RESUMO
The analysis of patient blood transcriptional profiles offers a means to investigate the immunological mechanisms relevant to human diseases on a genome-wide scale. In addition, such studies provide a basis for the discovery of clinically relevant biomarker signatures. We designed a strategy for microarray analysis that is based on the identification of transcriptional modules formed by genes coordinately expressed in multiple disease data sets. Mapping changes in gene expression at the module level generated disease-specific transcriptional fingerprints that provide a stable framework for the visualization and functional interpretation of microarray data. These transcriptional modules were used as a basis for the selection of biomarkers and the development of a multivariate transcriptional indicator of disease progression in patients with systemic lupus erythematosus. Thus, this work describes the implementation and application of a methodology designed to support systems-scale analysis of the human immune system in translational research settings.
Assuntos
Perfilação da Expressão Gênica/métodos , Genômica/métodos , Lúpus Eritematoso Sistêmico/sangue , Lúpus Eritematoso Sistêmico/genética , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Adolescente , Criança , Biologia Computacional/métodos , Progressão da Doença , Feminino , Humanos , MasculinoRESUMO
OBJECTIVE: We hypothesized that type 1 diabetes (T1D) is accompanied by changes in gene expression in peripheral blood mononuclear cells due to dysregulation of adaptive and innate immunity, counterregulatory responses to immune dysregulation, insulin deficiency, and hyperglycemia. RESEARCH DESIGN AND METHODS: Microarray analysis was performed on peripheral blood mononuclear cells from 43 patients with newly diagnosed T1D, 12 patients with newly diagnosed type 2 diabetes (T2D), and 24 healthy controls. One- and 4-month follow-up samples were obtained from 20 of the T1D patients. RESULTS: Microarray analysis identified 282 genes differing in expression between newly diagnosed T1D patients and controls at a false discovery rate of 0.05. Changes in expression of IL1B, early growth response gene 3, and prostaglandin-endoperoxide synthase 2 resolved within 4 months of insulin therapy and were also observed in T2D, suggesting that they resulted from hyperglycemia. With use of a knowledge base, 81 of 282 genes could be placed within a network of interrelated genes with predicted functions including apoptosis and cell proliferation. IL1B and the MYC oncogene were the most highly connected genes in the network. IL1B was highly overexpressed in both T1D and T2D, whereas MYC was dysregulated only in T1D. CONCLUSION: T1D and T2D likely share a final common pathway for beta-cell dysfunction that includes secretion of IL-1beta and prostaglandins by immune effector cells, exacerbating existing beta-cell dysfunction, and causing further hyperglycemia. The results identify several targets for disease-modifying therapy of diabetes and potential biomarkers for monitoring treatment efficacy.
Assuntos
Diabetes Mellitus/sangue , Diabetes Mellitus/genética , Perfilação da Expressão Gênica , Leucócitos Mononucleares/metabolismo , Adolescente , Criança , Pré-Escolar , Diabetes Mellitus/metabolismo , Feminino , Citometria de Fluxo , Regulação da Expressão Gênica , Redes Reguladoras de Genes , Humanos , Masculino , Redes e Vias Metabólicas/genética , Análise de Sequência com Séries de OligonucleotídeosRESUMO
Artemisinin-containing antimalarial combination therapies are recommended to confront drug-resistant Plasmodium falciparum malaria. Among the questions surrounding whether these complex multidose treatments will be practical is to what extent patients complete the recommended doses. Combination therapy through coadministration of sulfadoxine-pyrimethamine plus artesunate was introduced as a first-line treatment for uncomplicated malaria in one district in Tanzania. Interventions to optimize correct use were also implemented. We observed 453 patient encounters at one health facility and recorded key practices as health workers dispensed the combination. A total of 253 patients were followed-up at 24 or 48 hours. Complete adherence measured at 48 hours reached 75.0%, based on self-report and tablet counts. This is substantially better than reported elsewhere and compares favorably with intervention studies to optimize adherence to chloroquine. Counseling about what to do if a patient vomits appears to have been an independent risk factor for nonadherence.
