Serum Levels Of Growth Factors Research Articles

Elevation of serum apelin-13 associated with proliferative diabetic retinopathy in type 2 diabetic patients.

To compare apelin-13, a ligand of G-protein-coupled receptor which has been shown to be involved in retinal angiogenesis, and vascular endothelial growth factor (VEGF) serum levels in type 2 diabetes mellitus (T2DM) with or without retinopathy, and to investigate the relationship between the serum concentration of apelin-13 and diabetes retinopathy. Sixty-nine patients with T2DM were enrolled. Of the 69 patients, 16 had proliferative diabetic retinopathy (PDR group), 23 had non-PDR (NPDR group) and 30 had no retinopathy (T2DM group). Subjects' information, including demographics, medical history, and use of medications were recorded. Their serum samples were collected for measuring the levels of C-reactive protein (CRP), serum lipid and glycosylated hemoglobin. Apelin-13 and VEGF serum levels were measured by enzyme-linked immunosorbent assay. Kruskal-Wallis test and one-way ANOVA were used to compare the differences among these groups. Chi-square test was used to assess categorical variables. Correlations between variables were investigated by Spearman rho correlation test and stepwise regression analysis. All statistical analyses were performed through SPSS 17.0 software. Sex, age, body mass index (BMI), blood pressure, CRP, hemoglobin A1c (HbA1c) have no significantly difference in the three groups. Serum level of apelin-13 was significantly elevated in PDR group as compared with T2DM group (P=0.041). Differences of VEGF serum concentration in the three groups were statistically significant (P=0.007, P=0.007 and P<0.001, respectively). Spearman rho correlation test showed that serum apelin-13 was positively correlated with BMI, serum triglycerides, VEGF, but not with age, duration of diabetes, blood pressure, CRP, HbA1c and total-cholesterol. Stepwise regression analysis showed that BMI also significantly associated with serum apelin-13 (P=0.002), while VEGF and serum triglycerides were irrelevant. This study elucidated a positive association of apelin-13 serum level with PDR, but not with VEGF. Apelin-13 may influence the promotion of PDR but unrelated with VEGF.

Genetic variants of EGF and VEGF predict prognosis of patients with advanced esophageal squamous cell carcinoma.

PurposeTo investigate the association between genetic polymorphisms of growth factor-related genes and prognosis in patients with advanced esophageal squamous cell carcinoma (ESCC).Patients and MethodsA total of 334 ESCC patients with advanced tumor stages (stages IIB, III and IV) were enrolled in the study. The genotypes of 14 candidate single nucleotide polymorphisms (SNPs) involved in growth factor-related functions were analyzed using iPLEX Gold technology from the genomic DNA of peripheral leukocytes, and were correlated with the clinical outcome of patients. Serum levels of growth factors were examined by enzyme-linked immunosorbent assay (ELISA).ResultsThe genetic polymorphisms of EGF:rs4444903, EGF:rs2237051 and VEGF:rs2010963 showed significant associations with overall survival (OS) of advanced ESCC patients (A/A+ A/G vs. GG, [HR = 0.77, 95% CI = 0.60–0.99, P = 0.039 for rs4444903; A/G+ G/G vs. A/A, [HR = 0.74, 95% CI = 0.58–0.95, P = 0.019 for rs2237051; G/G+G/C vs. C/C, [HR] inves = 0.69, 95% CI = 0.50–0.95, P = 0.023 for rs2010963). EGFR:rs2227983 and 3 SNPs of PIK3CA also showed borderline significant correlation with OS of advanced ESCC patients (P = 0.058 for rs2227983; P = 0.069, 0.091 and 0.067 for rs6443624, rs7651265 and rs7621329 of PIK3CA respectively). According to cumulative effect analysis of multiple SNPs, patients carrying 4 unfavorable genotypes exhibited more than a 3-fold increased risk of mortality. Finally, both EGF and VEGF expression levels significantly associated with patient mortality.ConclusionThe genetic variants and expression levels of EGF and VEGF can serve as prognostic predictors in patients with advanced ESCC, and thus provide more information for optimizing personalized therapies for patients with ESCC.

Changes in Serum Growth Factors in Stroke Rehabilitation Patients and Their Relation to Hemiparesis Improvement

Predicting recovery from hemiparesis after stroke is important for rehabilitation. A few recent studies reported that the levels of some growth factors shortly after stroke were positively correlated with the clinical outcomes during the chronic phase. The aim of this study was to examine the relationships between the serum levels of growth factors (vascular endothelial growth factor [VEGF], insulin-like growth factor-I [IGF-I], and hepatocyte growth factor [HGF]) and improvement in hemiparesis in stroke patients who received rehabilitation in a postacute rehabilitation hospital. Subjects were 32 stroke patients (cerebral infarction: 21 and intracerebral hemorrhage [ICH]: 11). We measured serum levels of VEGF, IGF-I, and HGF and 5 items of the Stroke Impairment Assessment Set (SIAS) for hemiparesis on admission and at discharge. Age-matched healthy subjects (n=15) served as controls. Serum levels of VEGF and HGF in cerebral infarct patients on admission were higher than those in control subjects, and the serum levels of IGF-I in stroke patients were lower than those in controls. The level of HGF in ICH patients on admission was negatively correlated with gains in SIAS, and higher outliers in HGF concentration were correlated with lower gains in SIAS. Focusing on the extremely high levels of these factors may be a predictor of the low recovery from hemiparesis after stroke.

Placental growth factor, soluble fms-like tyrosine kinase 1 and progesterone as diagnostic biomarkers for ectopic pregnancy and missed abortion

ObjectiveThe aim of this study is to investigate if progesterone, placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFlt1) serum levels are useful markers to differentiate between ectopic pregnancy (EP), missed abortion (MA) and viable intrauterine implantation pregnancy (IUP). MethodsWe designed a retrospective case–control study which included 100 pregnant women (50 EP and 50 MA) at 6–8weeks of gestation with βhCG serum levels between 800 and 3500UI/L and a viable IUP group. Progesterone, PlGF and sFlt-1 levels were measured with an electrochemiluminescence assay (Roche Diagnostics®, Manheim, Alemania). A non parametric test was used to compare the markers in the different groups and we used receiver operating characteristic (ROC) curve analysis to calculate the area under the curve (AUC). ResultsWhen we compared the EP group with the MA group, we didn't find significant differences for PlGF (15.1[13.2–17.4]/16.7[12.8–18.7] pg/mL) (p=0.275). We only obtained significant differences for progesterone (9.1[3.1–16.8]/2.6[1.3–6.1] ng/mL) (p<0.001) and sFlt-1 (84[65–96]/126[94–256] pg/mL) (p<0.001).The AUC for progesterone was 0.756 and the cutoff point with better sensitivity and lower false positive rate was 6ng/mL (sensitivity=60%, specificity=72.7%). The AUC for sFlt-1 was 0.842 and the cutoff point was 93pg/mL (sensitivity=84.5%, specificity=86.3%). The combination of both markers allowed us to increase the AUC to 0.910. ConclusionsIn conclusion, the present study suggests that sFlt-1 could be a useful marker to differentiate between an EP or a MA when βhCG levels are similar in both groups. The combination of sFlt-1 with progesterone helps to increase the diagnostic performance.

Dynamics of Chemokine, Cytokine, and Growth Factor Serum Levels in BRAF-Mutant Melanoma Patients during BRAF Inhibitor Treatment

The purpose of this study is to profile the changes in the serum levels of a range of chemokines, cytokines, and growth and angiogenic factors in MAPK inhibitor-treated metastatic melanoma patients and to correlate these changes with clinical outcome and changes in melanoma tissue biopsies taken from the same patients. Forty-two chemokine, cytokine, angiogenic, and growth factors were measured in the sera of 20 BRAF inhibitor-treated and four combination BRAF and MEK inhibitor-treated metastatic melanoma patients using a multiplex chemokine assay. The changes were correlated with Ki-67 and CD8(+) tumor-infiltrating lymphocytes in the tumor biopsies taken at the same time points, as well as clinical outcome, including response rate, progression-free survival, and overall survival. Serum levels of IFN-γ, CCL4, and TNF-α were significantly increased, whereas CXCL8 significantly decreased from pretreatment (PRE) to early during treatment (EDT) serum samples. The decrease in serum CXCL8 levels from PRE to EDT significantly correlated with decreases in markers of melanoma proliferation (Ki-67) and increases in cytotoxic tumor-infiltrating T cells in corresponding tumor biopsies. In addition, a greater fold reduction in CXCL8 serum levels from PRE to EDT serum samples was associated with decreased overall survival. These results suggest that BRAF inhibition causes decreased CXCL8 secretion from melanoma cells and induce an immune response against the tumor associated with increased IFN-γ, CCL4, and TNF-α. Further studies are needed to determine if CXCL8 is predictive of response and to confirm the functions of these chemokine and cytokine in BRAF-mutant melanoma under BRAF inhibition.

Insulin-like growth factors (IGF), IGF-binding proteins (IGFBP), and vascular endothelial growth factor (VEGF) in blood serum of patients with colorectal cancer.

Serum levels of insulin-like growth factors (IGF-1 and IGF-2), IGF-binding proteins (IGFBP-1, IGFBP-2, and IGFBP-3) and vascular endothelial growth factor (VEGF) were measured by standard ELISA technique in 95 primary colorectal cancer patients and 48 healthy individuals. Significant increase in serum levels of IGF-1, IGFBP-2, and VEGF and decrease in IGFBP-3 level were demonstrated in patients in comparison with the control group; in male patients, serum level of IGF-2 was also increased. Sensitivity of IGF-1 as the prospective diagnostic marker of colorectal cancer was 80% and specificity was 75% at the threshold level of 140 ng/ml. Serum levels of IGF-1 significantly decreased with age in both patients and healthy donors, but in patients, this correlation was much weaker. These parameters did not correlate with the main clinical and morphological indices, such as dissemination, localization, and histological structure of colorectal cancer.

N-acetylglucosaminidase, myeloperoxidase and vascular endothelial growth factor serum levels in breast cancer patients

Inflammatory cells surround breast carcinomas and may act promoting tumor development or stimulating anti-tumor immunity. N-acetylglucosaminidase (NAG) has been employed to detect macrophage accumulation/activation. Myeloperoxidase (MPO) is considered a marker for neutrophils activity/accumulation. Vascular Endothelial Growth Factor (VEGF) is as strong pro-angiogenic cytokine. The aim of this study was to measure the systemic inflammatory response by measuring serum levels of NAG, MPO and VEGF in women diagnosed with breast cancer and associate this response to the peritumoral inflammatory infiltrate and to prognostic factors. Serum samples obtained from women with no evidence of disease (n=31) and with breast cancer (n=68) were analyzed for the activities of NAG, MPO and VEGF by enzymatic assay. Serum levels of NAG and VEGF were higher in healthy volunteers (P<0.0001) and serum levels of MPO were higher in patients with breast cancer (P=0.002). Serum levels of NAG were positively correlated to serum levels of MPO and VEGF (P<0.0001 and P=0.0012, respectively) and MPO and VEGF serum levels had also a positive correlation (P=0.0018). The inflammatory infiltrate was not associated to serum levels of the inflammatory markers, and higher levels of MPO were associated to lymphovascular invasion negativity (P=0.0175).

Serial Changes of Serum Growth Factor Levels and Liver Regeneration after Partial Hepatectomy in Healthy Humans

This study aimed to investigate the associations of the serial changes of serum levels of various growth factors with liver regeneration after hepatectomy in healthy liver donors. Sixteen healthy liver donors who underwent conventional liver resection were included. Serum levels of various growth factors before hepatectomy and on postoperative day (POD) 1, 3, 5 and 7 were measured. Liver volume data calculated by multi-detector computed tomography using workstation. The ratio of remnant liver volume on POD 0 to liver volume before the operation was 51% ± 20%. The ratio of liver volume on POD 14 to liver volume on POD 0 were inversely correlated with remnant liver volume on POD 0 (r = −0.91). The ratio of liver volume on POD 14 to liver volume on POD 0 were significantly correlated with serum hepatocyte growth factor (HGF) levels on POD 1 (r = 0.54), serum leptin levels on POD 1 (r = 0.54), and serum macrophage colony-stimulating factor (M-CSF) levels on POD 5 (r = 0.76) and POD 7 (r = 0.80). These results suggest that early-phase elevation of serum levels of HGF, leptin and M-CSF may be associated with the acceleration of liver regeneration after hepatectomy in humans.

Diagnostic value of vascular endothelial growth factor determination in chronic pyelonephritis in children

Aim. This paper is devoted to the evaluation of clinical and diagnostic value of vascular endothelial growth factor detection in chronic pyelonephritis in children. Methods. The study included 62 patients with different compensation degrees of the disease. Patients were divided into 2 groups - subcompensation (37 patients), and decompensation (25 patients). Renal function was assessed by glomerular filtration rate. Vascular endothelial growth factor concentration was determined by the enzyme-linked immunosorbent assay. To assess the renal vasculature, triplex ultrasonography using pulsed Doppler was performed. The endothelial dysfunction was examined by postocclusion test with reactive hyperemia. Results. Vascular endothelial growth factor level had been significantly increasing in patients according to the severity of the disease. The vascular endothelial growth factor concentration exceeded 600 pg/ml all patients who has later developed chronic renal failure. The sensitivity of this indicator at the abovementioned critical point was assessed as 80%. The change of resistance index reflected renal vascularization disorders. The endothelial dysfunction in postocclusion test was also revealed in patients with pyelonephritis. The vascular endothelial growth factor level highly correlated with the glomerular filtration rate and resistance index. Conclusion. Detecting the vascular endothelial growth factor serum level is one of the tools for endothelial dysfunction laboratory monitoring and renal function assessment in in children with chronic pyelonephritis.

Relationship between VEGFA polymorphisms and serum VEGF protein levels and recurrent spontaneous miscarriage

Is recurrent spontaneous miscarriage (RSM) associated with changes in vascular endothelial growth factor (VEGF) serum levels, and with polymorphisms in the VEGFA gene? Reduced serum VEGF levels, and VEGFA -460T/C (rs833061), 398G/A (rs833068), -583T/C (rs3025020) variants, were associated with RSM. Reduced expression of VEGF has been linked with spontaneous miscarriage, likely due to defective fetal and placental angiogenesis. Since VEGF production is in part inherited, VEGFA polymorphisms associated with altered VEGF secretion have been investigated for their association with RSM, often with variable conclusions. A retrospective case-control study, which was conducted between January 2011 and April 15, 2012. Subjects comprised 296 women with RSM (mean age: 31.6 ± 5.4 year), and 305 age-matched (mean age: 31.6 ± 4.9 year) control Arab women, who had attended outpatient obstetrics and gynecology clinics in two teaching hospitals in Bahrain. VEGFA -2578C/A (rs699947), -460T/C (rs833061), -1154G/A (rs15703060), -634G/C (rs2010963), 398G/A (rs833068), 497G/A (rs833070), -583T/C (rs3025020) and 936C/T (rs3025039) genotyping was done by real-time PCR, with defined clusters; VEGF serum levels were measured by ELISA. Higher minor allele frequency (MAF) and genotype distribution of -460T/C [corrected P (Pc) = 0.003], 398G/A (Pc = 0.016) and -583T/C (Pc < 0.001) single nucleotide polymorphisms (SNPs) were seen in RSM cases than control women. Increased RSM risk was seen with homozygous -460T/C and 398G/A SNPs and with heterozygous -583T/C, which had a stronger effect when homozygous. Serum VEGF levels were significantly reduced in RSM cases compared with control women (P = 0.016), and correlated with -460T/C, 398G/A and -583T/C genotypes. Haploview analysis revealed heterogeneity in linkage disequilibrium between VEGFA variants, and two blocks were identified: Block 1 comprising -2578C/A, -460T/C and -1154G/A, while Block 2 contained -634G/C, 398G/A, 497G/A, -583T/C and 936C/T. Both negatively and positively RSM-associated 3-locus (Block 1) and 5-locus (Block 2) VEGFA haplotypes were identified, after controlling for a number of covariates. The study was retrospective and can only demonstrate association and not a cause-effect relationship. Furthermore, it was limited to Bahraini Arabs,thereby necessitating parallel studies on other ethnic groups. Reduced VEGF secretion, and specific VEGFA variants may contribute to the pathogenesis of RSM. However, the association of VEGFA SNPs with RSM appears to be independent of their association with altered VEGF serum levels. The differential association of VEGFA variants with RSM is in line with previous findings on the contribution of ethnicity/racial background to genetic association studies.

Determination of Tear and Serum Inflammatory Cytokines in Patients with Rosacea Using Multiplex Bead Technology

Purpose: To compare serum and tear inflammatory and anti-inflammatory cytokine levels of rosacea patients with the healthy controls and evaluate the correlation of tear cytokine levels with tear function parameters.Methods: Tear and serum interleukin (IL)-1α, IL-6, IL-8, IL-10, monocyte chemotactic protein-1 (MCP-1), macrophage inflammatory protein-1α (MIP-1α), epidermal growth factor (EGF), and vascular endothelial growth factor (VEGF) levels were measured using multiplex bead (Luminex) technology in 12 rosacea patients without ocular involvement (group 1), 20 rosacea patients with ocular involvement (group 2), and 22 healthy subjects (group 3). The correlation of the cytokines with tear function parameters was analyzed using Spearman correlation test.Results: Tear IL-10 and VEGF levels were significantly lower in group 1 (median: 35.78 pg/mL and 427.29, respectively) and group 2 (median: 26.25 pg/mL and 348.31, respectively) than in group 3 (median: 75.96 pg/mL and 480.12, respectively) (p < 0.05). Mean serum IL-8 level was significantly lower in group 2 (median = 0) compared to group 3 (median = 3.98) (p = 0.02). Tear breakup time was found to be positively correlated with IL-10 (r = 0.46, p = 0.013) and inversely correlated with MCP-1 (r = −0.52, p = 0.004).Conclusions: Tear and serum levels of cytokines and growth factors measured with Luminex technology showed a large variation in rosacea and healthy subjects. Decreased levels of tear IL-10, an anti-inflammatory cytokine, may lead to an inflammatory ocular surface environment, exacerbate ocular surface inflammation, and deteriorate tear function tests. A bigger sample size, including rosacea patients with corneal involvement, is needed to confirm the role of cytokines in the pathogenesis of rosacea-associated ocular inflammation.

FRI0474 Association of serum vascular endothelial growth factor and angiopoietin-2 levels with clinical manifestations and nailfold capillaroscopic changes in patients with raynaud’s phenomenon

BackgroundRaynaud’s phenomenon (RP) is an exaggerated vasospastic response to cold and emotion, which can be primary (idiopathic) or secondary to a number of different conditions, including rheumatological diseases. Functional and/or...

Increased Nerve Growth Factor Serum Levels in Top Athletes

The nerve growth factor (NGF) is the main neurotrophin, which, besides being an important growth factor for nerves, plays an important role as a mediator of inflammation. Nerve growth factor has been shown to increase in relation to stress stimuli and in allergic diseases in humans as well as after physical exercise in animal models. This study aims at evaluating NGF serum levels in top athletes, a population sample in which allergic and neuro-immune diseases are reported with a significantly increased prevalence. Observational, cross-sectional, multicenter study. Institutional, tertiary care. Ninety-six Italian pre-Olympic athletes (44 allergic and 52 nonallergic) and 49 matched controls selected within the Italian National Olympic delegation (n = 435). Nerve growth factor serum levels determined through an enzyme-linked immunosorbent assay. Parametric or nonparametric tests were used for comparing NGF serum levels among different study groups depending on value distributions. Nerve growth factor serum levels were significantly higher in athletes than in controls independently from the presence of allergy. Nerve growth factor mean values were 368.3 ± 776.3 pg/mL in the sample of athletes and 174.1 ± 483.7 pg/mL in the control group (P < 0.001). This is the first study showing that intense and prolonged physical exercise is associated with an increase of NGF serum levels in athletes. Whether the increased NGF production might be linked to the prevalent Th2 response observed in allergic diseases and after physical exercise and whether it might be related to the patophysiology of neuro-immune disorders as such amyotrophic lateral sclerosis, reported with a higher prevalence in athletes, should deserve further investigations.

Inflammatory responses in mice exposed to various doses of TiO2 nanoparticles (P5084)

Abstract Application of TiO2 nanoparticles has increased tremendously in recent years. Consumer products containing a significant amount of these nanoparticles range from paints, plastics, papers, tooth paste, food colorants, cosmetics, sunscreens to medicine pills and beverages. Ti is generally considered biologically inert, but Ti-nanoparticles were observed to cause significant toxicity including DNA damage in recent studies. In this study, C57-BL6/J mice were administered intraperitoneally TiO2 rutile crystals (30-50nm) at the rate of 333 and 1332 mg/kg body weight. Serum levels of proinflammatory cytokines, chemokines and angiogenesis growth factors (IL-1a, IL-1b, IL-6, TNFα, IFN-γ, IL-2, Rantes, G-CSF, GMCSF, MCP-1 VEGF, EGF, IGF-1and Leptin) were determined. The majority of cytokines or growth factors in exposed mice were not significantly different than in vehicle control, but VEGF level was, approximately, 50% reduced in mice exposed to the high dose, relative to control. Mice belonging to this group also demonstrated a significant decrease in the body weight, and an increase in their liver weight. The study on transcriptional activation of the related cytokine genes is in progress.

Role of irbesartan in protection against pulmonary toxicity induced by bleomycin in rats

Bleomycin (BLM) is an anti-neoplastic, antibiotic drug that produces dose and time dependant pulmonary fibrosis. Recent studies reported some mechanisms of irbesartan in attenuating lung and skin fibrosis in mice. Therefore, the current study was conducted to examine the effect of irbesartan focusing on angiogenesis and plasminogen activator inhibitor-1(PAI-1) expression as possible mechanisms in protection against BLM-induced lung fibrosis in rats. The effect of irbesartan on the serum and tissue levels of growth factors and mRNA expression of PAI-1 were studied. Oral administration of irbesartan (10, 20 and 40 mg/kg/day) to rats for 21 days, starting from the first day of bleomycin injection (10 mg/kg/day/10 days, i.p.) attenuated the severity of BLM-induced pulmonary fibrosis, enhanced the histopathological features of the lungs, reduced serum transforming growth factor-β1 (TGF-β1) compared to BLM group without any improvement in the survival percentage. In addition, immunohistochemical staining revealed lower expression of angiotensin-II type 1 receptor (AT1) and α-smooth muscle actin (α-SMA) in lung tissues after treatment with irbesartan (20 and 40mg/kg) compared to BLM-treated group. Importantly, irbesartan (10, 20 and 40mg/kg) suppressed the expression of PAI-1 gene in lung tissues while increased both serum level and immunohistochemical staining of vascular endothelial growth factor (VEGF) compared to BLM-treated group. So that, the present study concluded that the ameliorating effect of irbesartan against BLM-induced pulmonary fibrosis in rats involves increasing angiogenesis, reduction of PAI-1 gene expression and modulation of growth factors.

Abstract 3991: The genetic variants of growth factor-related genes associate with the prognosis of patients with advanced esophageal squamous cell carcinoma .

Abstract PURPOSE: To investigate the association between the genetic polymorphisms of growth factor-related genes and the prognosis of patients with advanced esophageal squamous cell carcinoma (ESCC). PATIENTS AND METHODS: A total of 336 ESCC patients with advanced tumor stages (stage 2b+3+4) were enrolled in the study. These subjects were randomly assigned to a training set (n=95) and a replication set (n=241).The genotypes of candidate single nucleotide polymorphism (SNPs) were analyzed using iPLEX Gold technology from the genomic DNA of peripheral leukocytes, and were correlated with the clinical outcome of patients in training, replication, and combined groups. Serum levels of growth factors were examined by enzyme-link immunosorbent assay (ELISA). RESULTS: In training group, the genotyping of 16 candidate SNPs was successfully performed. Seven SNPs, rs4444903, rs2010963, rs2272037, rs713646, rs3025039, rs3025040, rs2016347, significant or borderline significant correlated with mortality or disease progression and were further evaluated in an independent replication group. In replication group, GG of rs4444903 at EGF gene and CC of rs2010903 at VEGF showed unfavorable trend for the mortality (P=0.286 for rs4444903; P=0.215 for rs2010963). These 2 SNPs showed significant effects on overall survival of the patients in combing group (GG vs. AA, adjusted [HR] = 1.29, 95% CI=1.01-1.66, P=0.045 for rs4444903; CC vs. GG, adjusted [HR] = 1.53, 95% CI=1.07-2.18, P=0.020 for rs2010963). Meanwhile, GA genotype of rs2272037at IGF1R gene also show unfavorable trend among all subjects (GA vs. GG, [HR] = 1.24, 95% CI=0.96-1.60, P=0.108). Combing these 3 SNPs, patients with 3 unfavorable genotypes showed 2-fold risk for mortality compared to patients without any of the unfavorable genotypes (accumulated unfavorable genotypes 3 vs. 0, [HR] = 2.00, 95% CI=1.10-3.64, P=0.023). Additionally, GG genotype of EGF_rs4444903 correlated with increase serum levels of EGF in patients with advanced ESCC. Finally, both EGF and VEGF expression levels significant associated with the mortality of patients. CONCLUSION: The genetic variants in growth factor-related can serve as prognostic predictors of the patients with advanced ESCC, and thus provide more information for the personalized therapies for the patients with ESCC. Citation Format: Jang-Ming Lee, Pei-Wen Yang, Ya-Chuan Huang, Min-Shu Hsieh, Ching-Yueh Hsieh, Pei-Ming Huang, Hsao-Hsun Hsu, Jin-Shing Chen, Shuenn-Wen Kuo. The genetic variants of growth factor-related genes associate with the prognosis of patients with advanced esophageal squamous cell carcinoma . [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3991. doi:10.1158/1538-7445.AM2013-3991

Changes in Serum Adhesion Molecules, Chemokines, Cytokines, and Tissue Remodeling Factors in Euthyroid Women Without Thyroid Antibodies Who Are at Risk for Autoimmune Thyroid Disease: A Hypothesis on the Early Phases of the Endocrine Autoimmune Reaction

The target glands in spontaneous animal models of endocrine autoimmune disease show, prior to the autoimmune reaction, growth and connective tissue abnormalities, whereas the autoimmune reaction is initiated by an early accumulation of macrophages and dendritic cells in the target glands. The aim of the study was to test the hypothesis that serum factors related to these growth and connective tissue abnormalities and the early accumulation of immune cells, ie, tissue growth/remodeling factors, adhesion molecules, chemokines, and pro- and anti-inflammatory cytokines, are related to thyroid peroxidase autoantibodies (TPO-Abs) seroconversion in subjects at risk to develop autoimmune thyroid disease (AITD). A controlled study on 64 TPO-Ab-negative euthyroid female relatives with at least 1 first- or second-degree relative with documented autoimmune hyper- or hypothyroidism, 32 of whom did and 32 who did not seroconvert to TPO-Ab positivity in 5-year follow-up. The relatives were compared with 32 healthy controls. In all subjects we measured serum levels of chemokine (C-C motif) ligand (CCL)-2, CCL3, CCL4, soluble vascular cell adhesion molecule, soluble intercellular adhesion molecule-1, thrombospondin-1, vascular endothelial growth factor-A, angiopoietin 1 receptor-2, metalloproteinase-13, platelet-derived growth factor-BB, fibronectin, IL-1β, IL-6, TNF-α, IL-10, and growth differentiation factor-15 by multiplex (cytometric bead array) or a single commercial ELISA. Both seroconverting and nonseroconverting family members showed an up-regulation of fibronectin and a down-regulation of platelet-derived growth factor-BB and the adhesion and migration factors CCL2, CCL4, soluble vascular cell adhesion molecule-1, angiopoietin 1 receptor-2, and metalloproteinase-13. The seroconverters differed from the nonseroconverters by an up-regulation of the proinflammatory compounds Il-1β, IL-6, and CCL3. This study shows that euthyroid females within AITD families show a characteristic pattern of abnormalities in serum levels of tissue remodeling factors, growth factors, chemokines, (vascular) adhesion molecules, and cytokines prior to the occurrence of TPO-Abs in serum. The results provide proof of principle that preseroconversion stages and seroconversion to AITD might be predicted using serum analytes related to growth/connective tissue abnormalities and migration/accumulation abnormalities of macrophages and dendritic cells.

The suppression of hematopoiesis function in Balb/c mice induced by prolonged exposure of microcystin-LR

Microcystins (MCs) cause normocytic anemia in patients in a hemodialysis unit in Caruaru, Brazil in 1996, but the underlying mechanisms are still unclear. In the present study, Balb/c mice were intraperitoneally injected with microcystin-LR (MC-LR) at the doses of 0.5, 2 and 8μg/kg body weight (bw) every 48h for 30d. After the prolonged exposure of MC-LR, significant decreases of red blood cell count (RBC), hemoglobin (Hb) and hematocrit (Ht) were observed in 2 and 8μg/kg bw groups, but erythrocyte mean corpuscular volume (MCV) showed no significant changes. Significantly elevated micronucleus frequency was observed in bone marrow cells (BMCs) in all MC-LR treatments. The proliferation of BMCs significantly declined in both 2 and 8μg/kg bw groups. Serum levels of some hematopoietic growth factors significantly changed in 8μg/kg bw group, mainly including granulocyte-macrophage (GM-CSF), erythropoietin (EPO), interleukin-3 (IL-3) and TNF-α. The transcriptional levels of these 4 genes in BMCs were also significantly changed in 8μg/kg bw group. MC-LR exposure significantly increased the apoptosis rates in all MC-LR treatments. The present study indicates prolonged exposure of MC-LR induces normocytic anemia, and the disturbed hematopoietic growth factors and BMCs apoptosis are responsible for this normocytic anemia.

Decreased pool of mesenchymal stem cells is associated with altered chemokines serum levels in atrophic nonunion fractures

Nonunion fractures can cause severe dysfunction and are often difficult to treat mainly due to a poor understanding of their physiopathology. Although many aspects of impaired fracture healing have been extensively studied, little is known about the cellular and molecular mechanisms leading to atrophic nonunion. Therefore, the aim of the present study was to assess the pools and biological functions of bone marrow-derived mesenchymal stem cells (hMSCs) and circulating endothelial progenitor cells (EPCs) in atrophic nonunion patients compared to healthy subjects, and the systemic levels of growth factors involved in the recruitment, proliferation and differentiation of these cells. In nonunions, the pool of hMSCs was decreased and their proliferation delayed. However, once committed, hMSCs from nonunions were able to proliferate, differentiate into osteoblastic cells and mineralize in vitro as efficiently as hMSCs from healthy subjects. In parallel, we found altered serum levels of chemokines and growth factors involved in the chemotaxis and proliferation of hMSCs such as leptin, interleukin-6 (IL-6) and its soluble receptor, platelet-derived growth factor-BB (PDGF-BB), stem cell factor (SCF) and insulin-like growth factor-1 (IGF-1). Moreover, we showed that the number of EPCs and their regulating growth factors were not affected in nonunion patients. If nonunion is generally attributed to a vascular defect, our results also support a role for a systemic mesenchymal and osteogenic cell pool defect that might be related to alterations in systemic levels of factors implicated in their chemotaxis and proliferation.

Growth Factors Serum Levels in Coronary Artery Disease Patients Scheduled for Bypass Surgery: Perioperative Dynamics and Comparisons with Healthy Volunteers

Background. Vascular endothelial growth factors are important mediators for neovascularization of chronically ischemic adult heart, but their elevated values have also been connected with acute ischemia. Coronary artery bypass grafting (CABG) is associated with activation of inflammatory processes. We aimed to clarify whether the latter is also accompanied with acute changes in concentrations of vascular growth factors. Methods. Concentrations of growth factors VEGF and EGF, monocyte chemoattractant protein-1 (MCP-1), and a set of cytokines of 39 patients with stable coronary artery disease (CAD) were evaluated before and after CABG. Preoperative values were compared with data of healthy volunteers. Results. In comparison with CAD patients, healthy controls had significantly higher values of VEGF (15.5 (10.05–35.3) and 119.4 (55.7–136.9) pg/mL, resp.), EGF (1.70 (1.14–3.18) and 37.3 (27.1–51.9) pg/mL, resp.), and MCP-1 (111.6 (81.75–171.9) and 156.9 (134.7–241.3) pg/mL, resp.). MCP-1, but not others, demonstrated a significant rise throughout the postoperative period. Proinflammatory interleukin-6 was significantly higher and anti-inflammatory IL-4 and IL-10 lower in patients with CAD. Conclusions. Patients with stable CAD have lower serum levels of growth factors than healthy volunteers. MCP-1, but not VEGF and EGF, becomes elevated immediately after CABG. Inflammatory status of CAD patients was drifted towards proinflammatory state.