donor samples, respectively. - Results: Our DL platform segments bone marrow cells with a mean average precision and a mean average recall of both 0.97. Further, it achieves high accuracy in detecting APL by distinguishing between APL and non-APL AML as well as APL and healthy donors with an area under the receiver operating characteristic of 0.8575 and 0.9585, respectively, using visual image data only. - Conclusions: Our study underlines not only the feasibility of DL to detect distinct morphologies that accompany a cytogenetic aberration like t(15;17) in APL, but also shows the capability of DL to abstract information from a small medical data set, i. e. 51 APL patients, and infer correct predictions. This demonstrates the suitability of DL to assist in the diagnosis of rare cancer entities. As our DL platform predicts APL from bone marrow smear images alone, this may be used to diagnose APL in regions were molecular or cytogenetic subtyping is not routinely available and raise attention to suspected cases of APL for expert evaluation.