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OBJECTIVE: The aim is to evaluate the diagnostic value of Activin A levels in serum and pleural fluid on Parapneumonic Pleural Effusion (PPE). METHODS: The authors collected serum and pleural fluid from 86 PPE and 37 Non-PPE (NPPE) patients. Including Activin A, levels of biomarkers such as Lactate Dehydrogenase (LDH), Procalcitonin (PCT), and C-Reactive Protein (CRP) were measured. All factors were calculated for association with days after admission. The diagnostic potential of biomarkers on PPE was considered by Receiver Operating Characteristic (ROC) curve analysis. RESULTS: Levels of Activin A in serum and pleural fluid of PPE patients were significantly higher than those of the NPPE patients. Moreover, concentrations of Activin A in pleural fluid showed a more obvious relevant days after admission. ROC curve analysis found that Activin A in pleural fluid had AUCs of 0.899 with 93% sensitivity and 84% specificity for PPE diagnosis. CONCLUSION: Activin A in pleural fluid correlated with disease severity could act to diagnose PPE.
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Derrame Pleural , Humanos , Derrame Pleural/diagnóstico , Exsudatos e Transudatos/metabolismo , Pleura , Curva ROC , Biomarcadores/metabolismo , Diagnóstico DiferencialRESUMO
Abstract Objective The aim is to evaluate the diagnostic value of Activin A levels in serum and pleural fluid on Parapneumonic Pleural Effusion (PPE). Methods The authors collected serum and pleural fluid from 86 PPE and 37 Non-PPE (NPPE) patients. Including Activin A, levels of biomarkers such as Lactate Dehydrogenase (LDH), Procalcitonin (PCT), and C-Reactive Protein (CRP) were measured. All factors were calculated for association with days after admission. The diagnostic potential of biomarkers on PPE was considered by Receiver Operating Characteristic (ROC) curve analysis. Results Levels of Activin A in serum and pleural fluid of PPE patients were significantly higher than those of the NPPE patients. Moreover, concentrations of Activin A in pleural fluid showed a more obvious relevant days after admission. ROC curve analysis found that Activin A in pleural fluid had AUCs of 0.899 with 93% sensitivity and 84% specificity for PPE diagnosis. Conclusion Activin A in pleural fluid correlated with disease severity could act to diagnose PPE.
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The aim of the present study was to investigate serum and urine levels of activin A in different moments of gestation, in primigravidae and in multigravidae, to understand whether these variables (biological sample and first gestation) affect activin A as a biomarker in pregnancy. We prospectively included 43 pairs of serum and urine samples from 25 women examined at different gestational ages (range 45 to 268 days). In the group of primigravidae (n = 16 samples from 9 participants), there was no significant change in serum activin A levels across gestation. Conversely, the group of multigravidae (n = 27 samples from 16 women) had higher serum activin A levels in the third trimester (2676 ± 840 pg/ml) compared to the first (583 ± 408 pg/ml) and second (1040 ± 384) trimesters (p = .025). Urine activin A concentrations did not differ between the two groups and did not change according to the gestation phase. There was no correlation between serum and urinary levels of activin A (r = 0.149, p = .359). These data suggest that activin A secretion may vary less during the first pregnancy, while urine activin A is unlikely to be a surrogate for the systemic levels of this hormone in pregnant women.
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Ativinas , Terceiro Trimestre da Gravidez , Ativinas/sangue , Ativinas/urina , Estudos Transversais , Feminino , Humanos , Gravidez , Estudos ProspectivosRESUMO
Poor prognosis associated with the dysregulated expression of activin A in a number of malignancies has been related to with numerous aspects of tumorigenesis, including angiogenesis. The present study investigated the prognostic significance of activin A immunoexpression in blood vessels and cancer cells in a number of oral squamous cell carcinoma (OSCC) cases and applied in vitro strategies to determine the impact of activin A on angiogenesis. In a cohort of 95 patients with OSCC, immunoexpression of activin A in both blood vessels and tumor cells was quantified and the association with clinicopathological parameters and survival was analyzed. Effects of activin A on the tube formation, proliferation and migration of human umbilical vein endothelial cells (HUVECs) were evaluated in gainoffunction (treatment with recombinant activin A) or lossoffunction [treatment with activin Aantagonist follistatin or by stable transfection with short hairpin RNA (shRNA) targeting activin A] conditions. Conditioned medium from an OSCC cell line with shRNAmediated depletion of activin A was also tested. The profile of pro and antiangiogenic factors regulated by activin A was assessed with a human angiogenesis quantitative PCR (qPCR) array. Vascular endothelial growth factor A (VEGFA) and its major isoforms were evaluated by reverse transcriptionqPCR and ELISA. Activin A expression in blood vessels demonstrated an independent prognostic value in the multivariate analysis with a hazard ratio of 2.47 [95% confidence interval (CI), 1.304.71; P=0.006) for diseasespecific survival and 2.09 (95% CI, 1.074.08l: P=0.03) for diseasefree survival. Activin A significantly increased tubular formation of HUVECs concomitantly with an increase in proliferation. This effect was validated by reduced proliferation and tubular formation of HUVECs following inhibition of activin A by follistatin or shRNA, as well as by treatment of HUVECs with conditioned medium from activin Adepleted OSCC cells. Activin Aknockdown increased the migration of HUVECs. In addition, activin A stimulated the phosphorylation of SMAD2/3 and the expression and production of total VEGFA, significantly enhancing the expression of its proangiogenic isoform 121. The present findings suggest that activin A is a predictor of the prognosis of patients with OSCC, and provide evidence that activin A, in an autocrine and paracrine manner, may contribute to OSCC angiogenesis through differential expression of the isoform 121 of VEGFA.
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Ativinas/metabolismo , Neoplasias Bucais/patologia , Neovascularização Patológica/patologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Fator A de Crescimento do Endotélio Vascular/metabolismo , Ativinas/análise , Ativinas/antagonistas & inibidores , Ativinas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Comunicação Autócrina/efeitos dos fármacos , Comunicação Autócrina/genética , Movimento Celular , Proliferação de Células , Feminino , Folistatina/farmacologia , Folistatina/uso terapêutico , Técnicas de Silenciamento de Genes , Células Endoteliais da Veia Umbilical Humana , Humanos , Masculino , Pessoa de Meia-Idade , Mucosa Bucal/patologia , Neoplasias Bucais/irrigação sanguínea , Neoplasias Bucais/tratamento farmacológico , Neoplasias Bucais/mortalidade , Comunicação Parácrina/efeitos dos fármacos , Comunicação Parácrina/genética , Fosforilação/efeitos dos fármacos , Fosforilação/genética , Prognóstico , Isoformas de Proteínas/metabolismo , Proteína Smad2/metabolismo , Proteína Smad3/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/irrigação sanguínea , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Carcinoma de Células Escamosas de Cabeça e Pescoço/mortalidadeRESUMO
BACKGROUND: Although chiefly a B-lymphocyte disorder, several research groups have identified common variable immunodeficiency (CVID) subjects with numeric and/or functional TH cell alterations. The causes, interrelationships, and consequences of CVID-associated CD4+ T-cell derangements to hypogammaglobulinemia, autoantibody production, or both remain unclear. OBJECTIVE: We sought to determine how circulating CD4+ T cells are altered in CVID subjects with autoimmune cytopenias (AICs; CVID+AIC) and the causes of these derangements. METHODS: Using hypothesis-generating, high-dimensional single-cell analyses, we created comprehensive phenotypic maps of circulating CD4+ T cells. Differences between subject groups were confirmed in a large and genetically diverse cohort of CVID subjects (n = 69) by using flow cytometry, transcriptional profiling, multiplex cytokine/chemokine detection, and a suite of in vitro functional assays measuring naive T-cell differentiation, B-cell/T-cell cocultures, and regulatory T-cell suppression. RESULTS: Although CD4+ TH cell profiles from healthy donors and CVID subjects without AICs were virtually indistinguishable, T cells from CVID+AIC subjects exhibited follicular features as early as thymic egress. Follicular skewing correlated with IgA deficiency-associated endotoxemia and endotoxin-induced expression of activin A and inducible T-cell costimulator ligand. The resulting enlarged circulating follicular helper T-cell population from CVID+AIC subjects provided efficient help to receptive healthy donor B cells but not unresponsive CVID B cells. Despite this, circulating follicular helper T cells from CVID+AIC subjects exhibited aberrant transcriptional profiles and altered chemokine/cytokine receptor expression patterns that interfered with regulatory T-cell suppression assays and were associated with autoantibody production. CONCLUSIONS: Endotoxemia is associated with early commitment to the follicular T-cell lineage in IgA-deficient CVID subjects, particularly those with AICs.
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Linfócitos B/imunologia , Diferenciação Celular/imunologia , Imunodeficiência de Variável Comum/imunologia , Endotoxemia/imunologia , Deficiência de IgA/imunologia , Linfócitos T Reguladores/imunologia , Adolescente , Adulto , Linfócitos B/patologia , Criança , Pré-Escolar , Imunodeficiência de Variável Comum/patologia , Endotoxemia/patologia , Feminino , Humanos , Deficiência de IgA/patologia , Masculino , Pessoa de Meia-Idade , Linfócitos T Reguladores/patologiaRESUMO
OBJECTIVE: Muscle wasting contributes to the reduced quality of life and increased mortality in chronic obstructive pulmonary disease (COPD). Muscle atrophy in mice with cachexia was caused by Activin A binding to ActRIIB. The role of circulating Activin A leading to muscle atrophy in COPD remains elusive. METHODS: In the present study, we evaluated the relationship between serum levels of Activin A and skeletal muscle wasting in COPD patients. The expression levels of serum Activin A were measured in 78 stable COPD patients and in 60 healthy controls via ELISA, which was also used to determine the expression of circulating TNF-α levels. Total skeletal muscle mass (SMM) was calculated according to a validated formula by age and anthropometric measurements. The fat-free mass index (FFMI) was determined as the fat-free mass (FFM) corrected for body surface area. RESULTS: Compared to the healthy controls, COPD patients had upregulated Activin A expression. The elevated levels of Activin A were correlated with TNF-α expression, while total SMM and FFMI were significantly decreased in COPD patients. Furthermore, serum Activin A expression in COPD patients was negatively associated with both FFMI and BMI. CONCLUSION: The above results showed an association between increased circulating Activin A in COPD patients and the presence of muscle atrophy. Given our previous knowledge, we speculate that Activin A contributes to skeletal muscle wasting in COPD.
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Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Idoso , Atrofia Muscular/etiologia , Doença Pulmonar Obstrutiva Crônica/complicações , Ativinas/sangue , Caquexia/metabolismo , Atrofia Muscular/metabolismo , Atrofia Muscular/sangue , Índice de Massa Corporal , Estudos de Casos e Controles , Fator de Necrose Tumoral alfa/metabolismo , Fator de Necrose Tumoral alfa/sangue , Músculo Esquelético/fisiopatologia , Doença Pulmonar Obstrutiva Crônica/sangue , Ativinas/metabolismo , Subunidades beta de InibinasRESUMO
Activin-A is a member of the TGFß superfamily found in maternal and umbilical cord blood throughout gestation. We investigated whether human umbilical vein endothelial cells (HUVEC) express activin-A in vivo and tested the effects of vasoactive (endothelin-1), pro-inflammatory (interferon-γ, interleukin-8) and anti-inflammatory (dexamethasone, urocortin) factors on activin-A release by isolated HUVEC in vitro. Activin ßA subunit protein and mRNA were strongly localized in the endothelial cells of umbilical veins and were also detectable in scattered cells of the cord connective tissue. Dimeric activin-A was detected in the HUVEC culture medium at picomolar concentrations. Activin-A release by HUVEC decreased after cell incubation with urocortin (p < 0.01), whereas no effect was observed with interleukin-8, interferon-γ, endothelin-1 or dexamethasone. In summary, activin-A is present in the human umbilical vein endothelium in vivo and is produced and released by isolated HUVEC. Activin-A secretion is inhibited in vitro by urocortin, a neuropeptide with predominantly anti-inflammatory action.
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Ativinas/metabolismo , Células Endoteliais da Veia Umbilical Humana/metabolismo , Ativinas/genética , Células Cultivadas , Feminino , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Humanos , Cordão Umbilical/citologia , Cordão Umbilical/metabolismo , Urocortinas/farmacologiaRESUMO
BACKGROUND: The presence of regional lymph node metastasis has an important impact on clinical management and prognostication of patients with oral tongue squamous cell carcinoma (SCC). Approximately 30% to 50% of patients with oral tongue SCC have regional metastasis at diagnosis, but the limited sensibility of the current diagnostic methods used for neck staging does not allow detection of all cases, leaving a significant number of undiagnosed metastasis (occult lymph node metastasis). In this study, we evaluated whether clinicopathologic features and immunohistochemical detection of carcinoma-associated fibroblasts (CAFs) and activin A could be predictive markers for occult lymph node metastasis in oral tongue SCC. METHODS: One hundred ten patients with primary oral tongue SCC, who were classified with early stage tumor (stage I and II) and received surgical treatment with elective neck dissection, were enrolled in the study. RESULTS: Among all examined features, only high immunohistochemical expression of activin A was significantly associated with presence of occult lymph node metastasis (p = .006). Multivariate survival analysis using the Cox proportional hazard model showed that the expression of activin A was an independent marker of reduced overall survival with a 5-year survival of 89.7% for patients with low expression compared to 76.5% for those with high expression (hazard ratio [HR], 2.44; 95% confidence interval [CI], 1.55-3.85; p = .012). CONCLUSION: Our results demonstrated that immunodetection of activin A can be useful for prognostication of oral tongue SCC, revealing patients with occult lymph node metastasis and lower overall survival.
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Ativinas/metabolismo , Carcinoma de Células Escamosas/metabolismo , Neoplasias de Cabeça e Pescoço/metabolismo , Neoplasias da Língua/metabolismo , Idoso , Carcinoma de Células Escamosas/mortalidade , Feminino , Neoplasias de Cabeça e Pescoço/mortalidade , Humanos , Imuno-Histoquímica , Excisão de Linfonodo , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Prognóstico , Carcinoma de Células Escamosas de Cabeça e Pescoço , Neoplasias da Língua/mortalidadeRESUMO
Nonalcoholic fatty liver disease (NAFLD) is characterized by fat accumulation in the liver and is associated with obesity and insulin resistance. Activin A is a member of the transforming growth factor beta (TGF)-β superfamily and inhibits hepatocyte growth. Follistatin antagonizes the biological actions of activin. Exercise is an important therapeutic strategy to reduce the metabolic effects of obesity. We evaluated the pattern of activin A and follistatin liver expression in obese rats subjected to swimming exercise. Control rats (C) and high-fat (HF) diet-fed rats were randomly assigned to a swimming training group (C-Swim and HF-Swim) or a sedentary group (C-Sed and HF-Sed). Activin βA subunit mRNA expression was significantly higher in HF-Swim than in HF-Sed rats. Follistatin mRNA expression was significantly lower in C-Swim and HF-Swim than in either C-Sed or HF-Sed animals. There was no evidence of steatosis or inflammation in C rats. In contrast, in HF animals the severity of steatosis ranged from grade 1 to grade 3. The extent of liver parenchyma damage was less in HF-Swim animals, with the severity of steatosis ranging from grade 0 to grade 1. These data showed that exercise may reduce the deleterious effects of a high-fat diet on the liver, suggesting that the local expression of activin-follistatin may be involved.
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Animais , Masculino , Ativinas/metabolismo , Terapia por Exercício , Folistatina/metabolismo , Hepatopatia Gordurosa não Alcoólica/metabolismo , Obesidade/terapia , Esforço Físico , Peso Corporal , Glicemia/análise , Modelos Animais de Doenças , Dieta Hiperlipídica/efeitos adversos , Fígado Gorduroso/metabolismo , Fígado Gorduroso/patologia , Expressão Gênica , Hepatopatia Gordurosa não Alcoólica/terapia , Obesidade/metabolismo , Distribuição Aleatória , Ratos Wistar , RNA Mensageiro/metabolismo , NataçãoRESUMO
[...] No experimento 1, foi verificado que a adição de LH a partir do dia 6 de cultivo aumentou as taxas de oócitos ? 110 µm, bem como a taxa de retomada da meiose (P<0,05). Por outro lado, quando o LH foi adicionado no início do cultivo foram obtidos apenas oócitos em estádio de vesícula germinativa. No experimento 2, no dia 6 de cultivo de cultivo, a adição de 50 ng/mL de EGF aumentou as taxas de formação do antro, em comparação com o controle cultivado, e após 18 dias resultou em maiores taxas de retomada da meiose quando comparado aos demais tratamentos (P<0,05). Na presença de EGF, a taxa de crescimento folicular diária foi superior em comparação ao controle cultivado (P<0,05). Após 18 dias, os níveis de RNAm para o FSH-R e aromatase P450 foram superiores ao controle não cultivado (P<0,05). No experimento 3 no dia 6 de cultivo, a taxa de formação de antro foi superior na presença de ativina-A quando comparado ao controle cultivado (P<0,05). A adição de 50 ng/mL de ativina-A aumentou a taxa de crescimento folicular do D12 para o D18, resultando em maiores taxas de retomada da meiose (P<0,05). No D6, a ativina-A (50 ng/ml) aumentou os níveis de RNAm para seu receptor (ActR-IA) quando comparado ao controle cultivado (P<0,05). Após 18 dias, a adição de 50 ng/ml de ativina-A aumentou significativamente seus próprios níveis de RNAm comparado ao controle não cultivado. Além disso, este tratamento reduziu os níveis de RNAm para aromatase P450 quando comparado ao controle cultivado (P <0,05). Em conclusão, o momento de adição de LH no meio de cultivo afetou o desenvolvimento de folículos pré-antrais caprinos cultivados. Os efeitos do EGF e os níveis de mRNA para o EGF, EGF-R, FSH-R aromatase P450 variaram de acordo com a fase de desenvolvimento folicular. A adição de ativina-A, de forma dependente, ao meio de cultivo promoveu o desenvolvimento de folículos pré-antrais caprinos após o cultivo.
[...] In experiment 1, was verified that the addition of LH from D6 onward of culture significantly increased the rates of oocytes ≥ 110 μm and the resumption of meiosis rate. On the other hand, when the LH was added since the beginning of culture, only oocytes at the germinal vesicle stage were obtained. In experiment 2, after 6 days of culture, the addition of 50 ng/ml EGF increased the rates of antrum formation compared to the cultured control, and after 18 days this treatment produced oocytes with higher rates of meiosis resumption compared to the other treatments (P<0.05). In the presence of EGF, the follicular growth rate was higher compared to the cultured control (P<0.05). After 18 days, the mRNA levels for FSH-R and P 450 aromatase were higher than the non-cultured control (P<0.05). In experiment 3, after 6 days of culture, the rate of antrum formation was higher in the presence of activin-A compared to the cultured control (P<0.05). The addition of 50 ng/ml activin-A increased the follicular growth rate from D12 to D18, resulting in higher rates of meiosis resumption (P<0.05). On D6, the activin-A (50 ng/ml) increased the mRNA levels for its own receptor (ActR-IA) compared to the cultured control (P<0.05). After 18 days, the addition of 50 ng/ml activin-A also significantly increased its own mRNA levels compared to the non-cultured control. Furthermore, this treatment reduced the mRNA levels for P 450 aromatase compared to the cultured control (P<0.05). In conclusion, the moment of LH addition to the culture medium affects the development of cultured goat preantral follicles. The effects of EGF and mRNA levels for EGF, EGF-R, FSH-R and P 450 aromatase varied according to the follicular developmental stage. The addition of activin-A to the culture medium promoted the development of goat preantral follicles after culture.