RESUMO
AIM: To evaluate ethiodised oil retention of transarterial embolisation using ethiodised oil (ethiodised oil marking) before computed tomography (CT)-guided percutaneous cryoablation (PCA) according to renal cell carcinoma (RCC) subtype. MATERIALS AND METHODS: Ethiodised oil marking was performed 1-3 days before PCA in 99 patients with 99 RCCs from 2016 to 2020. Ethiodised oil retention on CT images was evaluated retrospectively and CT attenuation values in the tumour were measured. Regions of interest (ROI) were placed on the tumours to calculate: average (ROI-average), maximal (ROI-max), minimum (ROI-min), and standard deviation (ROI-SD). Qualitative scores comprising a five-point scale (5, excellent; 1, poor) were evaluated for the retention scores (RS) of ethiodised oil in the tumour (ethiodised oil-RS) and the visualisation scores (VS) of the boundary between the tumour and renal parenchyma (boundary-VS). RESULTS: The histological subtypes comprised clear cell (ccRCC; n=85), papillary (pRCC; n=6), and chromophobe/oncocytoma renal cell carcinoma (chrRCC; n=8). The mean ROI-average, ROI-max, and ROI-SD were significantly higher in ccRCCs than in chrRCCs and pRCCs (p<0.05). The mean ethiodised oil-RS was significantly lower in pRCCs than in ccRCCs (p=0.039), and the mean boundary-VS was >4 in all subtypes. Even with poor intratumour ethiodised oil retention (n=6), sufficient boundary-VS was obtained due to "inverted marking." All PCA procedures were completed without additional intravenous contrast material injection at the time of PCA. CONCLUSION: Regardless of the tumour subtypes, ethiodised oil marking aids in visualising the boundary between the tumour and parenchyma on non-contrast CT in PCA.
Assuntos
Carcinoma de Células Renais , Criocirurgia , Neoplasias Renais , Humanos , Carcinoma de Células Renais/diagnóstico por imagem , Carcinoma de Células Renais/cirurgia , Carcinoma de Células Renais/patologia , Neoplasias Renais/diagnóstico por imagem , Neoplasias Renais/cirurgia , Neoplasias Renais/patologia , Óleo Etiodado , Estudos Retrospectivos , Tomografia Computadorizada por Raios X , Diagnóstico DiferencialRESUMO
BACKGROUND: The number of patients living with depression continues to increase in Japan. The economic effects of depression include loss of productivity due to both absenteeism and presenteeism. Gender differences have been reported in prevalence, onset pathways and subjective symptoms of depression. AIMS: To understand how workers with major depressive disorder (MDD) perceive problems in the workplace and examine gender differences in their self-perceived levels of functioning at work, noticed during the initial stages of depression. METHODS: This is a cross-sectional study of Japanese workers with MDD. Participants' self-perceived changes in the level of functioning at work were surveyed after the diagnosis during the first visit. The relationship between gender and changes in the level of functioning at work as initially perceived by the participants themselves was analysed using the chi-square test, supplemented by a residual analysis. RESULTS: We administered the survey to 147 workers with MDD. In terms of gender differences in initial self-perceived changes in the level of functioning at work, the proportion of men reporting reduced work efficiency was significantly higher than that of women, while the proportion of women reporting deterioration in relationships with colleagues and superiors was significantly higher than that of men. CONCLUSIONS: The findings suggest that greater attention to reduced work efficiency by men and to deterioration in work relationships by women with MDD should be essential components of self-care. Managers need to pay attention to the level of functioning and provide adequate social support for employees.
Assuntos
Depressão , Transtorno Depressivo Maior , Absenteísmo , Estudos Transversais , Feminino , Humanos , Japão , Masculino , Caracteres Sexuais , Inquéritos e Questionários , Local de TrabalhoRESUMO
To examine genes expressed specifically in labial salivary glands (LSGs) of patients with Sjögren's syndrome (SS) in comparison with those of patients with immunoglobulin (Ig)G4-related disease (IgG4-RD), and to identify the genes involved in the pathogenesis of SS. Gene expression in LSGs of SS patients, IgG4-RD patients and healthy controls (HC) was analysed by cDNA microarray. Quantitative polymerase chain reaction (qPCR) was used to validate the up-regulation of differentially expressed genes (DEGs) in SS. Protein production of the validated gene in LSGs was examined by immunofluorescence (IF) assay. The association of molecular functions of the gene with the pathological conditions in SS was examined using peripheral blood lymphocytes. Among 1320 DEGs up-regulated in SS, qPCR confirmed the up-regulation of NR4A2 in LSGs of SS compared with IgG4-RD. IF staining showed higher production of NR4A2 in nuclei of CD4+ T cells and interleukin (IL)-17-producing cells in LSGs of SS, compared with IgG4-RD. Over-expression of NR4A2 mRNA was observed in peripheral CD4+ T cells of SS patients, compared with HC. Nuclear NR4A2 expression in T helper type 17 (Th17)-polarized CD4+ T cells determined by cellular IF was significantly higher in SS than in HC. Importazole, an inhibitor of importin-ß, inhibited nuclear transport of NR4A2 and Th17 polarization along with IL-21 expression in naive CD4+ T cells under Th17-polarizing conditions, but did not alter retinoic acid receptor-related orphan receptor C (RORC) expression. NR4A2 seems to promote Th17 polarization via increased expression and intranuclear localization in CD4+ T cells of SS patients, which could play a critical role in the pathogenesis of SS.
Assuntos
Membro 2 do Grupo A da Subfamília 4 de Receptores Nucleares/metabolismo , Quinazolinas/uso terapêutico , Glândulas Salivares/fisiologia , Síndrome de Sjogren/metabolismo , Células Th17/imunologia , Transporte Ativo do Núcleo Celular/efeitos dos fármacos , Adulto , Idoso , Diferenciação Celular/efeitos dos fármacos , Células Cultivadas , DNA Complementar/análise , Feminino , Perfilação da Expressão Gênica , Humanos , Doenças do Sistema Imunitário/genética , Doenças do Sistema Imunitário/metabolismo , Imunoglobulina G/imunologia , Imunoglobulina G/metabolismo , Interleucinas/metabolismo , Pessoa de Meia-Idade , Membro 2 do Grupo A da Subfamília 4 de Receptores Nucleares/genética , Quinazolinas/farmacologia , Glândulas Salivares/patologia , Síndrome de Sjogren/tratamento farmacológico , Síndrome de Sjogren/genética , Células Th17/efeitos dos fármacos , Análise Serial de Tecidos/métodos , beta Carioferinas/antagonistas & inibidoresRESUMO
We showed recently that M3 muscarinic acetylcholine receptor (M3R)-reactive CD3+ T cells play a pathogenic role in the development of murine autoimmune sialadenitis (MIS), which mimics Sjögren's syndrome (SS). The aim of this study was to determine the effectiveness and mechanism of action of retinoic acid-related orphan receptor-gamma t (RORγt) antagonist (A213) in MIS. Splenocytes from M3R knockout (M3R-/- ) mice immunized with murine M3R peptide mixture were inoculated into recombination-activating gene 1 knockout (Rag-1-/- ) mice (M3R-/- âRag-1-/- ) with MIS. Immunized M3R-/- mice (pretransfer treatment) and M3R-/- âRag-1-/- mice (post-transfer treatment) were treated with A213 every 3 days. Salivary volume, severity of sialadenitis and cytokine production from M3R peptide-stimulated splenocytes and lymph node cells were examined. Effects of A213 on cytokine production were analysed by enzyme-linked immunosorbent assay (ELISA) and on T helper type 1 (Th1), Th17 and Th2 differentiation from CD4+ T cells by flow cytometry. Pretransfer A213 treatment maintained salivary volume, improved MIS and reduced interferon (IFN)-γ and interleukin (IL)-17 production significantly compared with phosphate-buffered saline (PBS) (P < 0·05). These suppressive effects involved CD4+ T cells rather than CD11c+ cells. Post-transfer treatment with A213 increased salivary volume (P < 0·05), suppressed MIS (P < 0·005) and reduced IFN-γ and IL-17 production (P < 0·05). In vitro, A213 suppressed IFN-γ and IL-17 production from M3R-stimulated splenocytes and CD4+ T cells of immunized M3R-/- mice (P < 0·05). In contrast with M3R specific responses, A213 suppressed only IL-17 production from Th17 differentiated CD4+ T cells without any effect on Th1 and Th2 differentiation in vitro. Our findings suggested that RORγt antagonism is potentially suitable treatment strategy for SS-like sialadenitis through suppression of IL-17 and IFN-γ production by M3R-specific T cells.
Assuntos
Aminopiridinas/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/antagonistas & inibidores , Receptor Muscarínico M3/metabolismo , Sialadenite/tratamento farmacológico , Síndrome de Sjogren/tratamento farmacológico , Sulfonamidas/uso terapêutico , Células Th1/efeitos dos fármacos , Células Th17/efeitos dos fármacos , Transferência Adotiva , Animais , Células Cultivadas , Modelos Animais de Doenças , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fragmentos de Peptídeos/imunologia , Receptor Muscarínico M3/genética , Receptor Muscarínico M3/imunologia , Sialadenite/induzido quimicamente , Células Th1/imunologia , Células Th17/imunologiaRESUMO
BACKGROUND: Genetic markers of susceptibility to asthma exacerbations in adults remain unclear. OBJECTIVE: To identify genetic markers of asthma exacerbations, particularly in patients with type-2 inflammatory endotype. METHODS: In this observational study of patients enrolled in the Kinki Hokuriku Airway disease Conference multicenter study, frequency of exacerbations requiring systemic corticosteroids during 2 years after enrolment and associated risk factors was determined. For genetic marker analysis, interleukin-4 receptor α (IL4RA) rs8832 and a disintegrin and metalloprotease 33 (ADAM33) S_2 (rs528557), T_1 (rs2280091), T_2 (rs2280090), and V_4 (rs2787094) variants were included. Elevated serum periostin levels at enrolment (≥95 ng/mL, defined as type-2 inflammatory endotype) were considered in the analysis. RESULTS: Among 217 patients who were successfully followed up for 2 years after enrolment, 60 patients showed at least one asthma exacerbation during the 2 years. Airflow limitation (%FEV1 <80%) and recent exacerbations but not genetic variants were identified as risk markers of exacerbations. A total of 27 patients showed type-2 inflammatory endotype (serum periostin ≥95 ng/mL at enrolment) and subsequent exacerbations; risk factors in these patients were airflow limitation (odds ratio, 6.51; 95% confidence interval (CI): 2.37-18.6; P=.0003), GG genotype of IL4RA rs8832 (odds ratio, 4.01; 95% CI: 1.47-11.0; P=.007), and A allele of ADAM33 T_2 (odds ratio, 2.81; 95% CI: 1.05-7.67; P=.04) by multivariate analysis. In addition, GG genotype of IL4RA rs8832 was associated with type-2 endotype, whereas A allele of ADAM33 T_2 was associated with mixed type of eosinophilic/type-2 and neutrophilic inflammations. CONCLUSIONS AND CLINICAL RELEVANCE: IL4RA and ADAM33 variants may be risk markers of asthma exacerbations in type-2 inflammatory endotype. Precise endotyping may facilitate the identification of genetic risk markers of asthma exacerbations.
Assuntos
Proteínas ADAM , Asma/sangue , Asma/genética , Subunidade alfa de Receptor de Interleucina-4 , Proteínas ADAM/sangue , Proteínas ADAM/genética , Adulto , Idoso , Asma/tratamento farmacológico , Seguimentos , Marcadores Genéticos , Humanos , Subunidade alfa de Receptor de Interleucina-4/sangue , Subunidade alfa de Receptor de Interleucina-4/genética , Pessoa de Meia-Idade , Fatores de RiscoRESUMO
This study investigated rare variants associated with atopic dermatitis. We performed exome analyses on 37 patients who were diagnosed with atopic dermatitis by board-certified dermatologists and had total serum IgE levels greater than 1000 IU/ml. The exome analysis identified seven variants with <1% allele frequency in Asian (ASN) population of 1000 Genomes Project phase 1 data and >5% allele frequency in the atopic dermatitis exome samples. We then conducted a replication study using 469 atopic dermatitis patients with total serum IgE ≥1000 IU/ml and 935 Japanese controls to assess the presence of these 7 candidate variants. The replication study confirmed that CYP27A1 rs199691576 (A/G) was associated with atopic dermatitis with high serum IgE levels (P = 0.012, odds ratio = 2.1). CYP27A1 is involved in the metabolism of vitamin D3, which plays important roles in modulating immune function. Previous studies have reported polymorphisms in vitamin D pathway genes that are associated with allergy-related phenotypes. Our data confirm the importance of genes regulating the vitamin D pathway in the development of atopic dermatitis.
Assuntos
Colestanotriol 26-Mono-Oxigenase/genética , Dermatite Atópica/sangue , Dermatite Atópica/genética , Predisposição Genética para Doença , Variação Genética , Imunoglobulina E/sangue , Adulto , Alelos , Dermatite Atópica/imunologia , Feminino , Frequência do Gene , Genótipo , Humanos , Imunoglobulina E/imunologia , Masculino , Mutação de Sentido Incorreto , Razão de Chances , Polimorfismo de Nucleotídeo Único , Adulto JovemRESUMO
OBJECTIVE: The objective of this paper is to identify predictors for the response to treatment of acute lupus hemophagocytic syndrome (ALHS). METHODS: We reviewed seven cases with ALHS admitted to our hospital and published ALHS cases identified in the 2001-2014 Medline database, and then conducted univariate and multivariate analyses to identify predictors for the response to treatment. RESULTS: Review of our cases showed a significant and negative correlation between serum ferritin and anti-DNA antibody (p = 0.0025). All three patients treated with cyclosporine A (CsA) were considered responders despite high serum ferritin and corticosteroid resistance. We also reviewed 93 patients with ALHS identified in 46 articles. Multiple logistic regression analysis identified C-reactive protein (CRP) (OR 0.83, p = 0.042) and hemoglobin (OR 1.53, p = 0.026) measured at diagnosis of ALHS as significant predictors of the response to corticosteroid monotherapy. Moreover, among 32 patients treated with CsA, serum ferritin was significantly higher in CsA responders (12163 ± 16864 µg/l, n = 22) than in non-responders (3456 ± 6267/µg/l, p = 0.020, n = 10). Leukocyte count was significantly lower in the CsA responders (1940.0 ± 972.3/µl) than in the non-responders (3253 ± 2198/µl, p = 0.034). CONCLUSION: Low CRP and high hemoglobin can predict a positive response to corticosteroid monotherapy while high serum ferritin and low leukocyte count can predict a positive response to CsA in patients with ALHS and therefore, when corticosteroid monotherapy is not effective in such cases, CsA could be the first choice of an additional immunosuppressive agent.
Assuntos
Linfo-Histiocitose Hemofagocítica/sangue , Linfo-Histiocitose Hemofagocítica/tratamento farmacológico , Doença Aguda , Adolescente , Adulto , Idoso , Anti-Inflamatórios/uso terapêutico , Anticorpos Antinucleares/sangue , Proteína C-Reativa/metabolismo , Ciclosporina/uso terapêutico , Feminino , Ferritinas/sangue , Hemoglobinas/metabolismo , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Imunossupressores/uso terapêutico , Linfo-Histiocitose Hemofagocítica/patologia , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prednisolona/administração & dosagem , Prednisolona/uso terapêutico , Estudos Retrospectivos , Adulto JovemRESUMO
BACKGROUND: It is increasingly clear that asthma is not a single disease, but a disorder with vast heterogeneity in pathogenesis, severity, and treatment response. To date, 30 genomewide association studies (GWASs) of asthma have been performed, including by our group. However, most gene variants identified so far confer relatively small increments in risk and explain only a small proportion of familial clustering. OBJECTIVE: To identify additional genetic determinants of susceptibility to asthma using a selected Japanese population with reduced tobacco smoking exposure. METHODS: We performed a GWAS by genotyping a total of 480 098 single-nucleotide polymorphisms (SNPs) for a Japanese cohort consisting of 734 healthy controls and 240 patients with asthma who had smoked for no more than 10 pack-years. The SNP with the strongest association was genotyped in two other independent Japanese cohorts consisting of a total of 531 healthy controls and 418 patients with asthma who had smoked for no more than 10 pack-years. For the hyaluronan synthase 2 (HAS2) gene, we investigated SNP-gene associations using an expression quantitative trait loci (eQTL) database and also analysed its gene expression profiles in 13 different normal tissues. RESULTS: In the discovery GWAS, a SNP located upstream of HAS2, rs7846389, showed the strongest statistical significance (P = 1.43 × 10(-7) ). In the two independent replication cohorts, rs7846389 was consistently associated with asthma (nominal P = 0.0152 and 0.0478 in the first and second replication cohorts, respectively). In the meta-analysis, association of rs7846389 with susceptibility to asthma reached the level of genomewide significance (P = 7.92 × 10(-9) ). This variant was strongly correlated with HAS2 mRNA expression. The strongest expression of the gene was detected in the lung. CONCLUSIONS: Our study identified HAS2 as a novel candidate gene for susceptibility to adult asthma.
Assuntos
Povo Asiático/genética , Asma/genética , Predisposição Genética para Doença , Glucuronosiltransferase/genética , Adulto , Idoso , Asma/diagnóstico , Estudos de Casos e Controles , Cromossomos Humanos Par 8 , Enganação , Feminino , Expressão Gênica , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Hialuronan Sintases , Japão , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , RNA Mensageiro/genética , Fatores de RiscoRESUMO
BACKGROUND: In steroid-naive patients with asthma, several gene variants are associated with a short-term response to inhaled corticosteroid (ICS) treatment; this has mostly been observed in Caucasians. However, not many studies have been conducted for other ethnicities. Here, we aimed to determine the relationship between the annual decline in forced expiratory flow volume in one second (FEV1 ) and the variant of the glucocorticoid-induced transcript 1 gene (GLCCI1) in Japanese patients with asthma receiving long-term ICS treatment, taking into account the effect of high serum periostin levels, a known association factor of pulmonary function decline and a marker of refractory eosinophilic/Th2 inflammation. METHODS: In this study, 224 patients with asthma receiving ICS treatment for at least 4 years were enrolled. The effects of single-nucleotide polymorphisms (SNPs) in GLCCI1, stress-induced phosphoprotein 1 (STIP1), and T gene on the decline in FEV1 of 30 ml/year or greater were determined. RESULTS: Besides the known contributing factors, that is, the most intensive treatment step, ex-smoking, and high serum periostin levels (≥95 ng/ml), the GG genotype of GLCCI1 rs37973, and not other SNPs, was independently associated with a decline in FEV1 of 30 ml/year or greater. When patients were stratified according to their serum periostin levels, the GG genotype of rs37973 was significantly associated with blood eosinophilia (≥250/µl) in the high serum periostin group. CONCLUSIONS: A GLCCI1 variant is a risk factor of pulmonary function decline in Japanese patients with asthma receiving long-term ICS treatment. Thus, GLCCI1 may be associated with response to ICS across ethnicities.
Assuntos
Asma/genética , Asma/fisiopatologia , Variação Genética , Receptores de Glucocorticoides/genética , Administração por Inalação , Corticosteroides/administração & dosagem , Corticosteroides/uso terapêutico , Idoso , Asma/tratamento farmacológico , Asma/imunologia , Moléculas de Adesão Celular/sangue , Eosinófilos/imunologia , Feminino , Volume Expiratório Forçado , Estudos de Associação Genética , Proteínas de Choque Térmico/genética , Humanos , Contagem de Leucócitos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Testes de Função Respiratória , Fatores de RiscoRESUMO
The first centromeric protein identified in any species was CENP-A, a divergent member of the histone H3 family that was recognised by autoantibodies from patients with scleroderma-spectrum disease. It has recently been suggested to rename this protein CenH3. Here, we argue that the original name should be maintained both because it is the basis of a long established nomenclature for centromere proteins and because it avoids confusion due to the presence of canonical histone H3 at centromeres.
Assuntos
Autoantígenos/genética , Proteínas Cromossômicas não Histona/genética , Histonas/genética , Autoantígenos/metabolismo , Centrômero , Proteína Centromérica A , Proteínas Cromossômicas não Histona/metabolismo , Histonas/metabolismo , Humanos , Cinetocoros , Escleroderma Sistêmico/genética , Terminologia como AssuntoRESUMO
BACKGROUND: Allergic rhinitis (AR) is a very common disorder peaking in the teenage years that is mediated by hypersensitivity responses to environmental allergens. Although it is well established that the ORMDL3 locus at chromosome 17q21 is associated with susceptibility to bronchial asthma, the genetic influences of the polymorphisms of the locus in allergic rhinitis are unclear. OBJECTIVE: To examine whether the polymorphisms in the 17q21 asthma susceptibility locus are associated with allergic rhinitis in the Japanese population. METHODS: We performed linkage disequilibrium (LD) mapping of the locus using the HapMap database and conducted an association study of the locus with a total of 15 tag SNPs in two independent populations. We further evaluated correlations of genotypes with changes in expression of genes at the region in lymphoblastoid cell lines in the Japanese population and assessed the expression levels of the genes in nasal epithelium and various human tissues. RESULTS: We found a significant association between a total of five polymorphisms in the 17q21 asthma susceptibility locus, rs9303277, rs7216389, rs7224129, rs3744246, and rs4794820, and AR (minimum P(combined) = 0.00074, rs4794820). The expression level of the ORMDL3 transcript was significantly correlated with the genotype of rs12150079, rs7216389, rs3744246, and rs4794820 with P < 0.01 (minimum P = 0.0058, rs7216389), and ORMDL3 mRNA was highly expressed in nasal epithelium. CONCLUSION: Genetic variants in the 17q21 asthma susceptibility locus are significantly associated with AR in the Japanese population.
Assuntos
Povo Asiático/genética , Cromossomos Humanos Par 17 , Predisposição Genética para Doença , Proteínas de Membrana/genética , Polimorfismo de Nucleotídeo Único , Rinite Alérgica Perene/genética , Adulto , Idoso , Alelos , Estudos de Casos e Controles , Feminino , Perfilação da Expressão Gênica , Frequência do Gene , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Japão , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Mucosa Nasal/metabolismo , Rinite Alérgica , Adulto JovemAssuntos
Fáscia/patologia , Imageamento por Ressonância Magnética , Poliangiite Microscópica/complicações , Vasculite/patologia , Idoso , Humanos , Masculino , Poliangiite Microscópica/tratamento farmacológico , Poliangiite Microscópica/patologia , Fibras Musculares Esqueléticas/patologia , Prednisolona/uso terapêutico , Resultado do Tratamento , Vasculite/diagnóstico , Vasculite/tratamento farmacológicoRESUMO
BACKGROUND: Human IL-12B gene on chromosome 5q31 encodes the common p40 subunit of IL-12 and IL-23. IL-12 is known to play critical roles in the generation of T-helper type 1 (TH(1)) cells, whereas IL-23 is involved in maintenance and/or population expansion of TH(17) cells. Although several reports suggested an association between a polymorphism (-6415CTCTAA/GC) in IL-12B and asthma, the molecular mechanism how this polymorphism is involved in allergic inflammation is still unclear. METHODS: The transcription activity was analysed by reporter assay. A transcription factor binding to -6415 polymorphic site was identified by electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP) assay. The amount of cytokines produced from peripheral monocytes were determined by ELISA. RESULTS: Reporter assay showed that the transcription activity of the GC allele was higher than that of the CTCTAA allele. A transcription factor Sp1 bound to the region including the GC allele with a higher affinity than that of the CTCTAA allele in EMSA. In vivo binding of Sp1 to IL-12B gene carrying -6415GC was confirmed by ChIP assay. Overexpression of Sp1 up-regulated transcription activity of promoter carrying GC allele sequence, whereas the CTCTAA promoter was not affected by Sp1. We examined the correlation between -6415CTCTA/GC polymorphism and production of cytokine IL-12/23p40, IL-12p70, and IL-23 on peripheral blood monocytes, and monocytes with the GC/GC allele exhibited significantly higher expression of IL-12p70 protein than those with the CTCTAA/CTCTAA allele (P=0.009). CONCLUSIONS: The -6415 polymorphism is involved in cytokine production potential by affecting Sp1-mediated transcription activity.
Assuntos
Subunidade p40 da Interleucina-12/genética , Polimorfismo Genético , Regiões Promotoras Genéticas/genética , Linhagem Celular Tumoral , Imunoprecipitação da Cromatina , Ensaio de Desvio de Mobilidade Eletroforética , Genes Reporter/genética , Heterozigoto , Homozigoto , Humanos , Interferon gama/farmacologia , Interleucina-12/metabolismo , Subunidade p40 da Interleucina-12/metabolismo , Interleucina-23/metabolismo , Lipopolissacarídeos/farmacologia , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Ligação Proteica/genética , Fator de Transcrição Sp1/genética , Fator de Transcrição Sp1/metabolismo , Ativação Transcricional/fisiologia , Transfecção , Células U937RESUMO
BACKGROUND: Allergic diseases such as asthma and allergic rhinitis are major causes of morbidity in developed countries. The pathology underlying allergic respiratory diseases is considered to be IgE-mediated type I allergy characterized by mucosal inflammation that occurs in response to allergen exposure. They are common diseases involving a complex inheritance. Complement systems are known to play an important role in allergic diseases. Decay-accelerating factor (DAF) is important for the regulation of the complement system and is a good candidate for determining the susceptibility to allergic diseases. OBJECTIVE: The present study aimed to investigate whether polymorphisms in the DAF gene are associated with allergic respiratory diseases in the Japanese population. METHODS: We performed mutation screenings of DAF and conducted a tag single-nucleotide polymorphisms (SNP) association analysis for 684 unrelated adult individuals with seasonal allergic rhinitis (SAR) with Japanese ceder pollen, 188 mite-sensitive adults with asthma, and 346 unrelated non-allergic healthy controls. RESULTS: DAF is located in the tight linkage disequilibrium (LD) block spanning 62 kb. The tag SNP analysis revealed that rs10746463 was significantly associated with SAR (P=0.00033) and mite-sensitive adult asthma (P=0.044). The rs2564978 and rs3841376 haplotypes, which are located in the promoter region of DAF, were in complete LD with rs10746463 (r2=1). Luciferase reporter assays with constructs containing the 5' flanking regions of DAF showed that the plasmid with rs2564978 C/rs3841376 deletion (the risk haplotype) had a statistically significantly lower transcriptional activity than that containing the rs2564978 T/rs3841376 insertion. CONCLUSIONS: Our results suggest that DAF is one of the genes involved in conferring susceptibility to allergic respiratory diseases and show that decreased levels of DAF may be associated with the enhanced specific IgE responses occurring in allergic diseases in the Japanese population.
Assuntos
Asma/genética , Antígenos CD55/genética , Predisposição Genética para Doença , Desequilíbrio de Ligação/genética , Polimorfismo de Nucleotídeo Único , Rinite Alérgica Sazonal/genética , Adulto , Idoso , Povo Asiático , Asma/metabolismo , Antígenos CD55/metabolismo , Feminino , Haplótipos/genética , Humanos , Imunoglobulina E/metabolismo , Japão , Masculino , Pessoa de Meia-Idade , Rinite Alérgica Sazonal/metabolismoRESUMO
The mitotic apparatus plays a pivotal role in dividing cells to ensure each daughter cell receives a full set of chromosomes and complement of cytoplasm during mitosis. A human homologue of the Drosophila warts tumor suppressor, h-warts/LATS1, is an evolutionarily conserved serine/threonine kinase and a dynamic component of the mitotic apparatus. We have identified an interaction of h-warts/LATS1 with zyxin, a regulator of actin filament assembly. Zyxin is a component of focal adhesion, however, during mitosis a fraction of cytoplasmic-dispersed zyxin becomes associated with h-warts/LATS1 on the mitotic apparatus. We found that zyxin is phosphorylated specifically during mitosis, most likely by Cdc2 kinase, and that the phosphorylation regulates association with h-warts/LATS1. Furthermore, microinjection of truncated h-warts/LATS1 protein, including the zyxin-binding portion, interfered with localization of zyxin to mitotic apparatus, and the duration of mitosis of these injected cells was significantly longer than that of control cells. These findings suggest that h-warts/LATS1 and zyxin play a crucial role in controlling mitosis progression by forming a regulatory complex on mitotic apparatus.
Assuntos
Actinas/metabolismo , Proteínas de Drosophila , Metaloproteínas/metabolismo , Proteínas Quinases , Proteínas Serina-Treonina Quinases/metabolismo , Fuso Acromático/metabolismo , Sequência de Aminoácidos , Animais , Especificidade de Anticorpos , Proteína Quinase CDC2/metabolismo , Células COS/citologia , Células COS/metabolismo , Proteínas do Citoesqueleto , Expressão Gênica/fisiologia , Genes Supressores de Tumor/fisiologia , Glicoproteínas , Células HeLa , Humanos , Metaloproteínas/genética , Metaloproteínas/imunologia , Mitose/fisiologia , Dados de Sequência Molecular , Fragmentos de Peptídeos/imunologia , Fosforilação , Plasmídeos , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/imunologia , Dedos de Zinco/genética , ZixinaRESUMO
BACKGROUND: IL-33, an IL-1-like cytokine, is a ligand for IL1RL1, which is an important effector molecule of type 2 T helper responses. Although IL-33/IL1RL1 interaction has been suggested to be important in induction of allergic airway inflammation, serum levels of IL-33 and the genetic influences of the polymorphisms of IL-33 in human allergic diseases are unclear. OBJECTIVE: The aim of this study was to examine whether the serum IL-33 level and polymorphisms in IL-33 are associated with Japanese cedar (JC) pollinosis, the most common form of allergic rhinitis, and a major public health problem, in Japan. METHODS: We performed linkage disequilibrium (LD) mapping of the gene using the HapMap database, and two selected tag single nucleotide polymorphisms were genotyped. We conducted an association study of IL-33 (JC pollinosis, n=170; normal controls, n=100) and measured the IL-33 levels in sera of the 270 subjects by ELISA. RESULTS: Serum levels of IL-33 were significantly higher in patients with JC pollinosis (P=0.0018) than in controls. In genetic association analysis, we found a positive association between the polymorphism and JC pollinosis (P=0.048). CONCLUSION: Our results support a role for IL-33 in the pathogenesis of JC pollinosis.
Assuntos
Alérgenos/efeitos adversos , Cryptomeria/imunologia , Interleucinas/sangue , Interleucinas/genética , Pólen/efeitos adversos , Rinite Alérgica Sazonal/imunologia , Adulto , Suscetibilidade a Doenças , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Imunoglobulina E/sangue , Interleucina-33 , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Rinite Alérgica Sazonal/sangue , Rinite Alérgica Sazonal/genética , Adulto JovemRESUMO
Adherens junctions (AJs) and tight junctions (TJs) comprise a junctional complex which plays key roles not only in cell adhesion and polarization but also in regulation of cell movement and proliferation in epithelial cells. E-Cadherin and nectin are major cell-cell adhesion molecules (CAMs) at AJs, whereas claudin is a major CAM at TJs. We have shown that the cadherin-based cell-cell adhesion is not formed in MDCK cells in which annexin II, a Ca(2+)- and phospholipid-binding protein, is knocked down. Here, we found that TJs and the nectin-based cell-cell adhesions were formed in annexin II-knockdown cells. The formation of TJs in annexin II-knockdown MDCK cells required the nectin-based cell-cell adhesion and afadin, a nectin- and actin-filament-binding protein. In addition, it required the activation of Cdc42 and Rac small G proteins and subsequent reorganization of the IQGAP1-dependent actin cytoskeleton which were induced by the nectin-based cell-cell adhesion. These results indicate that the nectin-based cell-cell adhesion and afadin, but not the cadherin-based cell-cell adhesion, are necessary for the formation of TJs and that the signaling by nectin and the subsequent reorganization of the actin cytoskeleton are also necessary for the formation of TJs under certain conditions.
Assuntos
Anexina A2/deficiência , Moléculas de Adesão Celular/fisiologia , Junções Íntimas/fisiologia , Animais , Anexina A2/genética , Sequência de Bases , Caderinas/fisiologia , Cálcio/fisiologia , Linhagem Celular , Cães , Deleção de Genes , Nectinas , RNA/genética , RNA Interferente Pequeno/genéticaRESUMO
N-Methyl-N'-nitro-N-nitrosoguanidine (MNNG) was administered orally to male Wistar rats at a concentration of 83 microgram/ml in the drinking water for 2, 4, 5, and 7 months; the rats were killed at about month 15. Intestinal metaplasia was found in the stomachs of 80-100% of the rats treated with MNNG for 4 or more months, of 37.5% treated with MNNG for 2 months, and of 10% of the controls. Metaplastic glands, composed of goblet cells and columnar cells with striated borders, were found in the pyloric region. Paneth's cells were found at the bottom of metaplastic glands in a rat treated with MNNG for 4 months. The incidence of well-differentiated adenocarcinomas of the stomach was 63-90% in rats treated with MNNG for 4 or more months and 25% in those treated with MNNG for 2 months.
Assuntos
Adenocarcinoma/induzido quimicamente , Intestinos/efeitos dos fármacos , Metilnitronitrosoguanidina/toxicidade , Lesões Pré-Cancerosas/induzido quimicamente , Neoplasias Gástricas/induzido quimicamente , Animais , Intestinos/patologia , Masculino , Metaplasia/induzido quimicamente , Neoplasias Experimentais/induzido quimicamente , Piloro , Ratos , Fatores de TempoRESUMO
Intestinal metaplasia of the human stomach was classified into two types, complete and incomplete. The complete type was associated with the intestinal marker enzymes sucrose alpha-D-glucohydrolase, alpha, alpha-trehalase, aminopeptidase (microsomal) (APM), and alkaline phosphatase (ALP). Tissue of this type contained goblet cells and Paneth's cells but not high-iron diamine (HID)-positive mucin staining with HID-Alcian blue. The incomplete type of intestinal metaplasia was associated with sucrose alpha-D-glucohydrolase, APM, goblet cells, and HID-positive mucin but not with alpha, alpha-trehalase, ALP, or Paneth's cells. For the examination of the distribution of the complete and incomplete types in 84, 27, and 16 resected specimens of human stomach with gastric carcinoma, gastric ulcer, and duodenal ulcer, respectively, disaccharidases were located with Tes-Tape. Specimens with intestinal metaplasia were divided into three classes: complete type only (class I), incomplete type only (class II), and a mixture of areas of the complete and incomplete types (class III). Of the 84 specimens from patients with gastric carcinoma, intestinal metaplasia was found in 76 (01%), and the percentages of specimens of classes I, II, and III were 32, 22, and 46, respectively. In these specimens, the percent incidence of class I increased and that of class II decreased with age. Of the 27 specimens from patients with gastric ulcer, 16 (59%) shopwed intestinal metaplasia and 10 of the 16 (63%) specimens were of class II. Of the 16 specimens from patients with duodenal ulcer, only 3 (19%) specimens showed intestinal metaplasia and all of them were of class II. The relationships of the complete and incomplete types of intestinal metaplasia to gastric carcinoma wre studied in 26 foci of minute carcinoma of the stomach less than 5 mm in largest diameter. Nineteen of 20 (05%) foci of the intestinal type of minute carcinoma were surrounded by intestinal metaplasia and 16 foci (80%) were surrounded by the incomplete type of intestinal metaplasia.
Assuntos
Intestinos/patologia , Metaplasia/enzimologia , Mucinas/análise , Neoplasias Gástricas/enzimologia , Adulto , Fatores Etários , Idoso , Fosfatase Alcalina/análise , Aminopeptidases/análise , Úlcera Duodenal/enzimologia , Feminino , Histocitoquímica , Humanos , Masculino , Pessoa de Meia-Idade , Lesões Pré-Cancerosas/enzimologia , Estômago/análise , Estômago/enzimologia , Úlcera Gástrica/enzimologia , Sacarase/análise , Trealase/análiseRESUMO
Previously a new glucocorticoid receptor (Peak C), which eluted with 0.12 to 0.14 M NaCl from DEAE-cellulose column, was identified in addition to another receptor (Peak B), a classic type of glucocorticoid receptor, which eluted with 0.05 to 0.08 M NaCl. Peak C appeared after stress or injection of a high dose (20 micrograms/100 g body weight) of dexamethasone into rats. Peak C was also detected in the liver of rats bearing various tumors, but it was not found in malignant tumors (Yoshida sarcoma and Yoshida ascites hepatoma AH 130), a less malignant Yoshida ascites hepatoma (LY-5), or in minimal deviation-type hepatomas (Morris hepatomas 7316A and 7794A). The absence of Peak C in these tumors coincided with the inability of the glucocorticoid to induce tryptophan oxygenase in these tumors and in the liver of rats during early postnatal development. Peak B was consistently observed in various hepatomas and immature rat liver with capability to induce tyrosine aminotransferase. Thus Peak C appeared to be a highly differentiated type of glucocorticoid receptor mediating specific hormone actions and to be present in mature liver cells, but not in immature liver or tumor cells, even of the minimal deviation type.