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[This corrects the article DOI: 10.18632/oncotarget.5734.].
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14-3-3ε is overexpressed in hepatocellular carcinoma (HCC) and its expression significantly associates with a poor prognostic outcome. To uncover how 14-3-3ε contributes to the tumor progression of HCC, we investigated the potential downstream targets regulated by 14-3-3ε. We found that 14-3-3ε increases expression and nuclear translocation of ß-catenin and that 14-3-3ε-induced cell proliferation is attenuated by ß-catenin silencing in HCC cells. Moreover, 14-3-3ε induces aldo-keto reductase family 1 member B10 (AKR1B10) expression through the activation of ß-catenin signaling. Knockdown of AKR1B10 by siRNAs abolished 14-3-3ε-induced in vitro cell proliferation, anchorage-independent growth as well as in vivo tumor growth. Furthermore, AKR1B10 silencing increased retinoic acid (RA) levels in the serum of tumor-bearing mice and RA treatment attenuated 14-3-3ε-induced HCC cell proliferation. We further examined 14-3-3ε and AKR1B10 expression and clinicopathological characteristics of HCC tumors. Although the expression of AKR1B10 was significantly correlated with 14-3-3ε, an increase of AKR1B10 expression in 14-3-3ε positive patients paradoxically had better overall survival and disease-free survival rates as well as lower metastatic incidence than those without an AKR1B10 increase. Finally, we found a loss of AKR1B10 expression in cells exhibiting a high capacity of invasiveness. Silencing of AKR1B10 resulted in inducing snail and vimentin expression in HCC cells. These results indicate that AKR1B10 may play a dual role during HCC tumor progression. Our results also indicate that 14-3-3ε regulates AKR1B10 expression by activating ß-catenin signaling. A combination of 14-3-3ε with AKR1B10 is a potential therapeutic target and novel prognostic biomarker of HCC.
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Proteínas 14-3-3/metabolismo , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/metabolismo , Proteínas 14-3-3/genética , Carcinoma Hepatocelular/enzimología , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patología , Línea Celular Tumoral , Proliferación Celular/fisiología , Femenino , Humanos , Neoplasias Hepáticas/enzimología , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patología , Masculino , Pronóstico , Transducción de SeñalRESUMEN
BACKGROUND: 14-3-3σ is implicated in promoting tumor development of various malignancies. However, the clinical relevance of 14-3-3σ in hepatocellular carcinoma (HCC) tumor progression and modulation and pathway elucidation remain unclear. METHODS: We investigated 14-3-3σ expression in 109 HCC tissues by immunohistochemistry. Overexpression and knockdown experiments were performed by transfection with cDNA or siRNA. Protein expression and cell migration were determined by Western blot and Boyden chamber assay. RESULTS: In this study, we found that 14-3-3σ is abundantly expressed in HCC tumors. Stable or transient overexpression of 14-3-3σ induces the expression of heat shock factor-1α (HSF-1α) and heat shock protein 70 (HSP70) in HCC cells. Moreover, expression of 14-3-3σ significantly correlates with HSF-1α/HSP70 in HCC tumors and both 14-3-3σ and HSP70 overexpression are associated with micro-vascular thrombi in HCC patients, suggesting that 14-3-3σ/HSP70 expression is potentially involved in cell migration/invasion. Results of an in vitro migration assay indicate that 14-3-3σ promotes cell migration and that 14-3-3σ-induced cell migration is impaired by siRNA knockdown of HSP70. Finally, 14-3-3σ-induced HSF-1α/HSP70 expression is abolished by the knockdown of ß-catenin or activation of GSK-3ß. CONCLUSIONS: Our findings indicate that 14-3-3σ participates in promoting HCC cell migration and tumor development via ß-catenin/HSF-1α/HSP70 pathway regulation. Thus, 14-3-3σ alone or combined with HSP70 are potential prognostic biomarkers for HCC.
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Proteínas 14-3-3/metabolismo , Biomarcadores de Tumor/metabolismo , Carcinoma Hepatocelular/genética , Exorribonucleasas/metabolismo , Proteínas HSP70 de Choque Térmico/biosíntesis , Neoplasias Hepáticas/genética , Anciano , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Movimiento Celular/genética , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Femenino , Regulación Neoplásica de la Expresión Génica , Proteínas HSP70 de Choque Térmico/metabolismo , Factores de Transcripción del Choque Térmico , Células Hep G2 , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Masculino , Persona de Mediana Edad , Pronóstico , Transducción de Señal , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , beta Catenina/genética , beta Catenina/metabolismoRESUMEN
Cordycepin, also known as 3-deoxyadenosine, is an analogue of adenosine extracted from the traditional Chinese medicine "Dong Chong Xia Cao". Cordycepin is an active small molecular weight compound and is implicated in modulating multiple physiological functions including immune activation, anti-aging and anti-tumor effects. Several studies have indicated that cordycepin suppresses tumor progression. However, the signaling pathways involved in cordycepin regulating cancer cell motility, invasiveness and epithelial-mesenchymal transition (EMT) remain unclear. In this study, we found that cordycepin inhibits hepatocellular carcinoma (HCC) cell proliferation and migration/invasion. Treatment of cordycepin results in the increasing expression of epithelial marker, Ecadherin while no significant effect was found on N-cadherin α-catenin and ß-catenin. Furthermore, although the expression of focal adhesion kinase (FAK) was slightly reduced, the level of phosphorylated FAK was significantly reduced by the treatment of cordycepin. In addition, cordycepin significantly suppresses the expression of integrin α3, integrin α6 and integrin ß1 which are crucial interacting partners of FAK in regulating the focal adhesion complex. These results suggest cordycepin may contribute to EMT, antimigration/ invasion and growth inhibitory effects of HCC by suppressing E-cadherin and integrin/FAK signaling. Thus, cordycepin is a potential therapeutic or supplementary agent for preventing HCC tumor progression.
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Antineoplásicos Fitogénicos/farmacología , Carcinoma Hepatocelular/metabolismo , Desoxiadenosinas/farmacología , Transición Epitelial-Mesenquimal/efectos de los fármacos , Proteína-Tirosina Quinasas de Adhesión Focal/metabolismo , Integrina alfa3beta1/metabolismo , Integrina alfa6beta1/metabolismo , Neoplasias Hepáticas/metabolismo , Cadherinas/metabolismo , Carcinoma Hepatocelular/patología , Línea Celular Tumoral/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Humanos , Integrina alfa3beta1/genética , Integrina alfa6beta1/genética , Neoplasias Hepáticas/patología , Transducción de SeñalRESUMEN
BACKGROUND: Leukemia stem cells (LSCs) are a limitless cell source for the initiation and maintenance of leukemia. Activation of the Wnt/ß-catenin pathway is required for the survival and development of LSCs. Therefore, targeting ß-catenin is considered a therapeutic strategy for the treatment of leukemia. The goal of this study was to explore whether cordycepin, an active component of the traditional medicine Cordyceps sinensis, regulates ß-catenin expression in leukemia cells. METHODOLOGY AND PRINCIPAL FINDINGS: In this study, we found that cordycepin significantly suppressed cell proliferation in all malignant cancer cells, including U937, K562, A549, HepG2, SK-Hep1 and MCF7 in a dose-dependent manner. However, cordycepin reduced ß-catenin levels in U937, K562 and THP1 leukemia cells and had no effect on other solid cancer cells. In addition, treatment with cordycepin significantly suppressed leukemia colony formation in soft agar assay. Cordycepin enhanced proteasome-dependent degradation and inhibited nuclear translocation of ß-catenin in leukemia cells. Cordycepin-reduced ß-catenin stability was restored by the addition of a pharmacological inhibitor of GSK-3ß, indicating that cordycepin-suppressed ß-catenin stability is mediated by the activation of GSK-3ß. Furthermore, cordycepin abolished the effect of Wnt3a-induced ß-catenin in leukemia cells. In addition, cordycepin-impaired ß-catenin is regulated by Akt activation but is not significantly influenced by AMPK or mTOR signal pathways. SIGNIFICANCE: Our findings show for the first time that codycepin selectively reduces ß-catenin stability in leukemia but not in other solid tumor cells. This suppressive effect is mediated by regulating GSK-3ß. A synergistic combination of cordycepin with other treatments should be used as a novel strategy to eradicate leukemia via elimination of LSCs.
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Desoxiadenosinas/farmacología , Glucógeno Sintasa Quinasa 3/metabolismo , Leucemia/tratamiento farmacológico , Leucemia/fisiopatología , Células Madre Neoplásicas/efectos de los fármacos , Transducción de Señal/fisiología , beta Catenina/metabolismo , Western Blotting , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Técnica del Anticuerpo Fluorescente , Glucógeno Sintasa Quinasa 3 beta , Humanos , Leucemia/metabolismo , Transducción de Señal/efectos de los fármacos , Ensayo de Tumor de Célula MadreRESUMEN
In recent years, zebrafish has emerged as a useful animal model for biomedical research. The deciphering of the zebrafish genome has revealed that many of the enzymes involved in the metabolism of endogenous compounds and xenobiotics are conserved between zebrafish and humans. This review summarizes the information currently available concerning the zebrafish cytosolic sulfotransferases (SULTs), a group of phase II enzymes that have been proposed to be involved in the regulation and homeostasis of key endogenous compounds and the detoxification of xenobiotics. To date, 20 zebrafish SULTs that fall into six major SULT gene families have been identified. Of the 20 SULTs 18 have been cloned, expressed, purified and characterized. These zebrafish SULTs were shown to exhibit differential substrate specificities for endogenous compounds such as monoamine transmitters, steroid/thyroid hormones and bile salts, as well as xenobiotics including environmental toxicants and drugs. These findings provide a foundation for using zebrafish as a model for investigating further the physiological, pharmacological, and toxicological involvement of the SULTs.
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Modelos Animales , Sulfotransferasas/metabolismo , Xenobióticos/metabolismo , Proteínas de Pez Cebra/metabolismo , Pez Cebra/metabolismo , Secuencia de Aminoácidos , Animales , Ácidos y Sales Biliares/metabolismo , Monoaminas Biogénicas/metabolismo , Datos de Secuencia Molecular , Alineación de Secuencia , Especificidad por Sustrato , Sulfotransferasas/química , Hormonas Tiroideas/metabolismo , Pez Cebra/embriología , Pez Cebra/genética , Proteínas de Pez Cebra/químicaRESUMEN
BACKGROUND: 14-3-3ε is implicated in regulating tumor progression, including hepatocellular carcinoma (HCC). Our earlier study indicated that elevated 14-3-3ε expression is significantly associated with higher risk of metastasis and lower survival rates of HCC patients. However, the molecular mechanisms of how 14-3-3ε regulates HCC tumor metastasis are still unclear. METHODOLOGY AND PRINCIPAL FINDINGS: In this study, we show that increased 14-3-3ε expression induces HCC cell migration and promotes epithelial-mesenchymal transition (EMT), which is determined by the reduction of E-cadherin expression and induction of N-cadherin and vimentin expression. Knockdown with specific siRNA abolished 14-3-3ε-induced cell migration and EMT. Furthermore, 14-3-3ε selectively induced Zeb-1 and Snail expression, and 14-3-3ε-induced cell migration was abrogated by Zeb-1 or Snail siRNA. In addition, the effect of 14-3-3ε-reduced E-cadherin was specifically restored by Zeb-1 siRNA. Positive 14-3-3ε expression was significantly correlated with negative E-cadherin expression, as determined by immunohistochemistry analysis in HCC tumors. Analysis of 14-3-3ε/E-cadherin expression associated with clinicopathological characteristics revealed that the combination of positive 14-3-3ε and negative E-cadherin expression is significantly correlated with higher incidence of HCC metastasis and poor 5-year overall survival. In contrast, patients with positive 14-3-3ε and positive E-cadherin expression had better prognostic outcomes than did those with negative E-cadherin expression. SIGNIFICANCE: Our findings show for the first time that E-cadherin is one of the downstream targets of 14-3-3ε in modulating HCC tumor progression. Thus, 14-3-3ε may act as an important regulator in modulating tumor metastasis by promoting EMT as well as cell migration, and it may serve as a novel prognostic biomarker or therapeutic target for HCC.
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Proteínas 14-3-3/metabolismo , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Transición Epitelial-Mesenquimal , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Cadherinas/metabolismo , Carcinoma Hepatocelular/genética , Línea Celular Tumoral , Movimiento Celular/genética , Transición Epitelial-Mesenquimal/genética , Regulación Neoplásica de la Expresión Génica , Proteínas de Homeodominio/metabolismo , Humanos , Estimación de Kaplan-Meier , Neoplasias Hepáticas/genética , Persona de Mediana Edad , Metástasis de la Neoplasia , Pronóstico , Factores de Transcripción de la Familia Snail , Factores de Transcripción/metabolismo , Regulación hacia Arriba/genética , Homeobox 1 de Unión a la E-Box con Dedos de ZincRESUMEN
BACKGROUND: G. hollisae thermostable direct hemolysin (Gh-TDH) is produced by most strains of G. hollisae. This toxin has been reported to be absorbed in the intestines in humans. Secondary liver injury might be caused by venous return of the toxin through the portal system. We aimed to firstly analyze the in vitro and in vivo hepatotoxicity of Gh-TDH. METHODS: Liver cells (primary human non-cancer cell and FL83B mouse cells) were treated and mice (BALB/c) were fed with this toxin to investigate its hepatotoxicity. Morphological examination and cytotoxicity assays using liver cells were also performed. Fluorescein isothiocyanate-conjugated toxin was used to analyze the localization of this protein in liver cells. Mice were subjected to liver function measurements and liver biopsies following toxin treatment and wild-type bacterial infection. PET (positron emission tomography)/CT (computed tomography) images were taken to assess liver metabolism during acute injury and recovery. RESULTS: The effect of hepatotoxicity was dose and time dependent. Cellular localization showed that the toxin was initially located around the cellular margins and subsequently entered the nucleus. Liver function measurements and liver biopsies of the mice following treatment with toxin or infection with wild-type Grimontia hollisae showed elevated levels of transaminases and damage to the periportal area, respectively. The PET/CT images revealed that the reconstruction of the liver continued for at least one week after exposure to a single dose of the toxin or bacterial infection. CONCLUSIONS: The hepatotoxicity of Gh-TDH was firstly demonstrated. The damage was located in the periportal area of the liver, and the liver became functionally insufficient.
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Proteínas Hemolisinas/toxicidad , Hepatopatías/microbiología , Hepatopatías/patología , Hígado/patología , Vibrionaceae/química , Secuencia de Aminoácidos , Animales , Toxinas Bacterianas/administración & dosificación , Toxinas Bacterianas/química , Toxinas Bacterianas/aislamiento & purificación , Toxinas Bacterianas/toxicidad , Enfermedades Cardiovasculares/microbiología , Enfermedades Cardiovasculares/patología , Fluoresceína-5-Isotiocianato , Fluorodesoxiglucosa F18 , Proteínas Hemolisinas/administración & dosificación , Proteínas Hemolisinas/química , Proteínas Hemolisinas/aislamiento & purificación , Hemólisis/efectos de los fármacos , Humanos , Enfermedades Renales/microbiología , Enfermedades Renales/patología , Hígado/efectos de los fármacos , Hígado/fisiopatología , Hepatopatías/diagnóstico por imagen , Hepatopatías/fisiopatología , Pruebas de Función Hepática , Ratones , Ratones Endogámicos BALB C , Datos de Secuencia Molecular , Tomografía de Emisión de Positrones , Transporte de Proteínas/efectos de los fármacos , Proteínas Recombinantes/administración & dosificación , Proteínas Recombinantes/química , Proteínas Recombinantes/aislamiento & purificación , Proteínas Recombinantes/toxicidad , Fracciones Subcelulares/efectos de los fármacos , Fracciones Subcelulares/metabolismoRESUMEN
Partitioning defective 3 (Par-3), a crucial component of partitioning-defective complex proteins, controls cell polarity and contributes to cell migration and cancer cell epithelial-to-mesenchymal transition. However, the clinical relevance of Par-3 in tumor progression and metastasis has not been well elucidated. In this study, we investigated the impact and association of Par-3 expression and clinical outcomes with hepatocellular carcinoma (HCC). We first confirmed that Par-3 was abundantly expressed in HCC cell lines by Western blot analysis. We used immunohistochemistry to analyze the association of Par-3 expression and clinicopathological characteristics in primary and subsequent metastatic tumors of patients with HCC. Par-3 was overexpressed in 47 of 111 (42.3%) primary tumors. Increased expression of Par-3 in primary tumors predicted an increased five-year cumulative incidence of extrahepatic metastasis. In addition, multivariate analysis revealed that Par-3 overexpression was an independent risk factor of extrahepatic metastasis. Increased Par-3 expression in primary tumors was associated with poor five-year overall survival rates and was an independent prognostic factor on Cox regression analysis. In conclusion, we show for the first time that increased Par-3 expression is associated with distant metastasis and poor survival rates in patients with HCC. Par-3 may be a novel prognostic biomarker and therapeutic target for HCC.
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Carcinoma Hepatocelular/metabolismo , Proteínas de Ciclo Celular/metabolismo , Neoplasias Hepáticas/metabolismo , Proteínas de la Membrana/metabolismo , Proteínas 14-3-3/metabolismo , Proteínas Adaptadoras Transductoras de Señales , Western Blotting , Carcinoma Hepatocelular/patología , Línea Celular Tumoral , Femenino , Células Hep G2 , Humanos , Inmunohistoquímica/estadística & datos numéricos , Neoplasias Hepáticas/patología , Modelos Logísticos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Metástasis de la Neoplasia , Valor Predictivo de las Pruebas , Pronóstico , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , Análisis de SupervivenciaRESUMEN
Focal adhesion kinase (FAK) is implicated in cancer cell survival, proliferation and migration. Expression of FAK expression is elevated and associated with tumor progression and metastasis in various tumors, including hepatocellular carcinoma (HCC). Increased 14-3-3ε expression is shown to be a potential prognostic factor to predict higher risk of distant metastasis and worse overall survival in HCC. The aim of this study is to investigate whether FAK is associated or regulated by 14-3-3ε to modulate tumor progression in HCC. In this study, 114 primary HCC tumors including 34 matched metastatic tumors were subjected to immunohistochemistry analysis of FAK and 14-3-3ε expression. Overexpression of FAK was significantly associated with increased risk of extrahepatic metastasis (p=0.027) and reduced 5-year overall survival rate (p=0.017). A significant correlation of FAK and 14-3-3ε expression was observed in primary tumor (p < 0.001) and also metastatic tumors. Furthermore, overexpression of 14-3-3 ε induced FAK expression and promoter activity which were determined by Western blotting analysis and luciferase-reporter assay. Moreover, 14-3-3ε enhanced NFκB activation and increased nuclear translocation of NFκB. Results from chromatin immunoprecipitation assay revealed that 14-3-3ε induced NFκB binding on FAK promoter region. These findings suggest that FAK expression is correlated with and upregulated by 14-3-3ε via activation of NFκB. Target to suppress or inactivate FAK alone, or combine with 14-3-3ε is thus considered as the potential therapeutic strategy for preventing HCC tumor progression.
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Proteínas 14-3-3/metabolismo , Carcinoma Hepatocelular/metabolismo , Proteína-Tirosina Quinasas de Adhesión Focal/metabolismo , Neoplasias Hepáticas/metabolismo , FN-kappa B/metabolismo , Regulación hacia Arriba , Proteínas 14-3-3/antagonistas & inhibidores , Proteínas 14-3-3/biosíntesis , Antineoplásicos/farmacología , Ácidos Borónicos/farmacología , Bortezomib , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/tratamiento farmacológico , Supervivencia Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Proteína-Tirosina Quinasas de Adhesión Focal/antagonistas & inhibidores , Proteína-Tirosina Quinasas de Adhesión Focal/biosíntesis , Humanos , Estimación de Kaplan-Meier , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/tratamiento farmacológico , Masculino , Persona de Mediana Edad , FN-kappa B/antagonistas & inhibidores , Pirazinas/farmacología , Relación Estructura-Actividad , Células Tumorales Cultivadas , Regulación hacia Arriba/efectos de los fármacosRESUMEN
14-3-3ß is implicated in cell survival, proliferation, migration, and tumor growth; however, its clinical relevance in tumor progression and metastasis have never been elucidated. To evaluate the clinical significance of 14-3-3ß, we analyzed the association of 14-3-3ß expression and clinicopathologic characteristics in primary and subsequent metastatic tumors of hepatocellular carcinoma patients. 14-3-3ß was expressed abundantly in 40 of 55 (70.7%) primary tumors. Increased 14-3-3ß expression in primary tumors predicted a higher 5-year cumulative incidence of subsequent extrahepatic metastasis, and multivariate analysis revealed 14-3-3ß overexpression was an independent risk factor for extrahepatic metastasis. Patients with increased 14-3-3ß expression in primary tumors had worse 5-year overall survival rates, and 14-3-3ß overexpression was an independent prognostic factor on Cox regression analysis. Furthermore, stably overexpressed 14-3-3ß enhanced hepatocellular carcinoma cell migration and proliferation and increased anchorage-independent cell growth. In addition, in vivo study in a nude-mice model showed tumor formation significantly increased with 14-3-3ß overexpression. In conclusion, this is the first report to show that increased 14-3-3ß expression is associated with subsequent extrahepatic metastasis and worse survival rates, as well as cancer progression of hepatocellular carcinoma. Thus, 14-3-3ß may be a novel prognostic biomarker and therapeutic target in hepatocellular carcinoma.
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Proteínas 14-3-3/metabolismo , Biomarcadores de Tumor/metabolismo , Carcinoma Hepatocelular/mortalidad , Neoplasias Hepáticas/mortalidad , Adulto , Anciano , Animales , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Línea Celular Tumoral , Movimiento Celular/fisiología , Proliferación Celular , Progresión de la Enfermedad , Femenino , Humanos , Estimación de Kaplan-Meier , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Persona de Mediana Edad , Metástasis de la Neoplasia , Trasplante de Neoplasias , Trasplante HeterólogoRESUMEN
BACKGROUND: This paper reports the characteristics, outcomes and clinical features of children with poisoning treated at an emergency department (ED). METHODS: This retrospective study at an emergency department consisted of 140 children with poison exposure who were aged under 18 years. Their characteristics were analyzed in order to understand the differences between accidental and non-accidental poisoning. The poisonous materials were divided into two major categories (pharmaceuticals and non-pharmaceuticals) and their associations with patient outcomes were analyzed. Furthermore, the association was analyzed between the incidence of poison exposure and the season in which the poison exposure occurred. RESULTS: The incidence of poison exposure was highest among adolescents and pre-school age children. Nonaccidental poisoning was more common in older girls and accidental poisoning was more common in younger boys (P<0.001). Neurological system agents were the most common cause of poisoning in the pharmaceutical group and cleansing products were the most common cause of poisoning in the non-pharmaceutical group. Neurological and gastrointestinal symptoms were the most common clinical presentations for the pharmaceutical and non-pharmaceutical groups, respectively. Furthermore, poisoning due to cleansing products and analgesics were associated with the longest duration of hospitalization. March was the highest risk month for pediatric poisoning (P=0.018). CONCLUSIONS: Cleansing products and analgesics were associated with the longest duration of hospitalization and intentional poison was more common in girls.
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Intoxicación/terapia , Accidentes Domésticos/estadística & datos numéricos , Adolescente , Analgésicos/envenenamiento , Niño , Preescolar , Detergentes/envenenamiento , Servicio de Urgencia en Hospital , Femenino , Humanos , Lactante , Tiempo de Internación , Masculino , Plaguicidas/envenenamiento , Intoxicación/diagnóstico , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
BACKGROUND: Pharmaceuticals involved in childhood poisoning vary, and treatment of poison exposure can be a challenge for primary physicians when children are unconscious or histories are lacking. Knowledge of the clinical manifestations and prognosis of poisoning will help primary physicians perform appropriate clinical assessments. In this study, we aim to report on patient characteristics, outcomes, and clinical features of pediatric poisoning in the emergency department. METHODS: We retrospectively evaluated the medical records of 87 children younger than 18 years of age and presented to the emergency department with pharmaceutical poisoning (2001-2008). The detailed categories of pharmaceutical were reported, and their associations with patient outcomes were analyzed. Furthermore, children were divided into two groups, based on the reasons for poison exposure (accidental or intentional poisoning). Clinical features and outcomes between accidental or intentional poisoning were analyzed, and the cut-off age for high risk of intentional poisoning was also calculated. RESULTS: Age groups of adolescents (48.3%) and preschool age (32.2%) children were the major representation. Neurologic system agents (48.3%) and analgesics (18.4%) were the most common causes of poisoning. Among the two major agents above, anxiolytic/hypnotic drugs (lorazepam) and acetaminophen were the most frequent causes. Of all children, 70.1% had duration of major symptoms for ≤1 day, and intentional poisoning caused significantly longer duration of hospital stay than accidental poisoning did (p=0.008). Moreover, female gender (p<0.001), older age (p<0.001), and analgesics (p=0.008) were more predominantly associated with intentional poisoning in children, and the cut-off age for high risk of intentional poisoning was over 10.5 years. CONCLUSION: Neurologic system agents and analgesics were responsible for the majority of cases. Intentional poisoning caused longer hospital length of stay than accidental poisoning, and the factors associated with intentional poisoning were older age, female, and neurologic system agents.
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Servicio de Urgencia en Hospital/organización & administración , Preparaciones Farmacéuticas , Intoxicación/diagnóstico , Intoxicación/terapia , Adolescente , Distribución de Chi-Cuadrado , Niño , Preescolar , Femenino , Humanos , Lactante , Tiempo de Internación/estadística & datos numéricos , Modelos Logísticos , Masculino , Intoxicación/epidemiología , Pronóstico , Estudios Retrospectivos , Factores de Riesgo , Taiwán/epidemiología , Resultado del TratamientoRESUMEN
The 14-3-3γ protein is an important regulator of various cellular and physiologic functions. Overexpression promotes cell proliferation and induces cancer cell polyploidization. Production is up-regulated in human hepatocellular carcinoma. However, the clinical significance of 14-3-3γ for human hepatocellular carcinoma metastasis and survival has not been clarified. In this study, 55 patients with human hepatocellular carcinoma were enrolled; and 18 of them were identified as having extrahepatic metastases. Expression of 14-3-3γ in these primary and metastatic samples was measured with semiquantitative immunohistochemistry analysis. Overexpression of 14-3-3γ was observed in 38 (69.1%) of the primary tumors, correlated significantly with a high α-fetoprotein concentration (P = .003), and predicted a higher probability of extrahepatic metastasis (cumulative probabilities at 5 years: 42.2% ± 8.0% versus 5.9% ± 5.7%, 14-3-3γ positive versus negative; P = .012). Furthermore, 14-3-3γ overexpression was associated with a worse 5-year overall survival rate (81.6% ± 9.6% versus 59.5% ± 8.1%, respectively) and a worse 5-year progression-free survival rate (75.6% ± 10.6% versus 48.6% ± 8.2%, respectively). Elevated expression of 14-3-3γ in human hepatocellular carcinoma predicts extrahepatic metastasis and worse survival. The protein thus is a candidate biomarker and a potential target for novel therapies against human hepatocellular carcinoma progression and metastasis.
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Proteínas 14-3-3/biosíntesis , Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/patología , Carcinoma Hepatocelular/mortalidad , Carcinoma Hepatocelular/fisiopatología , Carcinoma Hepatocelular/secundario , Femenino , Humanos , Neoplasias Hepáticas/mortalidad , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia/fisiopatología , Pronóstico , Tasa de SupervivenciaRESUMEN
Cytosolic sulfotransferases (SULTs) are traditionally known as the Phase II drug-metabolizing or detoxifying enzymes that serve for the detoxification of drugs and other xenobiotics. These enzymes in general catalyze the transfer of a sulfonate group from the active sulfate, 3'-phosphoadenosine 5'-phosphosulfate (PAPS), to low-molecular weight substrate compounds containing hydroxyl or amino group(s). Despite considerable efforts made in recent years, some fundamental aspects of the SULTs, particularly their ontogeny, cell type/tissue/organ-specific distribution, and physiological relevance, particularly their involvement in drug metabolism and detoxification, still remain poorly understood. To better understand these fundamental issues, we have embarked on developing the zebrafish as a model for studies concerning the SULTs. To date, fifteen zebrafish SULTs have been cloned, expressed, purified, and characterized. These zebrafish SULTs, which fall into four major SULT gene families, exhibited differential substrate specificities and distinct patterns of expression at different stages during embryogenesis, through larval development, and on to maturity. The information obtained, as summarized in this review, provides a foundation for further investigation into the physiological and pharmacological involvement of the SULTs using the zebrafish as a model.
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Citosol/enzimología , Modelos Animales , Sulfotransferasas/metabolismo , Pez Cebra/metabolismo , Secuencia de Aminoácidos , Animales , Humanos , Datos de Secuencia Molecular , Familia de Multigenes , Sulfotransferasas/biosíntesis , Sulfotransferasas/genética , Pez Cebra/genéticaRESUMEN
PURPOSE: The study aimed to determine the factors predictive of sustained return of spontaneous circulation (ROSC) in children with out-of-hospital cardiac arrest (OHCA) of noncardiac origin. METHODS: Eighty children were included in this retrospective study. The variables that lead to sustained ROSC and those that do not lead to sustained ROSC were analyzed. Survival analyses, including chance of achieving sustained ROSC and sum duration of ROSC, were conducted according to the duration of in-hospital cardiopulmonary resuscitation (CPR). RESULTS: Etiologies of noncardiac OHCA differed significantly across different age groups (P < .001). Only 8.8% of children had initial arrest rhythms that were shockable. Predictors of sustained ROSC included the initial cardiac rhythm (P = .002), a shorter period between collapse and the first chest compression (P = .002), a shorter in-hospital CPR duration (P = .004), and prehospital CPR (P = .007). In children where ROSC was initially sustained, those with in-hospital CPR of more than 20 minutes, ROSC was sustained for less time (P < .001). CONCLUSIONS: Few children with noncardiac OHCA present with shockable cardiac rhythms. Furthermore, long-term ROSC is difficult to maintain in children who receive in-hospital CPR for more than 20 minutes.
Asunto(s)
Reanimación Cardiopulmonar/métodos , Paro Cardíaco/etiología , Paro Cardíaco/terapia , Adolescente , Distribución de Chi-Cuadrado , Niño , Preescolar , Femenino , Humanos , Lactante , Recién Nacido , Modelos Logísticos , Masculino , Valor Predictivo de las Pruebas , Estudios Retrospectivos , Factores de Riesgo , Estadísticas no Paramétricas , Análisis de Supervivencia , Factores de Tiempo , Resultado del TratamientoRESUMEN
AIM OF THE STUDY: Although sustained return of spontaneous circulation (ROSC) can be initially established after resuscitation from non-traumatic out-of-hospital cardiac arrest (OHCA) in some children, many of the children lose spontaneous circulation during hospital stay and do not survive to discharge. The aim of this study was to determine the clinical features during the first hour after ROSC that may predict survival to hospital discharge. METHODS: We retrospectively evaluated the medical records of 228 children who presented to the emergency department without spontaneous circulation following non-traumatic OHCA during the period January 1996 to December 2008. Among these children, 80 achieved sustained ROSC for at least 20 min. The post-resuscitative clinical features during the first hour after achieving sustained ROSC that correlated with survival, median duration of survival, and death were analyzed. RESULTS: Among the 80 children who achieved sustained ROSC for at least 20 min, 28 survived to hospital discharge and 6 had good neurologic outcomes (PCPC scale=1 or 2). Post-resuscitative clinical features associated with survival included sinus cardiac rhythm (p=0.012), normal heart rate (p=0.008), normal blood pressure (p<0.001), urine output>1 ml/kg/h (p=0.002), normal skin color (p=0.016), lack of cardiopulmonary resuscitation (CPR)-induced rib fracture (p=0.044), initial Glasgow Coma Scale score>7 (p<0.001), and duration of in-hospital CPR
Asunto(s)
Circulación Sanguínea/fisiología , Paro Cardíaco/mortalidad , Resucitación , Adolescente , Presión Sanguínea/fisiología , Niño , Preescolar , Femenino , Escala de Coma de Glasgow , Paro Cardíaco/terapia , Frecuencia Cardíaca/fisiología , Humanos , Lactante , Recién Nacido , Masculino , Estudios Retrospectivos , Factores de Tiempo , OrinaRESUMEN
A simple methodology for the identification of hemostatic proteins that are subjected to posttranslational tyrosine sulfation was developed. The procedure involves sequence analysis of members of the three hemostatic pathways using the Sulfinator prediction algorithm, followed by [(35)S]sulfate labeling of cultured HepG2 human hepatoma cells, immunoprecipitation of targeted [(35)S]sulfate-labeled hemostatic proteins, and tyrosine O-[(35)S]sulfate analysis of immunoprecipitated proteins. Three new tyrosine-sulfated hemostatic proteins-protein S, prekallikrein, and plasminogen-were identified. Such a target-specific approach will allow investigation of tyrosine-sulfated proteins of other biochemical/physiological pathways/processes and contribute to a better understanding of the functional role of posttranslational tyrosine sulfation.
Asunto(s)
Electroforesis en Gel Bidimensional/métodos , Plasminógeno/química , Precalicreína/química , Proteína S/química , Sulfatos/química , Tirosina/metabolismo , Secuencia de Aminoácidos , Línea Celular Tumoral , Humanos , Inmunoprecipitación , Datos de Secuencia Molecular , Procesamiento Proteico-Postraduccional , Isótopos de Azufre/químicaRESUMEN
Cytosolic sulfotransferases (SULTs) constitute a family of Phase II detoxification enzymes that are involved in the protection against potentially harmful xenobiotics as well as the regulation and homeostasis of endogenous compounds. Compared with humans and rodents, the zebrafish serves as an excellent model for studying the role of SULTs in the detoxification of environmental pollutants including environmental estrogens. By searching the expressed sequence tag database, two zebrafish cDNAs encoding putative SULTs were identified. Sequence analysis indicated that these two putative zebrafish SULTs belong to the SULT1 gene family. The recombinant form of these two novel zebrafish SULTs, designated SULT1 ST7 and SULT1 ST8, were expressed using the pGEX-2TK glutathione S-transferase (GST) gene fusion system and purified from transformed BL21 (DE3) cells. Purified GST-fusion protein form of SULT1 ST7 and SULT1 ST8 exhibited strong sulfating activities toward environmental estrogens, particularly hydroxylated polychlorinated biphenyls (PCBs), among various endogenous and xenobiotic compounds tested as substrates. pH-dependence experiments showed that SULT1 ST7 and SULT1 ST8 displayed pH optima at 6.5 and 8.0, respectively. Kinetic parameters of the two enzymes in catalyzing the sulfation of catechin and chlorogenic acid as well as 3-chloro-4-biphenylol were determined. Developmental expression experiments revealed distinct patterns of expression of SULT1 ST7 and SULT1 ST8 during embryonic development and throughout the larval stage onto maturity.
Asunto(s)
Arilsulfotransferasa/genética , Arilsulfotransferasa/aislamiento & purificación , Citosol/enzimología , Proteínas de Pez Cebra/genética , Proteínas de Pez Cebra/aislamiento & purificación , Pez Cebra/metabolismo , Secuencia de Aminoácidos , Animales , Arilsulfotransferasa/metabolismo , Secuencia de Bases , Clonación Molecular , Electroforesis en Gel de Poliacrilamida , Escherichia coli/genética , Regulación del Desarrollo de la Expresión Génica , Regulación Enzimológica de la Expresión Génica , Concentración de Iones de Hidrógeno , Larva , Datos de Secuencia Molecular , Filogenia , Proteínas Recombinantes de Fusión/genética , Proteínas Recombinantes de Fusión/aislamiento & purificación , Proteínas Recombinantes de Fusión/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Alineación de Secuencia , Maduración Sexual/genética , Xenobióticos/metabolismo , Pez Cebra/embriología , Pez Cebra/crecimiento & desarrollo , Proteínas de Pez Cebra/metabolismoRESUMEN
Sulfotransferase (ST)-catalyzed sulfation plays an important role in various neuronal functions such as homeostasis of catecholamine neurotransmitters and hormones. Drosophila is a popular model for the study of memory and behavioral manifestations because it is able to mimic the intricate neuroregulation and recognition in humans. However, there has been no evidence indicating that cytosolic ST(s) is(are) present in Drosophila. The aim of this study is to investigate whether or not cytosolic ST(s) is(are) expressed in the Drosophila nervous system. Immunoblot analysis demonstrated the presence of dehydroepiandrosterone (DHEA) ST-like protein in Drosophila brain and a sensitive fluorometric assay revealed its sulfating activity toward DHEA. Immunohistochemical staining demonstrated this DHEA ST-like protein to be abundant in specific neurons as well as in several bundles of nerve fibers in Drosophila. Clarification of a possible link between ST and a neurotransmitter-mediated effect may eventually aid in designing approaches for alleviating neuronal disorders in humans.