RESUMO
BACKGROUND: Hepatitis B virus (HBV) infection is a major global health problem, and healthcare workers (HCWs) are at high risk for HBV infection. Current guidelines strongly recommend immunization and screening for high-risk groups. AIMS: We evaluated immunization and screening for HBV vaccination, assessed post-vaccination immune status of HCW's and characterized potential risk factors associated with poor immune response. MATERIALS AND METHODS: From January 2010 to December 2018, we retrospectively analyzed comprehensive health checkup data for a total of 303 HCWs who received an HBV vaccination. After vaccination, HBV surface antibody (anti-HBs) titers were collected and the distribution of immune response types was determined. Risk factors for poor immune responses were identified using logistic regression. RESULTS: A total of 213 HCWs were analyzed after exclusion based on the exclusion criteria. In total, 28 (13.2%) HCWs had anti-HBs titers <100 mIU/mL (hyporesponsive/nonresponsive groups), and 185 (86.8%) had anti-HBs titers ≥100 mIU/mL (hyperresponsive group). Follow-up observations found that 75% (21/28) of the hyporesponsive/nonresponsive groups did not have increased anti-HBs titers or did not maintain an increased response. A multivariate analysis showed that HBV antibody titers at the time of employment were a significant risk factor (OR, 6.12; CI, 1.34-27.93; P = 0.019). CONCLUSIONS: More attention should be paid to groups that are hyporesponsive/nonresponsive after vaccination and to those with low anti-HBs titers at the beginning of employment. HCWs can be further protected from HBV if their results are discussed at postvaccination follow-ups.
Assuntos
Antígenos de Superfície da Hepatite B , Hepatite B , Pessoal de Saúde , Hepatite B/prevenção & controle , Anticorpos Anti-Hepatite B , Vacinas contra Hepatite B , Humanos , Imunidade , Estudos Retrospectivos , VacinaçãoRESUMO
BACKGROUND AND AIMS: Metabolic syndrome (MetS) is a cluster of multiple risk factors including central obesity that may lead to cardiac damage and cardiovascular events. We investigated whether visceral obesity induces cardiac structural and functional remodeling independently from central obesity and other risk factors in subjects with suspected MetS. METHODS AND RESULTS: We studied 229 participants with suspected MetS. Visceral fat area (VFA) was measured by bioelectrical impedance analysis. Left ventricular (LV) mass index, early diastolic velocity of mitral annulus (e'), and LV global longitudinal strain (GLS) were measured by echocardiography. Subjects were categorized into high and low VFA group (VFAh and VFAl). MetS was more prevalent in the VFAh than in the VFAl (p = 0.004). The VFAh had a higher waist circumference (WC) than the VFAl (p < 0.001). LV mass index was higher, but e' and GLS were lower in the VFAh than in VFAl (all p < 0.05). VFA was well correlated with blood pressure, fasting blood glucose, triglyceride, high-sensitivity C-reactive protein and adiponectin (all p < 0.05). VFA was correlated to LV mass index, e', and GLS (all p < 0.05) and was independently associated with GLS after adjustment for other risk factors, including WC (p = 0.005). CONCLUSIONS: Visceral obesity assessed by VFA was well correlated with parameters of MetS. Visceral obesity, but not central obesity measured by WC, was independently associated with structural and functional cardiac remodeling in subjects with suspected MetS. It suggests that visceral obesity should be considered as an important risk factor for cardiac damage in dysmetabolic subjects. TRIAL REGISTRATION: NCT02077530 (date of registration: November 1, 2013).
Assuntos
Gordura Abdominal/fisiopatologia , Adiposidade , Doenças Cardiovasculares/fisiopatologia , Gordura Intra-Abdominal/fisiopatologia , Síndrome Metabólica/fisiopatologia , Obesidade Abdominal/fisiopatologia , Função Ventricular Esquerda , Remodelação Ventricular , Gordura Abdominal/diagnóstico por imagem , Gordura Abdominal/metabolismo , Biomarcadores/sangue , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/diagnóstico por imagem , Ecocardiografia Doppler de Pulso , Impedância Elétrica , Feminino , Humanos , Gordura Intra-Abdominal/diagnóstico por imagem , Gordura Intra-Abdominal/metabolismo , Masculino , Síndrome Metabólica/sangue , Síndrome Metabólica/diagnóstico por imagem , Pessoa de Meia-Idade , Obesidade Abdominal/sangue , Obesidade Abdominal/diagnóstico por imagem , Prognóstico , Estudos Prospectivos , Fatores de Risco , Tomografia Computadorizada por Raios X , Circunferência da CinturaRESUMO
AIM: To assess the relationship between plasma neutrophil gelatinase-associated lipocalin (NGAL) levels and diabetic retinopathy in patients with Type 2 diabetes. METHODS: In total, 204 patients with Type 2 diabetes were investigated in this cross-sectional study. They were classified as having no diabetic retinopathy, non-proliferative diabetic retinopathy (NPDR) or proliferative retinopathy (PDR), according to the degree of diabetic retinopathy. Thus, diabetic retinopathy in the patients in this study was either NPDR or PDR. RESULTS: Plasma NGAL concentrations were significantly higher in patients with diabetic retinopathy than in those without. The mean plasma NGAL levels differed significantly according to the severity of diabetic retinopathy (no diabetic retinopathy, 120.8 ng/ml; NPDR, 217.8 ng/ml; PDR, 372.4 ng/ml; P for trend = 0.002) after adjustment for other covariates. In multivariable analysis, plasma NGAL levels were significantly associated with diabetic retinopathy (odds ratio for each standard deviation increase in the logarithmic value, 7.75; 95% confidence interval, 2.04-29.41, P = 0.003). CONCLUSION: Plasma NGAL levels were positively associated with diabetic retinopathy in patients with Type 2 diabetes.
Assuntos
Diabetes Mellitus Tipo 2/etiologia , Retinopatia Diabética/etiologia , Lipocalina-2/fisiologia , Idoso , Análise de Variância , Biomarcadores/metabolismo , Estudos Transversais , Diabetes Mellitus Tipo 2/sangue , Retinopatia Diabética/sangue , Feminino , Humanos , Lipocalina-2/metabolismo , Masculino , Pessoa de Meia-IdadeRESUMO
AIMS: Although severe hyperbilirubinaemia causes kernicterus in neonates, normal to modestly elevated bilirubin concentrations have been reported to be neuroprotective. However, the relationship between serum bilirubin concentrations and cardiovascular autonomic neuropathy in patients with Type 2 diabetes is currently unknown. This study assessed the relationships between physiological serum total bilirubin concentrations and cardiovascular autonomic neuropathy in patients with Type 2 diabetes. METHODS: A total of 2991 patients with Type 2 diabetes were investigated in this cross-sectional study. Cardiovascular autonomic neuropathy was diagnosed by a cardiovascular reflex test. According to the American Diabetes Association criteria, the degree of cardiovascular autonomic dysfunction was graded into normal, early, definite and severe. Cardiovascular autonomic neuropathy was either definite or severe in the present study. An analysis of covariance after adjustment for other covariates was performed. A logistic regression model was used to assess an association of cardiovascular autonomic neuropathy with serum total bilirubin tertiles. RESULTS: Serum total bilirubin concentrations were significantly lower in subjects with cardiovascular autonomic neuropathy. The mean total bilirubin values differed significantly according to the severity of cardiovascular autonomic dysfunction (normal 13.0 µmol/l; early 12.3 µmol/l; definite 11.8 µmol/l; severe 10.1 µmol/l; P for trend < 0.001) after adjustment for other covariates. In multivariate analysis, serum total bilirubin levels were significantly associated with cardiovascular autonomic neuropathy (odds ratio 0.36; 95% CI 0.21-0.63 for the highest vs. the lowest bilirubin tertile, P < 0.001). CONCLUSIONS: Serum total bilirubin concentrations within the physiologic range are inversely associated with the prevalence of cardiovascular autonomic neuropathy in patients with Type 2 diabetes.
Assuntos
Bilirrubina/sangue , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/epidemiologia , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/epidemiologia , Neuropatias Diabéticas/sangue , Neuropatias Diabéticas/epidemiologia , Adulto , Idoso , Doenças do Sistema Nervoso Autônomo/sangue , Doenças do Sistema Nervoso Autônomo/epidemiologia , Doenças do Sistema Nervoso Autônomo/etiologia , Doenças Cardiovasculares/etiologia , Estudos Transversais , Diabetes Mellitus Tipo 2/complicações , Neuropatias Diabéticas/etiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Fatores de RiscoRESUMO
AIMS: To investigate the relationship between physiological serum total bilirubin concentrations and serum C-peptide levels in Korean patients with Type 2 diabetes. METHODS: A total of 588 patients with Type 2 diabetes were investigated in this cross-sectional study. Fasting C-peptide level, 2-h postprandial C-peptide level and ΔC-peptide (postprandial C-peptide minus fasting C-peptide) level were measured in all patients. RESULTS: Fasting C-peptide level, postprandial C-peptide level and ΔC-peptide level tended to be higher in patients with higher bilirubin concentrations. Partial correlation analysis showed that serum bilirubin levels were significantly correlated with fasting C-peptide level (r = 0.159, P < 0.001), postprandial C-peptide level (r = 0.209, P < 0.001) and ΔC-peptide level (r = 0.186, P < 0.001) after adjustment for other covariates. In the multivariate model, the association between serum bilirubin concentrations and serum C-peptide levels remained significant after adjustment for confounding factors including age, gender, familial diabetes, hypertension, hyperlipidaemia, BMI, HbA1c , duration of diabetes and associated liver function tests (fasting C-peptide level: ß = 0.083, P = 0.041; postprandial C-peptide level: ß = 0.106, P = 0.005; ΔC-peptide level: ß = 0.096, P = 0.015, respectively). CONCLUSIONS: Serum bilirubin concentrations within the physiological range were positively associated with serum C-peptide levels in patients with Type 2 diabetes.
Assuntos
Bilirrubina/sangue , Peptídeo C/sangue , Diabetes Mellitus Tipo 2/sangue , Células Secretoras de Insulina/metabolismo , Insulina/metabolismo , Estresse Oxidativo , Adulto , Idoso , Biomarcadores/sangue , Estudos Transversais , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/fisiopatologia , Progressão da Doença , Jejum , Feminino , Hospitais Universitários , Humanos , Hipoglicemiantes/uso terapêutico , Secreção de Insulina , Células Secretoras de Insulina/efeitos dos fármacos , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Ambulatório Hospitalar , Estresse Oxidativo/efeitos dos fármacos , Período Pós-Prandial , República da CoreiaRESUMO
BACKGROUND: Surrogate biomarkers for metastatic colorectal cancer (mCRC) are urgently needed to achieve the best outcomes for targeted therapy. METHODS: A clinical association analysis was performed to examine the three single-nucleotide polymorphisms (SNPs) that were previously proposed as markers of chemosensitivity to the cetuximab (124 patients) and bevacizumab regimens (100 patients) in mCRC patients. In addition, biological correlations were examined for the candidate SNPs in terms of their regulatory pathway. RESULTS: For cetuximab regimens, patients homozygous for the wild-type alleles (GG) of LIFR rs3729740 exhibited a 1.9 times greater overall response rate (ORR) and 1.4 months longer progression-free survival (PFS) than those homozygous or heterozygous for the mutant allele (GA and AA; P=0.022 and 0.027, respectively). For bevacizumab regimens, patients homozygous for the minor alleles (TT) of ANXA11 rs1049550 exhibited an ORR twice as high as those homozygous or heterozygous for the ancestral allele (CC and CT; P=0.031). Overall response rate gain was achieved up to 10% in patients with wild-type LIFR rs3729740 patients either with wild-type KRAS or skin toxicity (P=0.001) respectively. Specifically in clones treated with cetuximab and bevacizumab regimens, active p-ERK and MMP-9 expressions were significantly reduced in clones expressing wild-type LIFR rs3729740 (P=0.044) and in those expressing minor-type ANXA11 rs1049550 (P=0.007), respectively. CONCLUSION: LIFR rs3729740 and possibly ANXA11 rs1049550 may be useful as biomarkers for predicting whether mCRC patients are sensitive to relevant target regimens, although further validation in large cohorts is needed.
Assuntos
Anexinas/genética , Neoplasias Colorretais/tratamento farmacológico , Subunidade alfa de Receptor de Fator Inibidor de Leucemia/genética , Terapia de Alvo Molecular , Metástase Neoplásica/tratamento farmacológico , Adulto , Idoso , Inibidores da Angiogênese/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bevacizumab , Biomarcadores Tumorais/genética , Cetuximab , Neoplasias Colorretais/genética , Intervalo Livre de Doença , MAP Quinases Reguladas por Sinal Extracelular/biossíntese , MAP Quinases Reguladas por Sinal Extracelular/genética , Feminino , Genótipo , Humanos , Masculino , Metaloproteinase 9 da Matriz/biossíntese , Metaloproteinase 9 da Matriz/genética , Pessoa de Meia-Idade , Metástase Neoplásica/genética , Polimorfismo de Nucleotídeo Único , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas p21(ras) , Proteínas ras/genéticaRESUMO
Expansion of a CTG trinucleotide repeat in the 3' UTR of the gene DMPK at the DM1 locus on chromosome 19 causes myotonic dystrophy, a dominantly inherited disease characterized by skeletal muscle dystrophy and myotonia, cataracts and cardiac conduction defects. Targeted deletion of Dm15, the mouse orthologue of human DMPK, produced mice with a mild myopathy and cardiac conduction abnormalities, but without other features of myotonic dystrophy, such as myotonia and cataracts. We, and others, have demonstrated that repeat expansion decreases expression of the adjacent gene SIX5 (refs 7,8), which encodes a homeodomain transcription factor. To determine whether SIX5 deficiency contributes to the myotonic dystrophy phenotype, we disrupted mouse Six5 by replacing the first exon with a beta-galactosidase reporter. Six5-mutant mice showed reporter expression in multiple tissues, including the developing lens. Homozygous mutant mice had no apparent abnormalities of skeletal muscle function, but developed lenticular opacities at a higher rate than controls. Our results suggest that SIX5 deficiency contributes to the cataract phenotype in myotonic dystrophy, and that myotonic dystrophy represents a multigenic disorder.
Assuntos
Catarata/etiologia , Catarata/genética , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Distrofia Miotônica/genética , Regiões 3' não Traduzidas/genética , Animais , Catarata/enzimologia , Catarata/patologia , Éxons/genética , Marcação de Genes , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Distrofia Miotônica/enzimologia , Miotonina Proteína Quinase , Proteínas Serina-Treonina Quinases/genética , Expansão das Repetições de Trinucleotídeos/genéticaRESUMO
An expansion of a CTG repeat at the DM1 locus causes myotonic dystrophy (DM) by altering the expression of the two adjacent genes, DMPK and SIX5, and through a toxic effect of the repeat-containing RNA. Here we identify two CTCF-binding sites that flank the CTG repeat and form an insulator element between DMPK and SIX5. Methylation of these sites prevents binding of CTCF, indicating that the DM1 locus methylation in congenital DM would disrupt insulator function. Furthermore, CTCF-binding sites are associated with CTG/CAG repeats at several other loci. We suggest a general role for CTG/CAG repeats as components of insulator elements at multiple sites in the human genome.
Assuntos
Metilação de DNA , Proteínas de Ligação a DNA/metabolismo , Distrofia Miotônica/genética , Proteínas Repressoras , Fatores de Transcrição/metabolismo , Repetições de Trinucleotídeos/genética , Sítios de Ligação/fisiologia , Fator de Ligação a CCCTC , Linhagem Celular , Sistema Livre de Células , Ilhas de CpG/genética , Proteínas de Homeodomínio/genética , Humanos , Dados de Sequência Molecular , Miotonina Proteína Quinase , Matriz Nuclear/metabolismo , Nucleossomos/metabolismo , Proteínas Serina-Treonina Quinases/genética , Homologia de Sequência do Ácido NucleicoRESUMO
BACKGROUND: Keloid scarring is a dermal fibroproliferative disorder characterized by increased fibroblast proliferation and excessive production of collagen and extracellular matrix (ECM) components. To date, the role of cytokines in keloid pathogenesis has not been completely unravelled. Interleukin (IL)-18 is a pro-inflammatory cytokine that plays important roles in wound healing, fibrogenesis and carcinogenesis. OBJECTIVES: Our aim was to study the role of the IL-18 system in keloid pathogenesis. MATERIALS AND METHODS: Expression and localization of IL-18 and its receptor (IL-18R) were investigated in normal skin and keloid tissues using Western blot and immunohistochemistry. We further studied the expression of the IL-18 system in normal and keloid-derived cell lines in a coculture model. RESULTS: Results from Western blot and immunohistochemistry revealed that IL-18, IL-18Rα and IL-18Rß expression was elevated in keloid tissue compared with normal skin tissue. Studies on the expression of IL-18 and its antagonist, IL-18 binding protein (IL-18BP), using a coculture model demonstrated severe IL-18/IL-18BP imbalance in keloid keratinocyte/keloid fibroblast (KK/KF) cocultures with significant elevation of bioactive IL-18 whereas IL-18BP levels remained the same. This overproduction of bioactive IL-18 in keloid cocultures could be due to increased caspase-1 and decreased caspase-3 expression in keloid tissue, as well as decreased soluble IL-10 levels observed in keloid cocultures. The important inductive effects of IL-18 on KFs were further underscored by the observation that exposure of KF to IL-18 resulted in increased collagen and ECM component synthesis, and increased secretion of profibrotic cytokines such as IL-6 and IL-8. Finally, the addition of phosphatidylinositol 3-kinase (PI3K), mitogen activation protein kinase (MAPK), specificity protein 1 (Sp1) and mammalian target of rapamycin (mTOR) inhibitors inhibited IL-18 secretion in keloid cocultures. CONCLUSIONS: The present study has proven that the IL-18 system plays an important role in keloid pathogenesis via epithelial-mesenchymal interactions. It also suggests a therapeutic potential of PI3K, MAPK, Sp1 and mTOR inhibitors in the treatment of keloid scarring.
Assuntos
Transição Epitelial-Mesenquimal/fisiologia , Interleucina-18/fisiologia , Queloide/etiologia , Caspase 1/metabolismo , Caspase 3/metabolismo , Células Cultivadas , Colágeno/metabolismo , Inibidores Enzimáticos/farmacologia , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Humanos , Interleucina-18/farmacologia , Interleucina-6/metabolismo , Interleucina-8/metabolismo , Queratinócitos/efeitos dos fármacos , Queratinócitos/metabolismo , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Receptores de Interleucina-18/metabolismo , Fator de Transcrição Sp1/metabolismo , Serina-Treonina Quinases TOR/metabolismoRESUMO
Xanthoma disseminatum (XD) is a rare and potentially progressive non-Langerhans-cell histiocytosis. To date, a few cases of XD with spontaneous complete resolution have been described. The present report describes a 16-year-old girl who presented with yellow to red-brown papules and nodules on her eyelids, cheeks, axillae, back and buttocks. Indirect laryngoscopy showed multiple xanthomatous plaques on the larynx, posterior pharynx, epiglottis, and vocal cords. Additional findings were polyuria, polydipsia, and amenorrhea. Skin biopsy and electron microscopy results confirmed the diagnosis of XD. The patient was treated with fenofibrate, simvastatin, desmopressin, and sex-hormone replacement therapy. Her skin lesions began to slowly fade 6 years after disease onset, eventually resolving spontaneously and completely, but leaving an atrophic scar, frank anetoderma, and persisting diabetes insipidus. This case report together with a review of the English-language literature on the long-term follow-up of XD patients provides additional information on the natural history of this disease.
Assuntos
Histiocitose de Células não Langerhans/diagnóstico , Adolescente , Amenorreia/diagnóstico , Amenorreia/tratamento farmacológico , Anetodermia/diagnóstico , Anetodermia/tratamento farmacológico , Antidiuréticos/uso terapêutico , Biópsia , Cicatriz/patologia , Desamino Arginina Vasopressina/uso terapêutico , Fármacos Dermatológicos/uso terapêutico , Diabetes Insípido/diagnóstico , Diabetes Insípido/tratamento farmacológico , Feminino , Fenofibrato/uso terapêutico , Gadolínio DTPA , Histiocitose de Células não Langerhans/diagnóstico por imagem , Histiocitose de Células não Langerhans/tratamento farmacológico , Histiocitose de Células não Langerhans/patologia , Terapia de Reposição Hormonal , Humanos , Cintilografia , Remissão Espontânea , Sinvastatina/uso terapêuticoRESUMO
South East Asia has some of the highest prevalence rates of hepatitis B virus (HBV) infection (>or=8%) in the world, and the emergence of hepatitis B surface antigen (HBsAg) mutant strains is a growing problem. Assays with the highest levels of sensitivity, including mutant detection, should be used for routine HBsAg screening. In this large multicenter study, the clinical and technical performance of the fully automated Elecsys HBsAg II assay was compared with the Architect, AxSYM, and Advia Centaur HBsAg assays for HBsAg screening. Nine laboratories (three each from Thailand, Korea, and Singapore) compared the Elecsys HBsAg II assay with their routine HBsAg screening assay against a range of stored and routine clinical samples, including recombinant mutants. The Elecsys HBsAg II assay demonstrated equivalent sensitivity and specificity to the Architect HBsAg assay. However, the Elecsys HBsAg II assay recognized a native mutant sample (L94S, L97V, L98V, T123A) that the Architect HBsAg assay failed to detect. The AxSYM and Advia Centaur HBsAg assays appeared less sensitive for the detection of early HBV infection and also failed to detect some of the recombinant mutant strains. There was almost complete agreement between the Elecsys HBsAg II assay and comparator assays with respect to routine serum samples. The results of this study demonstrate that the Elecsys HBsAg II assay is a highly sensitive and specific screening assay for HBsAg and detects reliably the most important and clinically relevant HBV mutants and genotypes. It is suitable for routine HBsAg screening in Asia.
Assuntos
Técnicas de Laboratório Clínico/métodos , Antígenos de Superfície da Hepatite B/sangue , Hepatite B/diagnóstico , Programas de Rastreamento/métodos , Kit de Reagentes para Diagnóstico , Automação , Humanos , Imunoensaio/métodos , República da Coreia , Sensibilidade e Especificidade , Singapura , TailândiaRESUMO
This paper assesses the feasibility of transcatheter embolisation of arteriovenous shunts in patients with hepatocellular carcinoma, and reviews available embolic agents, based on our experience and a literature review. From 2001 to 2007, 11 patients with unresectable hepatocellular carcinoma and significant arteriovenous shunts underwent transcatheter embolisation of liver arteriovenous shunts. The age range was 36 to 80 years. A total of 17 embolisations were performed using different embolic agents including absolute ethanol (n=11), histoacryl (n=1), coils (n=2), and polyvinyl alcohol particles (n=1). We reviewed the degree of shunt occlusion and the clinical outcomes. There were 15 arteriovenous shunts. Nine (60%) were arterioportal venous shunts and six were arteriohepatic venous shunts. Two were classified as 'simple' types, according to our protocol, and 13 were 'complex' types. More than 80% occlusion was achieved in 80% of the shunts. In the simple shunts, coil embolisation achieved complete occlusion. In complex shunts with multiple feeders and draining veins, liquid or particulate agents were required to achieve satisfactory occlusion. Managing arteriovenous shunts with embolisation was feasible. The choice of embolic agent should be based on good understanding of the underlying mechanism of the shunts and their angio-architecture.
Assuntos
Fístula Arteriovenosa/terapia , Carcinoma Hepatocelular/terapia , Quimioembolização Terapêutica/métodos , Neoplasias Hepáticas/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Hepatocelular/complicações , Quimioembolização Terapêutica/efeitos adversos , Feminino , Artéria Hepática/diagnóstico por imagem , Humanos , Neoplasias Hepáticas/complicações , Masculino , Pessoa de Meia-Idade , RadiografiaRESUMO
Apaf-1-interacting protein (APIP) was previously isolated as an inhibitor of mitochondrial cell death interacting with Apaf-1. Here, we report a hypoxia-selective antiapoptotic activity of APIP that induces the activation of AKT and extracellular signal-regulated kinase (ERK)1/2. Stable expression of APIP in C2C12 (C2C12/APIP) cells suppressed cell death induced by hypoxia and etoposide. Unlike etoposide, however, APIP induces the sustained activation of AKT and ERK1/2 and the phosphorylation of caspase-9 during hypoxia. Inhibition of AKT and ERK1/2 activation by the treatments with phosphatidylinositol 3'-kinase and mitogen-activated protein kinase kinase (MEK)1/2 inhibitors sensitized C2C12/APIP cells to hypoxic cell death and abolished the hypoxia-induced phosphorylation of caspase-9. Further, overexpression of phosphorylation-mimic caspase-9 mutants (caspase-9-T125E and caspase-9-S196D), but not phosphorylation-defective caspase-9 mutants (caspase-9-T125A and caspase-9-S196A), effectively suppressed hypoxia-induced death of C2C12 cells. These results elucidate a novel Apaf-1-independent antiapoptotic activity of APIP during hypoxic cell death, inducing the sustained activation of AKT and ERK1/2 and leading to caspase-9 phosphorylation.
Assuntos
Apoptose , Fator Apoptótico 1 Ativador de Proteases/metabolismo , Caspase 9/metabolismo , Hipóxia , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Animais , Antineoplásicos Fitogênicos/farmacologia , Fator Apoptótico 1 Ativador de Proteases/genética , Caspase 9/genética , Caspases/metabolismo , Células Cultivadas/efeitos dos fármacos , Células Cultivadas/metabolismo , Eletroforese em Gel Bidimensional , Ativação Enzimática , Etoposídeo/farmacologia , Humanos , Camundongos , Mutação/genética , Fosforilação , Transdução de SinaisRESUMO
Cell migration and angiogenesis are key steps in tumor metastasis. However, the mechanism of migration regulated by vascular endothelial growth factor (VEGF), a potent regulator of angiogenesis, is not completely understood. This study examined the relationship between VEGF and migration, along with the mechanism involved in the VEGF-regulated migration of human gastric cancer cells. The level of cell migration was increased by recombinant human (rh)VEGF-165 in the VEGF receptor-2-expressing SNU-601 cells. Interleukin (IL)-18 is associated with the malignant progression of tumors. Accordingly, this study examined the effect of IL-18 on the migration of cancer cells in order to identify the factors involved in VEGF-enhanced migration. Inhibiting IL-18 markedly reduced the level of VEGF-enhanced migration, and IL-18 increased cell migration directly through filamentous-actin polymerization and tensin downregulation. It was confirmed that rhVEGF-165 increased IL-18 production significantly. An antioxidant and an extracellular signal-regulated kinase (ERK)1/2-specific inhibitor blocked rhVEGF-165-enhanced IL-18 production. Accordingly, rhVEGF-165 increased the generation of region of interest (ROI) and activated the ERK1/2 pathway. These results suggest that rhVEGF-165 enhances IL-18 production via the generation of ROI and ERK1/2 phosphorylation, which results in the increased migration of gastric cancer cells.
Assuntos
Interleucina-18/fisiologia , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Fator A de Crescimento do Endotélio Vascular/farmacologia , Actinas/metabolismo , Movimento Celular/efeitos dos fármacos , Humanos , MAP Quinase Quinase Quinases/metabolismo , Proteínas dos Microfilamentos/metabolismo , Proteínas Recombinantes/farmacologia , Tensinas , Células Tumorais CultivadasRESUMO
Intestinal epithelial cells express a low level of HLA class II molecules constitutively, with elevated levels seen in the setting of mucosal inflammation including inflammatory bowel disease. The ability of intestinal epithelial cells to act as antigen presenting cells for alphabeta CD4(+) T lymphocytes was examined through a molecular analysis of the HLA class II antigen processing pathway. We have shown that intestinal epithelial cells contain abundant constitutive levels of the cathepsin proteases proven to function in HLA class II mediated antigen presentation. Activation of these cells by gamma-IFN induced the expression of invariant chain and HLA-DM alphabeta, thus facilitating the formation of compact, SDS-stable HLA- DR alphabeta heterodimers. Using HLA-DR-restricted T cells and retroviral mediated gene transfer of HLA-DR alleles into the intestinal epithelial cell lines HT-29 and T84, we demonstrated efficient antigen processing and presentation to CD4(+) T lymphocytes in the presence of the proinflammatory cytokine gamma-IFN. The class II processing pathway and presentation in the presence of gamma-IFN was indistinguishable from that observed with a conventional antigen presenting cell. Antigen processing also occurred in intestinal epithelial cells in the absence of gamma-IFN, and in contrast to that seen after stimulation with gamma-IFN, required high concentration of antigen and was not inhibited by the protease inhibitor leupeptin. These data suggest the use of two distinct pathways of HLA class II antigen processing in enterocytes with differential immunomodulatory properties in the presence or absence of mucosal inflammation.
Assuntos
Endopeptidases , Antígenos HLA-D/biossíntese , Antígenos HLA-DQ/biossíntese , Antígenos HLA-DR/biossíntese , Antígenos de Histocompatibilidade Classe II , Mucosa Intestinal/imunologia , Linfócitos T CD4-Positivos/imunologia , Catepsina B/metabolismo , Catepsina H , Catepsina L , Catepsinas/metabolismo , Neoplasias do Colo , Cisteína Endopeptidases/metabolismo , Primers do DNA , Dimerização , Humanos , Interferon gama/farmacologia , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/enzimologia , Leupeptinas/farmacologia , Reação em Cadeia da Polimerase , Inibidores de Proteases/farmacologia , Proteínas Recombinantes/biossíntese , Transfecção , Células Tumorais CultivadasRESUMO
The high concentration of foreign antigen in the lumen of the gastrointestinal tract is separated from the underlying lymphocytes by a single cell layer of polarized epithelium. Intestinal epithelial cells can express HLA class II antigens and may function as antigen-presenting cells to CD4(+) T cells within the intestinal mucosa. Using tetanus toxoid specific and HLA-DR-restricted T lymphocytes, we show that polarized intestinal epithelial cells directed to express HLA-DR molecules are able to initiate class II processing only after internalization of antigen from their apical surface. Coexpression of the class II transactivator CIITA in these cells, which stimulates highly efficient class II processing without the characteristic decline in barrier function seen in polarized monolayers treated with the proinflammatory cytokine gamma-IFN, facilitates antigen processing from the basolateral surface. In both cases, peptide presentation to T cells via class II molecules was restricted to the basolateral surface. These data indicate a highly polarized functional architecture for antigen processing and presentation by intestinal epithelial cells, and suggest that the functional outcome of antigen processing by the intestinal epithelium is both dependent on the cellular surface at which the foreign antigen is internalized and by the underlying degree of mucosal inflammation.
Assuntos
Apresentação de Antígeno , Linfócitos T CD4-Positivos/imunologia , Polaridade Celular , Células Epiteliais/imunologia , Antígenos HLA-D/imunologia , Antígenos de Histocompatibilidade Classe II , Mucosa Intestinal/imunologia , Macrolídeos , Proteínas Nucleares , Antibacterianos/farmacologia , Apresentação de Antígeno/efeitos dos fármacos , Linfócitos T CD4-Positivos/citologia , Células Clonais , Citocalasina D/farmacologia , Células Epiteliais/citologia , Antígenos HLA-D/genética , Antígenos HLA-DR/genética , Antígenos HLA-DR/imunologia , Humanos , Interferon gama/farmacologia , Mucosa Intestinal/citologia , Modelos Imunológicos , Proteínas Recombinantes/imunologia , Toxoide Tetânico/imunologia , Transativadores/biossíntese , Transativadores/genéticaRESUMO
AIMS: Previous studies have reported that cystatin C is associated with degenerative disorder in the nervous system. However, the relationship between serum cystatin C concentrations and cardiovascular autonomic neuropathy (CAN) in patients with type 2 diabetes is currently unknown. The aim of this study was to assess the relationships between serum cystatin C levels and CAN in patients with type 2 diabetes. METHODS: A total of 357 patients with type 2 diabetes were studied in this cross-sectional study. CAN was diagnosed by a cardiovascular autonomic reflex test. According to the American Diabetes Association criteria, the degree of cardiovascular autonomic dysfunction was graded as normal, early, definite, or severe. CAN was either definite or severe in the subjects of the present study. RESULTS: Serum cystatin C concentrations were significantly higher in patients with CAN than in those without CAN. The mean cystatin C levels differed significantly according to the degree of cardiovascular autonomic dysfunction (normal, 0.78 mg/l; early, 0.79 mg/l; definite, 0.87 mg/l; severe, 0.90 mg/l; P for trend=0.021) after adjustment for other covariates. In multivariate analysis, serum cystatin C levels were significantly associated with CAN (odds ratio [OR] of each standard deviation increase in the logarithmic value, 5.25; 95% confidence interval [CI], 1.17-23.70, P=0.025). CONCLUSIONS: Serum cystatin C levels are positively associated with CAN in patients with type 2 diabetes.
Assuntos
Doenças Cardiovasculares/sangue , Cistatina C/sangue , Diabetes Mellitus Tipo 2/sangue , Neuropatias Diabéticas/sangue , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
In order to identify the target cell recognition molecules involved in the interaction between natural killer (NK) cells and target cells, we have generated monoclonal antibodies to K562, NK-sensitive target cells. After screening by FACScan for the reactivity to K562, one monoclonal antibody (mAb), 4A60, was selected. MAb 4A60 was found to inhibit the proliferation of NK cells induced by IL-2 and K562 cells. However, this monoclonal antibody could not significantly block the conjugate formation between NK and target cells. Moreover, mAb 4A60 only slightly inhibited the cytotoxicity of NK cells induced by IL-2. Protein analysis showed that mAb 4A60 recognized a 53-kDa protein of K562 cells. Taken together, these data suggest that mAb 4A60 inhibits the proliferation of NK cells induced by IL-2 and target cells, and the 53-kDa protein, a tentative ligand of this mAb of K562, may be involved in this process.
Assuntos
Células Matadoras Naturais/imunologia , Animais , Anticorpos Monoclonais/imunologia , Linhagem Celular , Humanos , Fosfatos de Inositol/metabolismo , Interleucina-2/farmacologia , Células Jurkat , Células Matadoras Naturais/efeitos dos fármacos , Camundongos , Mitógenos/farmacologia , Receptores de IgG/imunologia , Células Tumorais CultivadasRESUMO
Interleukin-18 (IL-18) has been found to have multiple effects upon various cells involved in inflammatory response. Recently we reported that B16 murine melanoma cells are able to produce IL-18, which is involved in the regulation of intracellular reactive oxygen intermediates (ROI) and Fas-ligand expression, indicating that IL-18 plays key role in the tumor activity of melanoma. In this study, we investigated the pattern of IL-18 expression in the human system. IL-18 production was tested by enzyme linked immunosorbent assay (ELISA) assay in various tumor cell lines, including Raji (Burkitt's lymphoma), IM-9 (B lymphoblast), Jurkat (acute T cell leukemia), SK-MES-1 (squamous cell carcinoma (SCC) cell line), SK-MEL-2, G-361, DM-4, and DX-3 (melanoma cell lines). ELISA tests showed that IL-18 was highly expressed in malignant skin tumors such as SK-MES-1, SK-MEL-2, G-361, DM-4, and DX-3 cell lines, thus suggesting that IL-18 production may be associated with the malignancy of skin tumors. Here, we report that enhanced IL-18 expression is positively correlated with malignant skin tumors such as SCC and melanoma, suggesting the importance role of IL-18 in malignancy of skin tumors. Taken together, expression of IL-18 by tumor cells in human skin tissue may provide an important clue to understand the pathogenesis of malignant skin tumors.