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1.
PLoS One ; 11(8): e0161875, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27564851

RESUMO

OBJECTIVE: To explore the effect of hyaluronan oligosaccharides (HAoligos) on interactions between HA and its principal receptor, CD44, in rheumatoid synovial fibroblasts (RSFs) and matrix metalloproteinase (MMP) production. METHODS: RSFs were isolated from rheumatoid synovial tissue. HA distribution was visualized by immunocytochemistry. MMP-1 and MMP-3 induction was analyzed by real-time RT-PCR and immunoblotting. The interaction between HAoligos and their MMP-producing receptors was tested by blocking with anti-CD44 and anti-Toll-like receptor 4 (TLR-4). Phosphorylation of nuclear factor κB (NF-κB) and mitogen-activated protein kinase (MAPK) was analyzed by immunoblotting. RESULTS: Endogenous HA decreased after treatment with HAoligos, while MMP-1 and MMP-3 expression increased in a dose-dependent manner. Pretreatment with anti-CD44 or anti-TLR-4 antibody significantly reduced the effect of HAoligos on MMP-1 and MMP-3 mRNA expression. NF-κB and p38 MAPK phosphorylation was enhanced by HAoligos pretreated with anti-TLR-4, and HAoligo-induced MMP production was blocked with an inhibitor of NF-κB and p38 MAPK pathways. CONCLUSIONS: Disruptive changes in CD44-HA interactions by HAoligos enhanced MMP-1 and MMP-3 production via activation of NF-κB and p38 MAPK signaling pathways in RSFs.


Assuntos
Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Metaloproteinase 1 da Matriz/metabolismo , Metaloproteinase 3 da Matriz/metabolismo , NF-kappa B/metabolismo , Oligossacarídeos/farmacologia , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Células Cultivadas , Humanos , Receptores de Hialuronatos , Ácido Hialurônico/metabolismo , Immunoblotting , Metaloproteinase 1 da Matriz/genética , Metaloproteinase 3 da Matriz/genética , NF-kappa B/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Proteínas Quinases p38 Ativadas por Mitógeno/genética
2.
PLoS One ; 11(4): e0153142, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27054952

RESUMO

The Toll-like receptor (TLR) signaling pathway is activated in synovial fibroblast cells in patients with rheumatoid arthritis (RA). The receptor activator of nuclear factor-κB (RANK) and its ligand, RANKL, are key molecules involved in the differentiation of osteoclasts and joint destruction in RA. Hyaluronan (HA) is a major extracellular component and an important immune regulator. In this study, we show that lipopolysaccharide (LPS) stimulation significantly increases RANKL expression via a TLR-4 signaling pathway. We also demonstrate that HA suppresses LPS-induced RANKL expression, which is dependent on CD44, but not intercellular adhesion molecule-1 (ICAM-1). Our study provides evidence for HA-mediated suppression of TLR-4-dependent RANKL expression. This could present an alternative target for the treatment of destructed joint bones and cartilages in RA.


Assuntos
Artrite Reumatoide/metabolismo , Ácido Hialurônico/farmacologia , Ligante RANK/metabolismo , Receptor 4 Toll-Like/metabolismo , Artrite Reumatoide/genética , Diferenciação Celular/efeitos dos fármacos , Células Cultivadas , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Ligante RANK/genética , Membrana Sinovial/citologia , Membrana Sinovial/efeitos dos fármacos , Membrana Sinovial/metabolismo , Receptor 4 Toll-Like/genética
3.
Rheumatol Int ; 35(10): 1707-16, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25991396

RESUMO

This observational retrospective study examined whether abatacept efficacy could be augmented with concomitant methotrexate (MTX) or tacrolimus (TAC) in patients with rheumatoid arthritis (RA) who experienced failure with prior biological disease-modifying antirheumatic drugs (DMARDs) and in whom favorable therapeutic efficacy is difficult to achieve. All patients with a prior biological DMARD history who were treated with abatacept for 52 weeks and registered in a Japanese multicentre registry were included. Clinical efficacy and safety of abatacept according to the concomitant drug used, i.e., none (ABT-mono), MTX (ABT-MTX), and TAC (ABT-TAC), were compared. A greater mean percent change of DAS28-ESR was observed in the ABT-TAC group compared with the ABT-mono group at weeks 12 (-20.5 vs. -5.4 %, p = 0.035) and 24 (-25.0 vs. -11.0 %, p = 0.036). ABT-MTX and ABT-TAC groups had a significantly higher proportion of patients who achieved low disease activity (LDA) within 52 weeks compared with the respective baselines, while no significant change was observed in the ABT-mono group. A higher proportion of patients in the ABT-TAC group achieved EULAR moderate response compared with the ABT-mono group at week 52 (66.7 vs. 35.0 %, p = 0.025). Multivariate logistic regression analysis revealed that concomitant TAC use was independently associated with the achievement of LDA and EULAR response at 52 weeks, while concomitant MTX use was not. Concomitant TAC use may offer a suitable option for RA patients treated with abatacept after prior biological DMARD failure, likely because both abatacept and TAC affect T cell activation.


Assuntos
Abatacepte/uso terapêutico , Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Metotrexato/uso terapêutico , Tacrolimo/uso terapêutico , Idoso , Sinergismo Farmacológico , Quimioterapia Combinada , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Indução de Remissão , Estudos Retrospectivos , Resultado do Tratamento
4.
Arthritis Care Res (Hoboken) ; 67(10): 1363-70, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25832554

RESUMO

OBJECTIVE: To determine the effects of concomitant methotrexate (MTX) on the incidence of large joint replacement resulting from the progression of large joint destruction in patients with rheumatoid arthritis (RA) treated with tumor necrosis factor (TNF) inhibitors. METHODS: A retrospective cohort study was performed using a multicenter registry. In total, 803 patients with RA who received etanercept or adalimumab were included. The first large joint replacement during treatment with etanercept or adalimumab was used as the outcome variable in predictive analyses. The cumulative incidence of large joint replacement was estimated using Kaplan-Meier curves, and the impact of concomitant MTX on the incidence of large joint replacement was assessed with Cox proportional hazards models. Propensity score matching was used to reduce selection bias. RESULTS: Of all patients, 601 (75%) received concomitant MTX at a median dosage of 8 mg/week (interquartile range 6-8). A total of 49 patients (62 joints) underwent large joint replacement during treatment with etanercept or adalimumab. The incidence of large joint replacement for patients with concomitant MTX was significantly lower than that for patients without MTX (P < 0.001). Multivariate analysis revealed that concomitant MTX independently predicted large joint replacement (hazard ratio 0.36, 95% confidence interval 0.20-0.65). Additionally, propensity score-matched analysis demonstrated that patients with concomitant MTX had a significantly lower incidence of large joint replacement than those without concomitant MTX (P = 0.032). CONCLUSION: Concomitant MTX reduces the incidence of large joint replacement in patients with RA treated with TNF inhibitors.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/cirurgia , Artroplastia de Substituição/estatística & dados numéricos , Prótese Articular , Metotrexato/administração & dosagem , Adulto , Idoso , Análise de Variância , Artrite Reumatoide/complicações , Artroplastia de Substituição/métodos , Estudos de Coortes , Terapia Combinada , Quimioterapia Combinada , Feminino , Seguimentos , Humanos , Incidência , Japão , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Valor Preditivo dos Testes , Modelos de Riscos Proporcionais , Sistema de Registros , Estudos Retrospectivos , Medição de Risco , Índice de Gravidade de Doença , Resultado do Tratamento
5.
Rheumatology (Oxford) ; 54(1): 113-20, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25102861

RESUMO

OBJECTIVE: The purpose of this study was to identify the effects of concomitant use of MTX and baseline characteristics for remission in the treatment of RA with tocilizumab (TCZ) in daily clinical practice. METHODS: A total of 240 RA patients who received TCZ were selected from the multicentre Tsurumai Biologics Communication Registry. Predictive baseline factors for remission [28-item DAS (DAS28) < 2.6] at 52 weeks were determined by logistic regression analysis. To confirm whether the associations varied by the level of baseline disease activity, we also assessed the model including the interaction term (each baseline variable × DAS28). RESULTS: In total, 49.3% of the study participants used MTX with TCZ. Even after controlling for the baseline DAS28, shorter disease duration (≤3 year) [odds ratio (OR) 3.58 (95% CI 1.81, 7.07)], less structural damage [Steinbroker stage ≤II, OR 2.33 (95% CI 1.32, 4.12)] and concomitant prednisolone use [OR 0.38 (95% CI 0.21, 0.68)] showed significant predictive values for remission. Concomitant MTX use failed to show a significant association with remission, whereas a significant interaction was observed among concomitant MTX use × DAS28 (P = 0.006). In patients with high baseline disease activity (DAS28 > 5.1), concomitant MTX use was associated with increased odds for remission [adjusted OR for all baseline variables 2.54 (95% CI 1.11, 5.83)], while no association was indicated between them in patients with low to moderate baseline disease activity (DAS28 ≤ 5.1). CONCLUSION: Concomitant MTX use is an important component of TCZ treatment for RA patients with high disease activity.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Metotrexato/uso terapêutico , Índice de Gravidade de Doença , Adulto , Idoso , Sedimentação Sanguínea , Estudos de Coortes , Quimioterapia Combinada , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Indução de Remissão , Resultado do Tratamento
6.
Mod Rheumatol ; 25(2): 251-6, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25211402

RESUMO

OBJECTIVES: The purpose of this study was to explore drug retention rates of second biologic agents after switching from tumor necrosis factor inhibitors (TNFi) in clinical practice in patients with rheumatoid arthritis (RA) on low-dose methotrexate (MTX) or without MTX. METHODS: A total of 169 RA patients who had been withdrawn from first-course TNFi therapy and received a different TNFi or tocilizumab (TCZ) as a second biologic agent were selected from the Tsurumai Biologics Communication Registry, an observational cohort database. Retention rates of second biologic treatment were compared by the type of first TNFi and second biologic agents. RESULTS: Eighty-six patients received first-course infliximab (IFX) or adalimumab (ADA) therapy, and 83 patients received first-course etanercept (ETN) therapy. The former group had a significantly higher retention rate (IFX, 81.1%; ADA, 83.3%) of the second biologic therapy compared to the latter (56.6%, p < 0.001, log-rank test). Drug retention rates of the second biologic agent after switching from IFX/ADA were significantly higher with ETN (90.0%) and TCZ (94.7%) than with ADA/IFX (59.3%). Drug retention rates of the second biologic agent after switching from ETN were significantly higher with TCZ (75.9%) than with ADA/IFX (46.3%). The differences were significant even after adjusting for baseline clinical variables using the Cox proportional hazards model. CONCLUSIONS: Drug retention rates of IFX and ADA after switching from the first TNFi were significantly lower compared to those of ETN and TCZ in patients on low-dose MTX or without MTX.


Assuntos
Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Produtos Biológicos/uso terapêutico , Substituição de Medicamentos , Metotrexato/uso terapêutico , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Adulto , Idoso , Quimioterapia Combinada , Feminino , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento
7.
Rheumatology (Oxford) ; 54(5): 854-9, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25339638

RESUMO

OBJECTIVE: Only a few studies have assessed predictive factors for the long-term efficacy of abatacept. This study aimed to provide clinical evidence of an adequate observational period for predicting low disease activity (LDA) achievement at 52 weeks in RA patients treated with abatacept. METHODS: Participants were all patients registered in a Japanese multicentre registry who were treated with abatacept and had at least 52 weeks of follow-up (n = 254). RESULTS: Areas under the receiver operating characteristic curves for the 28-joint count with CRP (DAS28-CRP) at each time point for LDA achievement at 52 weeks were: 0.686 (cut-off score: 4.6) at baseline, 0.780 (3.8) at 4 weeks, 0.875 (3.3) at 12 weeks, and 0.900 (3.0) at 24 weeks. Although patients with a DAS28-CRP score < 3.0 at 24 weeks had the highest proportion of LDA achievement at 52 weeks (79.3%), the proportion for those with a score < 3.3 at 12 weeks was comparable (77.2%, P = 0.697). Proportions were significantly lower in patients with a score < 3.8 at 4 weeks or < 4.6 at baseline. Multivariate logistic regression demonstrated that a DAS28 score of < 3.3 at 12 weeks was an independent strong predictor for LDA at 52 weeks (adjusted odds ratio: 15.2, P < 0.001). CONCLUSION: Twelve weeks is an adequate observational period to judge the long-term clinical efficacy of abatacept, and is about as early as the period for assessing TNF blockade therapy.


Assuntos
Antirreumáticos/uso terapêutico , Artrite Reumatoide/diagnóstico , Artrite Reumatoide/tratamento farmacológico , Imunoconjugados/uso terapêutico , Sistema de Registros , Índice de Gravidade de Doença , Abatacepte , Idoso , Artrite Reumatoide/epidemiologia , Biomarcadores/sangue , Proteína C-Reativa/metabolismo , Feminino , Seguimentos , Humanos , Japão/epidemiologia , Modelos Logísticos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos Retrospectivos , Resultado do Tratamento , Fator de Necrose Tumoral alfa/antagonistas & inibidores
8.
Clin Rheumatol ; 33(9): 1247-54, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24970596

RESUMO

The aim of this study was to compare the efficacy and retention rates of three biologics (abatacept, tocilizumab, and etanercept) after switching from first-course anti-TNF monoclonal antibody therapy. We performed a retrospective multicenter study of 89 patients who underwent second-course biologic therapy for 52 weeks after switching from first-course anti-TNF monoclonal antibody therapy. Patients at baseline had a mean age of 58.7 years, mean disease duration of 9.8 years, and mean clinical disease activity index (CDAI) of 22.4. There was no significant difference between the three drugs, except in rheumatoid factor positivity. Retention rates for abatacept, tocilizumab, and etanercept treatment at 52 weeks were 72.0, 89.5 and 84.6 %, respectively. The evaluation of CDAI indicated no significant difference at 52 weeks among the three drugs. Discontinuation due to all unfavorable causes did not significantly differ among the three drugs in hazard ratio-based evaluations. Our results show that patients treated with abatacept, tocilizumab, and etanercept achieved a high response rate with no significant differences in drug retention rates and clinical efficacy. These drugs represent good therapeutic options for patients with RA who are refractory to anti-TNF monoclonal antibody therapy.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Imunoconjugados/uso terapêutico , Imunoglobulina G/uso terapêutico , Receptores do Fator de Necrose Tumoral/uso terapêutico , Abatacepte , Adulto , Idoso , Substituição de Medicamentos , Etanercepte , Feminino , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do Tratamento
9.
Arthritis Care Res (Hoboken) ; 66(5): 679-86, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24127403

RESUMO

OBJECTIVE: We previously reported that depression and inflammation have independent effects on pain severity in patients with rheumatoid arthritis (RA). Alexithymia is a personality trait characterized by deficits in cognitive processing and regulation of emotions. A broad association between alexithymia and various health problems has been suggested, including depression, inflammation, and pain. The objective of this study was to examine the independent influence of alexithymia on pain perception and its relationship to depression and inflammation. METHODS: We evaluated 213 RA outpatients who completed self-administered questionnaires, including the Beck Depression Inventory-II (BDI-II) to measure depression severity, the 20-item Toronto Alexithymia Scale (TAS-20) to measure degree of alexithymia, and a visual analog scale to quantify perceived pain. Serum C-reactive protein (CRP) levels were measured to quantify inflammation severity. RESULTS: An initial significant positive association between the TAS-20 score and pain severity (P = 0.01) lost significance after controlling for BDI-II score and CRP level using regression analysis. An interaction was observed among alexithymia, depression, and inflammation with regard to perceived pain. Among those without alexithymia, pain severity increased linearly with the CRP tertile levels regardless of the presence of depression (P < 0.001 for trend). No linear association between pain severity and CRP level was observed among those with alexithymia. Moreover, depressed patients with alexithymia (BDI-II score ≥14 and TAS-20 score ≥61) reported severe pain even at low CRP levels. CONCLUSION: Alexithymia might have a substantial role in pain perception as well as depression in patients with RA. A biopsychosocial approach is essential to achieve better pain control.


Assuntos
Sintomas Afetivos/diagnóstico , Artrite Reumatoide/diagnóstico , Depressão/diagnóstico , Dor/diagnóstico , Adolescente , Adulto , Sintomas Afetivos/epidemiologia , Sintomas Afetivos/psicologia , Idoso , Idoso de 80 Anos ou mais , Artrite Reumatoide/epidemiologia , Artrite Reumatoide/psicologia , Depressão/epidemiologia , Depressão/psicologia , Feminino , Humanos , Inflamação/diagnóstico , Inflamação/epidemiologia , Inflamação/psicologia , Masculino , Pessoa de Meia-Idade , Dor/epidemiologia , Dor/psicologia , Inquéritos e Questionários , Adulto Jovem
10.
Clin Rheumatol ; 33(1): 39-47, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24057092

RESUMO

Favourable clinical results in rheumatoid arthritis (RA) patients with high disease activity (HDA) are difficult to achieve. This study evaluated the clinical efficacy of abatacept according to baseline disease activity compared to adalimumab and tocilizumab. This study included all patients registered in a Japanese multicenter registry treated with abatacept (n = 214), adalimumab (n = 175), or tocilizumab (n = 143) for 24 weeks. Clinical efficacy of abatacept in patients with HDA (DAS28-CRP > 4.1) and low and moderate disease activity was compared. Clinical efficacy of abatacept, adalimumab, and tocilizumab was compared in patients with HDA at baseline. In patients treated with abatacept, multivariate logistic regression identified HDA at baseline as an independent predictor for achieving low disease activity (LDA; DAS28-CRP < 2.7) [OR 0.26, 95 % CI 0.14-0.50] or remission (DAS28-CRP < 2.3) [OR 0.26, 95 % CI 0.12-0.56] at 24 weeks. In patients with HDA at baseline, logistic regression did not identify treatment with adalimumab or tocilizumab as independent predictors of LDA or remission compared to abatacept. Retention rates based on insufficient efficacy were significantly higher in patients treated with abatacept compared to adalimumab and lower than tocilizumab. Retention rates based on adverse events in patients treated with abatacept were significantly lower compared to tocilizumab. Clinical efficacy of abatacept was affected by baseline disease activity. There were no significant differences between the three different classes of biologics regarding clinical efficacy for treating RA patients with HDA, although definitive conclusions regarding long-term efficacy will require further research.


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Antirreumáticos/administração & dosagem , Artrite Reumatoide/tratamento farmacológico , Imunoconjugados/administração & dosagem , Abatacepte , Adalimumab , Adulto , Idoso , Produtos Biológicos/administração & dosagem , Feminino , Humanos , Masculino , Metotrexato/administração & dosagem , Pessoa de Meia-Idade , Análise Multivariada , Prednisolona/administração & dosagem , Sistema de Registros , Indução de Remissão , Estudos Retrospectivos , Resultado do Tratamento
11.
Mod Rheumatol ; 23(5): 904-12, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22975734

RESUMO

OBJECTIVES: The purpose of this study was to examine the treatment retention and efficacy of abatacept, the first member of a new class of biologic agents, in Japanese rheumatoid arthritis (RA) patients during clinical practice. METHODS: A retrospective multicenter study was conducted with patients who underwent abatacept therapy for 24 weeks (n = 143). RESULTS: Patients at baseline had a mean age of 63.5 years, a mean disease duration of 11.3 years, and a mean disease activity score in 28 joints (DAS28) of 4.5. Overall retention of abatacept treatment was 83.2 % at 24 weeks, when 46.2 % of patients achieved DAS28-defined low disease activity (LDA; DAS28 <3.2) and 26.6 % achieved DAS28-defined remission (DAS28 <2.6). LDA was achieved in a significantly higher proportion of patients without prior biologics therapy compared to those with prior biologics (60.9 vs. 34.2 %, p = 0.001). There was no significant difference between patients with or without concomitant methotrexate (MTX) therapy (45.2 vs. 47.5 %). CONCLUSIONS: Abatacept therapy appears to be highly effective and well tolerated during clinical treatment of RA. Abatacept was particularly effective in patients with no history of biologics use, and did not appear to be dependent on concomitant MTX therapy.


Assuntos
Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Imunoconjugados/uso terapêutico , Abatacepte , Idoso , Povo Asiático , Quimioterapia Combinada , Feminino , Humanos , Japão , Masculino , Metotrexato/uso terapêutico , Pessoa de Meia-Idade , Indução de Remissão , Estudos Retrospectivos , Índice de Gravidade de Doença , Resultado do Tratamento
12.
Biochem Biophys Res Commun ; 430(2): 519-22, 2013 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-23232115

RESUMO

Rheumatoid synovial fibroblasts (RSF) are activated by toll-like receptor (TLR) signaling pathways during the pathogenesis of rheumatoid arthritis (RA). Cathepsin K is highly expressed by RSF, and is known to play a key role in the degradation of type I and type II collagen. Cathepsin K is considered to be implicated in the degradation of bone and cartilage in RA. Recent observations have shown that hyaluronan (HA) is an important inhibitor of inflammation. In the present study, we show that lipopolysaccharide (LPS) stimulation significantly increases cathepsin K expression by real-time PCR and western blotting analysis via a TLR-4 signaling pathway. Furthermore, we demonstrate that HA suppresses LPS-induced cathepsin K expression, which is dependent on CD44 but not intercellular adhesion molecule-1 (ICAM-1) interaction. We also show that HA suppresses LPS-induced matrix metalloproteinase-1 (MMP-1) expression, which is dependent on both CD44 and ICAM-1 interaction. We conclude that the anti-inflammatory effect of HA occurs through crosstalk between more than one HA receptor. Our study provides evidence for HA mediated suppression of LPS-induced cathepsin K and MMP-1 expression, supporting a protective effect of HA in RA.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Catepsina K/antagonistas & inibidores , Ácido Hialurônico/farmacologia , Metaloproteinase 1 da Matriz/biossíntese , Receptor 4 Toll-Like/biossíntese , Catepsina K/biossíntese , Linhagem Celular , Fibroblastos/efeitos dos fármacos , Fibroblastos/enzimologia , Humanos , Lipopolissacarídeos , Receptor 4 Toll-Like/agonistas
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