Serum Activin Research Articles

Abstract A16: Overexpression of activin A is associated with poor prognosis in patients with oral squamous cell carcinoma and promotes the proliferation, motility and invasion of oral cancer cells.

Abstract Objective: Both activin A, a member of transforming growth factor superfamily, and its inhibitor follistatin have been shown to be overexpressed in various cancers. We examined the expression of activin A and follistatin in tissue and blood samples from patients with oral squamous cell carcinoma. Methods: The study population comprises 92 patients with oral squamous cell carcinoma. activin A and follistatin levels in tissues and sera were examined by qRT-PCR, immunohistochemistry and ELISA, respectively. Effects of activin A on oral cancer cells were investigated by trans-well migration/invasion assays and RNA interference. Results: Overexpression of immunohistochemically detected activin A was correlated with positive N stage, poor histological differentiation, and perineural invasion (P = 0.029, 0.002, and 0.014, respectively). Statistical significant correlations between activin A and FST were observed in both mRNA and immunohistochemical expression (Pearson's correlation r = 0.507, P = 0.008 and r = 0.354 and P = 0.0005, respectively). In survival analyses, patients with oral squamous cell carcinoma whose tumors overexpressed activin A had a worse prognosis for overall survival and disease-free survival (P = 0.009 and 0.007). However, expression of follistatin in tumor was not correlated with overall survival or disease-free survival. Serum activin A and follistatin levels in 111 untreated patients were neither significantly different from those of 91 control samples nor associated with any clinicopathological manifestations. In vitro suppression of activin A expression in OC3 cells using specific interfering RNA attenuated cell proliferation, migration, and invasiveness. Conclusion: These findings suggest that activin A overexpression in oral squamous cell carcinomas is associated with patients survival and may contribute to tumor progression and metastasis. Citation Information: Clin Cancer Res 2010;16(7 Suppl):A16

Overexpression of Activin A in Oral Squamous Cell Carcinoma: Association with Poor Prognosis and Tumor Progression

Both activin A, a member of transforming growth factor beta superfamily, and its inhibitor follistatin have been shown to be overexpressed in various cancers. We examined the potential role of activin A and follistatin in tissue and blood samples from patients with oral squamous cell carcinoma. For activin A and follistatin, the expression of tissue samples from 92 patients was examined by immunohistochemical study, and the serum levels of blood samples from 111 patients and 91 healthy controls were measured by enzyme-linked immunosorbent assay. We found that overexpression of immunohistochemically detected activin A was correlated with positive N stage, poor histological differentiation, and perineural invasion (P = 0.029, 0.002, and 0.014, respectively). In survival analyses, patients with oral squamous cell carcinoma, whose tumors overexpressed activin A, had a worse prognosis for overall survival and disease-free survival (P = 0.009 and 0.007). However, expression of follistatin in tumor was not correlated with overall survival or disease-free survival. Serum activin A and follistatin levels in 111 untreated patients were neither significantly different from those of 91 control samples nor associated with any clinicopathological manifestations. In vitro suppression of activin A expression in OC3 cells using specific interfering RNA-attenuated cell proliferation, migration, and invasiveness. These findings suggest that activin A overexpression in oral squamous cell carcinomas is associated with patients' survival and may contribute to tumor progression and metastasis.

The need for serum biomarker development for diagnosing and excluding tubal ectopic pregnancy.

The need for serum biomarker development for diagnosing and excluding tubal ectopic pregnancy.

Activin A in asphyxiated full-term newborns with hypoxic ischemic encephalopathy

Activin-A is a protein over-expressed and secreted by the brain after neuronal destruction. We evaluated whether serum activin-A increases in asphyxiated full-term newborns (AFTNs) at risk of hypoxic-ischemic-encephalopathy (HIE). 105 consecutive infants (35 affected by perinatal asphyxia due to acute fetal distress; 70 healthy gestational-age matched newborns) underwent cranial assessment and neurologic examination at 12, 24 and 72 hours after birth and, on discharge from the hospital and; activin-A and monitoring laboratory variables assessment at birth. According to the occurrence of HIE within 7-days after birth, AFTNs were subdivided in Group A (n= 20; no/mild HIE with good prognosis) and Group B (n= 15; moderate/severe HIE with a greater risk of neurological handicap). Activin-A was significantly (P less than 0.0001) higher in Groups A and B than controls and highest (P less than 0.001) in Group B. At 0.66 ng/L activin-A achieved a sensitivity of 93.33 per cent and a specificity of 96.63 per cent, respectively, as HIE diagnostic test. These findings show that activin A increased in AFTNs with HIE before the appearance of related signs.

Maternal Serum Activin A at 11–13 Weeks of Gestation in Hypertensive Disorders of Pregnancy

Objectives: To investigate whether the maternal serum concentration of activin A at 11–13 weeks of gestation in pregnancies that subsequently develop hypertensive disorders is different from those with a normal outcome and to examine whether any possible differences are related to uterine artery pulsatility index (PI), serum pregnancy-associated plasma protein A (PAPP-A) and serum tumor necrosis factor-α receptor-1 (TNF-R1). Material and Methods: Serum activin A, TNF-R1, PAPP-A and uterine artery PI were determined in a case-control study of 126 cases that developed preeclampsia, 88 that developed gestational hypertension and 214 controls. Results: In preeclampsia, compared to controls, uterine artery PI, serum activin A and serum TNF-R1 were higher and serum PAPP-A was lower. In gestational hypertension, compared to controls, serum activin A was higher but uterine artery PI, serum PAPP-A and serum TNF-R1 were not significantly different. There were no significant associations between serum activin A and either uterine artery PI or serum TNF-R1 in either the hypertensive groups or the controls. Discussion: The data do not support the hypothesis linking activin A with impaired trophoblastic invasion of the maternal spiral arteries, placental hypoxia and the release of cytokines which in turn cause endothelial dysfunction and the development of the clinical symptoms of the disease.

Activin A as a marker of intrauterine infection in women with preterm prelabour rupture of membranes

To assess maternal serum activin A, an early phase response protein in systemic infection, as an early marker of intrauterine infection in women with preterm prelabour rupture of membranes (PPROM). A prospective cohort study of women with singleton pregnancies complicated by PPROM at 24 to 34 weeks' gestation. Serum was collected for activin A and cytokine measurements. Activin A was measured using commercial enzyme-linked immunosorbent assay. Cytokines were measured using commercial multiplex assay. Pregnancy outcomes including infection were determined by case-record review. Eighteen women with PPROM were studied, with seven developing intrauterine infection. Serum activin A in women with and without infection did not differ. Peripheral white cell count, interleukin (IL)-6 and IL-10 were higher (P=0.03, 0.05 and 0.009, respectively) and IL-7 lower (P=0.04) 72 h before delivery in women with infection. Activin A is not a clinically useful marker of intrauterine infection in women with PPROM.

The use of serum inhibin A and activin A levels in predicting the outcome of 'pregnancies of unknown location'

The aim was to evaluate the role of serum inhibin A and activin A in the prediction of the outcome of women with 'pregnancies of unknown location' (PULs). Serum human chorionic gonadotrophin (hCG), progesterone, inhibin A and activin A levels were measured at 0 and 48 h. Differences in the mean levels and the change in levels over 48 h expressed as a ratio (48/0 h) were examined between the three outcome groups--failing PUL, intrauterine pregnancy (IUP) or ectopic pregnancy. Variables were incorporated into logistic regression models to predict the pregnancy outcomes, which were evaluated using receiver operator characteristic curves. One hundred and forty-one women were classified as PULs: 67 failing PULs (47.5%), 58 IUPs (41.1%) and 16 ectopic pregnancies (11.4%). Activin A levels were not significantly different between the three outcome groups. Inhibin A levels were significantly lower in failing PULs. The logistic regression model based on serum inhibin levels gave an area under the curve (AUC) of 0.88 for failing PUL, 0.87 for IUP and 0.60 for ectopic pregnancy. The model based on serum activin levels gave an AUC of 0.61 for failing PUL, 0.64 for IUP and 0.51 for ectopic pregnancy, and the model based on serum hCG levels gave an AUC of 0.95 for failing PUL, 0.97 for IUP and 0.67 for ectopic pregnancy. Serum activin A levels at 0 and 48 h are not helpful in predicting the outcome of PULs. Although serum inhibin A levels may be of use in the prediction of failing PULs and IUPs in the PUL populations, they do not perform as well as serum hCG levels.

Single Serum Activin A Testing to Predict Ectopic Pregnancy

Most fatal cases of maternal deaths in early pregnancy from ectopic pregnancy (EP) result from delayed diagnosis. Transvaginal sonography (TVS), the method of choice for initial diagnosis, fails to identify 8–31% of women with EP. For these women, either surgical or biochemical assessment (usually by measurement of serum levels of human chorionic gonadotropin (β-hCG) and/or progesterone) is used to make the correct diagnosis. None of these methods, however, has the accuracy, reproducibility, and simplicity to become a universal predictive marker for EP. Levels of activin A, a placental glycoprotein, increase in the maternal circulation throughout pregnancy until delivery. Addition of activin A to primary human placental cell cultures stimulates progesterone production and the release of β-hCG. This prospective observational study assessed the possible role of activin A as a diagnostic marker among 535 pregnant women with unknown pregnancy location (UPL) presenting at a tertiary referral center between 2004 and 2005. Following clinical examination, the women were evaluated with TVS, β-hCG, and progesterone, and blood levels of activin A were measured. The sensitivity and specificity of activin A as a diagnostic test for the detection of EP in women with UPL was assessed with the receiver operating curve (ROC) test. Pregnancy outcomes were evaluated in 155 (28.9%) viable intrauterine pregnancies (IUP), 305 (56.9%) first-trimester spontaneous abortions (SAB), and 76 (14.2%) EP. SAB had lower β-hCG and progesterone concentrations compared to both EP or IUP (P < 0.001 for each). Among women with EP, both β-hCG and progesterone levels were significantly lower than those with IUP or SAB (P < 0.001 for both). In contrast, levels of activin A were lowest among women with EP, being significantly lower in comparison to either SAB or IUP (P < 0.001 for each). Activin A levels were significantly lower in women with IUP than those with SAB (P < 0.001). ROC analysis showed that activin A had the highest accuracy for prediction of EP in women with UPL at the cutoff of 0.37 ng/ml; the sensitivity was 100% with a specificity of 99.6%. These findings suggest that measurement of activin A may be a useful biochemical marker to identify EP in women with UPL.

Changes in the reproductive function and developmental phenotypes in mice following intramuscular injection of an activin betaA-expressing plasmid

BackgroundThe TGF-beta family protein activin has numerous reported activities with some uncertainty in the reproductive axis and development. The precise roles of activin in in vivo system were investigated using a transient gain of function model.MethodsTo this end, an expression plasmid, pCMV-rAct, with the activin betaA cDNA fused to the cytomegalovirus promoter, was introduced into muscle of the female adult mice by direct injection.ResultsActivin betaA mRNA was detected in the muscle by RT-PCR and subsequent Southern blot analysis. Activin betaA was also detected, and western blot analysis revealed a relatively high level of serum activin with correspondingly increased FSH. In the pCMV-rAct-injected female mice, estrus stage within the estrous cycle was extended. Moreover, increased numbers of corpora lutea and a thickened granulosa cell layer with a small antrum in tertiary follicles within the ovary were observed. When injected female mice were mated with males of proven fertility, a subset of embryos died in utero, and most of those that survived exhibited increased body weight.ConclusionTaken together, our data reveal that activin betaA can directly influence the estrous cycle, an integral part of the reproduction in female mice and activin betaA can also influence the embryo development as an endocrine fashion.

Relationship between activin A level and infarct size in patients with acute myocardial infarction undergoing successful primary coronary intervention

Background Activin A, a member of the transforming growth factor-β cytokine family, has been suggested to have a role in inflammation. We examined the serum level of activin A in patients with acute myocardial infarction (AMI) undergoing successful primary percutaneous coronary intervention (PCI). Methods The subjects were 30 AMI patients, 20 stable angina pectoris (AP) patients and 20 normal subjects. The serum levels of activin A in AMI patients were measured before PCI and on days 1, 2, 7, and 14. Results Activin A levels before PCI in AMI patients (557 ± 255 pg/ml) showed a significantly higher value than those in AP patients (364 ± 159 pg/ml) and control subjects (316 ± 144 pg/ml). Increased serum activin A level before PCI was decreased on day 2, and then gradually re-elevated on days 7 and 14. The serum activin A level before PCI was correlated with log-transformed peak creatine kinase (CK) as a surrogate of infarct size ( r = 0.48, p = 0.008). Stepwise multiple regression analysis demonstrated that the serum activin A level before PCI was an independent predictor of peak CK. Conclusions The serum activin A level, increased in AMI, was positively correlated with peak CK and CK-MB levels which are measures of infarction size.

Maternal serum inhibin‐A and activin‐A levels in the first trimester of pregnancies developing pre‐eclampsia

To evaluate whether measurement of maternal serum inhibin-A and activin-A at 11 + 0 to 13 + 6 weeks of gestation, alone or in combination with second-trimester uterine artery pulsatility measured by Doppler velocimetry, is useful in predicting those women who will develop pre-eclampsia. This was a nested case-control study of pre-eclampsia cases with controls matched for gestational age and storage time for the maternal serum. Samples were collected as part of a first-trimester prenatal chromosomal anomaly screening program. Activin-A and inhibin-A were measured using a commercial enzyme-linked immunosorbent assay and the clinical outcomes were blinded to the operator. All the patients underwent uterine artery Doppler flow velocimetry to measure the mean pulsatility index at 22-24 weeks' gestation. In total there were 64 cases with pre-eclampsia, with 34 delivering prior to 35 weeks of gestation. The control group included 240 cases. In the control group the levels of activin-A and inhibin-A did not change across the narrow gestational window and the median levels were 2.16 ng/mL and 231.13 pg/mL, respectively. In the pre-eclamptic group levels of activin-A and inhibin-A were significantly increased, at 2.52 ng/mL and 286.64 pg/mL (1.24 multiples of the median (MoM) and 1.17 MoM, respectively). There was no difference in the median MoM in those delivering prior to 35 weeks and those delivering later. At cut-offs of the 90(th) centile of normal, activin-A and inhibin-A levels would have identified 20% and 35%, respectively, of cases that would develop pre-eclampsia. When combined with uterine artery Doppler, activin-A measurement could have increased the detection rate from 55% to 63% and inhibin-A measurement could have increased it to 68% at a 5% false positive rate. Although increased in the first trimester, levels of activin-A and inhibin-A are probably too low to make a significant contribution to screening for pre-eclampsia at this time.

Endometrial Inhibin/Activin β-B Subunit Expression Is Related to Decidualization and Is Reduced in Tubal Ectopic Pregnancy

Ectopic pregnancy is common but remains difficult to diagnose accurately. There is no serum test to differentiate ectopic from intrauterine gestation. Our objective was to investigate differential gene expression in decidualized endometrium of ectopic pregnancy. Tissue and serum analysis informed by microarray study was performed. The study was performed at a large United Kingdom teaching hospital. Women undergoing surgical termination of pregnancy (n = 8), evacuation of uterus for miscarriage (n = 6), and surgery for tubal ectopic pregnancy (n = 11) were included in the study. Endometrium was collected from normally cycling women undergoing hysterectomy. Decidualized endometrium was subjected to microarray analysis, morphological assessment, and immunohistochemistry. Endometrial stromal fibroblasts were cultured in the presence of decidualizing stimuli. Differential expression of potentially secreted molecules was calculated. Inhibin/activin beta-B expression was lower in decidualized endometrium from ectopic pregnancies when compared with that of ongoing pregnancies (P < 0.01) or miscarriages (P < 0.01). The localization of the beta-B subunit was more marked in decidualized than nondecidualized stroma. Decidualization of stromal fibroblasts in vitro was associated with increased beta-B expression (P < 0.05). Endometrial stroma of ectopic pregnancies was less decidualized morphologically (P < 0.05), with lower prolactin (P < 0.01) and IGF binding protein-1 (P < 0.005) expression. Serum activin B was lower in ectopic pregnancies (P < 0.005) than in intrauterine pregnancies, whereas there was no difference in progesterone concentrations. Despite similar concentrations of progesterone, the endometrium of ectopic pregnancies is less decidualized than intrauterine pregnancies. Expression of the beta-B subunit is related to decidualization and can be detected in the circulation as activin B. Serum activin B concentrations are lower in ectopic pregnancy.

Single Serum Activin A Testing to Predict Ectopic Pregnancy

Single Serum Activin A Testing to Predict Ectopic Pregnancy

Abstract 3167: Serum Activin A Level Is Associated With Infarct Size In Patients With Acute Myocardial Infarction Who Undergo Successful Primary Percutaneous Coronary Intervention

PURPOSE: Activin A, a member of the transforming growth factor-beta cytokine family, has been suggested to play a role in inflammation and have pleiotropic functions. We examined the alteration of serum activin A level in patients with ST-segment elevation myocardial infarction (STEMI) who received successful primary percutaneous coronary intervention (PCI) within 12 hours, and investigated whether serum activin A was associated with infarct size. METHODS: We examined 26 patients with STEMI, 20 consecutive stable angina pectoris (AP) patients and 20 normal subjects. In STEMI patients, blood samples were collected before PCI (day0) and days 1, 2, 7 and 14. Serum activin A level was measured by enzyme-linked immunoassay. Change of activin A between day 2 and day0 (delta 2d) was also examined. The serum levels of activin A were compared with infarct size, as indicated with peak CK. RESULTS: Patients with STEMI demonstrated significantly higher serum activin A level (before PCI) than control subjects and patients with AP (316±112, 369±153 and 569±272 pg/ml, p&lt;0.001 and p=0.007, respectively). The activin A level was significantly elevated and peaked on day 0 and reduced on days 2, and then gradually increased until days 14. Log-transformed peak CK was significantly correlated with serum activin A level on day0 (r=0.55, p=0.004) and delta 2d (r=0.58, p=0.023). In stepwise analysis, serum activin A level (beta=0.37, p=0.022) as well as age, culprit lesion (LAD) and smoking was an independent predictor of peak CK. CONCLUSIONS: The findings suggest that serum activin A level was elevated in STEMI and it may be associated with infarct size in STEMI patients.

Effects of CDB-4022 on Leydig Cell Function in Adult Male Rats1

CDB-4022, an indenopryridine, suppresses spermatogenesis and decreases inhibin secretion in adult male rats. In the present study, we investigated the effects of CDB-4022 on Leydig cell function. A single oral dose of CDB-4022 (2.5 mg/kg) resulted in a 2-fold decrease in serum testosterone levels after 7 days that was paralleled by a decrease in Cyp17a1 mRNA and protein levels and 17alpha hydroxylase enzymatic activity compared with vehicle-treated rats. Consistent with the lower serum testosterone levels, pituitary Lhb and Fshb mRNA levels were increased 3.2- and 2.3-fold, respectively, by CDB-4022 treatment. Ultrastructural analysis of pituitary gonadotrophs showed distended endoplasmic reticulum (ER) and fewer secretory granules in CDB-4022-treated rats, characteristic of enhanced secretory activity. Conversely, CDB-4022 increased serum progesterone levels, testicular Star mRNA and protein expression, and the number of Leydig cells per testis. Serum inhibin B levels were undetectable in CDB-4022-treated rats, while serum activin A levels were similar to controls, indicating that the CDB-4022-treated rats have an elevated activin A:inhibin B ratio. In the presence of hCG stimulation, activin A directly suppressed testosterone secretion but enhanced progesterone secretion from rat Leydig cell primary cultures. Likewise, treatment of MA-10 cells with activin A was found to enhance cAMP-stimulated progesterone secretion and STAR expression. Together, our data indicate that CDB-4022 treatment inhibits CYP17A1 and stimulates STAR expression, thereby decreasing testosterone but increasing progesterone production. We propose that unopposed actions of activin A most likely contribute to the steroid profile in rats after CDB-4022 treatment. Our findings establish CDB-4022 as a new model to examine intratesticular control mechanisms that modulate Leydig cell gene expression and function.

Activin a and follistatin in chronic heart failure

Activin A a member of TGF-B superfamily has been involved in several pathologic processes. It is also accused to have a pathognomonic role in atherogenesis and the development of heart failure. Its activity is regulated by a glycoprotein called follistatin that bind activin preventing its function. uPA is a serine protease that activates plasminogen thus initiating a cascade of fibrinolysis and extra cellular proteolysis. The aim of this study is to assess the role of activinA, follistatin and uPA in patients with chronic heart failure and to find if there is any correlation among their levels. The present study was conducted on 30 patients with chronic heart failure as a result of cardiomyopathy or ischemic heart diseases (group I). There were 20 healthy subjects of matched age and sex involved in the study as a control group (group II). In both groups serum activin A, follistatin, uPA and lipid profile that included serum T.G, total cholesterol, LDLc and HDLc were estimated. Results:there was a significant increase in serum activin A and follistatin and a significant decrease of uPA in group I as compared to controls. As regard to lipid profile there was a significant increase in serum T.G, serum total cholesterol and serum LDLc in group I than group II while there was a significant decrease in patients than the controls regarding HDLc. There was significant positive correlation between activin A and urokinase plasminogen activator (uPA) in group 1. Conclusion:activin A/follistatin system may play a role in the pathogenesis of heart failure; also uPA could be suggested to have an important role in atherosclerosis and ischemic vascular disease that predisposes to heart failure due to the possible role of activin A cytokine in the fibrinolytic activity of uPA.

Single Serum Activin A Testing to Predict Ectopic Pregnancy

Ectopic pregnancy (EP) is an important cause of maternal deaths in early pregnancy because most fatal cases result from delayed diagnosis and inappropriate investigation. We evaluated whether the measurement of activin A may be useful in the diagnosis of EP in women with unknown pregnancy location. The study was designed as an open observational study. The study was set in a tertiary referral center for obstetric care. Patients were women with unknown pregnancy location (n = 536) who had complaints of bleeding, pain, or cramping. Interventions included clinical examination; transvaginal ultrasound scan; human chorionic gonadotropin (hCG), progesterone, and activin A measurements; laparoscopy; uterine curettage; and histological examination. Main outcome measures were pregnancy outcomes and evaluation of sensitivity, specificity, and predictive values of hCG, progesterone, and activin A as diagnostic tests for the detection of EP. Pregnancy outcomes included 155 (28.9%) viable intrauterine pregnancies (IUP), 305 (56.9%) first-trimester spontaneous abortion (SAB), and 76 (14.2%) EP. SAB had the lowest (P < 0.0001) hCG and progesterone concentrations, significantly lower than EP (P < 0.001) and IUP (P < 0.001). In EP, levels were significantly (P < 0.001) lower than in IUP. On the contrary, activin A levels were lowest (P < 0.0001) in EP, significantly lower than in SAB (P < 0.001) and IUP (P < 0.001). IUP had significantly (P < 0.001) lower activin A levels than SAB. When evaluated by the receiver operating curve analysis, activin A at the cutoff of 0.37 ng/ml combined a sensitivity and a specificity of 100 and 99.6%, respectively, for prediction of EP. When activin A concentrations were below the cutoff, the positive predictive value for EP was 97.43%, and 0% for concentrations higher than 0.37 ng/ml. Activin A measurement may identify patients at risk of EP with a high sensibility and specificity.

Sonic Hedgehog and Other Soluble Factors from Differentiating Embryoid Bodies Inhibit Pancreas Development

Success of cell-replacement therapy for diabetes will largely depend on the establishment of alternative sources of pancreatic islet grafts. Embryonic stem (ES) cell differentiation toward pancreatic insulin-producing cells offers such perspectives, but there are still many challenges to overcome. Our previous studies suggested that the limited amount of insulin-positive cells derived from ES cells is related to the activation of pancreas inhibitory signals. To confirm this hypothesis, we report here that exposure of mouse embryonic pancreas explants to soluble factors from embryoid bodies (EBs) inhibits growth, morphogenesis, and endocrine and exocrine differentiation as evaluated by explant size and mRNA and protein expression. Sonic Hedgehog (Shh), an established pancreas repressor both at early and late developmental stages, was produced and secreted by EBs, and participated in the inhibitory effect by inducing its target Gli1 in the explants. Inhibition of Hedgehog pathway rescued the differentiation of Insulin-positive cells in the explants. In contrast to pancreatic cells, hepatic progenitors exposed to EB-conditioned medium showed improved differentiation of albumin-positive cells. In a model system of ES cell differentiation in vitro, we found that definitive endoderm induction by serum removal or activin A treatment further increased Hedgehog production and activity in EBs. Concomitantly, downregulation of the pancreas marker Pdx1 was recorded in activin-treated EBs, a phenomenon that was prevented by antagonizing Hedgehog signaling with Hedgehog interacting protein. These data strongly suggest that Hedgehog production in EBs limits pancreatic fate acquisition and forms a major obstacle in the specification of pancreatic cells from ES-derived definitive endoderm. Disclosure of potential conflicts of interest is found at the end of this article.

Activin A Release into Cerebrospinal Fluid in a Subset of Patients with Severe Traumatic Brain Injury

Activin A is a member of the transforming growth factor-beta superfamily and has been demonstrated to be elevated during inflammation and to have neuroprotective properties following neural insults. In this study, we examined whether traumatic brain injury (TBI) induced a response in activin A or in the concentrations of its binding protein, follistatin. Thirty-nine patients with severe TBI had daily, matched cerebrospinal fluid (CSF) and serum samples collected post-TBI and these were assayed for activin A and follistatin using specific immunoassays. Concentrations of both molecules were assessed relative to a variety of clinical parameters, such as the Glasgow Coma Score, computer tomography classification of TBI, measurement of injury markers, cell metabolism and membrane breakdown products. In about half of the patients, there was a notable increase in CSF activin A concentrations in the first few days post-TBI. There were only minor perturbations in either serum activin or in either CSF or serum follistatin concentrations. The CSF activin A response was not related to any of the common TBI indices, but was strongly correlated with two common markers of brain damage, neuronal specific enolase and S100-beta. Further, activin A levels were also associated with indices of metabolism, such as lactate and pyruvate, excitotoxicity (glutamate) and membrane lipid breakdown products such as glycerol. In one of the two patients who developed a CSF infection, activin A concentrations in CSF became markedly elevated. Thus, some TBI patients have an early release of activin A into the CSF that may result from activation of inflammatory and/or neuroprotective pathways.

Possible contribution of serum activin A and IGF-1 in the development of hepatocellular carcinoma in Egyptian patients suffering from combined hepatitis C virus infection and hepatic schistosomiasis

Objectives: The present study evaluated the role of activin A, insulin-like growth factor 1 (IGF-1) and insulin-like growth factor binding protein 3 (IGFBP-3) in Egyptian patients suffering from combined hepatitis C virus (HCV) infection and hepatic schistosomiasis. Design and methods: Four groups were included in the present study. Group I: 30 healthy subjects were included as controls; Group II (HCV): 30 patients with chronic liver disease due to HCV infection without evidence of schistosomiasis; Group III (SHF + HCV): 30 patients with combined disease, chronic schistosomal hepatic fibrosis (SHF) and chronic hepatitis C infection; Group IV (HCC): 30 patients with hepatocellular carcinoma associated with chronic hepatitis C virus and schistosomal infection. Results: Patients with HCV, HCV + SHF and those with HCC had a significantly higher serum activin A compared with the control group ( P < 0.001). Serum activin A level (mean ± SD) was 5.7 ± 2.76, 10.59 ± 3.59, 15.39 ± 4.61 and 19.93 ± 5.43 ng/mL in controls, HCV patients, HCV + SHF patients and HCC patients, respectively. Serum IGF-1 was significantly lower in HCV patients, HCV + SHF patients and HCC patients compared to the control group ( P < 0.001). Serum IGF-1 was 121.7 ± 73.4, 76.7 ± 23.5, 35.7 ± 17.6 and 39.9 ± 25.9 ng/mL in controls, HCV patients, HCV + SHF patients and HCC patients, respectively. Similarly, serum IGFBP-3 was significantly lower in HCV patients, HCV + SHF patients and HCC patients compared to the control group ( P < 0.001). Furthermore, serum insulin-like growth factor binding protein 3 (IGFBP-3) was significantly lower in patients with HCC compared to patients with HCV or those with HCV + SHF ( P < 0.01 and P = 0.024, respectively). The median (range) of serum IGFBP-3 was 4452 (352.2–8965), 3457 (1114–6000), 2114 (867–5901) and 1202 (576–3994) ng/mL in controls, HCV patients, HCV + SHF patients and HCC patients, respectively. Serum activin A correlated positively with Child-Pugh scoring in patients with HCV, HCV + SHF and those with HCC. The correlation coefficient was significant, at 0.001, in total cases. Conclusions: We conclude that patients with HCV, HCV + SHF and those with HCC have a significantly higher serum activin A when compared with controls. Serum activin A level was significantly higher in patients with HCV + SHF compared to those with HCV alone ( P < 0.01) with a significant positive correlation between the serum activin A level and Child-Pugh scoring in patients with HCV, HCV + SHF and those with HCC. Furthermore, serum IGF-1 and IGFBP-3 levels were significantly reduced in patients with HCV, HCV + SHF and those with HCC compared to the control group. We suggest that this pattern (high activin A and low IGF-1 and its binding protein 3) may play a role in development of HCC in Egyptian patients suffering from combined hepatitis C virus infection and hepatic schistosomiasis.