RESUMO
BACKGROUND: The rapid growth of opioid abuse and the related mortality across the United States has spurred the development of predictive models for the allocation of public health resources. These models should characterize heterogeneous growth across states using a drug epidemic framework that enables assessments of epidemic onset, rates of growth, and limited capacities for epidemic growth. METHODS: We used opioid overdose mortality data for 146 North and South Carolina counties from 2001 through 2014 to compare the retrodictive and predictive performance of a logistic growth model that parameterizes onsets, growth, and carrying capacity within a traditional Bayesian Poisson space-time model. RESULTS: In fitting the models to past data, the performance of the logistic growth model was superior to the standard Bayesian Poisson space-time model (deviance information criterion: 8,088 vs. 8,256), with reduced spatial and independent errors. Predictively, the logistic model more accurately estimated fatality rates 1, 2, and 3 years in the future (root mean squared error medians were lower for 95.7% of counties from 2012 to 2014). Capacity limits were higher in counties with greater population size, percent population age 45-64, and percent white population. Epidemic onset was associated with greater same-year and past-year incidence of overdose hospitalizations. CONCLUSION: Growth in annual rates of opioid fatalities was capacity limited, heterogeneous across counties, and spatially correlated, requiring spatial epidemic models for the accurate and reliable prediction of future outcomes related to opioid abuse. Indicators of risk are identifiable and can be used to predict future mortality outcomes.
Assuntos
Overdose de Drogas , Overdose de Opiáceos , Transtornos Relacionados ao Uso de Opioides , Analgésicos Opioides , Teorema de Bayes , Overdose de Drogas/epidemiologia , Humanos , Pessoa de Meia-Idade , Transtornos Relacionados ao Uso de Opioides/epidemiologia , South Carolina/epidemiologia , Estados Unidos/epidemiologiaRESUMO
The aim of this study was to identify genes with higher expression in solid tumor cells by comparing human tumor biopsies with healthy blood samples using both in silico statistical analysis and experimental validations. This approach resulted in a novel panel of 80 RNA biomarkers with high discrimination power to detect circulating tumor cells in blood samples. To identify the 80 RNA biomarkers, Affymetrix HG-U133 plus 2.0 microarrays datasets were used to compare breast tumor tissue biopsies and breast cancer cell lines with blood samples from patients with conditions other than cancer. A total of 859 samples were analyzed at the discovery stage, consisting of 417 mammary tumors, 41 breast lines, and 401 control samples. To confirm this discovery, external datasets of eight types of tumors were used, and experimental validation studies (NanoString n-counter gene expression assay) were performed, totaling 5028 samples analyzed. In these analyses, the 80 biomarkers showed higher expression in all solid tumors analyzed relative to healthy blood samples. Experimental validation studies using NanoString assay confirmed the results were not dependent of the gene expression platform. A panel of 80 RNA biomarkers was described here, with the potential to detect solid tumor cells present in the blood of multiple tumor types.
Assuntos
Biomarcadores Tumorais , Neoplasias/genética , Transcriptoma , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Células Neoplásicas Circulantes/metabolismo , Reprodutibilidade dos TestesRESUMO
Introducción. El dengue puede manifestarse como una enfermedad leve o evolucionar hasta una enfermedad grave, llamada fiebre hemorrágica por dengue, cuyos mecanismos de inmunopatogénesis no son claros. Objetivo. Utilizar un análisis de microarreglos para identificar los genes de la respuesta inmunitaria diferencialmente expresados en niños colombianos con dengue leve y grave. Materiales y métodos. Se evaluaron los cambios de la expresión génica de células mononucleares de sangre periférica de niños con fiebre de dengue y fiebre hemorrágica por dengue en fase aguda, mediante el microarreglo de Affymetrix HG-U133_Plus_2. Resultados. Los pacientes con fiebre hemorrágica por dengue expresaron transcritos para interleucina 6, quimiocinas, complemento y pentraxina 3, al igual que inhibidores de la actividad de linfocitos (gen 3 de activación de linfocitos y catepsina L1). Un modelo de interacción desarrollado para estos genes mostró al factor tisular como central en la red generada. Por el contrario, los pacientes con fiebre de dengue expresaron inhibidores de la actividad de citocinas, complemento y leucotrienos lactotransferrina, inhibidor peptidasa serpina del complemento C1, leucotrieno B (4-omega hidroxilasa 2). Conclusiones. Los resultados podrían indicar que durante la fiebre de dengue, los inhibidores de citocinas y del complemento logran controlar el daño al endotelio y el aumento de la permeabilidad vascular, mientras que, en los pacientes con fiebre hemorrágica por dengue, la disfunción de las células inmunitarias y la acción no regulada del complemento y de las citocinas, conducen a un estado de hipercoagulacion y daño endotelial. La identificación del papel patógeno de las moléculas encontradas podría contribuir a la interpretación de la patogenia y al desarrollo de fármacos terapéuticos. Palabras clave: dengue, transcripción genética, análisis de micromatrices, fiebre hemorrágica del dengue, proteínas del sistema del complemento, citocinas.
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Análise em Microsséries , Dengue , Dengue Grave , Transcrição Gênica , Proteínas do Sistema Complemento , CitocinasRESUMO
INTRODUCTION: Dengue infection demonstrates a wide spectrum of clinical manifestations from mild disease (dengue fever) to severe dengue hemorrhagic fever, but the immunopathogenic mechanisms involved in disease severity are not clear. OBJECTIVE: Differentially expressed genes associated to immune response were identified from peripheral blood mononuclear cells of Colombian children with dengue fever and dengue hemorrhagic fever. MATERIALS AND METHODS: Microarray analysis was used as a tool to establish and compare transcriptional profiles of peripheral blood mononuclear cells of six children in acute phase of dengue fever and dengue hemorrhagic fever. The commercial gene chip used was Affymnetrix GeneChip HG_U133_Plus_2. RESULTS: Dengue hemorrhagic fever patients expressed interleukin 6, chemokines, complement proteins and pentraxin 3, along with the lymphocyte inhibitors lymphocyte-activation gene 3 and cathepsin L1. An interaction model for these genes showed tissue factor playing a central role in the network generated. In contrast, dengue fever patients expressed cytokines, complement and the leukotrienes inhibitors lactotransferrin, C1 inhibitor, and leukotriene-B (4-omega-hydroxylase 2). CONCLUSIONS: These results indicate that in dengue fever, cytokine and complement inhibitors are able to limit endothelial damage and prevent increases in vascular permeability, whereas dengue- hemorrhagic fever patients have immune cell dysfunction and unregulated complement and cytokine action. This leads to "hypercoagulation" and endothelial damage, thereby increasing disease severity. Verification of the pathogenic role of the identified molecules will contribute to understanding of dengue pathogenesis and lead to rational development of therapeutic drugs.
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Dengue/genética , Dengue/imunologia , Regulação da Expressão Gênica/imunologia , Dengue Grave/genética , Dengue Grave/imunologia , Transcrição Gênica , Adolescente , Criança , Pré-Escolar , Dengue/fisiopatologia , Feminino , Perfilação da Expressão Gênica , Redes Reguladoras de Genes , Humanos , Sistema Imunitário/imunologia , Lactente , Masculino , Análise em Microsséries , Dengue Grave/fisiopatologiaRESUMO
BACKGROUND: Dengue fever is one of the most significant re-emerging tropical diseases, despite our expanding knowledge of the disease, viral tropism is still not known to target heart tissues or muscle. METHODS: A prospective pediatric clinical cohort of 102 dengue hemorrhagic fever patients from Colombia, South America, was followed for 1 year. Clinical diagnosis of myocarditis was routinely performed. Electrocardiograph and echocardiograph analysis were performed to confirm those cases. Immunohistochemistry for detection of dengue virus and inflammatory markers was performed on autopsied heart tissue. In vitro studies of human striated skeletal fibers (myotubes) infected with dengue virus were used as a model for myocyte infection. Measurements of intracellular Ca2+ concentration as well as immunodetection of dengue virus and inflammation markers in infected myotubes were performed. RESULTS: Eleven children with dengue hemorrhagic fever presented with symptoms of myocarditis. Widespread viral infection of the heart, myocardial endothelium, and cardiomyocytes, accompanied by inflammation was observed in 1 fatal case. Immunofluorescence confocal microscopy showed that myotubes were infected by dengue virus and had increased expression of the inflammatory genes and protein IP-10. The infected myotubes also had increases in intracellular Ca2+ concentration. CONCLUSIONS: Vigorous infection of heart tissues in vivo and striated skeletal cells in vitro are demonstrated. Derangements of Ca2+ storage in the infected cells may directly contribute to the presentation of myocarditis in pediatric patients.
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Vírus da Dengue/fisiologia , Coração/virologia , Músculo Esquelético/virologia , Dengue Grave/patologia , Tropismo Viral , Cálcio/análise , Células Cultivadas , Criança , Pré-Escolar , Estudos de Coortes , Colômbia , Citosol/química , Vírus da Dengue/patogenicidade , Ecocardiografia , Eletrocardiografia , Feminino , Humanos , Imuno-Histoquímica , Lactente , Mediadores da Inflamação/análise , Masculino , Microscopia , Músculo Esquelético/patologia , Miocárdio/patologia , Estudos ProspectivosRESUMO
We used gene expression profiling of human primary cells infected in vitro with dengue virus (DENV) as a tool to identify secreted mediators induced in response to the infection. Affymetrix GeneChip analysis of human primary monocytes, B cells and dendritic cells infected with DENV in vitro showed strong induction of monocyte chemotactic protein 2 (MCP-2/CCL8), interferon gamma-induced protein 10 (IP-10/CXCL10) and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL/TNFSF10). The expression of these genes was confirmed in dendritic cells infected with DENV in vitro at mRNA and protein levels. A prospectively enrolled cohort of DENV-infected Venezuelan patients was used to measure the levels of these proteins in serum during three different periods of the disease. Results showed significant increase of MCP-2, IP-10, and TRAIL levels in patients infected with DENV during the febrile period, when compared to healthy donors and patients with other febrile illnesses. MCP-2 and IP-10 levels were still elevated during the post-febrile period while TRAIL levels dropped close to normal after defervescense. Patients with primary infections had higher TRAIL levels than patients with secondary infections during the febrile period of the disease. Increased levels of IP-10, TRAIL and MCP-2 in acute DENV infections suggest a role for these mediators in the immune response to the infection. MCP-2 was identified in this work as a new unreported and important dengue-related protein and IP-10 was confirmed as a novel and strong pro-inflammatory marker in acute disease.