RESUMEN
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.
Asunto(s)
Proteínas Portadoras/genética , Fibrosis Pulmonar Idiopática/genética , Mutación con Pérdida de Función , Proteínas Nucleares/genética , ARN/metabolismo , Telomerasa/metabolismo , Animales , Encéfalo/enzimología , Encéfalo/fisiopatología , Línea Celular , Cilios/genética , Femenino , Ligamiento Genético , Células HCT116 , Humanos , Fibrosis Pulmonar Idiopática/enzimología , Fibrosis Pulmonar Idiopática/fisiopatología , Masculino , Ratones , Ratones Noqueados , Trastornos del Neurodesarrollo/genética , Linaje , Procesamiento Postranscripcional del ARN/genética , Acortamiento del Telómero/genéticaRESUMEN
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.
Asunto(s)
Halcones , Leiomioma/veterinaria , Proventrículo/patología , Neoplasias Gástricas/veterinaria , Animales , Enfermedades de las Aves/patología , Resultado Fatal , Femenino , Leiomioma/patología , Neoplasias Gástricas/patologíaRESUMEN
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.
Asunto(s)
Escherichia coli Enterotoxigénica/metabolismo , Infecciones por Escherichia coli/epidemiología , beta-Lactamasas/metabolismo , Cefalosporinas/uso terapéutico , Brotes de Enfermedades , Escherichia coli Enterotoxigénica/efectos de los fármacos , Humanos , Plásmidos/genética , República de Corea/epidemiologíaRESUMEN
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.
Asunto(s)
Ciclo Celular/fisiología , Hipoxia de la Célula/fisiología , Neoplasias/metabolismo , Neoplasias/patología , Animales , Ciclo Celular/genética , Hipoxia de la Célula/genética , Respiración de la Célula , Expresión Génica , Genes Mitocondriales , Genes Reporteros , Células HEK293 , Xenoinjertos , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Proteínas Luminiscentes/genética , Proteínas Luminiscentes/metabolismo , Masculino , Ratones , Ratones Desnudos , Modelos Biológicos , Trasplante de Neoplasias , Neoplasias/genética , Oncogenes , Consumo de OxígenoRESUMEN
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.
Asunto(s)
Enterovirus Humano A/genética , Enfermedad de Boca, Mano y Pie/epidemiología , Adolescente , Adulto , Líquido Cefalorraquídeo/virología , Niño , Preescolar , Estudios Transversales , Brotes de Enfermedades , Enterovirus Humano A/clasificación , Enterovirus Humano A/aislamiento & purificación , Heces/virología , Femenino , Genotipo , Enfermedad de Boca, Mano y Pie/mortalidad , Enfermedad de Boca, Mano y Pie/virología , Humanos , Lactante , Masculino , Filogenia , ARN Viral/aislamiento & purificación , ARN Viral/metabolismo , República de Corea/epidemiología , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Tasa de Supervivencia , Proteínas Virales/genética , Proteínas Virales/metabolismo , Adulto JovenRESUMEN
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.
Asunto(s)
Infecciones por Enterovirus/virología , Enterovirus/aislamiento & purificación , Meningitis/virología , ARN Viral/genética , Reacción en Cadena en Tiempo Real de la Polimerasa/métodos , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/métodos , Enterovirus/genética , Infecciones por Enterovirus/líquido cefalorraquídeo , Infecciones por Enterovirus/diagnóstico , Humanos , Meningitis/líquido cefalorraquídeo , Meningitis/diagnóstico , Técnicas de Diagnóstico Molecular , ARN Viral/líquido cefalorraquídeoRESUMEN
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.
Asunto(s)
Brotes de Enfermedades , Infecciones por Enterovirus/diagnóstico , Enterovirus/genética , Adolescente , Adulto , Distribución por Edad , Proteínas de la Cápside/genética , Niño , Preescolar , Errores Diagnósticos , Infecciones por Enterovirus/epidemiología , Monitoreo Epidemiológico , Genotipo , Humanos , Lactante , Persona de Mediana Edad , Técnicas de Diagnóstico Molecular , Tipificación Molecular , Prevalencia , Reacción en Cadena en Tiempo Real de la Polimerasa , República de Corea/epidemiología , Estaciones del Año , Sensibilidad y Especificidad , Análisis de Secuencia de ADN , Adulto JovenRESUMEN
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.
Asunto(s)
Enterovirus Humano A/aislamiento & purificación , Enfermedad de Boca, Mano y Pie/diagnóstico , Técnicas de Diagnóstico Molecular/métodos , Reacción en Cadena de la Polimerasa Multiplex/métodos , Reacción en Cadena en Tiempo Real de la Polimerasa/métodos , Virología/métodos , Animales , Niño , Preescolar , Enterovirus Humano A/genética , Enfermedad de Boca, Mano y Pie/virología , Humanos , Sensibilidad y Especificidad , Factores de TiempoRESUMEN
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.
Asunto(s)
Infecciones por Coxsackievirus/epidemiología , Infecciones por Coxsackievirus/virología , Enterovirus/clasificación , Enterovirus/aislamiento & purificación , Adolescente , Niño , Preescolar , Análisis por Conglomerados , Enterovirus/genética , Femenino , Genotipo , Humanos , Lactante , Masculino , Epidemiología Molecular , Datos de Secuencia Molecular , Filogenia , Reacción en Cadena de la Polimerasa , ARN Viral/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , República de Corea/epidemiología , Análisis de Secuencia de ADN , Homología de Secuencia de Aminoácido , Proteínas Estructurales Virales/genéticaRESUMEN
BACKGROUND: Enterovirus (EV) infections are commonly associated with encephalitis and meningitis. Detection of enteroviral RNA in clinical specimens has been demonstrated to improve the management of patients, by ruling out other causes of disease. METHOD: To develop a sensitive and reliable assay for routine laboratory diagnosis, we developed a real-time one step reverse transcription polymerase chain reaction (RT-PCR) assay with minor groove binder probes and primers modified with complementary locked primer technology (TMC-PCR). We checked the sensitivity of the developed assay by comparing it to a previously published TaqMan probe real-time one-step RT-PCR (TTN-PCR) procedure using enteroviral isolates, Enterovirus Proficiency panels from Quality Control on Molecular Diagnostics (QCMD-2007), and clinical specimens from patients with suspected EV infections. RESULTS: One hundred clinical specimens from 158 suspected viral meningitis cases were determined to be positive by the TMC-PCR assay (63.29%), whereas only 60 were found to be positive by the TTN-PCR assay (37.97%). The positive and negative agreements between the TMC-PCR and TTN-PCR assays were 100% and 59.2%, respectively. CONCLUSION: This data suggest that the TMC-PCR assay may be suitable for routine diagnostic screening from patient suspected EV infection.
Asunto(s)
Cartilla de ADN/genética , Infecciones por Enterovirus/diagnóstico , Enterovirus/genética , Enterovirus/aislamiento & purificación , ARN Viral/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/métodos , Virología/métodos , Enterovirus/clasificación , Infecciones por Enterovirus/virología , Humanos , Sensibilidad y EspecificidadRESUMEN
An outbreak of echovirus 5 (ECV 5) occurred in Korea in 2006, marking the first time this virus had been identified in the country since enterovirus surveillance began in 1993. Using a sample isolated from a young male patient with aseptic meningitis, we performed sequencing of the Korean ECV 5 strain and compared it with a prototype strain (Noyce). At the nucleotide level, the P1 region (85.3%) had the highest identity value; at the amino acid level, the P3 region (98.0%) had the highest identity value. The two strains shared all cleavage sites, with the exception of the VP1/2A site, which was TY/GA in the Noyce strain but TR/GA in the Korean ECV 5 isolate. In Vero cells infected with the Korean ECV 5 isolate, no cytotoxicity was observed in the presence of azidothymidine, acyclovir, amantadine, lamivudine, or ribavirin, when the drugs were administered at a CC50 value >100 µg/mL. Of the five drugs, only amantadine (IC50: 1 ± 0.42 µg/mL, TI: 100) and ribavirin (IC50: 22 ± 1.36 µg/mL, TI: 4.55) had any antiviral activity against the Korean ECV 5 isolate.
Asunto(s)
Antivirales/farmacología , Infecciones por Echovirus/virología , Enterovirus Humano B/efectos de los fármacos , Enterovirus Humano B/genética , Variación Genética , Infecciones por Echovirus/tratamiento farmacológico , Infecciones por Echovirus/epidemiología , Enterovirus Humano B/clasificación , Enterovirus Humano B/aislamiento & purificación , Humanos , Corea (Geográfico)/epidemiología , Filogenia , Proteínas Virales/genéticaRESUMEN
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.
Asunto(s)
ATPasas Transportadoras de Cobre/genética , Cobre/toxicidad , Eliminación de Gen , Hepatocitos/metabolismo , Hepatocitos/patología , Degeneración Hepatolenticular/genética , Degeneración Hepatolenticular/patología , Animales , Biomarcadores/metabolismo , ATPasas Transportadoras de Cobre/deficiencia , Modelos Animales de Enfermedad , Glucosa/metabolismo , Glucógeno/metabolismo , Metabolismo de los Lípidos , Hígado/patología , Ratones Endogámicos C57BL , Ratones Noqueados , Fenotipo , Análisis de Componente Principal , Proteoma/metabolismo , Factores de TiempoRESUMEN
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.
RESUMEN
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.
Asunto(s)
Prueba de COVID-19/normas , COVID-19/diagnóstico , Laboratorios/normas , COVID-19/epidemiología , COVID-19/prevención & control , COVID-19/virología , China/epidemiología , Brotes de Enfermedades , Regulación Gubernamental , Humanos , Neumonía/diagnóstico , Neumonía/epidemiología , Neumonía/virología , SARS-CoV-2/genética , SARS-CoV-2/aislamiento & purificaciónRESUMEN
We assessed neurologic sequelae associated with an enterovirus 71 (EV71) outbreak in South Korea during 2009. Four of 94 patients had high signal intensities at brainstem or cerebellum on magnetic resonance imaging. Two patients died of cardiopulmonary collapse; 2 had severe neurologic sequelae. Severity and case-fatality rates may differ by EV71 genotype or subgenotype.
Asunto(s)
Enfermedades del Sistema Nervioso Central/epidemiología , Enfermedades del Sistema Nervioso Central/etiología , Enterovirus Humano A , Infecciones por Enterovirus/complicaciones , Infecciones por Enterovirus/epidemiología , Niño , Preescolar , Brotes de Enfermedades , Enterovirus Humano A/genética , Infecciones por Enterovirus/mortalidad , Femenino , Genotipo , Humanos , Lactante , Masculino , Datos de Secuencia Molecular , República de Corea/epidemiologíaRESUMEN
To increase detection sensitivity, we modified primers using complementary locked primer (CLP) technology. The sensitivity of the reverse transcription-PCR (RT-PCR) with CLP-modified primers was 10- to 100-fold higher than that of RT-PCR without these primers. CLP-modified primers can increase sensitivity, providing a widely accessible method for molecular diagnosis.
Asunto(s)
Cartilla de ADN/genética , Infecciones por Enterovirus/diagnóstico , Enterovirus/aislamiento & purificación , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/métodos , Enterovirus/genética , Humanos , Sensibilidad y EspecificidadRESUMEN
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.
Asunto(s)
Adenocarcinoma/genética , Envejecimiento/genética , Transformación Celular Neoplásica/genética , Neoplasias del Colon/genética , Metilación de ADN , Silenciador del Gen , Mutación , Proteínas Proto-Oncogénicas B-raf/genética , Células Madre/enzimología , Vía de Señalización Wnt/genética , Adenocarcinoma/enzimología , Adenocarcinoma/patología , Factores de Edad , Envejecimiento/metabolismo , Envejecimiento/patología , Animales , Transformación Celular Neoplásica/metabolismo , Transformación Celular Neoplásica/patología , Neoplasias del Colon/enzimología , Neoplasias del Colon/patología , Regulación Neoplásica de la Expresión Génica , Predisposición Genética a la Enfermedad , Humanos , Ratones Endogámicos NOD , Ratones Mutantes , Ratones SCID , Fenotipo , Proteínas Proto-Oncogénicas B-raf/metabolismo , Células Madre/patología , Factores de Tiempo , Técnicas de Cultivo de TejidosRESUMEN
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.
Asunto(s)
Escherichia coli O157/genética , Carne Roja/microbiología , Escherichia coli Shiga-Toxigénica/genética , Animales , Western Blotting , Bovinos , Electroforesis en Gel de Campo Pulsado , Escherichia coli O157/aislamiento & purificación , Escherichia coli O157/patogenicidad , Pruebas de Fijación de Látex , Tipificación de Secuencias Multilocus , Filogenia , República de Corea , Escherichia coli Shiga-Toxigénica/aislamiento & purificación , Escherichia coli Shiga-Toxigénica/patogenicidad , PorcinosRESUMEN
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.
Asunto(s)
Transformación Celular Neoplásica/genética , Islas de CpG/genética , Metilación de ADN/genética , Epigénesis Genética/genética , Animales , Senescencia Celular/genética , Humanos , Ratones , Ratones SCID , Neoplasias/genética , Regiones Promotoras Genéticas/genética , RiesgoRESUMEN
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.