Serum TGF-beta1 Levels Research Articles

Role of echocardiography on early diagnosis of atrial remodelling and fibrosis in elite athletes.

There is emerging data indicating that long-standing vigorous exercise may be associated with atrial structural remodelling. This remodelling process is may be the cause of the increasing frequency of atrial arrythmias in athletes. Early diagnosis of atrial remodelling by atrial imaging could have a role in management of atrial arrythmias in elite athletes. In this study we aimed to diagnose early phases of atrial remodelling in elite athletes. Two groups of athletes including professional weight lifters (n = 33), professional marathoners (n = 32) and sedentary participants (n = 30) were enrolled. We also studied patients who received cardiotoxic chemotherapy (n = 10) for comparison. Serum TGF-beta level as a marker of fibrosis was measured. Both left atrial (LA) 3D volume and strain values were analysed. There was a positive correlation between serum TGF-beta levels and LA volumes and negative correlation between TGF-beta levels and strain values. TGF-beta levels were higher among chemotherapy and weight lifter groups, compared to control and marathoner groups [mean 0.57 ± 0.3 and 0.55 ± 0.2 vs. 0.45 ± 0.2 and 0.47 ± 0.2, respectively, p = 0.005]. LA volumes were higher among chemotherapy and weight lifter groups [median 33 (26-38) and 31 (23-36) respectively, p = 0.005], and strain values were lower in these two groups [mean 20.3 ± 2.5 and 24.6 ± 4.5, respectively, p < 0.005] compared to control and marathoner groups. Total exercise volume was higher in weight lifter group compared to marathoners [13,780 (2496-36,400) vs. 4732 (780-44928), respectively, p = 0.001]. There wasn't any difference between any group regarding left ventricular systolic and diastolic functions. Vigorous exercise causes atrial remodelling and fibrosis in elite athletes. Strength exercise carries higher risk for atrial fibrosis than endurance exercise. Burden of exercise is correlated with the severity of cardiac fibrosis. Echocardiographic evaluation of the left atrium and TGF-beta levels may help to detect subclinical cardiac remodelling and fibrosis.

Prevalence of Bone Marrow Fibrosis in 47 Cases of Autoimmune Hemolytic Anemia Patients: Clinical and Biologic Relationships

AIHA is an uncommon and heterogeneous disease caused by autoantibodies directed against erythrocytes and classified as warm (direct antiglobulin test DAT typically positive with anti-IgG antisera and seldom with anti C3d), cold (CAD, usually IgM driven with DAT positive for C3d), mixed (DAT positive for both IgG and high titer C3d), and atypical (DAT negative and IgA driven) forms. The disease is generally benign, but some cases show refractoriness to/relapse after first and further therapy lines, with a correlation with low Hb and inadequate bone marrow compensatory response at onset. Here we aimed to evaluate bone marrow histology (BMH) in 47 primary AIHA patients followed at our Institution, focusing on fibrosis, cellularity, dyserytrhopoiesis, and lymphocyte infiltrate, and their relationship with clinical, laboratory and immunological parameters, collected at enrolment (from January 2017), along with informed consent. BMH samples were revised by an expert hemopathologist and fibrosis graded (MF0 to MF3) according WHO 2016. The number of therapy lines (steroids, immunesuppressors, rituximab, splenectomy) were retrospectively collected. Serum levels of TGF-beta, IL-6, IL-10, IL-17, TNF-alpha, and IFN-gamma were evaluated in patients and in 40 age and sex matched healthy controls, using ELISA kits. Statistical analysis was performed using Student' t test for continuous variables and chi-square or Fischer exact probability test for categorical ones. Figure 1 shows main data of patients (14 males and 33 females; mean age 57 years; 26 CAD, 4 warm, 7 warm with C3d+, 5 mixed, and 5 atypical AIHA), divided according to bone marrow fibrosis (BMF) grade: BMF MF1 was observed in 36% of cases with no relationship with AIHA type, nor with mean Hb values, LDH levels, and the presence of splenomegaly; reticulocyte counts were higher in MF1 cases (p=0.02), although the incidence of inadequate reticulocytosis was comparable in the two groups (82% vs 93%). MF1 cases showed significantly increased cellularity (p=0.005) and dyserythropoiesis (p=0.04), without differences in lymphocyte infiltrate. Concerning cytokine levels, MF1 patients showed increased TGF-beta serum levels and reduced IL-6 (p=0.033), IL-10, IL-17, TNF-alpha, and IFN-gamma compared with MF0 cases. As regards treatment, no differences were observed among MF0 and MF1 cases considering the frequency of steroid and rituximab administration and their efficacy. Splenectomy was performed in 3 cases, all MF0, with 100% response, and cytotoxic immunesuppressors were given to both MF0 and MF1 with a response in the former patients only (67% vs 0%). Of note, MF1 cases more frequently required 2nd or further therapy lines (70 vs 53%), and displayed AIHA related complications (infections, acute renal failure and concomitant thrombocytopenia); at variance the occurrence of thrombosis was more common in MF0 cases.This is the first observation of BMF MF1 in more than 1/3 of AIHA cases. Although the number of patients is limited and the results preliminary, our data suggest that this subgroup is characterized by a hypercellular dyserythropoietic bone marrow and a higher rate of relapse and treatment requirement. Consistently, in MF1 cases, TFG-beta was the only cytokine increased among those tested. These chronic refractory cases may show clinical/pathologic features similar to low-risk myelodysplastic syndromes and recently described idiopathic cytopenia/dysplasia of unknown significance. On the other hand, MF0 AIHA patients seemed to present with a more florid hemolytic disease characterized by increased immune activation and cytokine release, more frequent thrombotic events, and a better response to immunesuppression.Figure1. Clinical and laboratory features of AIHA patients divided according to bone marrow fibrosis grade. Upper panel consists of a table showing clinical and laboratory parameters at diagnosis, therapy lines and complications. Lower panel consists of a graph showing cytokine levels in patients with or without bone marrow fibrosis. Data are given as median (range), if not better specified. TGF-β transforming growth factor beta; IL interleukin; TNF-α tumor necrosis factor alpha; IFN-γ interferon gamma. [Display omitted] DisclosuresBarcellini:Alexion: Honoraria; Agios: Honoraria, Research Funding; Novartis: Honoraria.

The comparison of serum TGF-beta levels and associated polymorphisms in patients with coronary artery ectasia and normal coronary artery

BackgroundCoronary artery ectasia (CAE) is described as the enlargement of a coronary artery segment by 1.5 times or more, which is generally associated with the atherosclerotic process. Atherosclerotic changes lead to arterial remodeling result in CAE. In our study, we measured serum transforming growth factor (TGF)-β1 levels, which have a protective role against atherosclerosis. Further, we aimed to assess the TGF-β1 gene variants rs1800469 (–509C>T, c.−1347C>T) and rs1800470 (c.+29T>C, p.Pro10Leu, rs1982073), which might have an effect on TGF production. Overall, 2877 patients were screened including 56 patients with CAE and 44 patients with normal coronary arteries who were included in the study. Serum TGF-β1 levels were measured using ELISA and compared between two groups. Additionally, TGF-β1 rs1800469 and rs1800470 gene variations were determined using TaqMan® SNP Genotyping Assays.ResultsSerum TGF-β1 levels were significantly lower in patients with CAE than in controls (p=0.012). However, there was no difference in terms of the genotype and allele distributions of TGF-β1 rs1800469 and rs1800470 polymorphisms. Serum TGF-β1 levels were higher in individuals carrying the TGF-β1 rs1800470 G allele (GG+AG) than in individuals with normal homozygous AA genotype in the CAE group (p=0.012).ConclusionOur findings suggest that lower serum TGF-β1 levels are associated with an increased risk for CAE development and that TGF-β1 polymorphisms exert a protective effect. Furthermore, TGF-β1 rs1800470 G allele carriers were shown to have higher TGF-β1 levels in the CAE group. This suggests that having the G allele in the TGF-β1 rs1800470 polymorphism could prevent CAE development.

Are epicardial adipose tissue and transforming growth factor beta1 risk factors of atrial fibrillation in patients with metabolic syndrome?

Objective. To determine the relationship between the thickness of epicardial adipose tissue (EAT) and the serum concentration of transforming growth factor beta1 (TGF-beta1) with the severity of left atrial myocardial fibrosis in patients with metabolic syndrome (MS) and to define the role of these factors in atrial fibrillation (AF) development.Design and methods. The study included 258 patients: patients with MS without AF (n = 57), patients with MS and AF (n = 83), patients with AF without MS (n = 36), and otherwise healthy subjects without cardiovascular disease and metabolic disorders (n = 82). Serum level of TGF-beta1 was assessed by ELISA. Epicardial adipose tissue thickness (EAT) was measured by ultrasound on the Vivid 7 apparatus (General Electric, USA). To assess fibrosis we constructed anatomical and amplitude maps of the left atrium (LA) using the non-fluoroscopic electro-anatomical mapping system CARTO3 (Biosense Webster, USA)Results. EAT in patients with MS and AF is higher than in patients with MS without AF (4,7 ± 1,9 and 4,2 ± 1,6 mm, respectively, p = 0,023), higher than in patients with AF without MS (4,7 ± 1,9 and 4,3 ± 1,7 mm, p = 0,01) and significantly higher than in healthy subjects (4,7 ± 1,9 and 2,3 ± 0,9 mm, respectively, p &lt; 0,001). The EAT positively correlated with the percentage of fibrosis of LA estimated by the mapping method (r = 0,549, p &lt; 0,0001). The serum concentration of TGF-beta1 in patients with AF and MS was 6700,2 [2588,4, 17500,3] pg/ml. It was 4,7 times higher than in healthy subjects (p &lt; 0,0001), 2,6 times higher than in patients with MS without AF and higher than in patients with AF without MS. Positive correlations were found between TGF-beta1 and LA volume (r = 0,203, p = 0,03). Binomial regression analysis showed that the probability of AF presence in patients with MS was higher when traditional predictors of this arrhythmia were present — the volume of the LA (odds ratio (OR) = 1,092, 95% confidence interval (CI) 1,026–1,162, p = 0,005), systolic blood pressure (OR = 1,093, 95% CI 1,021–1,169, p = 0,01), as well as EAT (OR = 2,21, 95% CI 1,111–4,386, p = 0,024) and TGF-beta1 (OR = 1,01, 95% CI 1,006–1,015, p = 0,002).Conclusions.Thickness of epicardial adipose tissue and transforming growth factor beta1 are associated with AF also in MS. Probably, epicardial fat and transforming growth factor beta1 stimulate atrial myocardial fibrosis which is the risk factor of AF.

Abstract 1681: The antitumor effect of a soluble recombinant human thrombomodulin as growth suppression against gastrointestinal tumor in murine peritonitis model

Abstract Introduction: Severe postoperative inflammatory response (PIR) with CARS increases the risk of tumor recurrence after cancer surgery by Tregs suppressing antitumor immunity. Also, cancer recruits Tregs into its tissue by secreting CCL22 and TGF-beta that strengthen its survival. We established a model to represent tumor dynamics undergo PIR by mice that are performed cecal ligation and puncture (CLP) followed by subcutaneous injection of cancer cells into the dorsum. In this model, we previously revealed significant tumor growth and increase number of Tregs both in tumor tissue and blood compared to the normal mice. A soluble recombinant human thrombomodulin (rhTM) is developed as a treatment drug against DIC. It has anti-inflammatory effect and several reports showed that it prevents cancer metastasis. We hypothesized that rhTM normalizes PIR and prevents cancer growth caused by inflammation. Method: Ten-week-old C57BL/6 mice were divided in CLP/rhTM, CLP/normal saline (NS), and control (simple laparotomy plus NS) groups. rhTM (3mg/kg/12hrs) was injected subcutaneously for 7 consecutive days from the day before CLP. CT26 cells (1×104) were implanted 4 hours after CLP. Mice were sacrificed 28 days after CLP. Then, the tumor tissue and blood were collected. To analyze dynamics of Treg, peripheral blood leukocytes the tumor cells were isolated. CD4, CD25 and Foxp3 were stained by fluorescent antibody and stained cells underwent flow cytometric analysis. The quantity of Tregs is measured by the rate of CD25+/Foxp3+ population in CD4+ T cells. The level of CCL22 and TGF-beta were measured both in serum and tumor tissue. The ELISA was used for analyzing serum samples. And for tumor tissue, immunostaing by DAB was performed and positively stained areas were calculated by image-editing software. Results: CLP/NS group mice exhibited significant enhanced tumor growth compared to controls (6.0±1.9 g vs. 3.5±1.6 g, p=0.03), while CLP/rhTM group produced significantly smaller tumors (2.2±1.1 g) than CLP/NS (p=0.01). The Tregs in the blood stream was smaller in CLP/rhTM group compared to CLP/NS group. Intratumoral Tregs showed significant difference between CLP/rhTM group and CLP/NS group (8.89±3.5 % vs. 24.1±15.0 %, p=0.02). We found significant elevation of serum TGF-beta level by CLP (4.7±1.2 pg/ml vs. 15.4±7.0 pg/ml, p=0.02) and relative reduction to 15.4±7.0 pg/ml by administration of rhTM (p=0.05). However, we did not recognize any change of serum CCL22 level in this study. Intratumoral rate of CCL22 positive areas increased by CLP (41% vs. 50%), while rhTM made it decreased to 43%. We found little difference of TGF-beta positive areas among three groups in this study. Conclusion: Acute inflammation induced by CLP enhances the growth of implanted tumors, while administration of rhTM suppresses tumor growth by possibly affecting dynamics Tregs via TGF-beta and CCL22. Citation Format: En Amada, Kazumasa Fukuda, Koshi Kumagai, Koichi Suda, Hiroya Takeuchi, Yuko Kitagawa. The antitumor effect of a soluble recombinant human thrombomodulin as growth suppression against gastrointestinal tumor in murine peritonitis model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1681. doi:10.1158/1538-7445.AM2017-1681

Suppressive Effects of Puerariae Radix on the Breast Tumor Incidence in Rats Treated with DMBA

Puerariae Radix (PR) is the root of Pueraria lobata, an herb widely used in traditional Chinese medicine and as a food seasoning. Owing to its potential anti-oxidative ability, the effects of PR on the inhibition of breast tumors were investigated in this study using the 7,12-dimethylbenz[a]anthracene (DMBA)-treated rat model. Thirty-two female Sprague-Dawley rats were randomly assigned to one of four different treatment groups, with or without PR and/or DMBA administration. At the age of 177 days, all rats were sacrificed, the number and size of tumors were recorded, and blood and tissue samples were collected for assessment of hematological parameters, redox status, and tumorigenesis-related factors. We found that PR supplementation decreased tumor incidence and WBC count but increased the IgM levels, and significantly altered the redox status, elevated serum TGF-Beta levels, and reduced serum VEGF-C and ICAM-1 levels. The mechanism by which PR decreased the incidence of DMBA-induced rat breast tumors might include ameliorating immunity, enhancing the antioxidant status, increasing the hepatic excretion of carcinogenic metabolites of DMBA, and influencing the expression of tumorigenesis-related factors.

RELATIONS OF SERUM TGF-BETA1 LEVELS WITH AGE, SEX, BMI, BLOOD PRESSURE AND GLOMERULAR FILTRATION RATE IN PATIENT WITH CHRONIC KIDNEY DISEASE

Renal fibrosis is the main cause leading to end-stage chronic kidney disease. Transforming growth factor - beta 1 (TGF-beta1) have a major role in the process of renal fibrosis. Objectives: To survey the relation of serum TGF beta1 level with: age, sex, BMI, blood pressure and glomerular filtration rate. Method: A cross-sectional study. Results: Levels of serum TGF-beta1; in patients &lt;40 year old, 40-60 year old and &gt; 60 year of age were respectively 39,97 ± 9,76 ng / ml; 36,07 ± 10,10 ng / ml and 38,29 ± 10,87 ng / ml, p&gt; 0,05. In men and women were respectively 36,71 ± 9,12 ng / ml and 40,43 ± 10,54, p&gt; 0,05. In patient group with BMI ≤ 23 and &gt; 23 were respectively 37,95 ± 9,85 ng / ml and 37,58 ± 12,38, p &gt; 0,05. Levels of serum TGF-beta1 positive correlated with systolic blood pressure index (r = 0,40; p &lt; 0,01) and negative correlated with glomerular filtration rate (r = - 0,29; p &lt;0,01). Conclusion: There are no difference of serum TGF-beta1 levels between men and women, between the age groups (&lt;40 years, 40 to &lt; 60 years and ≥ 60 years), between BMI groups &lt; 23 and BMI group ≥ 23. Level of serum TGF-beta1 positive correlated with systolic blood pressure index and negative correlated with glomerular filtration.vKey words: TGF-beta1, chronic kidney disease

Protective effects of thalidomide on pulmonary injuries in a rat model of paraquat intoxication.

BackgroundThis study was designed to evaluate the protective effects of thalidomide on paraquat (PQ)-induced lung injuries in a rat model and to explore the underlying mechanisms.MethodsRats were exposed to 50 mg/kg PQ by oral gavage, and treated with thalidomide through oral administration at 60 mg/kg once a day, 6 days/week for 2 weeks. Serum levels of IL-6, TNF-alpha, TGFbeta1 and COL1A1 were detected at different time points after paraquat exposure. At the end of the study, lung tissues were collected for pathological inspection as well as analyses of water content and expression levels of IL-6, TNF-alpha, TGFbeta1 and COL1A1 mRNA.ResultsThe results showed that thalidomide treatment could significantly alleviate PQ-induced pathological changes in lung tissue and severity of lung edema. Thalidomide treatment after PQ exposure resulted in significantly reduced serum levels of IL-6, TNF-alpha, TGF-beta1 and COL1A1, as compared to PQ group. PCR analysis demonstrated that expression levels of IL-6, TNF-alpha, TGF-beta1 and COL1A1 in lung tissue were significantly increased after PQ exposure but reduced by thalidomide, which were confirmed by immunohistochemistry staining.ConclusionsOur results indicated that inflammatory factors played important roles in PQ-induced lung injuries and thalidomide could protect rats from PQ-induced lung injuries by inhibiting the upregulation of inflammatory factors.

Changes and meaning of Serum IL-4, IL-10, IFN-gamma, TGF-beta 1 level in patients with delayed encepha-lopathy after carbon monoxide poisoning

Objective To study changes and meaning of serum IL-4,IL-10,IFN-gamma, TGF-beta 1 level in patients with delayed encephalopathy after carbon monoxide poisoning. Methods From January 2011 and June 2014 in our hospital,40 cases of DEACMP patients were selected as group A; the 40 patients with DEACMP was divided into 12 cases of mild cognitive dysfunction, mild cognitive dysfunction in 20 cases,8 cases of severe cognitive dysfunction.40 cases with acute carbon monoxide poisoning(ACMP)patients were selected as group B;40 cases of healthy subjects were selected as healthy controls. Serum interleukin 4 and interleukin 10(IL-4)(IL-10), interferon gamma(IFN-gamma), conversion, growth factor beta 1(TGF-beta 1)content were tested. Results In Group A and group B serum IL-4 levels were lower than that of healthy controls(P<0.01), and serum levels of IL-10 in group B were higher than that in group A and healthy controls(P<0.01), serum level of IFN-gamma in group A and group B was higher than the healthy controls(P<0.01), and in group A IFN-gamma levels were higher than group B(P<0.01), while in group A serum TGF-beta 1 level was lower than B group and the control group(P< 0.01), and in group B TGF-beta 1 level was higher than the control group(P<0.01);With cognitive impairment aggravating of DEACMP patients, IL-4,IL-10,TGF-beta 1 levels were on the decline, and IFN-gamma level was increasing(P<0.01). Conclusion DEACMP patients serum and cerebrospinal fluid of IL-4,IL-10, IFN-gamma, TGF-beta measures such as abnormal expression, showed that the onset of DEACMP may be related to neural immune injury. Serum IL-4,IL-10,IFN-gamma and TGF-beta of DEACMP patients exists abnormal expression Serum IL-4,IL-10,IFN-gamma and TGF-beta levels are also related to the degree of cognitive impairment of DEACMP patients. The onset and progress of DEACMP may be associated with neural immune injury. Key words: Carbon monoxide poisoning; Delayed encephalopathy after.Immune function damage; Mechanism

Does tamoxifen citrate prevent pulmonary fibrosis due to silica inhalation?

As shown in several studies, besides being used in breast cancer, tamoxifen is also known for its antifibrotic effects via reducing the serum TGF-beta levels. We investigated the possible preventive effect of tamoxifen in rats exposed to silica particles depending on the antifibrotic effect. A total of 102 adult female Wistar Albino rats were divided into five groups. First two groups (control and tmx) were free of silica and the last three groups (slc, tmx1 and tmx 10) were exposed to crystalline silica. The rats in tmx, tmx1 and tmx10 groups received 10 mg/kg, 1 mg/kg and 10 mg/kg of body weight tamoxifen, respectively. On day 84, all rats were sacrified and tissue samples were obtained together with blood samples. The differences in serum TGF-β levels, histological grades of fibrosis and inflammation in the lung and liver tissues together with addional biochemical markers were calculated between the groups. Silicosis occurred in slc, tmx1 and tmx10 groups in 100%, 91.7% and 52.1%, respectively. Liver fibrosis did not occur. The highest mean lung fibrosis scores were obtained in slc group while the scores were lower in tmx1 group and the lowest in tmx10 within silica-exposed rats. Nevertheless, the inflammation scores were higher in tamoxifen-administered rats in a dose-dependent pattern. Silica inhalation did not result in liver fibrosis. Tamoxifen is found to prevent lung fibrosis and reduce serum TGFβ-1 levels while increasing lung inflammation (Tab. 3, Fig. 3, Ref. 27).

Serum transforming growth factor-beta1 levels may have predictive and prognostic roles in patients with gastric cancer.

Transforming growth factor-beta1 (TGF-beta1) plays an important role in the pathogenesis of multiple malignancies, and also, its expression strongly affects the outcomes of cancer patients. The objective of this study was to determine the clinical significance of the serum levels of TGF-beta1 in gastric cancer patients. A total of 63 patients with a pathologically confirmed diagnosis of gastric cancer were enrolled into this study. Serum TGF-beta1 concentrations were determined by the solid-phase sandwich ELISA method. Thirty healthy age- and sex-matched controls were included in the analysis. The median age at diagnosis was 62 years, range 28 to 82 years. There was no significant difference in baseline serum TGF-beta1 levels between gastric cancer patients and the healthy control group (p = 0.08). The known clinical variables including age of patient, gender, site of lesion, histology, histological grade, stage of disease, and serum levels of lactate dehydrogenase (LDH), CEA, and carbohydrate antigen (CA) 19.9 were not found to be correlated with serum TGF-beta1 concentrations (p > 0.05). However, the chemotherapy-responsive patients had higher serum TGF-beta1 levels compared with chemotherapy-unresponsive ones (median values 330.50 v 49.54 pg/mL, respectively, p = 0.01). Moreover, patients with elevated serum TGF-beta1 concentrations had significantly favorable overall survival compared with those with lower levels (median 71.1 v 39.9 weeks, respectively, p = 0.04). In conclusion, serum levels of TGF-beta1 may have predictive and prognostic roles in patients with gastric cancer.

CONCENTRATION OF THE SERUM TGF-BETA1 IN HEALTHY ADULT PEOPLE

Elevated serum Transforming growth factor-beta1 (TGF-beta1) levels have been linked to tissue fibrosis including chronic kidney disease. Objectives: (1) Investigate serum TGF-beta1 levels in healthy adult people and (2) Examined the relation between serum TGF-beta1 level and gender, age, body mass index (BMI). Method: A cross-sectional study. TGF-beta1 were quantified by ELISA. Results: Levels of serum TGF-beta1 in healthy people were 13,45 ± 7,17 ng/mL mL (0,59 - 33,10 ng/mL). There are no difference of serum TGF-beta1 levels between men and women, between the age groups (&lt;40 years, 40 to &lt; 60 years and ≥ 60 years), between BMI groups &lt; 23 and BMI group ≥ 23. Key words: TGF-beta1, healthy people

Biological perspectives of delayed fracture healing

Fracture healing is a complex biological process that requires interaction among a series of different cell types. Maintaining the appropriate temporal progression and spatial pattern is essential to achieve robust healing. We can temporally assess the biological phases via gene expression, protein analysis, histologically, or non-invasively using biomarkers as well as imaging techniques. However, determining what leads to normal versus abnormal healing is more challenging. Since the ultimate outcome of fracture healing is to restore the original functions of bone, assessment of fracture healing should include not only monitoring the restoration of structure and mechanical function, but also an evaluation of the restoration of normal bone biology. Currently few non-invasive measures of biological factors of healing exist; however, recent studies that have correlated non-invasive measures with fracture healing outcome in humans have shown that serum TGFbeta1 levels appear to be an indicator of healing versus non-healing. In the future, developing additional measures to assess biological healing will improve the reliability and permit us to assess stages of fracture healing. Additionally, new functional imaging technologies could prove useful for better understanding both normal fracture healing and predicting dysfunctional healing in human patients.

Differential Pattern of Cytokine Production by Depressed Medical Students; Evidence for Involvement of Cytokine Network in Pathology of Depression

Previous studies revealed that the immune responses of depressed patients can be affected by alteration of immune system factors; however, the immune genes mainly influenced are yet to be fully understood. Therefore, the main aim of present study was to identify serum levels of drastic inflammatory cytokines including IL-17A, IL-12, and IL-6 as well as anti-inflammatory cytokines, IL-10 and TGF-beta, amongst Iranian depressed medical students. Peripheral blood specimens were collected from 38 Iranian medical student patients with moderate and severe depression along with 43 healthy students as control subjects. The serum levels of IL-17A, IL-12, IL-6, IL-10, and TGF-beta were assessed using the ELISA technique. Our results showed that the serum IL-10 level was significantly (p = 0.011) decreased in depressed patients (2.8 +/- 0.41 pg/mL) compared to healthy controls (4.3 +/- 0.4 pg/mL). The results also revealed that serum levels of TGF-beta were significantly increased in severely (12.75 +/- 5.22) compared to moderately (5.3 +/- 0.7) depressed patients (p = 0.045). According to the results of the present study, the decreased IL-10 level in the depressed patients may be responsible for the induction of inflammation in Iranian depressed patients. Additionally, increased serum levels of TGF-beta in severely compared to moderately depressed patients may be related to normal immune responses against inflammation in severely depressed patients.

The rs1800471 Polymorphism of TGFB1 Gene, Serum TGF-Beta1 Level and Chronic Kidney Disease Progression.

The aim of the study was to investigate whether rs1800471 polymorphism in TGFB1 gene is associated with the development and progression of non-diabetic chronic kidney disease. Moreover, we examined the serum TGF-beta1 concentration and its association with that polymorphism and progression of the disease. We applied two different methodological approaches. Firstly, a family based study was carried out, comprised of 109 patients with non-diabetic chronic kidney disease and their 218 healthy parents, using the transmission/disequilibrium test. The rs1800471 polymorphism and serum TGF-beta1 level were determined in all subjects. Serum TGF-beta1 concentration was also measured in 40 healthy controls. Secondly, we performed a case-control orientated study to determine whether rs1800471 polymorphism and other factors influence the progression of renal impairment. We found no relationships between rs1800471 polymorphism allele transfer and the incidence or progression of non-diabetic chronic kidney disease. We found, however, that the serum TGF-beta1 was significantly higher in patients than in controls. In conclusion, rs1800471 polymorphism in TGFB1 gene does not have an impact on the development and progression of non-diabetic chronic kidney disease caused by primary glomerulopathy and chronic interstitial nephritis. The increased serum TGF-beta1 concentration in such patients suggests its role in the pathomechanism of the disease. Circulating TGF-beta1 level is determined in a multifactorial way, not by rs1800471 polymorphism in TGFB1 gene.

Intestinal Helminthic Infection Increases Serum Levels of IL-2 and Decreases Serum TGF-Beta Levels in Nigerian Asthmatic Patients

Background: Asthma is less common in countries outside the organization for economic cooperation and development (OECD). One suggested mechanism for this disparity is the early life exposure to helminthic infection in non-OECD countries due to predominant Th1 immune response, which down-regulates Th2 responses required for exacerbation of asthma. This report is the first in the literature to describe the effects of helminthic infection on immune responses in asthmatic children compared to non-asthmatic controls. Methods: We administered the International Study of Asthma and Allergies in Childhood (ISAAC) questionnaire to 1690 high school students in three rural communities in southwestern Nigeria. Based on questionnaire responses and medical examination, identified asthma cases were matched with controls. Stool samples were collected from all subjects and screened for intestinal helminthic infection. The serum of 12 asthmatics and 12 non-asthmatics (6 with intestinal helminthic infection and 6 without intestinal helminthic infection in each group) were assayed for interleukin (IL)-2, IL-4, IL-5, IL-6, IL-10, IL-12, IL-13, IL-17A, interferon-gamma (IFN-γ), tumor necrosis factor-alpha (TNF-α), granulocyte macrophage colo- ny-stimulating factor (GM-CSF), and transforming growth factor-beta (TGF-β). Results: The mean (±SD) serum levels of IL-2 significantly increased in asthma cases with intestinal helminthic infection compared with asthma cases without infection (41.5 ± 9.7 vs. 29.7 ± 10.3; p = 0.035), controls with intestinal helminthic infection compared with cases without infection (52 ± 4.7 vs. 29.7 ± 10.3; p < 0.001), and controls with intestinal helminthic infection compared to controls without infection (52 ± 4.7 vs. 34.2 ± 10.4; p = 0.003). Mean levels of TGF-β significantly increased in controls without infection compared with asthma cases with infection (1833 ± 93.1 vs. 633.3 ± 294.4; p < 0.001), controls without intestinal helminthic infection compared with asthma cases without infection (1833 ± 93.1 vs. 916.7 ± 204.1; p < 0.001), controls with intestinal helminthic infection compared to controls without infection (2366.7 ± 760.7 vs. 1833 ± 93.1; p < 0.001), and controls with intestinal helminthic infection compared with asthma cases without infection (2366.7 ± 760.7 vs.916.71 ± 204.1; p = 0.007). Conclusion: Intestinal helminthic infection independently increases IL-2 levels, while asthma decreases the level of TGF-β, which is further depressed by intestinal helminthic infection.

Abstract IA27: Immunomodulation of breast cancer

Abstract Breast cancer is immunogenic and there is significant evidence that as breast cancer develops, tumors elicit an adaptive immune response. T-cells infiltrate most breast cancers and in several studies, the presence of elevated intratumoral CD8+ T-cells or elevated CD8+ T-cells in conjunction with a limited T-regulatory cell infiltration is associated with a favorable prognosis. Moreover, patients with breast cancer have been shown to develop immunity against specific proteins expressed by their tumors. Recent studies demonstrate that the development of humoral immunity directed against tumor associated antigens can be detected prior to a breast cancer diagnosis indicating the ability of the immune system to act as a sensor for exposure to aberrantly expressed proteins. Cellular immunity, directed against breast cancer antigens and elicited by exposure to malignancy, is present even while the disease progresses. The endogenous breast cancer specific cellular immune response is often of a Type II phenotype eliciting primarily antibody immunity rather than cytotoxic T-cells. Furthermore, type II cytokines secreted by T-cells actively dampen the development of a CD8 T-cell response. Type I cytokines, such as interferon gamma or TNF-alpha, are needed to activate antigen presenting cells allowing the presentation of tumor specific antigens via cross-priming, the primary mechanism by which cancer is recognized by T-cells. Immune cells which secrete Type I cytokines are rarely detected or found only in limited numbers in the tumors of most breast cancer patients. Several therapeutic modalities are under development and designed to increase or stimulate Type I T-cells capable of homing to breast tumors. Active immunization, targeting specific breast cancer antigens, has been shown to directly modulate the breast cancer microenvironment by enhancing cross-priming resulting in the development of epitope spreading. The identification of developing immunity against multiple tumor antigens during the course of treatment has been associated with a survival benefit after vaccination targeting HER-2/neu (HER2). High levels of vaccine induced Type I HER2 specific T-cells have been shown to be inversely associated with serum TGF-beta levels in patients with advanced stage breast cancer. Significantly increasing the number of Type I T-cells targeting breast cancer, via strategies such as adoptive T-cell therapy, has been associated with a measurable clinical response in advanced stage breast cancer. Ex vivo expansion of HER2 specific Th1 cells, after vaccine priming, and infusion of those cells into patients resulted in a 40% clinical response rate in patients with Stage IV treatment-refractory breast cancer. After infusion of Type I HER2 positive T-cells, responding patients developed multiple clonal CD4+ and CD8+ T-cell populations in their peripheral blood, which may be an indication of epitope spreading. The level of HER2 specific T-cells achieved in vivo and the development of a diversity of clonal T-cells was significantly associated with clinical response. Although breast cancer specific Type I T-cells may not be found in the malignancy at the time of diagnosis, such cells can be induced. The ability to circumvent the immune suppressive microenvironment opens the door for combination immune based therapies utilizing checkpoint blocking antibodies or specific chemotherapies shown to modulate immune suppression to further enhance the number and function of tumor specific Type I T-cells. Citation Format: Mary L. Disis. Immunomodulation of breast cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research: Genetics, Biology, and Clinical Applications; Oct 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2013;11(10 Suppl):Abstract nr IA27.

AB0094 Association of TGF-beta1 - 509c/t polymorphism and TGF-beta1 serum levels with systemic lupus erythematosus

BackgroundRecent evidences suggest a role of transforming growth factor-beta1 (TGF-beta1) in preventing autoimmune diseases, such as systemic lupus erythematosus (SLE).ObjectivesThe aim of this study was to investigate the relationship of...

Increased circulating Th17 cells and elevated serum levels of TGF-beta and IL-21 involved in human non-segmental vitiligo development (P3141)

Abstract Although it is widely believed that non-segmental vitiligo (NSV) results from the autoimmune destruction of melanocytes, the detailed immune mechanisms remain poorly understood. Th17 cells, a subset of CD4+ helper T cells, have been identified to be implicated in a variety of human autoimmune diseases. To comprehensively evaluate the role of Th17 cells and the pathways driving these T cell differentiations in NSV, we had compared the frequencies of peripheral blood Th17 cells and other IL-17 producing T cells by flow cytometry between 42 active NSV patients with 45 race-, gender- and age-matched healthy control subjects. Serum levels of IL-17A and Th17 cell differentiation related cytokines including TGF-beta1, IL-6, IL-23, IL-22 and IL-21 were detected by ELISA. Our results showed the increased circulating Th17 cell frequencies and elevated serum IL-17A, TGF-beta1 and IL-21 levels in NSV patients. Further more, the increased Th17 cell frequencies are positively correlated with serum TGF-beta1 levels and the body surface area (BSA) in NSV patients. These results indicate the involvement of Th17 cells in the development and progression of NSV, and more importantly, our data highly suggest that elevated serum TGF-beta and IL-21 could contribute to enhanced Th17 cell differentiation in NSV.

PP028. Serum cytokine profile in relation to the clinical features and laboratory parameters in women with preeclampsia

Preeclampsia is characterized by an excessive maternal systemic inflammatory response. To determine circulating levels of cytokines, chemokines and adhesion molecules in normal pregnancy and preeclampsia, and to investigate their relationship to the clinical features and laboratory parameters of the patients. Serum levels of IL-1beta, IL-1ra, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p40, IL-12p70, IL-18, IFN-gamma, TNF-alpha, TGF-beta1, IP-10, MCP-1, ICAM-1 and VCAM-1 were measured in 60 preeclamptic, 60 healthy pregnant and 59 healthy non-pregnant women. In addition to a shift towards Th1-type immunity (increased IL-2/IL-4 and IFN-gamma/IL-4 ratios), levels of the pro-inflammatory cytokines IL-6 and TNF-alpha, the chemokines IL-8, IP-10 and MCP-1, as well as the adhesion molecules ICAM-1 and VCAM-1, were raised in preeclampsia, resulting in an overall pro-inflammatory systemic environment. Increased IP-10, MCP-1, ICAM-1 and VCAM-1 concentrations of preeclamptic patients showed significant correlations with blood pressure values, renal and liver function parameters, as well as with CRP, malondialdehyde, von Willebrand factor antigen and fibronectin levels. Elevated amounts of pro-inflammatory cytokines, chemokines and adhesion molecules in the maternal circulation might play a central role in the excessive systemic inflammatory response, as well as in the generalized endothelial dysfunction characteristics of preeclampsia.