A ocorrência de doença cardiovascular não pode ser explicada somente pelo estilo de vida do adulto. Estudos ecológicos e epidemiológicos dos últimos vinte anos demonstraram maior incidência de doenças crônicas não transmissíveis em indivíduos que nasceram com baixo peso e tiveram um ganho de peso inadequado nos dois primeiros anos de vida. A hipótese aceita atualmente é a de que agravos, principalmente nutricionais, ocorridos durante a gestação alteram a programação de órgãos e sistemas para preservar, principalmente, o desenvolvimento cerebral, levando ao sacrifício metabólico de vários órgãos, como rins, fígado, coração, pâncreas, que ao serem solicitados na vida adulta, teriam menor capacidade funcional. Esta teoria foi chamada Hipótese de Barker ou do Fenótipo Poupador. Este trabalho tem como objetivo avaliar o peso de nascimento e do primeiro ano de vida de adultos usuários do Centro de Saúde-Escola Prof. Samuel B. Pessoa, que foram matriculados quando lactentes e que estão atualmente em seguimento nesta unidade de saúde, correlacionando com a sua condição de saúde atual, para tentar demonstrar a teoria das origens desenvolvimentistas da saúde e da doença em nosso meio. A anamnese clínica, medidas da cintura abdominal, cintura quadril, pressão arterial, freqüência cardíaca, e exames laboratoriais, tais como colesterol total e frações, triglicérides, glicemia de jejum foram estudados. Constituiu-se um grupo de 298 usuários, com média de idade de 25 anos, sendo 212 mulheres e 86 homens. Após a execução do estudo observamos que não houve diferença estatisticamente significante em relação a anamnese e aos exames laboratoriais alterados dos adultos, quando se compararam aos grupos com baixo peso de nascimento, nem quando comparados aos grupos com peso baixo com um ano de idade. O acompanhamento destes de adultos, por duas a três décadas, poderá trazer dados que venham a ajudar a comprovar a teoria das origens desenvolvimentistas da saúde e da doença em nosso meio. A prevenção primordial, isto é, antes do nascimento, das doenças crônicas não transmissíveis será o objetivo futuro da Pediatria Preventiva / The appearance of a cardiovascular disease cannot be explained only by the adults lifestyle. Ecological and epidemiological studies from the last twenty years show a more frequent incidence of non-communicable chronic diseases in individuals that were born under the ideal weight and had an inadequate gain of weight during their first two years. The hypothesis initially accepted is that certain deficiencies, mainly nutritional, that occurred during pregnancy alter the programming of organs and systems in order to preserve the cerebral development. This process may lead to metabolic sacrifice of many organs, including liver, kidneys, heart and pancreas, which will have a worse functional capacity when necessary in adult life. This theory was called Barker Hypothesis or Thrifty Phenotype Hypothesis. This research project has for objective the comparation of the weight at birth and during the first year of life from adults whose health is followed at Health Center School Prof. Samuel B. Pessoa. This group of adults was subscripted when its members were infants. A correlation between their present health and their health conditions when infants was made during this study in order to try to demonstrate in our environment the Developmental Origins of Health and Disease. The basis of the study was the clinical anamneses, the measures of the abdominal waist, hip, arterial pressure, cardiac frequency and some laboratorial examinations, such as total and fractional cholesterol, triglycerides, fasting glucose levels. A group of 298 patients was formed, with an average age of 25 years-old members. 212 of them were women and 86 were men. After this study, it was concluded that the underweight at birth and underweight during the first year of life do not lead to alterations statistically relevant in the anamneses and in the laboratorial examinations. The following of these adults during two or three decades may bring data that might help to prove the developmental origins of health and disease theory in our environment. The primordial prevention (before the child is born) of non-communicable chronic diseases will be the future target of Preventive Pediatrics

JUSTIFICATIVA E OBJETIVOS: As doenças cardiovasculares (DCV) constituem uma importante causa de mortalidade em todo mundo, sendo a principal causa de morte e incapacidade no Brasil, determinando um impacto social, econômico e médico de grandes proporções. O desenvolvimento das DCV está correlacionado a vários fatores de risco desde os primeiros anos de vida, com expressão na vida adulta. As sementes da aterosclerose são semeadas muitas décadas antes da manifestação dos pontos finais clínicos. A espessura da média-intimal da carótida (EMIC) é relevante na avaliação da repercussão dos fatores de risco sobre a parede arterial. As condições precursoras dos distúrbios metabólicos e das alterações vasculares relativas à aterosclerose podem ser evitadas ou interrompidas se identificados e tratados a tempo. Com base nessa premissa, o presente trabalho tem como objetivo estudar a relação entre história e condições de vida, fatores de risco cardiovascular e espessura da média-intimal da carótida em crianças escolares de 5 a 9 anos, procedentes de escolas públicas da região central da cidade de Fortaleza - Ceará - Brasil. MÉTODOS: estudo transversal observacional com dados primários colhidos por formulário aplicado a uma amostra da população escolar de instituições públicas em crianças de 5 a 9 anos da região central da cidade de Fortaleza, sorteadas aleatoriamente. Informações relacionadas às características sociodemográficas, dados antropométricos, medidas da pressão arterial, perfil metabólico, e avaliação da espessura da média-intimal da carótida pela ultrassonografia foram realizados. Para análises estatísticas, análises univariadas foram desenvolvidas por meio da comparação de proporções pelo Teste do Qui-quadrado e pela seleção de variáveis independentes, para compor os modelos de regressão logística múltipla. RESULTADOS: Foram investigadas quinhentas crianças de 5-9 anos, sendo do sexo feminino 260 crianças (52%). A medida da EMIC teve média e desvio padrão para EMIC esquerda de 0,42mm (±0,09) e para EMIC direita de 0,39mm (±0,07). Não houve diferenças significativas para os sexos. Houve associação estatisticamente significante e de forma crescente com a idade, sendo 5,02 vezes maior uma criança de 9 anos ter a EMIC aumentada (IC95% = 1,95 - 12,88; p=0,001). A EMIC esteve associada significantemente com o nível de instrução materna baixo (OR = 0,46; IC95% = 0,23 - 0,90), com hipertensão diastólica (OR = 7,61; IC95% = 2,18 - 26,53), com sobrepeso/obesidade (OR = 4,81; IC95% = 2,50 - 9,24), com hipercolesterolemia (OR = 20,8; IC95% = 10,17 - 42,92), com níveis de PCR elevados (OR = 3,03; IC95% = 1,27 - 7,21) e insulina de jejum elevados (OR = 10,4; IC95% = 3,03 - 36,24). CONCLUSÕES: A aterosclerose subclínica já pode ser detectada em crianças pré-púberes de 5 a 9 anos que contenham fatores de risco para doença cardiovascular, indicando doença cardiovascular incipiente. A medida da EMIC pode fornecer um marcador confiável para a saúde vascular, associado a outros critérios de risco, evidenciando que, especialmente no grupo etário pediátrico, a avaliação do risco cardiovascular é benéfica. Considerando a progressão das alterações vasculares ao longo da vida, parece prudente para detectar sinais subclínicos de danos arteriais e aterosclerose muito cedo, e para aliviar a carga aterosclerótica com medidas preventivas / BACKGROUND AND OBJECTIVES: Cardiovascular diseases (CVD) are a major cause of death worldwide. They are main cause of death and disability in Brazil and thus have large social, economic and medical impact. The development of CVD is correlated with several risk factors from the first years of life, with expression in adult life. The seeds of atherosclerosis are sown many decades before the manifestation of clinical symptoms. The carotid intima-media thickness (cIMT) is relevant in assessing the manifestation of risk factors on the arterial wall. The precursor conditions of metabolic disorders and vascular changes related to atherosclerosis can be avoided or disrupted if identified and treated in time. Based on this premise, the objective of this study was to study the relationship between history and life conditions, cardiovascular risk factors, and carotid intima-media thickness in public schoolchildren, aged 5 to 9, in the central region of the city of Fortaleza, Ceará, Brazil. METHODS: an observational cross-sectional study with primary data collected by a form supplied to a sample of the school population of public institutions in the central region of Fortaleza. The children were randomly selected and information related to sociodemographic characteristics, anthropometric data, blood pressure measurements, metabolic profile, and assessment of the carotid-mediated intima-media thickness were collected. For statistical analyzes, univariate analyses were developed by comparing proportions through the Chi-square test and a selection of independent variables to compose the multiple logistic regression models. RESULTS: Five hundred children aged 5-9 years were enrolled, of whom 260 (52%) were female. The cIMT measure had a mean and standard deviation for left cIMT of 0.42mm (± 0.09) and for right cIMT of 0.39mm (± 0.07). There were no significant differences for the sexes. There was a statistically significant and increasing association with age, with a 9-year-old child being 5.02 times more likely to have cIMT (95% CI = 1.95 - 12.88, p = 0.001). The cIMT was significantly associated with low maternal education (OR = 0.46, 95% CI = 0.23-0.90), with diastolic hypertension (OR = 7.61, 95% CI = 2.18-26, 53), overweight/obesity (OR = 4.81, 95% CI = 2.50-9.24), hypercholesterolemia (OR = 20.8, 95% CI = 10.17 - 42.92), high levels of CRP (OR = 3.03, 95% CI = 1.27 - 7.21), and high-fasting insulin (OR = 10.4, 95% CI = 3.03-36.24). CONCLUSIONS: Subclinical atherosclerosis can already be detected in prepubertal children aged 5 to 9 years who have risk factors for cardiovascular disease, indicating incipient cardiovascular disease. The cIMT measure can provide a reliable marker for vascular health, associated with other risk criteria. The measure shows that, especially in the pediatric age group, cardiovascular risk assessment is beneficial. Given the progression of vascular changes throughout life, it seems prudent to detect subclinical signs of arterial damage and atherosclerosis very early and to relieve atherosclerotic burden with preventative measures

O câncer de mama é a principal causa de mortalidade por câncer entre as mulheres. Alguns biomarcadores e características clínicas são utilizados para avaliar o prognóstico e prever a resposta a uma série de abordagens terapêuticas. A Homocisteína é conhecida como um fator de risco para doença vascular aterosclerótica, mas sua participação na biologia do câncer ainda é incerta. Cisteína é o aminoácido sulfurado derivado da Homocisteína no ciclo da Metionina. Este ciclo metabólico origina as bases nitrogenadas e também determina o nível de metilação da molécula de DNA. É atualmente reconhecido que a hipometilação global do genoma é um evento chave na transformação maligna das células. O objetivo deste estudo foi avaliar os níveis séricos de homocisteína e cisteína como biomarcadores de sobrevida e de progressão da doença em câncer de mama. Também foi avaliado o efeito de um curso de curta duração (um mês) de tratamento hormonal sobre os níveis de Homocisteína, Cisteína e metilação do DNA. Amostras de sangue foram obtidos por ocasião da biópsia inicial (pré-tratamento) em todas as pacientes e, de tumor e de tecido normal adjacente, ao diagnóstico eem um mês após, para as pacientes que receberam o regime hormonal neo-adjuvante (pré-operatório). Todas as pacientes eram mulheres na pós-menopausa, com tumores de mama ressecáveis, acompanhadas em dois hospitais públicos, que consentiram em participar de outros dois protocolos de pesquisa prévios. Homocisteína e Cisteína foram analisadas por HPLC e a metilação global do DNA do tecido foi determinada por meio da técnica de MSRE (Methylation-Sensitive Restriction Enzyme). Foi observada uma diferença significativa entre os níveis pré e póstratamento de Homocisteína e Cisteína em tumores avançados, sugerindo um papel prognóstico em pacientes com características clínicas reservadas. As variações nos níveis de Homocisteína se mostraram significativamente correlacionadas com a sobrevida livre de doença. O modelo de risco proporcional de Cox demonstrou que os níveis de homocisteína e o status dos linfonodos representaram fatores prognósticos independentes em termos de sobrevida livre de doença. Embora mais estudos sejam necessários para confirmar estes resultados, nossa pesquisa sugere que a Homocisteína pode ser usada como um biomarcador de prognóstico para câncer de mama / Breast cancer is the leading cause of cancer mortality among women. Some biomarkers and clinical features are used to evaluate prognosis and to predict response to a range of therapeutic approaches. Homocysteine is well known as a risk factor in atherosclerotic vascular diseases, but its participation in cancer biology is still unclear. Cysteine is a sulfur amino acid derived from Homocysteine in the Methionine cycle. This metabolic cycle originates the nitrogenous bases and determines the methylation level of the DNA molecule as well. It is currently recognized that the global hipomethylation of the genome is a key event in the malign transformation of cells. The aim of this study was to evaluate serum Homocysteine and Cysteine as biomarkers of survival and disease progression in breast tumor, as well as the methylation status of tumor and normal tissues. The effect of a short course (one month) of hormonal treatment on Homocysteine, Cysteine and DNA methylation levels was also evaluated. Blood samples were collected during the initial biopsy (pretreatment) in all patients and, tumor samples and normal adjacent tissue, at diagnosis and one month after, for the patients that received neo-adjuvant hormonal regimen (pre-treatment). All patients were post-menopausal women, with resectable breast tumors, followed at two public hospitals, and that had consented to participate in two previous research protocols related to their disease. Serum Homocysteine and Cysteine were analyzed by HPLC and tissue global DNA methylation was determined by the MSRE (Methylation- Sensitive Restriction Enzyme) technique. A significant difference was observed between pre- and post-treatment levels of Homocysteine and Cysteine in advanced tumors, suggesting a prognostic role in patients with poor clinical characteristics. Variations in Homocysteine levels were significantly correlated with disease free survival. Cox proportional risk model demonstrated that nodal status and Homocysteine levels were independent prognostic factors for Disease Free Survival. Although more studies are needed to confirm these results, our research suggests that Homocysteine might be used as a prognostic biomarker for breast cancer

Indiana University-Purdue University Indianapolis (IUPUI) / Several common diseases such as atherosclerosis, post-angioplasty restenosis, and graft vasculopathies, are associated with the changes in the structure and function of smooth muscle cells. During the pathogenesis of these diseases, smooth muscle cells have a marked alteration in the expression of many smooth muscle-specific genes and smooth muscle cells undergo a phenotypic switch from the contractile/differentiated status to the proliferative/dedifferentiated one. Serum response factor (SRF) is the major transcription factor that plays an essential role in coordinating a variety of transcriptional events during this phenotypic change. The first goal of my thesis studies is to determine how SRF regulates the expression of smooth muscle myosin light chain kinase (smMLCK) to mediate changes in contractility. Using a combination of transgenic reporter mouse and knockout mouse models I demonstrated that a CArG element in intron 15 of the mylk1 gene is necessary for maximal transcription of smMLCK. SRF binding to this CArG element modulates the expression of smMLCK to control smooth muscle contractility. A second goal of my thesis work is to determine how SRF coordinates the activity of chromatin remodeling enzymes to control expression of microRNAs that regulate the phenotypes of smooth muscle cells. Using both mouse knockout models and in vitro studies in cultured smooth muscle cells I showed how SRF acts together with Brg1-containing chromatin remodeling complexes to regulate expression of microRNAs-143, 145, 133a and 133b. Moreover, I found that SRF transcription cofactor myocardin acts together with SRF to regulate expression of microRNAs-143 and 145 but not microRNAs-133a and 133b. SRF can, thus, further modulate gene expression through post-transcriptional mechanisms via changes in microRNA levels. Overall my research demonstrates that through direct interaction with a CArG box in the mylk1 gene, SRF is important for regulating expression of smMLCK to control smooth muscle contractility. Additionally, SRF is able to harness epigenetic mechanisms to modulate expression of smooth muscle contractile protein genes directly and indirectly via changes in microRNA expression. Together these mechanisms permit SRF to coordinate the complex phenotypic changes that occur in smooth muscle cells.

Indiana University-Purdue University Indianapolis (IUPUI) / This thesis is aimed at creating a pipeline for analyzing DNA methylation epigenetics data and creating a data model structured well enough to store the analysis results of the pipeline. In addition to storing the results, the model is also designed to hold information which will help researchers to decipher a meaningful epigenetics sense from the results made available. Current major epigenetics resources such as PubMeth, MethyCancer, MethDB and NCBI’s Epigenomics database fail to provide holistic view of epigenetics. They provide datasets produced from different analysis techniques which raises an important issue of data integration. The resources also fail to include numerous factors defining the epigenetic nature of a gene. Some of the resources are also struggling to keep the data stored in their databases up-to-date. This has diminished their validity and coverage of epigenetics data. In this thesis we have tackled a major branch of epigenetics: DNA methylation. As a case study to prove the effectiveness of our pipeline, we have used stage-wise DNA methylation and expression raw data for Lung adenocarcinoma (LUAD) from TCGA data repository. The pipeline helped us to identify progressive methylation patterns across different stages of LUAD. It also identified some key targets which have a potential for being a drug target. Along with the results from methylation data analysis pipeline we combined data from various online data reserves such as KEGG database, GO database, UCSC database and BioGRID database which helped us to overcome the shortcomings of existing data collections and present a resource as complete solution for studying DNA methylation epigenetics data.

Unlike the adaptive immune system, the innate immune system has classically been characterized as being devoid of memory functions. However, recent research shows that innate myeloid and lymphoid cells have the ability to retain memory of prior pathogen exposure and become primed to elicit a robust, broad-spectrum response to subsequent infection. This phenomenon has been termed innate immune memory or trained immunity. Innate immune memory is induced via activation of pattern recognition receptors and the actions of cytokines on hematopoietic progenitors and stem cells in bone marrow and innate leukocytes in the periphery. The trained phenotype is induced and sustained via epigenetic modifications that reprogram transcriptional patterns and metabolism. These modifications augment antimicrobial functions, such as leukocyte expansion, chemotaxis, phagocytosis, and microbial killing, to facilitate an augmented host response to infection. Alternatively, innate immune memory may contribute to the pathogenesis of chronic diseases, such as atherosclerosis and Alzheimer's disease.