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Synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome is characterized by skin lesions and osteomyelitis. Although the pathogenesis of SAPHO syndrome remains unclear, chronic focal infection may play a role in the development of excessive immune responses.
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OBJECTIVES: To investigate trends in the treatment of patients with late-onset rheumatoid arthritis (LORA) using data from the National Database of Rheumatic Diseases in Japan (NinJa). METHODS: Patients registered in the NinJa were classified according to disease onset: at <65 years (young-onset rheumatoid arthritis [YORA]); at 65-74 years (early LORA); and at ≥75 years (late LORA). Chronological changes in the treatment and disease activity were compared. RESULTS: A total of 7,178, 13,171, 15,295, and 15,943 patients were evaluated in 2010, 2013, 2016, and 2019, respectively. In all groups, the use of methotrexate gradually decreased, whereas that of biological/targeted synthetic disease-modifying antirheumatic drugs (DMARDs) increased; the use of tumor necrosis factor inhibitors (TNFi) decreased, whereas that of non-TNFi increased. LORA was characterized by more single DMARD use, and less methotrexate and biological/targeted synthetic DMARD use. TNFi and interleukin-6 inhibitors were used less frequently, whereas abatacept was utilized more frequently in late versus early LORA. Conventional synthetic DMARD (excluding methotrexate) and glucocorticoid use was higher in late versus early LORA. CONCLUSIONS: This analysis revealed chronological changes in the treatment of LORA in Japan. Differences between early and late LORA suggest that patients are not a homogeneous population.
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OBJECTIVES: Rheumatoid arthritis (RA) is an autoimmune disease. Methotrexate (MTX) and prednisolone (PSL) are used in combination for severe RA therapy. However, it can increase the risk of osteoporosis and osteonecrosis. Saireito (114) can be used to reduce PSL dose owing to its immunosuppressive effects. However, the effect of combination therapy of PSL+114 on the immune system of RA patients remains unknown. This study compared the effect of PSL alone and PSL+114 on peripheral blood mononuclear cell (PBMC) proliferation, T-cell subsets, and cytokine production in adult RA patients receiving MTX monotherapy. METHODS: We isolated PBMCs from 14 consenting RA patients, and cultured them with PSL (0.0001-1.0 µM) in combination with or without 114 (300 µg/mL) for 96 h in the presence of concanavalin A. We measured the proliferation rates of PBMC, proportions of CD4+, CD8+, and CD4+CD25+Foxp3+T-cells (induced T-regulatory cells), and concentrations of interferon-γ, interleukin (IL)-6, IL-10, IL-17A, and tumour necrosis factor in the culture supernatant. RESULTS: Compared to the blank, the PBMC proliferation rate significantly decreased at a reduced PSL concentration after 114 administration. The 50% inhibition concentration was 0.43 µM PSL for the PSL-only group as compared to 0.29 µM PSL for the PSL+114 co-administration group. The PSL+114 co-administration group had a significantly higher concentration of IL-6 compared to the PSL-only group. CONCLUSIONS: The use of 114 in combination with low-concentration PSL intensified its immunosuppressive effect. However, the concentration of IL-6 was elevated in the co-administration group, suggesting exacerbation of RA activity.
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Antirreumáticos , Artritis Reumatoide , Adulto , Humanos , Prednisolona/efectos adversos , Antirreumáticos/efectos adversos , Leucocitos Mononucleares , Interleucina-6 , Metotrexato/efectos adversosRESUMEN
OBJECTIVES: This study aimed to develop clinical guidelines for the management of vascular Behçet's disease (BD) by the Behçet's Disease Research Committee of the Ministry of Health, Labour and Welfare of the Japanese Government. METHODS: A task force proposed clinical questions (CQs) concerning vascular BD based on a literature search. After screening, draft recommendations were developed for each CQ and brushed up in three blinded Delphi rounds, leading to the final recommendations. RESULTS: This study provides recommendations for 17 CQs concerning diagnosis and differential diagnoses, assessment of disease activity, and treatment. The guidelines recommend immunosuppressive treatments, for both arterial and venous involvement with active inflammation. Anticoagulation is also recommended for deep vein thrombosis except in high-risk patients. Surgical and endovascular therapies can be optional, particularly in patients with urgent arterial lesions undergoing immunosuppression. In addition, two sets of algorithms for diagnosis and treatment are shown for arterial and venous involvement. CONCLUSIONS: These recommendations are expected to serve as useful tools in the daily clinical practice of BD. This content has already been published in Japanese in the Guideline for the Management of Behçet's Disease 2020 and is submitted with permission from both the primary and secondary publishers.
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Síndrome de Behçet , Humanos , Síndrome de Behçet/complicaciones , Síndrome de Behçet/diagnóstico , Síndrome de Behçet/tratamiento farmacológico , Japón , Inmunosupresores/uso terapéuticoRESUMEN
OBJECTIVES: We performed post-hoc analyses of the ORIGAMI study to investigate whether concomitant methotrexate (MTX) influences the clinical outcomes of abatacept in biologic-naïve patients with rheumatoid arthritis. METHODS: Enrolled patients (n = 325) were divided into two groups according to whether abatacept was prescribed without (MTX-) or with (MTX+) concomitant MTX. We compared the changes in Simplified Disease Activity Index (SDAI), Disease Activity Score-28 with C-reactive protein (DAS28-CRP), and Japanese Health Assessment Questionnaire (J-HAQ) through to 52 weeks of treatment, the abatacept retention rate, and safety. RESULTS: At Week 52, the mean SDAI (8.9 vs. 8.8), DAS28-CRP (2.6 vs. 2.6), and J-HAQ (0.92 vs. 0.91) scores were comparable in the MTX- (n = 129) and MTX+ (n = 150) groups. Multivariable logistic regression revealed no significant association between MTX use and SDAI (low disease activity) or J-HAQ (minimum clinically important difference). The abatacept retention rates, estimated using the Kaplan-Meier method, were 73.2% and 66.7% in the MTX- and MTX+ groups, respectively. Adverse events occurred in 47.5% (of 139) and 52.2% (of 159) of patients in the MTX- and MTX+ groups, respectively. CONCLUSION: The effectiveness and safety of abatacept appeared comparable with or without concomitant MTX in this real-world clinical setting.
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Antirreumáticos , Artritis Reumatoide , Productos Biológicos , Humanos , Metotrexato/efectos adversos , Abatacept/efectos adversos , Antirreumáticos/efectos adversos , Artritis Reumatoide/tratamiento farmacológico , Resultado del Tratamiento , Quimioterapia Combinada , Productos Biológicos/uso terapéuticoRESUMEN
BACKGROUND: The importance of autotaxin, an enzyme that catalyzes lysophospholipid production, has recently been recognized in various diseases, including cancer and autoimmune diseases. Herein, we examined the role of autotaxin in systemic lupus erythematosus (SLE), utilizing data from ImmuNexUT, a comprehensive database consisting of transcriptome data and expression quantitative trait locus (eQTL) data of immune cells from patients with immune-mediated disorders. METHODS: Serum autotaxin concentrations in patients with SLE and healthy controls (HCs) were compared. The transcriptome data of patients with SLE and age- and sex-matched HCs were obtained from ImmuNexUT. The expression of ENPP2, the gene encoding autotaxin, was examined in peripheral blood immune cells. Next, weighted gene correlation network analysis (WGCNA) was performed to identify genes with expression patterns similar to ENPP2. The ImmuNexUT eQTL database and public epigenomic databases were used to infer the relationship between autotaxin and pathogenesis of SLE. RESULTS: Autotaxin levels were elevated in the serum of patients with SLE compared to HCs. Furthermore, the expression of ENPP2 was higher in plasmacytoid dendritic cells (pDCs) than in other immune cell subsets, and its expression was elevated in pDCs of patients with SLE compared to HCs. In WGCNA, ENPP2 belonged to a module that correlated with disease activity. This module was enriched in interferon-associated genes and included genes whose expression was influenced by single-nucleotide polymorphisms associated with SLE, suggesting that it is a key module connecting genetic risk factors of SLE with disease pathogenesis. Analysis utilizing the ImmuNexUT eQTL database and public epigenomic databases suggested that the increased expression of ENPP2 in pDCs from patients with SLE may be caused by increased expression of interferon-associated genes and increased binding of STAT3 complexes to the regulatory region of ENPP2. CONCLUSIONS: Autotaxin may play a critical role in connecting genetic risk factors of SLE to disease pathogenesis in pDCs.
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Enfermedades Autoinmunes , Lupus Eritematoso Sistémico , Humanos , Células Dendríticas/metabolismo , Interferones , Enfermedades Autoinmunes/genética , Enfermedades Autoinmunes/patología , Antivirales , Factores de RiesgoRESUMEN
OBJECTIVES: Approximately 30-60% of Behçet's disease patients exhibit joint symptoms. The aim of this study was to determine the clinical characteristics of such patients in Japan. METHODS: This study retrospectively analyzed 151 Behçet's disease patients with joint symptoms who had been treated at seven cooperative medical institutions from 2007 to 2017. We investigated their clinical characteristics and treatments. RESULTS: The most commonly affected joints were the knee, ankle, and proximal interphalangeal joints. Of the cases with pain and swelling, 18 of 293 joints (11 cases) displayed narrowing of the cleft or deformity by X-ray analysis. Improvement in their arthritis was observed in 80% of the patients who received steroids as initial treatment; however, the rate of improvement was lower in patients who had received prednisolone (PSL) at <10 mg/day. The recurrence of joint symptoms was significantly less common in the colchicine group than in the PSL group. CONCLUSIONS: These results suggest that PSL is effective for remission induction for the treatment of joint symptoms of Behçet's disease. Additionally, colchicine is effective in preventing the recurrence of joint symptoms in Behçet's disease. Furthermore, joint damages like joint space narrowing or with any deformity can often be observed in Behçet's disease.
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Síndrome de Behçet , Síndrome de Behçet/complicaciones , Síndrome de Behçet/diagnóstico , Síndrome de Behçet/tratamiento farmacológico , Colchicina/uso terapéutico , Humanos , Japón , Prednisolona/uso terapéutico , Estudios RetrospectivosRESUMEN
OBJECTIVE: To investigate the immunosuppressive effect of vitamin K2 against mitogen-activated peripheral blood mononuclear cells (PBMCs) of rheumatoid arthritis (RA) patients. MATERIALS AND METHODS: Concanavalin A-stimulated PBMC culture procedure was used to evaluate the pharmacodynamics of vitamin K2 in vitro. Methotrexate was set up as the positive control. The proliferation of PBMCs was detected by MTT assay. Relationship between IC50 values of drugs on PBMC proliferation and patient-related factors including laboratory data was analyzed by nonparametric Spearman correlation test. RESULTS: Vitamin K2 inhibited the proliferation of mitogen-activated PBMCs of RA patients with an IC50 value of 3,288.47 ± 4,910.02 ng/mL (mean ± SD). There was a significant correlation between IC50 values of vitamin K2 and patient-related factors of RA patients (p < 0.05), such as C-reactive protein (CRP), rheumatoid factor, anti-cyclic citrullinated peptide antibody (ACPA), matrix metalloproteinase-3, Pre-DAS-28 (CRP), and ∆DAS-28 (CRP). It would be possible to predict the pharmacodynamics of vitamin K2 in RA patients according to the above factors. Methotrexate inhibited the proliferation of mitogen-activated PBMCs of RA patients with a IC50 value of 22.83 ± 12.47 ng/mL (mean ± SD). IC50 values of methotrexate only showed significant correlation with ACPA (p = 0.0158, r = 0.6905), which suggests that ACPA might be a suitable predictor of the pharmacodynamics of methotrexate. CONCLUSION: The above information suggests that vitamin K2 could provide a benefit for the treatment of RA patients via its immunosuppressive function.
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Artritis Reumatoide , Mitógenos , Artritis Reumatoide/tratamiento farmacológico , Humanos , Inmunosupresores/química , Inmunosupresores/farmacología , Leucocitos Mononucleares , Mitógenos/farmacología , Vitamina K 2RESUMEN
Sinomenine (SN) is a plant-derived alkaloid isolated from Caulis Sinomenii. It has been approved by the State Food and Drug Administration of China for treating rheumatoid arthritis (RA) nearly 20 years ago. To investigate the anti-RA mechanism of SN, a lot of scholars reported the immunosuppressive effect of SN on T lymphocytes. We continued to evaluate the suppressive function of SN by using human peripheral blood mononuclear cells (PBMCs) isolated from RA patients. As the positive control, 10 ng/ml of methylprednisolone (MP) showed the antiproliferation effect on mitogen-activated PBMCs of RA patients significantly (*p < .05). Meanwhile, MP decreased the frequency of CD4+ CD25+ T cells and suppressed the secretion of inflammatory Th1/Th2/Th17 cytokines such as IL-4, IL-6, IL-10, IL-17, IFN-γ, and TNF-α. However, SN at concentrations of 0.3-30 µM, showed little suppressive effects on the proliferation of PBMCs of RA patients. We did not observe any suppressive effects of SN on percentages of CD4+ T cells and CD4+ CD25+ T cells in the mitogen-activated PBMCs of RA patients. The influence of SN on the percentage of CD4+ CD25+ Foxp3+ T cells was also limited. Finally, even 30 µM of SN did not influence the secretion of Th1/Th2/Th17 cytokine significantly. The present study provided evidence that anti-RA mechanism of SN seems not to be related with the suppressive effects on peripheral T cells.
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Antirreumáticos/uso terapéutico , Artritis Reumatoide/tratamiento farmacológico , Citocinas/antagonistas & inhibidores , Leucocitos Mononucleares/efectos de los fármacos , Morfinanos/uso terapéutico , Linfocitos T Reguladores/efectos de los fármacos , Adulto , Anciano , Antirreumáticos/farmacología , Artritis Reumatoide/sangre , Proliferación Celular/efectos de los fármacos , Proliferación Celular/fisiología , Células Cultivadas , Citocinas/metabolismo , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Leucocitos Mononucleares/metabolismo , Masculino , Persona de Mediana Edad , Morfinanos/farmacología , Linfocitos T Reguladores/metabolismo , Resultado del TratamientoRESUMEN
The patient was 75-year-old male, he has been diagnosed as ascending colon cancer resected by rt. hemicolectomy in September 2010. Final diagnosis was tub2, T4b, N1, Cy1, M0, pStage â ¢c. Despite adjuvant chemotherapy, a lung metastasis was found in April 2012, and it was treated by thoracoscopic partial lung resection. In July 2012, pelvic lymph node recurrence was found, and treated by radiation therapy. In August 2013, right testicular metastasis was resected. After 2 years chemotherapy free intervals, it was resumed by S-1âirinotecan(CPT-11)âregorafenib due to peritoneal disseminations. In July 2016, transverse colostomy was performed due to obstruction caused by peritoneal dissemination. Although, chemotherapy was continued after surgery by trifluridine plus bevacizumab(Bev)âCPT-11, recurrent tumor in rt spermatic cord was enlarged, which resected to reduce its pain. While continuing chemotherapy with CPT-11 plus Bev, rapid growth of peritoneal disseminated tumor with its rapture has induced peritonitis and sepsis, so it was forced to be resected by involving rectum, ileum, and ureter in February 2019. Finally, with totally 6 times these operations, continuing chemotherapy may be maintaining his QOL and prognosis.
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Neoplasias del Colon , Calidad de Vida , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Colon/cirugía , Humanos , Masculino , Recurrencia Local de Neoplasia , TiazolesRESUMEN
Both mucin 1 (MUC1) and trophoblast cell surface antigen 2 (Trop-2) are overexpressed in various epithelial tumor cells, and their high expression is correlated with a poor prognosis. Both proteins were expressed in a human breast cancer cell line, MCF-7â¯cells, but neither was in a human colon cancer cell line, HCT116â¯cells. When MUC1 cDNA was introduced into HCT116â¯cells (HCT116/MUC1), expression of Trop-2 was induced. Reciprocally, treatment of MCF-7â¯cells with MUC1 siRNA reduced the level of Trop-2. Mithramycin A, an inhibitor of specificity protein 1 (Sp1) transcription factor, effectively inhibited the expression of Trop-2. Consistently, treatment with Sp1 siRNA reduced the expression of Trop-2. To reveal the relationship between MUC1 and Sp1, coimmunoprecipitation assays were performed. Sp1 was coimmunoprecipitated with MUC1 and the level of coimmunoprecipitated Sp1 increased in relation to the level of induced Trop-2. It is known that galectin-3 is an endogenous ligand of MUC1. Binding of galectin-3 to MUC1 elevated the recruitment of Sp1 to MUC1, and knockdown of galectin-3 reduced the level of Trop-2. These results suggest that the binding of galectin-3 to MUC1 enhances the recruitment of Sp1, leading to promotion of the transcription of Trop-2.
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Antígenos de Neoplasias/genética , Moléculas de Adhesión Celular/genética , Galectina 3/metabolismo , Mucina-1/metabolismo , Regulación hacia Arriba , Proteínas Sanguíneas , Galectina 3/genética , Galectinas , Regulación Neoplásica de la Expresión Génica , Células HCT116 , Humanos , Células MCF-7 , Mucina-1/genética , Neoplasias/genética , Neoplasias/metabolismo , Unión Proteica , Factor de Transcripción Sp1/metabolismoRESUMEN
BACKGROUND: Previous studies suggest that RA activity is sensitive to seasonal changes. This study explored the influence of season on RA activity, particularly the distribution of affected joints, using a nationwide database in Japan. METHODS: We investigated 12,839 patients whose RA activity was recorded in spring (n = 3250), summer (n = 916), fall (n = 1021), and winter (n = 7652). Disease activity score (DAS) 28-CRP, simplified disease activity index (SDAI), and clinical disease activity index (CDAI) were used as indices of disease activity. Disease activity was also assessed according to DAS28-CRP scores (remission, low, moderate, or high). The affected joint distribution was investigated using novel joint indices (x, y, z), where x and y are indices for the upper and lower joints, respectively, and z is the index for large joint predominance. RESULTS: Mean DAS28-CRP and median SDAI and CDAI scores were highest in spring and lowest in fall. There was a significant difference in the DAS28-CRP for fall versus spring and winter. Fall was associated with a higher remission rate, and spring and winter with high and moderate RA activity, respectively. Significant differences in x, y, SDAI, and CDAI scores were found for spring versus summer, fall, and winter, in addition to fall versus winter (except in y). There was no seasonal difference in the z index. CONCLUSIONS: RA activity in the upper and lower extremities may be highest in spring, followed by winter. Seasonal changes should be considered in patients with RA to better understand their symptoms.
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Artritis Reumatoide/diagnóstico , Artritis Reumatoide/epidemiología , Estaciones del Año , Índice de Severidad de la Enfermedad , Anciano , Bases de Datos Factuales/tendencias , Progresión de la Enfermedad , Femenino , Humanos , Japón/epidemiología , Articulaciones/patología , Masculino , Persona de Mediana EdadRESUMEN
Both mucin 1 (MUC1) and galectin-3 are known to be overexpressed in various malignant tumors and associated with a poor prognosis. It has been extensively reported that MUC1 is involved in potentiation of growth factor-dependent signal transduction. Because some carbohydrate moieties carried on MUC1 change to preferable ones for binding of galectin-3 in cancer cells, we speculated that MUC1-mediated signaling may occur through direct binding of galectin-3. Immunochemical studies showed that the distribution of galectin-3 coincided with that of MUC1 in various human tumor tissues but not in human nonmalignant tissues, and the level of galectin-3 retained on the surface of various cancer cells paralleled that of MUC1. Treatment of MUC1-expressing cells with galectin-3 induced phosphorylation of ERK1/2 and Akt following enhanced phosphorylation of MUC1 C-terminal domain, consistently promoting tumor cell malignancy. It is also noted that this enhanced phosphorylation occurred independently of EGF receptor-mediated signaling in both EGF receptor- and MUC1-expressing cells, and multivalency of galectin-3 was important for initiation of MUC1-mediated signaling. Expectedly, both silencing of endogenous galectin-3 and treatment with galectin-3 antagonists down-regulated cell proliferation of MUC1-expressing cells. These results suggest that the binding of galectin-3 to MUC1 plays a key role in MUC1-mediated signaling. Thus, constitutive activation of MUC1-mediated signaling in an autocrine/paracrine manner caused by ligation of galectin-3 promotes uncontrolled tumor cell malignancy. This signaling may be another MUC1-mediated pathway and function in parallel with a growth factor-dependent MUC1-mediated signaling pathway.
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Neoplasias del Colon/patología , Galectina 3/metabolismo , Sistema de Señalización de MAP Quinasas , Mucina-1/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proliferación Celular , Neoplasias del Colon/enzimología , Neoplasias del Colon/metabolismo , Células HCT116 , Humanos , Fosforilación , Unión Proteica , Transducción de SeñalRESUMEN
BACKGROUND: Peptidylarginine deiminase type 4 (PADI4) has been identified as a susceptibility gene for rheumatoid arthritis (RA) by genome-wide association studies. PADI4 is highly expressed in the bone marrow, macrophages, neutrophils, and monocytes. Peptidyl citrulline is an interesting molecule in RA because it is a target antigen for anti-citrullinated peptide antibodies, and only PADs (translated proteins from PADI genes) can provide peptidyl citrulline via the modification of protein substrates. The aim of this study was to evaluate the importance of the PADI4 gene in the progression of RA. METHODS: We generated Padi4 knockout (Padi4(-/-)) DBA1J mice. The Padi4(-/-) DBA1J and wild-type mice were immunized with bovine type II collagen (CII) to develop collagen-induced arthritis (CIA). The expression of various inflammatory cytokines and Padi genes in immune cells was detected by the real-time TaqMan assay. Cytokine concentrations in sera were measured by enzyme-linked immunosorbent assays. Localization of the PAD4 and PAD2 proteins was indicated by immunohistochemistry. RESULTS: We demonstrated that the clinical disease score was significantly decreased in the Padi4(-/-) mice and Padi4 expression was induced by CII immunization. In the Padi4(-/-) mice, serum anti-type II collagen (CII) immunoglobulin M (IgM), IgG, and inflammatory cytokine levels were significantly decreased compared with those in the wild-type mice. Padi2 expression was induced in the immune cells of the Padi4(-/-) mice as a compensation for the defect in Padi4. CONCLUSIONS: Padi4 affected disease severity in the CIA mice and was involved in the enhancement of the collagen-initiated inflammatory responses.
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Artritis Experimental/genética , Artritis Reumatoide/genética , Autoanticuerpos/inmunología , Enfermedades Autoinmunes/genética , Citrulina/inmunología , Progresión de la Enfermedad , Hidrolasas/genética , Animales , Artritis Experimental/sangre , Artritis Experimental/inmunología , Artritis Reumatoide/inmunología , Autoanticuerpos/sangre , Enfermedades Autoinmunes/sangre , Enfermedades Autoinmunes/inmunología , Citrulina/metabolismo , Colágeno Tipo II/inmunología , Citocinas/sangre , Citocinas/metabolismo , Ensayo de Inmunoadsorción Enzimática , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Humanos , Hidrolasas/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Arginina Deiminasa Proteína-Tipo 4 , Índice de Severidad de la Enfermedad , Factor de Necrosis Tumoral alfa/sangreRESUMEN
Mucin 1 (MUC1) is overexpressed in various human malignant tumors and its expression is correlated with a poor prognosis. MUC1 engages in signal transduction by interacting with receptors for growth and differentiation factors, which contributes to the growth and survival of cancer cells. However, the mechanism by which MUC1 promotes cancer cell invasion remains unclear. Microarray analysis revealed that expression of urokinase-type plasminogen activator (uPA) was elevated in MUC1-overexpressing cells. Furthermore, up- and down-modulation of MUC1 expression was clearly correlated with the change of uPA expression. An immunochemical study showed that the distribution of uPA coincided with that of MUC1 in various human cancer tissues. The MUC1 C-terminal domain (MUC1-CD) was associated with nuclear factor-κB (NF-κB) p65 in MUC1-expressing cells. Chromatin immunoprecipitation (ChIP) assays demonstrated that MUC1-CD existed with NF-κB p65 on the uPA promoter. Luciferase assays indicated that the uPA transcriptional activity was correlated with the level of MUC1 expression and that this MUC1-enhancing effect on the uPA transcription was abolished by introduction of mutations into the NF-κB binding sites on the uPA promoter. These results indicate that formation of the MUC1-CD and NF-κB p65 complex enhanced nuclear translocation of NF-κB p65 and subsequent occupancy of NF-κB binding region on the uPA promoter, leading to elevated transcription of uPA. We also demonstrated that uPA induced by MUC1 enhanced the matrix metalloproteinase (MMP)-2 and -9 activities, and consequently promoted cancer cell invasion. Thus, a MUC1 co-operating NF-κB signaling pathway plays a critical role in cancer cell invasion in MUC1-expressing cells.
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Movimiento Celular/genética , Mucina-1/genética , Regiones Promotoras Genéticas/genética , Factor de Transcripción ReIA/genética , Activador de Plasminógeno de Tipo Uroquinasa/genética , Sitios de Unión/genética , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Dipéptidos/farmacología , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Células HCT116 , Humanos , Immunoblotting , Inmunohistoquímica , Metaloproteinasa 2 de la Matriz , Metaloproteinasa 9 de la Matriz , Mucina-1/metabolismo , Invasividad Neoplásica , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patología , Análisis de Secuencia por Matrices de Oligonucleótidos , Fenilendiaminas/farmacología , Unión Proteica/efectos de los fármacos , Interferencia de ARN , Factor de Transcripción ReIA/antagonistas & inhibidores , Factor de Transcripción ReIA/metabolismo , Activador de Plasminógeno de Tipo Uroquinasa/metabolismoRESUMEN
BACKGROUND: The G-Project committee was erected by the Japan Society for Gastroenterological Carcinogenesis with an aim of establishing a new classification scheme based on molecular biological characteristics that would supplement the conventional TNM classification to better predict outcome. METHODS: In a literature search involving 822 articles on gastric cancer, eight molecules including p53, vascular endothelial growth factor (VEGF)-A, VEGF-C, matrix metalloproteinase-7 (MMP-7), human epidermal growth factor receptor 2, Regenerating islet-derived family, member 4, olfactomedin-4 and Claudin-18 were selected as candidates to be included in the new molecular classification scheme named G-factor. A total of 210 cases of gastric cancer who underwent curative R0 resection were registered from four independent facilities. Immunohistochemical staining for the aforementioned molecules was performed for the surgically resected specimens of the 210 cases to investigate the correlation between clinicopathological factors and expression of each molecule. RESULTS: No significant correlation was observed between the immunostaining expression of any of the eight factors and postoperative recurrence. However, the expressions of p53 and MMP-7 were significantly correlated with overall survival (OS). When 210 gastric cancer patients were divided into three groups based on the expression of p53 and MMP-7 (G0 group: negative for both p53 and MMP-7, n = 69, G1 group: positive for either p53 or MMP-7, n = 97, G2 group: positive for both of the molecules, n = 44), G2 group demonstrated significantly higher recurrence rate (59%) compared to 38% in G0 (p = 0.047). The multivariate regression analysis revealed that G2 group was independently associated with a shorter disease-free survival (DFS) (hazard ratio 1.904, 95% CI 1.098-3.303; p = 0.022), although the association with OS was not significant. Stage II patients among the G2 group had significantly inferior prognosis both in terms of OS and DFS when compared with those among the G0/G1 group, with survival curves similar to those of Stage III cases. CONCLUSIONS: G-factor based on the expression of p53 and MMP-7 was found to be a promising factor to predict outcome of Stage II/III gastric cancer, and possibly to help select the treatment for Stage II cancer, thus supplementing the conventional TNM system.
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Biomarcadores de Tumor/metabolismo , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patología , Biomarcadores de Tumor/análisis , Claudinas/metabolismo , Supervivencia sin Enfermedad , Femenino , Humanos , Inmunohistoquímica/métodos , Japón , Estimación de Kaplan-Meier , Masculino , Metaloproteinasa 7 de la Matriz/metabolismo , Estadificación de Neoplasias , Pronóstico , Receptor ErbB-2/metabolismo , Sociedades Científicas , Neoplasias Gástricas/clasificación , Neoplasias Gástricas/cirugía , Factor A de Crecimiento Endotelial Vascular/metabolismo , Factor C de Crecimiento Endotelial Vascular/metabolismoRESUMEN
The patient, a 78-year-old man, had undergone distal gastrectomy for a gastric ulcer 35 years previously. As melena was observed, he was referred to our department, and was subsequently diagnosed with residual gastric cancer and ascending colon cancer. Peritoneal metastasis of gastric cancer was found, and palliative surgeries, including right hemicolectomy, total gastrectomy, and Roux-en-Y reconstruction were performed. Although postoperative chemotherapy was commenced, side effects led to a decreased performance status (PS), which resulted in the patient shifting to the best supportive care (BSC). Five months after surgery, the patient was urgently transferred to the hospital with upper abdominal pain, and underwent computed tomography (CT) scan. The patient was diagnosed with acute afferent loop obstruction due to peritoneal metastases. It was not possible to perform endoscopic drainage because of the stenosis; therefore, percutaneous transhepatic cholangiodrainage (PTCD) was performed to reduce the pressure in the duodenal afferent loop. Herein, we report on a case of afferent loop obstruction, for which we performed decompression of the afferent loop with PTCD, allowing the patient to continue BSC for approximately 3 months.
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Síndrome del Asa Aferente/terapia , Colon Ascendente/patología , Neoplasias del Colon/complicaciones , Neoplasias Primarias Múltiples/complicaciones , Neoplasias Gástricas/complicaciones , Dolor Abdominal/etiología , Síndrome del Asa Aferente/etiología , Anciano , Neoplasias del Colon/cirugía , Drenaje , Humanos , Masculino , Neoplasias Primarias Múltiples/cirugía , Neoplasias Gástricas/cirugía , Tomografía Computarizada por Rayos XRESUMEN
Because MUC1 carries a variety of sialoglycans that are possibly recognized by the siglec family, we examined MUC1-binding siglecs and found that Siglec-9 prominently bound to MUC1. An immunochemical study showed that Siglec-9-positive immune cells were associated with MUC1-positive cells in human colon, pancreas, and breast tumor tissues. We investigated whether or not this interaction has any functional implications for MUC1-expressing cells. When mouse 3T3 fibroblast cells and a human colon cancer cell line, HCT116, stably transfected with MUC1cDNA were ligated with recombinant soluble Siglec-9, ß-catenin was recruited to the MUC1 C-terminal domain, which was enhanced on stimulation with soluble Siglec-9 in dose- and time-dependent manners. A co-culture model of MUC1-expressing cells and Siglec-9-expressing cells mimicking the interaction between MUC1-expressing malignant cells, and Siglec-9-expressing immune cells in a tumor microenvironment was designed. Brief co-incubation of Siglec-9-expressing HEK293 cells, but not mock HEK293 cells, with MUC1-expressing cells similarly enhanced the recruitment of ß-catenin to the MUC1 C-terminal domain. In addition, treatment of MUC1-expressing cells with neuraminidase almost completely abolished the effect of Siglec-9 on MUC1-mediated signaling. The recruited ß-catenin was thereafter transported to the nucleus, leading to cell growth. These findings suggest that Siglec-9 expressed on immune cells may play a role as a potential counterreceptor for MUC1 and that this signaling may be another MUC1-mediated pathway and function in parallel with a growth factor-dependent pathway.
Asunto(s)
Antígenos CD/metabolismo , Antígenos de Diferenciación de Linfocitos B/metabolismo , Mucina-1/metabolismo , Lectinas Similares a la Inmunoglobulina de Unión a Ácido Siálico/metabolismo , Transducción de Señal , beta Catenina/metabolismo , Animales , Antígenos CD/genética , Antígenos CD/inmunología , Antígenos de Diferenciación de Linfocitos B/genética , Antígenos de Diferenciación de Linfocitos B/inmunología , Línea Celular Tumoral , Técnicas de Cocultivo , Células HEK293 , Humanos , Ratones , Mucina-1/genética , Mucina-1/inmunología , Células 3T3 NIH , Unión Proteica , Estructura Terciaria de Proteína , Lectinas Similares a la Inmunoglobulina de Unión a Ácido Siálico/genética , Lectinas Similares a la Inmunoglobulina de Unión a Ácido Siálico/inmunología , Nicho de Células Madre/genética , Nicho de Células Madre/inmunología , Microambiente Tumoral/genética , Microambiente Tumoral/inmunología , beta Catenina/genética , beta Catenina/inmunologíaRESUMEN
Rheumatoid arthritis is a common autoimmune disease with a complex genetic etiology. Here we identify a SNP in the promoter region of FCRL3, a member of the Fc receptor-like family, that is associated with susceptibility to rheumatoid arthritis (odds ratio = 2.15, P = 0.00000085). This polymorphism alters the binding affinity of nuclear factor-kappaB and regulates FCRL3 expression. We observed high FCRL3 expression on B cells and augmented autoantibody production in individuals with the disease-susceptible genotype. We also found associations between the SNP and susceptibility to autoimmune thyroid disease and systemic lupus erythematosus. FCRL3 may therefore have a pivotal role in autoimmunity.
Asunto(s)
Artritis Reumatoide/genética , Autoinmunidad/genética , Receptores Inmunológicos/genética , Artritis Reumatoide/inmunología , Artritis Reumatoide/metabolismo , Autoinmunidad/inmunología , Autoinmunidad/fisiología , Estudios de Casos y Controles , Cromosomas Humanos Par 1 , Regulación de la Expresión Génica/fisiología , Antígenos HLA-DR/genética , Antígenos HLA-DR/inmunología , Cadenas HLA-DRB1 , Humanos , Desequilibrio de Ligamiento , Datos de Secuencia Molecular , Familia de Multigenes , Mutación , Polimorfismo de Nucleótido Simple , Receptores Inmunológicos/metabolismoRESUMEN
OBJECTIVES: To investigate the influences of various factors on the relapse of acute neurological attacks in patients with Behçet's disease (BD). METHODS: Sixty-one patients, who met the international classification criteria for BD, had attacks of acute neuro-Behçet's disease (NBD) and could be followed up at least for 2 months, including 60 patients in our multicenter retrospective survey on BD patients in 2011. The factors associated with relapse of acute neurological attacks were assessed. RESULTS: Twenty-one of 61 patients had been taking cyclosporine A (CyA) at the onset of acute NBD. All the 21 patients with CyA and 33 of the 40 patients without CyA had eye involvement. There were no significant differences in demographic features, clinical symptoms, MRI findings, the need for, and responses to corticosteroid therapy including pulse therapy between patients with CyA and those without CyA. CyA was withdrawn in 19 of 21 patients with CyA. Of note, patients with CyA showed significantly lower relapse rates than those without CyA (HR 0.1283, 95% CI: 0.0788-0.7836, p = 0.0186 as calculated by log-rank test). Moreover, colchicine was found to reduce the relapse rates in patients with acute NBD without CyA (HR 0.2771, 95% CI: 0.0827-0.9422, p = 0.0450 [log-rank test]). CONCLUSION: These results indicate that CyA-related acute neurological manifestations are almost identical with CyA-unrelated acute events of NBD, except for the paucity of relapse on withdrawal of CyA. The data also demonstrate that colchicine is effective to prevent relapses of acute neurological attacks especially in patients with CyA-unrelated acute NBD.