Serum Platelet-derived Growth factor-BB Research Articles

Bone-derived PDGF-BB drives brain vascular calcification in male mice.

Brain vascular calcification is a prevalent age-related condition often accompanying neurodegenerative and neuroinflammatory diseases. The pathogenesis of large-vessel calcifications in peripheral tissue is well studied, but microvascular calcification in the brain remains poorly understood. Here, we report that elevated platelet-derived growth factor BB (PDGF-BB) from bone preosteoclasts contributed to cerebrovascular calcification in male mice. Aged male mice had higher serum PDGF-BB levels and a higher incidence of brain calcification compared with young mice, mainly in the thalamus. Transgenic mice with preosteoclast-specific Pdgfb overexpression exhibited elevated serum PDGF-BB levels and recapitulated age-associated thalamic calcification. Conversely, mice with preosteoclast-specific Pdgfb deletion displayed diminished age-associated thalamic calcification. In an ex vivo cerebral microvascular culture system, PDGF-BB dose-dependently promoted vascular calcification. Analysis of osteogenic gene array and single-cell RNA-Seq (scRNA-Seq) revealed that PDGF-BB upregulated multiple osteogenic differentiation genes and the phosphate transporter Slc20a1 in cerebral microvessels. Mechanistically, PDGF-BB stimulated the phosphorylation of its receptor PDGFRβ (p-PDGFRβ) and ERK (p-ERK), leading to the activation of RUNX2. This activation, in turn, induced the transcription of osteoblast differentiation genes in PCs and upregulated Slc20a1 in astrocytes. Thus, bone-derived PDGF-BB induced brain vascular calcification by activating the p-PDGFRβ/p-ERK/RUNX2 signaling cascade in cerebrovascular cells.

Serum platelet-derived growth factor-BB levels as a potential biomarker in assessing the metabolic activity of lesions in alveolar echinococcosis patients

BackgroundAlveolar echinococcosis (AE) is a chronic disease caused by the larval stage of Echinococcus multilocularis. Assessing the metabolic activity of AE lesions is critical to evaluate disease progression and survey treatment options. There is an urgent need to identify more rapid, convenient, and non-invasive clinical detection methods to substitute the current techniques. Herein, we evaluated the viability of platelet-derived growth factor-BB (PDGF-BB) as a biomarker for detecting the metabolic activity of AE patients and their correlations with clinicopathological features of AE patients. MethodsSera were collected from 28 AE patients and a homogenous cohort of 28 healthy individuals. The concentration of serum PDGF-BB homodimers (sPDGF-BB) was assessed via an enzyme-linked immunosorbent assay (ELISA). Liver tissue samples were obtained from a consecutive series of 28 AE patients who underwent surgical resection. Thereafter, we determined the expression levels of local PDGF-BB and platelet-derived growth factor receptor-β (PDGFR-β) through immunohistochemistry (IHC). Correlations of PDGF-BB expression levels with clinicopathological features of AE patients were analyzed using SPSS. ResultsThe concentrations of sPDGF-BB were significantly lower in AE patients (p < 0.0001), particularly in High Metabolically Active AE patients (HMAE) patients (p < 0.05). The expression levels of PDGF-BB and its receptor were both significantly higher in close liver tissue (CLT) in AE patients (p < 0.0001). We also found that metabolically active AE and sPDGF-BB are significantly negatively correlated (r = -0.624, p = 0.0004). Beside, the local expression levels of PDGF-BB was positively correlated with metabolic activity, PNM stage, and lesion size. Notably, the sPDGF-BB levels were proposed as a potential biomarker for assessing metabolic activity of AE, with 81.0% sensitivity and 85.7% specificity (95% confidence interval, p = 0.003). ConclusionsSerum levels of PDGF-BB could be a simple, non-invasive, and quick biomarker for assessing the metabolic activity of lesions in AE patients.

The effect of the geometry of the proximal anastomosis, markers of apoptosis and cell proliferation on the long-term patency following reconstructive interventions on the femoropopliteal arterial segment

Aim. To study changes in the topography of the orifice of the deep femoral artery (DFA), markers of proliferation, and apoptosis in patients after open interventions on the femoropopliteal arterial segment.&#x0D; Methods. The study included 35 patients with atherosclerotic peripheral arterial disease (PAD), femoral-popliteal occlusion, stage IIBIII of the disease according to the classification of A.V. PokrovskyFontaine, who underwent open surgery. The average age of the patients was 694.6 years. These patients included 26 men. Patients were divided into two groups: group A included 18 patients who underwent femoral-popliteal prosthetics (distal End-To-End bypass anastomoses), group B included 17 patients with femoral-popliteal bypass surgery (distal End-To-Side bypass anastomoses). The groups were comparable in terms of age and disease severity (p 0.05). Determination of serum platelet-derived growth factor BB (PDGF BB) and soluble form Fas (sFas) levels was carried out immediately before the intervention, on the 1st, 7th days, and 1 month after the operation. Duplex scanning (DS) was performed on day 7, after 1 and 18 months. Statistica 10.0 software was used for statistical data processing. The significance of differences between unrelated samples was assessed using the Student's t-test. The correlations between variables were analyzed by using Pearson's method.&#x0D; Results. On 1st day, there was a decrease in soluble Fas in patients of group A compared with group B (0.41 ng/ml vs 0.78 ng/ml, p=0.01). On the 7th day, the levels of serum platelet-derived growth factor BB were increased in patients of group A compared with group B (35.2 ng/ml vs 23.2 ng/ml, p=0.00001). After 1 month, the level of serum platelet-derived growth factor BB in patients of group A remained elevated compared with those in patients of group B (22.8 ng/ml vs 14.4 ng/ml, p=0.0003).&#x0D; Conclusion. Femoropopliteal prosthetics leads to a change in branching angle of the deep femoral artery up to 7080%, accompanied by changing dynamics of apoptotic markers and cell proliferation, leading to an increase in the thickness of neointimal hyperplasia and the progression of atherosclerosis.

Skeleton-secreted PDGF-BB mediates arterial stiffening.

Evidence links osteoporosis and cardiovascular disease but the cellular and molecular mechanisms are unclear. Here we identify skeleton-secreted platelet-derived growth factor-BB (PDGF-BB) as a key mediator of arterial stiffening in response to aging and metabolic stress. Aged mice and those fed high-fat diet (HFD), relative to young mice and those fed normal chow food diet, respectively, had higher serum PDGF-BB and developed bone loss and arterial stiffening. Bone/bone marrow preosteoclasts in aged mice and HFD mice secrete an excessive amount of PDGF-BB, contributing to the elevated PDGF-BB in blood circulation. Conditioned medium prepared from preosteoclasts stimulated proliferation and migration of the vascular smooth muscle cells. Conditional transgenic mice, in which PDGF-BB is overexpressed in preosteoclasts, had 3-fold higher serum PDGF-BB concentration and developed simultaneous bone loss and arterial stiffening spontaneously at a young age. Conversely, in conditional knockout mice, in which PDGF-BB is deleted selectively in preosteoclasts, HFD did not affect serum PDGF-BB concentration; as a result, HFD-induced bone loss and arterial stiffening were attenuated. These studies confirm that preosteoclasts are a main source of excessive PDGF-BB in blood circulation during aging and metabolic stress and establish the role of skeleton-derived PDGF-BB as an important mediator of vascular stiffening.

Platelet-derived growth factor BB: A potential diagnostic blood biomarker for differentiating bipolar disorder from major depressive disorder

Bipolar disorder (BD) is frequently misdiagnosed as major depressive disorder (MDD) due to overlapping depressive symptoms. This study investigated whether serum platelet-derived growth factor BB (PDGF-BB) is a differential diagnostic biomarker for BD and MDD. An initial SOMAscan proteomics assay of 1311 proteins in small samples from patients with BD and MDD and healthy controls (HCs) suggested that serum levels of PDGF-BB differed between BD and MDD. We then conducted a two-step, exploratory, cross-sectional, case–control study at our institute and five sites that included a total of 549 participants (157 with BD, 144 with MDD, and 248 HCs). Clinical symptoms were assessed using the Hamilton Depression Rating Scale and the Young Mania Rating Scale. In the initial analysis at our institute, serum PDGF-BB levels in the MDD group (n = 36) were significantly lower than those in the BD (n = 39) and HC groups (n = 36). In the multicenter study, serum PDGF-BB levels in the MDD group were again significantly lower than those in the BD and HC groups, with no significant difference between the BD and HC groups. Treatment with sodium valproate was associated with significantly lower serum PDGF-BB levels in patients with BD. After controlling for confounding factors (sex, age, body mass index, clinical severity, and valproate medication), serum PDGF-BB levels were lower in the MDD group than in the BD group regardless of mood state. Our findings suggest that serum PDGF-BB may be a potential biomarker to differentiate BD and MDD.

GIT1 is critical for formation of the CD31hiEmcnhi vessel subtype in coupling osteogenesis with angiogenesis via modulating preosteoclasts secretion of PDGF-BB.

G protein-coupled receptor kinase 2 interacting protein-1 (GIT1) is a scaffold protein that plays a vital role in bone modeling and remodeling during osteogenesis coupled with angiogenesis. Recent studies have shown that a specialized subset of vascular endothelium strongly positive for CD31 and Endomucin (CD31hiEmcnhi) is coupled with anabolic bone formation. Based on our previous finding that GIT1 knockout (GIT1 KO) mice have impaired angiogenesis and bone formation, we hypothesized that GIT1 affects formation of the CD31hiEmcnhi vessel subtype. In the current study, GIT1 knockout (GIT1 KO) mice displayed a significant decrease in trabecular bone mass and CD31hiEmcnhi vessel number, compared to their wild-type counterparts. In the fracture healing mouse model, GIT1 KO mice contained a lower number of CD31hiEmcnhi vessels in fracture callus at days 7 and 14. However, no significant differences in the number of preosteoclasts in bone marrow, trabecular bone and callus in GIT1 KO mice were observed, compared with wild-type mice. Notably, concentrations of serum platelet-derived growth factor-BB(PDGF-BB) secreted by preosteoclasts associated with CD31hiEmcnhi vessel formation were lower in GIT1 KO mice. In addition, PDGF-BB-associated expression of phosphorylated extracellular signal-regulated kinase- 1/2 (ERK1/2) and specificity protein 1 (SP1) was significantly decreased in preosteoclasts of GIT1 KO mice. These results collectively suggest that GIT1 is a critical participant in formation of the CD31hiEmcnhi vessel subtype, highlighting a novel biologic function of this scaffold protein in preosteoclasts.

Serum cytokines, adipokines and ferritin for non-invasive assessment of liver fibrosis in chronic liver disease: a systematic review.

Chronic liver disease (CLD) is a major health problem worldwide. Non-alcoholic fatty liver disease (NAFLD), chronic hepatitis C (CHC), chronic hepatitis B (CHB), and alcoholic liver disease (ALD) are the most common etiologies of CLD. Liver biopsy is the gold standard for assessment of liver fibrosis, however, it is an invasive method. This review attempts to evaluate the usefulness of serum adiponectin, serum leptin, serum ferritin, serum transforming growth factor-β1 (TGF-β1), and serum platelet derived growth factor-BB (PDGF-BB) as non-invasive markers in the diagnosis of liver fibrosis/cirrhosis. A systematic search in MEDLINE, Web of Science, Scopus, and local databases was performed to identify articles published in English or Persian as of November 2017. Studies conducted among CLD patients, with biopsy proven fibrosis/cirrhosis, and providing sufficient details of patients' clinicopathological characteristics were included. In the 95 studies included, there were a total of 15,548 CLD patients. More than 83% of studies were carried out in Asia and Europe. The relationship between liver fibrosis/cirrhosis and serum levels of ferritin, adiponectin, leptin, TGF-β1, and PDGF-BB was assessed in 42, 33, 27, nine, and three studies, respectively. Serum levels of the markers, particularly ferritin, could successfully predict liver fibrosis/cirrhosis, however, these data might not be clinically replicated and further studies are needed.

Serum IP-10 is useful for identifying renal and overall disease activity in pediatric systemic lupus erythematosus.

Traditional serological biomarkers often fail to assess systemic lupus erythematosus (SLE) disease activity and discriminate lupus nephritis (LN). The aim of this study was to identify novel markers for evaluating renal and overall disease activity in Chinese patients with pediatric systemic lupus erythematosus (pSLE). The study included 46 patients with pSLE (35 girls, 11 boys; average age 13.3 ± 2.6years) and 31 matched healthy controls (22 girls, 9 boys; average age 12.3 ± 2.4years). The SLE Disease Activity Index (SLEDAI) and renal SLEDAI were used to assess disease activity. Nine different soluble mediators in plasma, including tumor necrosis factor alpha (TNF-α), platelet-derived growth factor-BB (PDGF-BB), interferon (IFN) gamma inducible protein 10 (IP-10), interleukin (IL)-1β, IFN-γ, IL-17A, IL-2, Fas and Fas ligand, were measured by Luminex assay and compared between patients with active and inactive pSLE as well as between patients with pSLE with active and inactive renal disease. Receiver operating characteristic curve analysis was used to measure the discrimination accuracy. Of the 46 patients with pSLE, 30 (65.2%) had LN. These patients had significantly elevated levels of serum TNF-α, PDGF-BB, IP-10 and Fas. The serum levels of IP-10 were also significantly higher in patients with active pSLE. We found that IP-10 was also more sensitive and specific than conventional laboratory parameters, including anti-double-stranded DNA and complement components C3 and C4, for distinguishing active lupus from quiescent lupus. The serum level of IP-10 was also significantly increased in children with pSLE with active renal disease relative to those with inactive renal disease. There was also a positive correlation between serum IP-10 levels and renal SLEDAI scores as well as with 24h urine protein. Serum IP-10 is useful for identifying renal and overall disease activity in children with pSLE.

Serum platelet-derived growth factor BB levels: a potential biomarker for the assessment of liver fibrosis in patients with chronic hepatitis B.

Few studies have investigated serum levels of platelet-derived growth factor (PDGF) in patients with chronic hepatitis B (CHB). The present study aimed to determine whether PDGF-BB could serve as a potential biomarker for the detection of liver fibrosis. From October 2013 to August 2015, 465 patients with CHB were enrolled prospectively in this study. All patients underwent liver biopsy and staging based on the Ishak system. The serum PDGF-BB level was measured quantitatively by ELISA. The serum PDGF-BB level was negatively correlated with fibrosis stage in all patients (p = 0.003, Spearman's rho=-0.16) and was significantly different between fibrosis stages. The areas under the receiver operating characteristics curves (AUROCs) for serum PDGF-BB level and PGT score (a combination of PDGF-BB, gamma-glutamyl transpeptidase, and platelet levels) were 0.667 and 0.831, respectively, for patients with significant fibrosis and normal alanine aminotransferase (ALT) levels. The AUROCs for aspartate aminotransferase-to-platelet ratio (APRI) and fibrosis index based on four factors (FIB-4) were 0.823 and 0.821, respectively. Importantly, a cut-off value of 1.05 and 1.43, respectively, resulted in a sensitivity of 0.95 and 0.52, a specificity of 0.29 and 0.95, a positive predictive value of 0.30 and 0.79, and a negative predictive value of 0.96 and 0.86. The rate of correct diagnosis was up to 88.4% when using cut-offs of 1.05 and 1.43 for the absence or presence of significant fibrosis, respectively. Serum PDGF-BB decreased remarkably as fibrosis progressed, and this could be used as a non-invasive biomarker for the assessment of fibrosis stage in patients with CHB.

Serum PDGF-BB, sFlt-1 and U-II in patients with preeclampsia

Objective To explore the clinical diagnostic value of joint detection of serum platelet-derived growth factor BB (PDGF-BB), soluble vascular endothelial growth factor receptor -1 (sFlt-1) and urotensinⅡ(U-Ⅱ) in preeclampsia disease. Methods The cases of obstetric patients suffering from preeclampsia in the Third People's Hospital of Liaocheng, Shandong Province between October 2012 and April 2014 were enrolled, including 96 cases of mild preeclampsia and 81 cases of severe preeclampsia.Totally 68 cases of normal pregnant women with similar age and gestational age were selected as control group. A case-control study was applied for the following investigations. The concentrations of serum PDGF-BB, sFlt-1 and U-Ⅱwere measured using ELISA. The diagnostic value of PDGF-BB, sFlt-1 and U-Ⅱalone or in combination for preeclampsia was analyzed and evaluated with receiver operating characteristic curve (ROC) and Logistic regression analysis. Results Serum concentrations of PDGF-BB, sFlt-1 and U-Ⅱin mild preeclampsia group were(80.45±21.87)ng/L, (23.03±6.67)μg/L and(4.54±1.02)ng/L, and those in severe preeclampsia group were(124.91±47.54)ng/L, (35.65±12.45)μg/L and(6.29±2.31)ng/L, while those in control group were(60.89±19.38)ng/L, (17.19±7.867)μg/L and(3.81±1.01)ng/L, respectively. The three parameters in mild preeclampsia group and severe preeclampsia group were significantly higher than those in control group (P<0.01; F value was 79.43, 79.28 and 50.72 respectively). In the same situation, these three indicators in severe preeclampsia group were significantly higher than those in mild group (P<0.01). Moreover, the AUC of serum PDGF-BB, sFlt-1 and U-Ⅱalone or in combination were 0.821, 0.786, 0.772 and 0.933, respectively. The differences between joint detection and three individual detections were statistically significant (P<0.05), as combined detection having a sensitivity of 95.7% and a specificity of 86.6%. Conclusion The combined detection of Serum PDGF-BB, sFlt-1 and U-Ⅱ had an important value in early assessment and treatment of preeclampsia.(Chin J Lab Med, 2015, 38: 528-531) Key words: Pre-eclampsia; Vascular endothelial growth factor receptor-1; Urotensins

Blood neutrophil to lymphocyte ratio as a predictor in patients with advanced hepatocellular carcinoma treated with hepatic arterial infusion chemotherapy.

Inflammation plays a critical role in cancer. The aim of the present study was to investigate the impact of neutrophil to lymphocyte ratio (NLR) on patients with advanced hepatocellular carcinoma (HCC) treated with hepatic arterial infusion chemotherapy (HAIC). We retrospectively evaluated 266 patients with advanced HCC treated with HAIC between March 2003 and December 2012. NLR was calculated from the differential leukocyte count by dividing the absolute neutrophil count by the absolute lymphocyte count. The cut-off level of NLR was set as the median value of 2.87 among all patients in this study. The objective response rate in the patients with low NLR was 37.6%, which was significantly better than that of the patients with high NLR (21.1%; P < 0.01). Multivariate analysis revealed that low NLR remained associated with the response to HAIC (P = 0.024). Median progression-free survival and median overall survival in patients with high NLR were 3.2 and 8.0 months, respectively, which were significantly shorter than that of the patients with low NLR (5.6 and 20.7 months; P < 0.01 and P < 0.01, respectively). High NLR was an independent unfavorable prognostic factor in multivariate analysis. The patient outcome was stratified more clearly by NLR calculated after HAIC added to calculations before HAIC. Serum platelet-derived growth factor-BB level was positively correlated with NLR. Results suggest that NLR is a useful predictor in patients with advanced HCC treated with HAIC. These findings may be useful in determining treatment strategies or in designing clinical chemotherapy trials in future.

PDGF-BB secreted by preosteoclasts induces angiogenesis during coupling with osteogenesis.

Osteogenesis during bone modeling and remodeling is coupled with angiogenesis. A recent study shows that the specific vessel subtype, strongly positive for CD31 and Endomucin (CD31hiEmcnhi), couples angiogenesis and osteogenesis. We found that preosteoclasts secrete platelet derived growth factor-BB (PDGF-BB), inducing CD31hiEmcnhi vessels during bone modeling and remodeling. Mice with depletion of PDGF-BB in tartrate-resistant acid phosphatase positive (TRAP+) cell lineage (Pdgfb–/–) show significantly lower trabecular and cortical bone mass, serum and bone marrow PDGF-BB concentrations, and CD31hiEmcnhi vessels compared to wild-type mice. In the ovariectomized (OVX) osteoporotic mouse model, concentrations of serum and bone marrow PDGF-BB and CD31hiEmcnhi vessels are significantly decreased. Inhibition of cathepsin K (CTSK) increases preosteoclast numbers, resulting in higher levels of PDGF-BB to stimulate CD31hiEmcnhi vessels and bone formation in OVX mice. Thus, pharmacotherapies that increase PDGF-BB secretion from preosteoclasts offer a novel therapeutic target for osteoporosis to promote angiogenesis for bone formation.

Derivation and maturation of synthetic and contractile vascular smooth muscle cells from human pluripotent stem cells

Embryonic vascular smooth muscle cells (vSMCs) have a synthetic phenotype; in adults, they commit to the mature contractile phenotype. Research shows that human pluripotent stem cells (hPSCs) differentiate into vSMCs, but nobody has yet documented their maturation into the synthetic or contractile phenotypes. This study sought to control the fate decisions of hPSC derivatives to guide their maturation towards a desired phenotype. The long-term differentiation of hPSCs, including the integration-free-induced PSC line, in high serum with platelet-derived growth factor-BB (PDGF-BB) and transforming growth factor-β1, allowed us to induce the synthetic vSMC (Syn-vSMC) phenotype with increased extracellular matrix (ECM) protein expression and reduced expression of contractile proteins. By monitoring the expression of two contractile proteins, smooth muscle myosin heavy chain (SMMHC) and elastin, we show that serum starvation and PDGF-BB deprivation caused maturation towards the contractile vSMC (Con-vSMC) phenotype. Con-vSMCs differ distinctively from Syn-vSMC derivatives in their condensed morphology, prominent filamentous arrangement of cytoskeleton proteins, production and assembly of elastin, low proliferation, numerous and active caveolae, enlarged endoplasmic reticulum, and ample stress fibres and bundles, as well as their high contractility. When transplanted subcutaneously into nude mice, the human Con-vSMCs aligned next to the host's growing functional vasculature, with occasional circumferential wrapping and vascular tube narrowing. We control hPSC differentiation into synthetic or contractile phenotypes by using appropriate concentrations of relevant factors. Deriving Con-vSMCs from an integration-free hiPSC line may prove useful for regenerative therapy involving blood vessel differentiation and stabilization.

Association between Serum Platelet-Derived Growth Factor BB and Degree of Liver Damage, Fibrosis and Hepatitis B e Antigen (HBeAg) Status in CHB Patients

The objective of this study was to determine the association of PDGF-BB with degree of liver damage, fibrosis and HBeAg status in CHB patients. A total of 740 patients with previously untreated chronic hepatitis B were included in the study. We conducted the correlations analysis of se-rum PDGF-BB with the age, gender, medical history, se-rum HBV-DNA, liver function parameters and serum fibrosis markers (HA, PCIII, CIV, LN), analyzed the cor-relations of degree of liver damage with liver fibrosis markers and the serum levels of PDGF-BB and compared serum liver fibrosis markers and levels of PDGF- BB between HbeAg-negative and HbeAg-positive CHB patients. Liver function parameters and se-rum liver fibrosis markers were significantly correlated with serum PDGF-BB (p<0.01). Liver fibrosis markers and serum levels of PDGF-BB in CHB were positive correlated with degree of liver damage. Serum levels of PDGF-BB in HBeAg-negative CHB was significantly higher than that in the HBeAg-positive CHB (p<0.05). Serum levels of PDGF-BB can reflect degree of liver damage and degree of liver fibrosis in CHB.Serum levels of PDGF-BB in HBeAg-negative CHB were higher than the HBeAg-positive CHB.

Serum platelet-derived growth factor-BB in adult patients with aggressive non-Hodgkin's lymphoma

Background The importance of angiogenesis was proved first for solid tumors, and its importance in hematological malignancies was reported later. Aim of the work The present study aimed to evaluate the prognostic value of the angiogenesis marker platelet-derived growth factor-BB (PDGF-BB) in patients with aggressive non-Hodgkin’s lymphoma (NHL) and identify its significance on treatment response. Subjects and methods The serum level of PDGF-BB was measured in patients with aggressive NHL before and after chemotherapy and compared with that of a healthy control group, and its relationship with certain prognostic parameters was assessed. Results Pretreatment serum level of PDGF-BB did not show a significant change as compared with the control group. Its level showed no relation to Ann Arbor stages, International Prognostic Index scores, B symptoms, or extranodal involvement. Chemotherapy led to a considerable increase in serum PDGF-BB level in all NHL patients and in the noncomplete responder subgroup. Conclusion From the results mentioned above it could be concluded that PDGF-BB is not vital in the pathogenesis of NHL. Chemotherapy led to elevation of serum PDGF-BB, reflecting activation of angiogenesis, which can be considered one of the mechanisms of conferring chemoresistance to cancer cells or in identification of patients at risk for developing side effects. Future studies are recommended to prove this effect of chemotherapy. If this effect is confirmed, the use of agents blocking the angiogenic pathway of PDGF-BB in combination with chemotherapy may improve the therapeutic effectiveness and sensitize chemoresistant cells.

Coordinated Increase in Serum Platelet-Derived Growth Factor-BB and Transforming Growth Factor-β1 in Patients with Chronic Pancreatitis

Background: In vitro studies suggest that platelet-derived growth factor-BB (PDGF-BB) and transforming growth factor-β1 (TGF-β1) play an important role in pancreatic fibrosis. The aim of this study was to evaluate serum PDGF-BB and TGF-β1 concentrations in patients with chronic pancreatitis (CP). Methods: Forty male patients with a history of alcoholic CP and 35 age-matched healthy subjects were examined. Serum concentrations of PDGF-BB, TGF-β1, laminin and hyaluronic acid were determined by ELISA assay. Additionally, we determined serum concentrations of PDGF-BB and TGF(31 in patients with functional dyspepsia, ulcerative colitis and Crohn's disease. Results: Patients with advanced CP had significantly higher serum PDGF-BB and TGF-β1 concentrations compared to control subjects. A strong positive correlation between serum PDGF-BB and TGF-β1 concentrations was found in patientswith CP. Serum laminin and hyaluronic acid were also elevated in patients with CP. No increase in serum PDGF-BB and TGF-β1 concentrations was found in patients with functional dyspepsia, ulcerative colitis or Crohn's disease. Conclusion: The obtained results indicate for the first time that serum levels of PDGF-BB are elevated in patients with CP. However, ROC curve analysis suggests that PDGF-BB is not superior to laminin as a potential marker of advanced CP.

Idiopathic and secondary osteonecrosis of the femoral head show different thrombophilic changes and normal or higher levels of platelet growth factors

Background and purpose Thrombophilia represents a risk factor both for idiopathic and secondary osteonecrosis (ON). We evaluated whether clotting changes in idiopathic ON were different from corticosteroid-associated ON. As platelet-rich plasma has been proposed as an adjuvant in surgery, we also assessed whether platelet and serum growth factors were similar to those in healthy subjects.Methods 18 patients with idiopathic ON and 18 with corticosteroid-associated ON were compared with 44 controls for acquired and inherited thrombophilia. Platelet factor 4 (PF4), transforming growth factor-β1, platelet-derived growth factor-BB (PDGF-BB), and vascular endothelial growth factor were assayed in the supernatants of thrombin-activated platelets, in platelet lysates, and in serum from 14 ON patients and 10 controls.Results Idiopathic ON patients had higher plasminogen levels (median 118%) than controls (101%) (p = 0.02). Those with corticosteroid-associated ON had significantly higher D-dimer (333 ng/mL) and lower protein C levels (129%) than controls (164 ng/mL, p = 0.004; 160%, p = 0.02). The frequency of inherited thrombophilia was not different from the controls. No statistically significant differences were found between idiopathic and corticosteroid-associated ON. 20 of the 36 ON patients were smokers. (The controls were selected from smokers because nicotine favors hypercoagulability). ON patients had significantly higher serum PF4 levels (7,383 IU/mL) and PDGF-BB levels (3.1 ng/mL) than controls (4,697 IU/mL, p = 0.005; 2.2 ng/mL, p = 0.02).Interpretation Acquired hypercoagulability was common in both ON types, but the specific changes varied. The release of GF from platelets was not affected, providing a biological basis for platelet-rich plasma being used as an adjuvant in surgical treatment.

Serum proangiogenic factors in patients with testicular germ cell tumors

16050 Background: Angiogenesis has an established role in the initiation and maintenance of carcinogenesis, as well as a certain role in the establishment of metastatic foci. The role of angiogenesis in testicular germ cell tumors, although obvious, is not fully elucidated. The present study aims to clarify the role of serum proangiogenic factors in patients with testicular germ cell tumors. Methods: We measured serum basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), platelet derived growth factor BB (PDGF-BB) and angiopoietin-2 (Ang-2), using solid phase Elisa in 50 patients (mean age 32,3±9,1 years) with testicular cancer who underwent chemotherapy and in 16 healthy male, age-matched (mean age 31,8±7,12 years) controls. Three serum samples were obtained from patients with testicular cancer: prior to chemotherapy (baseline), before cycle 3, and 9–14 months after the completion of chemotherapy. One serum sample was obtained from controls. Informed consent was taken before the obtainment of the samples. Results: Baseline mean serum bFGF, VEGF, PDGF-BB, and Ang-2 were 666,5 ±550pg/ml, 228,3±181pg/ml, 10623,8pg/ml, 4089,82±3312pg/ml in patients and 1153,6±967pg/ml, 158,9±137pg/ml, 8726,1±4318pg/ml, 2647,2±1186pg/ml in controls (p=0,1, p=0,8, p=0,3 and p=0,013). Mean serum values 1 year after the completion of chemotherapy were 310,8±298pg/ml, 139±127pg/ml, 7500±3726pg/ml and 6275±5600pg/ml (p=0,044, p=0,198, p<0,001, p=0,008). As we can see, there was a trend toward normalization of proangiogenic factors values, especially for PDGF-BB and Ang-2, and there was a difference between patients and controls for Ang-2. Ang-2 was also statistically significant different between good (n=8) and intermediate-bad prognostic groups (n=42) (mean values 3413±2100 and 5291±3200, p=0,03). Conclusions: These results support the notion about the role of proangiogenic factors in germ cell carcinogenesis. Especially angiopoietin-2 seems to play a significant role, as it was the only factor with statistically significant difference between patients and controls and the only factor with difference between the various prognostic groups. Further study of angiopoietin-2 and its role in germ cell tumors is warranted. No significant financial relationships to disclose.

Diagnostic value of platelet derived growth factor-BB, transforming growth factor-beta1, matrix metalloproteinase-1, and tissue inhibitor of matrix metalloproteinase-1 in serum and peripheral blood mononuclear cells for hepatic fibrosis.

Noninvasive diagnosis of hepatic fibrosis has become the focus because of the limited biopsy, especially in the surveillance of treatment and in screening hepatic fibrosis. Recently, regulatory elements involved in liver fibrosis, such as platelet derived growth factor-BB (PDGF-BB), transforming growth factor-beta1 (TGF-beta1), matrix metalloproteinase-1 (MMP-1), and tissue inhibitor of matrix metalloproteinase-1 (TIMP-1), have been studied extensively. To determine whether these factors or enzymes could be used as the indices for the diagnosis of hepatic fibrosis, we investigated them by means of receiver operating characteristic (ROC) curve. Serum samples from sixty patients with chronic viral hepatitis B and twenty healthy blood donors were assayed to determine the level of PDGF-BB, TGF-beta1, MMP-1, and TIMP-1 with ELISA, and HA, PCIII, C-IV, and LN level with RIA. The message RNA (mRNA) expression of TIMP-1 and MMP-1 in peripheral blood mononuclear cells (PBMCs) was detected by RT-PCR and Northern blot hybridization. Liver biopsy was performed in all patients. The biopsy samples were histopathologically examined. The trial was double-blind controlled. The serum level of PDGF-BB, TIMP-1, the ratio of TIMP-1 and MMP-1 (TIMP-1/MMP-1), mRNA expression of TIMP-1 (TIMP-1mRNA), and the ratio of TIMP-1mRNA and MMP-1mRNA (TIMP-1mRNA/MMP-1mRNA) in patients was significantly higher than those in the healthy blood donors (t=2.514-11.435, P=0.000-0.016). The serum level of PDGF-BB, TIMP-1, TIMP-1/MMP-1, and TIMP-1mRNA was positively correlated with fibrosis stage and inflammation grade (r=0.239-0.565, P=0.000-0.033), while the serum level of MMP-1 was negatively correlated with fibrosis stage and inflammation grade, and TIMP-1mRNA/MMP-1mRNA was positively correlated with inflammation grade. Through the analysis by ROC curve, serum PDGF-BB was the most valuable marker, and its sensitivity was the highest among the nine indices. The markers with the highest specificity were TIMP-1mRNA and TIMP-1mRNA/MMP-1mRNA in PBMCs. The area under the curve (AUC) of PDGF-BB, TIMP-1mRNA, TIMP-1mRNA/MMP-1mRNA, TIMP-1/MMP-1, HA, PCIII, TIMP-1, C-IV, and LN was 0.985, 0.876, 0.792, 0.748, 0.728, 0.727, 0.726, 0.583, and 0.463, respectively. The sensitivity and the specificity in the parallel test was 99.0% and 95.0% when serum PDGF-BB, TIMP-1mRNA and TIMP-1mRNA/MMP-1mRNA was detected simultaneously. Serum level of PDGF-BB, TIMP-1mRNA, TIMP-1mRNA/MMP-1mRNA in PBMCs, and serum level of TIMP-1 and TIMP-1/MMP-1 can be used as the indices for the diagnosis of hepatic fibrosis, but the former three are more useful. The combination of serum PDGF-BB, TIMP-1mRNA and TIMP-1mRNA/MMP-1mRNA in PBMCs is even more efficient in screening liver fibrosis.

Macrophage lipoprotein lipase expression is increased in patients with heterozygous familial hypercholesterolemia

FH is associated with accelerated atherosclerosis. Based on the crucial role of macrophage LPL in atherogenesis, we determined in the present study macrophage LPL expression in patients with FH. Monocytes isolated from 13 FH patients and 13 control subjects were differentiated into macrophages by culturing the cells for 9 days in 20% autologous or heterologous serum. Macrophages of patients with FH cultured in their own sera showed a significant increase in LPL mRNA levels, extracellular LPL mass, and activity compared with macrophages of control subjects. Although these alterations positively correlated with the levels of serum platelet-derived growth factor-BB (PDGF-BB) in FH subjects, increased LPL secretion by cultured FH macrophages was reduced neither by immunoneutralizing FH serum with an anti-PDGF-BB antibody, nor by culturing these cells in sera from control subjects. With the exception of LPL, levels of other cytokines and 8-isoprostane were not increased in the supernatants of macrophages of FH patients. Serum from FH patients also enhances the levels of LPL secreted by macrophages from control subjects. Immunoneutralization of FH serum with an anti-PDGF-BB antibody totally reversed this alteration. Overall, this study demonstrates that macrophages from FH subjects overproduce LPL and that PDGF present in the serum from FH patients stimulates LPL secretion by control macrophages. These findings suggest that macrophage LPL induction in patients with FH might be related to the increased atherogenesis observed in these subjects.—Beauchamp, M-C., É. Letendre, and G. Renier. Macrophage lipoprotein lipase expression is increased in patients with heterozygous familial hypercholesterolemia.