RESUMO
The five-year survival rate for metastatic pancreatic cancer is currently only 3%, which increases to 13% with local invasion only and to 39% with localized disease at diagnosis. Here we evaluated repurposed mebendazole, an approved anthelminthic drug, to determine how mebendazole might work at the different stages of pancreatic cancer formation and progression. We asked if mebendazole could prevent initiation of pancreatic intraepithelial neoplasia precursor lesions, interfere with stromal desmoplasia, or suppress tumor growth and liver metastasis. In both the Kras LSL.G12D/+; Pdx1-Cre (KC) mouse model of caerulein-induced inflammatory pancreatitis and the Kras LSL.G12D/+; Tp53 R172H/+; Pdx1-Cre (KPC) mouse model of advanced pancreatic cancer, mebendazole significantly reduced pancreas weight, dysplasia and intraepithelial neoplasia formation, compared to controls. Mebendazole significantly reduced trichrome-positive fibrotic connective tissue and α-SMA-positive activated pancreatic stellate cells that heralds fibrogenesis. In the aggressive KPC model, mebendazole significantly suppressed pancreatic tumor growth, both as an early and late intervention. Mebendazole reduced the overall incidence of pancreatic cancer and severity of liver metastasis in KPC mice. Using early models of pancreatic cancer, treatment with mebendazole resulted in less inflammation, decreased dysplasia, with the later stage model additionally showing a decreased tumor burden, less advanced tumors, and a reduction of metastasis. We conclude that mebendazole should be investigated further as a component of adjuvant therapy to slow progression and prevent metastasis, and well as for primary prevention in the highest risk patients.
RESUMO
We report the response process of the Laboratory Analysis Task Force (LATF) for Unknown Disease Outbreaks (UDOs) at the Korea Disease Control and Prevention Agency (KDCA) during January 2020 to coronavirus disease 2019 (COVID-19), which developed as a UDO in Korea. The advanced preparedness offered by the laboratory diagnostic algorithm for UDOs related to respiratory syndromes was critical for the rapid identification of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and enabled us to establish and expand the diagnostic capacity for COVID-19 on a national scale in a timely manner.
Assuntos
Teste para COVID-19/normas , COVID-19/diagnóstico , Laboratórios/normas , COVID-19/epidemiologia , COVID-19/prevenção & controle , COVID-19/virologia , China/epidemiologia , Surtos de Doenças , Regulamentação Governamental , Humanos , Pneumonia/diagnóstico , Pneumonia/epidemiologia , Pneumonia/virologia , SARS-CoV-2/genética , SARS-CoV-2/isolamento & purificaçãoRESUMO
Wilson disease (WD) is caused by inactivation of the copper transporter Atp7b and copper overload in tissues. Mice with Atp7b deleted either globally (systemic inactivation) or only in hepatocyte recapitulate various aspects of human disease. However, their phenotypes vary, and neither the common response to copper overload nor factors contributing to variability are well defined. Using metabolic, histologic, and proteome analyses in three Atp7b-deficient mouse strains, we show that global inactivation of Atp7b enhances and specifically modifies the hepatocyte response to Cu overload. The loss of Atp7b only in hepatocytes dysregulates lipid and nucleic acid metabolisms and increases the abundance of respiratory chain components and redox balancing enzymes. In global knockouts, independently of their background, the metabolism of lipid, nucleic acid, and amino acids is inhibited, respiratory chain components are down-regulated, inflammatory response and regulation of chromosomal replication are enhanced. Decrease in glucokinase and lathosterol oxidase and elevation of mucin-13 and S100A10 are observed in all Atp7b mutant strains and reflect the extent of liver injury. The magnitude of proteomic changes in Atp7b-/- animals inversely correlates with the metallothioneins levels rather than liver Cu content. These findings facilitate identification of WD-specific metabolic and proteomic changes for diagnostic and treatment.
Assuntos
ATPases Transportadoras de Cobre/genética , Cobre/toxicidade , Deleção de Genes , Hepatócitos/metabolismo , Hepatócitos/patologia , Degeneração Hepatolenticular/genética , Degeneração Hepatolenticular/patologia , Animais , Biomarcadores/metabolismo , ATPases Transportadoras de Cobre/deficiência , Modelos Animais de Doenças , Glucose/metabolismo , Glicogênio/metabolismo , Metabolismo dos Lipídeos , Fígado/patologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fenótipo , Análise de Componente Principal , Proteoma/metabolismo , Fatores de TempoRESUMO
Short telomere syndromes manifest as familial idiopathic pulmonary fibrosis; they are the most common premature aging disorders. We used genome-wide linkage to identify heterozygous loss of function of ZCCHC8, a zinc-knuckle containing protein, as a cause of autosomal dominant pulmonary fibrosis. ZCCHC8 associated with TR and was required for telomerase function. In ZCCHC8 knockout cells and in mutation carriers, genomically extended telomerase RNA (TR) accumulated at the expense of mature TR, consistent with a role for ZCCHC8 in mediating TR 3' end targeting to the nuclear RNA exosome. We generated Zcchc8-null mice and found that heterozygotes, similar to human mutation carriers, had TR insufficiency but an otherwise preserved transcriptome. In contrast, Zcchc8-/- mice developed progressive and fatal neurodevelopmental pathology with features of a ciliopathy. The Zcchc8-/- brain transcriptome was highly dysregulated, showing accumulation and 3' end misprocessing of other low-abundance RNAs, including those encoding cilia components as well as the intronless replication-dependent histones. Our data identify a novel cause of human short telomere syndromes-familial pulmonary fibrosis and uncover nuclear exosome targeting as an essential 3' end maturation mechanism that vertebrate TR shares with replication-dependent histones.
Assuntos
Proteínas de Transporte/genética , Fibrose Pulmonar Idiopática/genética , Mutação com Perda de Função , Proteínas Nucleares/genética , RNA/metabolismo , Telomerase/metabolismo , Animais , Encéfalo/enzimologia , Encéfalo/fisiopatologia , Linhagem Celular , Cílios/genética , Feminino , Ligação Genética , Células HCT116 , Humanos , Fibrose Pulmonar Idiopática/enzimologia , Fibrose Pulmonar Idiopática/fisiopatologia , Masculino , Camundongos , Camundongos Knockout , Transtornos do Neurodesenvolvimento/genética , Linhagem , Processamento Pós-Transcricional do RNA/genética , Encurtamento do Telômero/genéticaRESUMO
We addressed the precursor role of aging-like spontaneous promoter DNA hypermethylation in initiating tumorigenesis. Using mouse colon-derived organoids, we show that promoter hypermethylation spontaneously arises in cells mimicking the human aging-like phenotype. The silenced genes activate the Wnt pathway, causing a stem-like state and differentiation defects. These changes render aged organoids profoundly more sensitive than young ones to transformation by BrafV600E, producing the typical human proximal BRAFV600E-driven colon adenocarcinomas characterized by extensive, abnormal gene-promoter CpG-island methylation, or the methylator phenotype (CIMP). Conversely, CRISPR-mediated simultaneous inactivation of a panel of the silenced genes markedly sensitizes to BrafV600E-induced transformation. Our studies tightly link aging-like epigenetic abnormalities to intestinal cell fate changes and predisposition to oncogene-driven colon tumorigenesis.
Assuntos
Adenocarcinoma/genética , Envelhecimento/genética , Transformação Celular Neoplásica/genética , Neoplasias do Colo/genética , Metilação de DNA , Inativação Gênica , Mutação , Proteínas Proto-Oncogênicas B-raf/genética , Células-Tronco/enzimologia , Via de Sinalização Wnt/genética , Adenocarcinoma/enzimologia , Adenocarcinoma/patologia , Fatores Etários , Envelhecimento/metabolismo , Envelhecimento/patologia , Animais , Transformação Celular Neoplásica/metabolismo , Transformação Celular Neoplásica/patologia , Neoplasias do Colo/enzimologia , Neoplasias do Colo/patologia , Regulação Neoplásica da Expressão Gênica , Predisposição Genética para Doença , Humanos , Camundongos Endogâmicos NOD , Camundongos Mutantes , Camundongos SCID , Fenótipo , Proteínas Proto-Oncogênicas B-raf/metabolismo , Células-Tronco/patologia , Fatores de Tempo , Técnicas de Cultura de TecidosRESUMO
An adult, female red-tailed hawk (Buteo jamaicensis) was presented for examination after being found unable to fly on a private citizen's property. Further diagnostic testing revealed a vascular, soft tissue mass arising from the serosal surface of the proximal proventriculus. Postmortem histological and immunohistochemical examination of the mass revealed an unusual mesenchymal tumor with features consistent with a leiomyoma or low-grade gastrointestinal stromal tumor.
Assuntos
Falcões , Leiomioma/veterinária , Proventrículo/patologia , Neoplasias Gástricas/veterinária , Animais , Doenças das Aves/patologia , Evolução Fatal , Feminino , Leiomioma/patologia , Neoplasias Gástricas/patologiaRESUMO
Overall shared DNA methylation patterns between senescence (Sen) and cancers have led to the model that tumor-promoting epigenetic patterns arise through senescence. We show that transformation-associated methylation changes arise stochastically and independently of programmatic changes during senescence. Promoter hypermethylation events in transformation involve primarily pro-survival and developmental genes, similarly modified in primary tumors. Senescence-associated hypermethylation mainly involves metabolic regulators and appears early in proliferating "near-senescent" cells, which can be immortalized but are refractory to transformation. Importantly, a subset of transformation-associated hypermethylated developmental genes exhibits highest methylation gains at all age-associated cancer risk states across tissue types. These epigenetic changes favoring cell self-renewal and survival, arising during tissue aging, are fundamentally important for stratifying cancer risk and concepts for cancer prevention.
Assuntos
Transformação Celular Neoplásica/genética , Ilhas de CpG/genética , Metilação de DNA/genética , Epigênese Genética/genética , Animais , Senescência Celular/genética , Humanos , Camundongos , Camundongos SCID , Neoplasias/genética , Regiões Promotoras Genéticas/genética , RiscoRESUMO
BACKGROUND: In June 2015, a local public health laboratory was notified that students had developed gastroenteritis symptoms after attending a camp. An outbreak investigation was conducted to determine the extent and cause of the outbreak. METHOD: A retrospective cohort study was conducted to determine the correlations between the illness and specific exposures at the school camp. All attendees were interviewed with a standard questionnaire that addressed clinical symptoms, food consumption, and environmental exposures. Clinical specimens were cultured using standard microbiological methods for bacterial and viral pathogens. The genetic relationships of all isolates were determined using pulsed-field gel electrophoresis (PFGE). RESULTS: A total 188 patients with symptoms of diarrhoea, abdominal pain, and nausea were identified. The completed questionnaires suggested that the consumption of drinking water was likely to be linked to this outbreak. Using microbiological methods, enterohaemorrhagic Escherichia coli, enteropathogenic E. coli, and enteroaggregative E. coli were isolated, and the isolates from both patient stool and environmental water samples displayed indistinguishable XbaI-PFGE patterns. The water system in the camp used groundwater drawn from a private underground reservoir for cooking and drinking. The environmental investigation revealed some problems with the water supply system, such as the use of inappropriate filters in the water purifier and a defect in the pipeline between the reservoir and the chlorination device. CONCLUSIONS: This outbreak points to the importance of drinking water quality management in group facilities where underground water is used and emphasizes the need for periodic sanitation and inspection to prevent possible waterborne outbreaks.
Assuntos
Acampamento , Água Potável/microbiologia , Infecções por Escherichia coli/etiologia , Doenças Transmitidas pela Água/etiologia , Estudos de Coortes , Diarreia/epidemiologia , Diarreia/etiologia , Diarreia/microbiologia , Surtos de Doenças , Eletroforese em Gel de Campo Pulsado , Escherichia coli/isolamento & purificação , Infecções por Escherichia coli/epidemiologia , Infecções por Escherichia coli/microbiologia , Gastroenterite/epidemiologia , Humanos , Estudos Retrospectivos , Instituições Acadêmicas , Doenças Transmitidas pela Água/epidemiologiaRESUMO
Herein, we report the pathogenic and phylogenetic characteristics of seven Shiga toxin (Stx)-producing Escherichia coli (STEC) isolates from 434 retail meats collected in Korea during 2006 to 2012. The experimental analyses revealed that all isolates (i) were identified as non-O157 STEC, including O91:H14 (3 isolates), O121:H10 (2 isolates), O91:H21 (1 isolate), and O18:H20 (1 isolate), (ii) carried diverse Stx subtype genes (stx1, stx2c, stx2e, or stx1 + stx2b) whose expression levels varied strain by strain, and (iii) lacked the locus of enterocyte effacement (LEE) pathogenicity island, a major virulence factor of STEC, but they possessed one or more alternative virulence genes encoding cytotoxins (Cdt and SubAB) and/or adhesins (Saa, Iha, and EcpA). Notably, a significant heterogeneity in glutamate-induced acid resistance was observed among the STEC isolates (p ï¼ 0.05). In addition, phylogenetic analyses demonstrated that all three STEC O91:H14 isolates were categorized into sequence type (ST) 33, of which two beef isolates were identical in their pulsotypes. Similar results were observed with two O121:H10 pork isolates (ST641; 88.2% similarity). Interestingly, 96.0% of the 100 human STEC isolates collected in Korea during 2003 to 2014 were serotyped as O91:H14, and the ST33 lineage was confirmed in approximately 72.2% (13/18 isolates) of human STEC O91:H14 isolates from diarrheal patients.
Assuntos
Escherichia coli O157/genética , Carne Vermelha/microbiologia , Escherichia coli Shiga Toxigênica/genética , Animais , Western Blotting , Bovinos , Eletroforese em Gel de Campo Pulsado , Escherichia coli O157/isolamento & purificação , Escherichia coli O157/patogenicidade , Testes de Fixação do Látex , Tipagem de Sequências Multilocus , Filogenia , República da Coreia , Escherichia coli Shiga Toxigênica/isolamento & purificação , Escherichia coli Shiga Toxigênica/patogenicidade , SuínosRESUMO
We investigated an outbreak of enterotoxigenic Escherichia coli (ETEC) O159:H20 associated with the consumption of a tossed-noodle dish in a high school in 2016. Thirty-three ETEC strains isolated from clinical and food samples were genetically indistinguishable. The outbreak strains were resistant to third-generation cephalosporins and harbored a blaCTX-M-15 gene on a 97-kb self-transferable IncK plasmid. This is the first outbreak caused by CTX-M-15-producing ETEC strains.
Assuntos
Escherichia coli Enterotoxigênica/metabolismo , Infecções por Escherichia coli/epidemiologia , beta-Lactamases/metabolismo , Cefalosporinas/uso terapêutico , Surtos de Doenças , Escherichia coli Enterotoxigênica/efeitos dos fármacos , Humanos , Plasmídeos/genética , República da Coreia/epidemiologiaRESUMO
BACKGROUND: Enterovirus (EV) 71 is the main pathogen associated with hand, foot and mouth disease (HFMD) or herpangina. Outbreaks of HFMD caused by EV71 infection are associated severe neurological disease and high mortality rates in children. Several sporadic cases of EV71 infection occurred in the Republic of Korea (ROK) in 2000, and EV71 infections were not reported thereafter until 2006. In this prospective study, we report the epidemic and virologic characteristics of the EV71 endemic from 2007 to 2012 in the Republic of Korea. METHODS: We analyzed characteristics of the EV71 infection-associated epidemic from collected specimens and clinical information from 9987 patients with suspected EV infection from the National EV Surveillance System in ROK. To identify the EV71 subgenotype, the homology of viral protein 1 sequences obtained using reverse transcription polymerase chain reaction was compared with the sequences on other countries available from GenBank database. RESULTS: EV71 was detected in 585 (16.7 %) specimens (cerebrospinal fluid, stool or rectal swabs, throat swabs and blood) during study period and was most frequently observed during epidemic seasons in 2009-2012. Major manifestations due to EV71 infection were HFMD (62.2 %) and HFMD with severe neurological complications (28.4 %). Five deaths (0.9 %) due to EV71 infection occurred, with an increased mortality rate during the period after 2009. Most patients (476; 81.4 %) were less than 5 years of age. Analysis of the monthly distribution showed that there was an obvious seasonal pattern to the epidemics, with infections appearing from June to August. The major subgenotype of EV71 isolates circulating in ROK was the C4a strain, which has also appeared in China, Japan and Vietnam. CONCLUSIONS: This surveillance provided valuable data on the epidemic characteristics of EV71 infections in ROK during a 6-year period. Our findings provide data to assist during future outbreaks of EV71 and associated acute neurologic disease.
Assuntos
Enterovirus Humano A/genética , Doença de Mão, Pé e Boca/epidemiologia , Adolescente , Adulto , Líquido Cefalorraquidiano/virologia , Criança , Pré-Escolar , Estudos Transversais , Surtos de Doenças , Enterovirus Humano A/classificação , Enterovirus Humano A/isolamento & purificação , Fezes/virologia , Feminino , Genótipo , Doença de Mão, Pé e Boca/mortalidade , Doença de Mão, Pé e Boca/virologia , Humanos , Lactente , Masculino , Filogenia , RNA Viral/isolamento & purificação , RNA Viral/metabolismo , República da Coreia/epidemiologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Taxa de Sobrevida , Proteínas Virais/genética , Proteínas Virais/metabolismo , Adulto JovemRESUMO
AIMS: Despite the observation that ErbB2 regulates sensitivity of the heart to doxorubicin or ErbB2-targeted cancer therapies, mechanisms that regulate ErbB2 expression and activity have not been studied. Since isoproterenol up-regulates ErbB2 in kidney and salivary glands and ß2AR and ErbB2 complex in brain and heart, we hypothesized that ß-adrenergic receptors (AR) modulate ErbB2 signalling status. METHODS AND RESULTS: ErbB2 transfection of HEK293 cells up-regulates ß2AR, and ß2AR transfection of HEK293 up-regulates ErbB2. Interestingly, cardiomyocytes isolated from myocyte-specific ErbB2-overexpressing (ErbB2(tg)) mice have amplified response to selective ß2-agonist zinterol, and right ventricular trabeculae baseline force generation is markedly reduced with ß2-antagonist ICI-118 551. Consistently, receptor binding assays and western blotting demonstrate that ß2ARs levels are markedly increased in ErbB2(tg) myocardium and reduced by EGFR/ErbB2 inhibitor, lapatinib. Intriguingly, acute treatment of mice with ß1- and ß2-AR agonist isoproterenol resulted in myocardial ErbB2 increase, while inhibition with either ß1- or ß2-AR antagonist did not completely prevent isoproterenol-induced ErbB2 expression. Furthermore, inhibition of ErbB2 kinase predisposed mice hearts to injury from chronic isoproterenol treatment while significantly reducing isoproterenol-induced pAKT and pERK levels, suggesting ErbB2's role in transactivation in the heart. CONCLUSION: Our studies show that myocardial ErbB2 and ßAR signalling are linked in a feedback loop with ßAR activation leading to increased ErbB2 expression and activity, and increased ErbB2 activity regulating ß2AR expression. Most importantly, ErbB2 kinase activity is crucial for cardioprotection in the setting of ß-adrenergic stress, suggesting that this mechanism is important in the pathophysiology and treatment of cardiomyopathy induced by ErbB2-targeting antineoplastic drugs.
Assuntos
Isoproterenol/farmacologia , Miocárdio/metabolismo , Miócitos Cardíacos/metabolismo , Receptor ErbB-2/metabolismo , Transdução de Sinais/efeitos dos fármacos , Agonistas Adrenérgicos beta/farmacologia , Animais , AMP Cíclico/metabolismo , Feminino , Ventrículos do Coração/efeitos dos fármacos , Ventrículos do Coração/metabolismo , Camundongos , Miócitos Cardíacos/efeitos dos fármacos , Receptor ErbB-2/genética , Receptores Adrenérgicos beta 1/metabolismo , Transdução de Sinais/fisiologiaRESUMO
BACKGROUND: Enteroviruses (EVs) are the leading cause of aseptic meningitis worldwide. Detection of enteroviral RNA in clinical specimens has been demonstrated to improve the management of patient care, especially that of neonates and young children. FINDINGS: To establish a sensitive and reliable assay for routine laboratory diagnosis, we compared the sensitivity and specificity of the GeneXpert Enterovirus Assay (GXEA) with that of the reverse transcription polymerase chain reaction (RT-PCR) based assay referred to as real-time one step RT-PCR (RTo-PCR). The sensitivity/specificity produced by GXEA and RTo-PCR were 100%/100% and 65%/100%, respectively. CONCLUSIONS: Both methods evaluated in this article can be used for detection of enterovirus in clinical specimens and these nucleic acid amplification methods are useful assays for the diagnosis of enteroviral infection.
Assuntos
Infecções por Enterovirus/virologia , Enterovirus/isolamento & purificação , Meningite/virologia , RNA Viral/genética , Reação em Cadeia da Polimerase em Tempo Real/métodos , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos , Enterovirus/genética , Infecções por Enterovirus/líquido cefalorraquidiano , Infecções por Enterovirus/diagnóstico , Humanos , Meningite/líquido cefalorraquidiano , Meningite/diagnóstico , Técnicas de Diagnóstico Molecular , RNA Viral/líquido cefalorraquidianoRESUMO
Although aerobic glycolysis provides an advantage in the hypoxic tumor microenvironment, some cancer cells can also respire via oxidative phosphorylation. These respiring ("non-Warburg") cells were previously thought not to play a key role in tumorigenesis and thus fell from favor in the literature. We sought to determine whether subpopulations of hypoxic cancer cells have different metabolic phenotypes and gene-expression profiles that could influence tumorigenicity and therapeutic response, and we therefore developed a dual fluorescent protein reporter, HypoxCR, that detects hypoxic [hypoxia-inducible factor (HIF) active] and/or cycling cells. Using HEK293T cells as a model, we identified four distinct hypoxic cell populations by flow cytometry. The non-HIF/noncycling cell population expressed a unique set of genes involved in mitochondrial function. Relative to the other subpopulations, these hypoxic "non-Warburg" cells had highest oxygen consumption rates and mitochondrial capacity consistent with increased mitochondrial respiration. We found that these respiring cells were unexpectedly tumorigenic, suggesting that continued respiration under limiting oxygen conditions may be required for tumorigenicity.
Assuntos
Ciclo Celular/fisiologia , Hipóxia Celular/fisiologia , Neoplasias/metabolismo , Neoplasias/patologia , Animais , Ciclo Celular/genética , Hipóxia Celular/genética , Respiração Celular , Expressão Gênica , Genes Mitocondriais , Genes Reporter , Células HEK293 , Xenoenxertos , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Proteínas Luminescentes/genética , Proteínas Luminescentes/metabolismo , Masculino , Camundongos , Camundongos Nus , Modelos Biológicos , Transplante de Neoplasias , Neoplasias/genética , Oncogenes , Consumo de OxigênioRESUMO
Human enterovirus (EV) 71 is the main etiological agent of hand, foot, and mouth disease (HFMD). It is associated with neurological complications, and caused fatalities during recent outbreaks in the Asia-Pacific region. Infections caused by EV71 could lead to many complications, ranging from brainstem encephalitis to pulmonary oedema, resulting in high mortality. In this study, a duplex real-time RT-PCR assay was developed in order to simultaneously detect pan-EV and EV71. EV71-specific primers and probes were designed based on the highly conserved VP1 region of EV71. Five EV71 strains were detected as positive, and no positive fluorescence signal was observed in the duplex real-time RT-PCR for other viral RNA, which showed 100% specificity for the selected panel, and no cross-reactions were observed in this duplex real-time RT-PCR. The EV71-specific duplex real-time RT-PCR was more sensitive than conventional RT-PCR, and detected viral titers that were 10-fold lower than those measured by the latter. Of the 381 HFMD clinical specimens, 196 (51.4%) cases were pan-EV-positive, of which 170 (86.7%) were EV71-positive when tested by pan-EV and EV71-specific duplex real-time RT-PCR. EV71-specific duplex real-time RT-PCR offers a rapid and sensitive method to detect EV71 from clinical specimens, and will allow quarantine measures to be taken more effectively during outbreaks.
Assuntos
Enterovirus Humano A/isolamento & purificação , Doença de Mão, Pé e Boca/diagnóstico , Técnicas de Diagnóstico Molecular/métodos , Reação em Cadeia da Polimerase Multiplex/métodos , Reação em Cadeia da Polimerase em Tempo Real/métodos , Virologia/métodos , Animais , Criança , Pré-Escolar , Enterovirus Humano A/genética , Doença de Mão, Pé e Boca/virologia , Humanos , Sensibilidade e Especificidade , Fatores de TempoRESUMO
The epidemiology of enteroviral infection in South Korea during 1999-2011 chronicles nationwide outbreaks and changing detection and subtyping methods used over the 13-year period. Of 14,657 patients whose samples were tested, 4,762 (32.5%) samples were positive for human enterovirus (human EV); as diagnostic methods improved, the rate of positive results increased. A seasonal trend of outbreaks was documented. Genotypes enterovirus 71, echovirus 30, coxsackievirus B5, enterovirus 6, and coxsackievirus B2 were the most common genotypes identified. Accurate test results correlated clinical syndromes to enterovirus genotypes: aseptic meningitis to echovirus 30, enterovirus 6, and coxsackievirus B5; hand, foot and mouth disease to coxsackievirus A16; and hand, foot and mouth disease with neurologic complications to enterovirus 71. There are currently no treatments specific to human EV infections; surveillance of enterovirus infections such as this study provides may assist with evaluating the need to research and develop treatments for infections caused by virulent human EV genotypes.
Assuntos
Surtos de Doenças , Infecções por Enterovirus/diagnóstico , Enterovirus/genética , Adolescente , Adulto , Distribuição por Idade , Proteínas do Capsídeo/genética , Criança , Pré-Escolar , Erros de Diagnóstico , Infecções por Enterovirus/epidemiologia , Monitoramento Epidemiológico , Genótipo , Humanos , Lactente , Pessoa de Meia-Idade , Técnicas de Diagnóstico Molecular , Tipagem Molecular , Prevalência , Reação em Cadeia da Polimerase em Tempo Real , República da Coreia/epidemiologia , Estações do Ano , Sensibilidade e Especificidade , Análise de Sequência de DNA , Adulto JovemRESUMO
This study was performed to analyze epidemiological and molecular characteristics of coxsakievirus (CV) B1 infection associated with severe neonatal illness cases and death in Korea during 2008-2009. Through a nationwide surveillance program, specimens were collected from 104 patients infected with CVB1. The detection of enteroviruses (EVs) from specimens was subjected to a diagnostic real-time polymerase chain reaction (RT-PCR) in the 5'-non-coding region (NCR). A semi-nested PCR was conducted to amplify sequences from the VP1 region and sequence comparison was performed with reference strains registered in Genbank. Male-to-female ratio confirmed approximately 5:4. The major clinical manifestation of patients infected with CVB1 was aseptic meningitis (55.8%). The other clinical symptoms were herpangina or hand-foot-mouth disease (22.1%) and neonatal sepsis (7.7%). The sequences of CVB1 isolates were divided into four genetic clusters (A-D) with at least 15% diversity between the clusters. Almost all the CVB1 isolates in Korea from 2008 to 2009 were in cluster D (except for 2 cases). The homology relationship was also similar between the Korean CVB1 strains and US strain (above 93%). It is possible that Korean CVB1 isolates found during 2008-2009 originated from the US strains found during 2006-2008. The identification of CVB1 in South Korea shows the potential of EVs to cause serious disease in an unpredictable fashion.
Assuntos
Infecções por Coxsackievirus/epidemiologia , Infecções por Coxsackievirus/virologia , Enterovirus/classificação , Enterovirus/isolamento & purificação , Adolescente , Criança , Pré-Escolar , Análise por Conglomerados , Enterovirus/genética , Feminino , Genótipo , Humanos , Lactente , Masculino , Epidemiologia Molecular , Dados de Sequência Molecular , Filogenia , Reação em Cadeia da Polimerase , RNA Viral/genética , Reação em Cadeia da Polimerase em Tempo Real , República da Coreia/epidemiologia , Análise de Sequência de DNA , Homologia de Sequência de Aminoácidos , Proteínas Estruturais Virais/genéticaRESUMO
Many biobanks were established as biorepositories for biomedical research, and a number of biobanks were founded in the 1990s. The main aim of the biobank is to store and to maintain biomaterials for studying chronic disease, identifying risk factors of specific diseases, and applying personalized drug therapies. This report provides a review of biobanks, including Korean biobanks and an analysis of sample volumes, regulations, policies, and ethical issues of the biobank. Until now, the top 6 countries according to the number of large-scale biobanks are the United Kingdom, United States, Sweden, France, the Netherlands, and Italy, and there is one major National Biobank of Korea (NBK) and 17 regional biobanks in Korea. Many countries have regulations and guidelines for the biobanks, and the importance of good management of biobanks is increasing. Meanwhile, according to a first survey of 456 biobank managers in the United States, biobankers are concerned with the underuse of the samples in their repositories, which need to be advertised for researchers. Korea Biobank Network (KBN) project phase II (2013-2015) was also planned for the promotion to use biospecimens in the KBN. The KBN is continuously introducing for researchers to use biospecimens in the biobank. An accreditation process can also be introduced for biobanks to harmonize collections and encourage use of biospecimens in the biobanks. KBN is preparing an on-line application system for the distribution of biospecimens and a biobank accreditation program and is trying to harmonize the biobanks.
RESUMO
BACKGROUND: Emerging evidence shows that ErbB2 signaling has a critical role in cardiomyocyte physiology, based mainly on findings that blocking ErbB2 for cancer therapy is toxic to cardiac cells. However, consequences of high levels of ErbB2 activity in the heart have not been previously explored. METHODOLOGY/PRINCIPAL FINDINGS: We investigated consequences of cardiac-restricted over-expression of ErbB2 in two novel lines of transgenic mice. Both lines develop striking concentric cardiac hypertrophy, without heart failure or decreased life span. ErbB2 transgenic mice display electrocardiographic characteristics similar to those found in patients with Hypertrophic Cardiomyopathy, with susceptibility to adrenergic-induced arrhythmias. The hypertrophic hearts, which are 2-3 times larger than those of control littermates, express increased atrial natriuretic peptide and ß-myosin heavy chain mRNA, consistent with a hypertrophic phenotype. Cardiomyocytes in these hearts are significantly larger than wild type cardiomyocytes, with enlarged nuclei and distinctive myocardial disarray. Interestingly, the over-expression of ErbB2 induces a concurrent up-regulation of multiple proteins associated with this signaling pathway, including EGFR, ErbB3, ErbB4, PI3K subunits p110 and p85, bcl-2 and multiple protective heat shock proteins. Additionally, ErbB2 up-regulation leads to an anti-apoptotic shift in the ratio of bcl-xS/xL in the heart. Finally, ErbB2 over-expression results in increased activation of the translation machinery involving S6, 4E-BP1 and eIF4E. The dependence of this hypertrophic phenotype on ErbB family signaling is confirmed by reduction in heart mass and cardiomyocyte size, and inactivation of pro-hypertrophic signaling in transgenic animals treated with the ErbB1/2 inhibitor, lapatinib. CONCLUSIONS/SIGNIFICANCE: These studies are the first to demonstrate that increased ErbB2 over-expression in the heart can activate protective signaling pathways and induce a phenotype consistent with Hypertrophic Cardiomyopathy. Furthermore, our work suggests that in the situation where ErbB2 signaling contributes to cardiac hypertrophy, inhibition of this pathway may reverse this process.
Assuntos
Cardiomiopatia Hipertrófica/genética , Cardiomiopatia Hipertrófica/patologia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Receptor ErbB-2/genética , Transdução de Sinais/genética , Animais , Arritmias Cardíacas/induzido quimicamente , Arritmias Cardíacas/genética , Cardiomiopatia Hipertrófica/fisiopatologia , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Fenômenos Eletrofisiológicos , Expressão Gênica , Isoproterenol/farmacologia , Lapatinib , Masculino , Camundongos , Camundongos Transgênicos , Tamanho do Órgão/efeitos dos fármacos , Especificidade de Órgãos , Biossíntese de Proteínas/efeitos dos fármacos , Biossíntese de Proteínas/genética , Quinazolinas/farmacologia , Ratos , Transdução de Sinais/efeitos dos fármacosRESUMO
BACKGROUND: Echovirus 30 (Echo30) is one of the most frequently identified human enteroviruses (EVs) causing aseptic meningitis and encephalitis. However the mechanism underlying the pathogenesis of Echo30 infection with significant clinical outcomes is not completely understood. The aim of this investigation is to illustrate molecular pathologic alteration in neuronal cells induced by Echo30 infection using clinical isolate from young patient with neurologic involvement. METHODOLOGY/PRINCIPAL FINDINGS: To characterize the neuronal cellular response to Echo30 infection, we performed a proteomic analysis based on two-dimensional gel electrophoresis (2-DE) and MALDI-TOF/TOF Mass Spectrophotometric (MS) analysis. We identified significant alteration of several protein expression levels in Echo30-infected SK-N-SH cells. Among these proteins, we focused on an outstanding up-regulation of Triple functional domain (TRIO) in Echo30-infected SK-N-SH cells. Generally, TRIO acts as a key component in the regulation of axon guidance and cell migration. In this study, we determined that TRIO plays a role in the novel pathways in Echo30 induced neuronal cell death. CONCLUSIONS/SIGNIFICANCE: Our finding shows that TRIO plays a critical role in neuronal cell death by Echo30 infection. Echo30 infection activates TRIO-guanine nucleotide exchange factor (GEF) domains (GEFD2) and RhoA signaling in turn. These results suggest that Echo30 infection induced neuronal cell death by activation of the TRIO-RhoA signaling. We expect the regulation of TRIO-RhoA signaling may represent a new therapeutic approach in treating aseptic meningitis and encephalitis induced by Echo30.