Performance of Fetal Medicine Foundation algorithm for first trimester preeclampsia screening in an indigenous south Asian population.

BACKGROUND: To evaluate the performance of the Fetal Medicine Foundation (FMF) preterm preeclampsia (PE) screening algorithm in an indigenous South Asian population. METHODS: This was a prospective observational cohort study conducted in a tertiary maternal fetal unit in Delhi, India over 2 years. The study population comprised of 1863 women carrying a singleton pregnancy and of South Asian ethnicity who were screened for preterm pre-eclampsia (PE) between 11 and 14 weeks of gestation using Mean Arterial Pressure (MAP), transvaginal Mean Uterine Artery Pulsatility Index (UtAPI) and biochemical markers - Pregnancy Associated Plasma Protein-A (PAPP-A) and Placental Growth Factor.. Absolutemeasurements of noted biomarkers were converted to multiples of the expected gestational median (MoMS) which were then used to estimate risk for preterm PE < 37 weeks using Astraia software. Women with preterm PE risk of ≥1:100 was classified as as high risk. Detection rates (DR) at 10% false positive rate were calculated after adjusting for prophylactic aspirin use (either 75 or 150 mg). RESULTS: The incidence of PE and preterm PE were 3.17% (59/1863) and 1.34% (25/1863) respectively. PAPP-A and PlGF MoM distribution medians were 0.86 and 0.87 MoM and significantly deviated from 1 MoM. 431 (23.1%) women had a risk of ≥1:100, 75 (17.8%) of who received aspirin. Unadjusted DR using ≥1:100 threshold was 76%.Estimated DRs for a fixed 10% FPR ranged from 52.5 to 80% depending on biomarker combination after recentering MoMs and adjusting for aspirin use. CONCLUSION: The FMF algorithm whilst performing satisfactorily could still be further improved to ensure that biophysical and biochemical markers are correctly adjusted for indigenous South Asian women.

Nested Case-Control Study of Corin Combined with sFlt-1/PLGF in Predicting the Risk of Preeclampsia.

BACKGROUND: Preeclampsia (PE), a serious pregnancy disorder, is responsible for maternal and fetal mortality worldwide. At present, numerous candidate biomarkers have been studied to predict PE. OBJECTIVE: To explore the role of Corin in PE risk prediction and then evaluate the predictive ability of soluble vascular endothelial growth factor receptor-1 (sFlt-1), placenta growth factor (PLGF), and sFlt-1/PLGF after the addition of Corin. METHODS: A total of 135 pregnant women from Affiliated Hospital of Shandong University of Traditional Chinese Medicine participated in this study in their first trimester. A nested case-control study was conducted and all subjects were divided into PE groups (n=46) and controls (n=89). The levels of PLGF, sFlt-1, sFlt-1/PLGF ratio, and Corin of the two groups at 12-16 weeks of gestation were measured and analyzed. Receiver operating characteristic (ROC) curve, net reclassification index (NRI) and integrated discrimination index (IDI) were calculated to evaluate the predictive ability of various biomarkers. RESULTS: The concentrations of sFlt-1, sFlt-1/PLGF, and Corin in PE group were significantly higher than that in controls, while the concentration of PLGF in the PE group was lower. The area under curve (AUC) of sFlt-1, PLGF and sFlt-1/PLGF for predicting PE was 0.786, 0.719 and 0.866, respectively. Combined with Corin, the prediction ability of the above biomarkers could be improved to 0.876, 0.847, and 0.897, respectively. Corin in combination with sFlt-1/PLGF resulted in improvements with 12.6% being reclassified and a resulting NRI of 0.142 (0.020~0.263) and IDI of 0.087 (0.037~0.137). CONCLUSION: The addition of Corin to sFlt-1, PLGF and sFlt-1/PLGF can improve the ability of each marker to predict PE risk. Corin in combination with sFlt-1/PLGF can be used as ideal markers to identify the pregnant women who subsequently develop PE, which will help in risk stratification and better therapeutic management.

Nephrotic syndrome due to preeclampsia before 20 weeks of gestation: a case report.

BACKGROUND: Preeclampsia (PE) refers to the development of hypertension and new-onset proteinuria or progressive organ damage (especially kidney) in a previously normotensive pregnant women after 20 weeks of gestation. Thus, new-onset nephrotic syndrome due to PE before 20 weeks of gestation seems to be rare, making its diagnosis difficult in this time period. CASE PRESENTATION: A 28-year-old woman presented with a new-onset nephrotic syndrome at 16 weeks of gestation. A high dose of oral glucocorticoids (prednisolone, 40 mg) was initiated for presumed glomerulonephritis since she presented with severe nephrotic syndrome before 20 weeks of gestation, however, the treatment was not effective. At 21 weeks of gestation, we confirmed that the soluble fms-like tyrosine kinase-1 (sFlt-1)/placental growth factor (PlGF) ratio was very high (sFlt-1, 13,400 pg/mL; PlGF, 21.9 pg/mL; serum sFlt-1/PlGF ratio 611.9). Therefore, we diagnosed nephrotic syndrome due to PE, and oral glucocorticoids were discontinued. After she underwent a cesarean section at 24 weeks & 3 days, we performed a kidney biopsy. Focal segmental sclerotic lesions with epithelial cell hyperplasia and foam cells in the tubular poles were seen on light microscopy. On immunofluorescence tests, C4d staining showed linear peripheral patterns in the glomeruli. Electron microscopy revealed diffuse subendothelial edema with focal foot process effacement. The histological diagnosis was severe glomerular endotheliosis with focal segmental glomerulosclerosis. Furthermore, the histology of placenta was consistent with PE. Eight months after delivery, her proteinuria disappeared completely. CONCLUSIONS: We not only confirmed an abnormal serum sFlt-1/PlGF ratio but also presented the histology compatible with pure PE in the kidney and placenta in a case of nephrotic syndrome before 20 weeks of gestation. The serum sFlt-1/PlGF ratio may be useful in determining the treatment strategy for atypical cases of pregnant women with nephrotic syndrome, particularly before 20 weeks of gestation.

Dendrobium nobile Lindley and its bibenzyl component moscatilin are able to protect retinal cells from ischemia/hypoxia by dowregulating placental growth factor and upregulating Norrie disease protein.

BACKGROUND: Presumably, progression of developmental retinal vascular disorders is mainly driven by persistent ischemia/hypoxia. An investigation into vision-threatening retinal ischemia remains important. Our aim was to evaluate, in relation to retinal ischemia, protective effects and mechanisms of Dendrobium nobile Lindley (DNL) and its bibenzyl component moscatilin. The therapeutic mechanisms included evaluations of levels of placental growth factor (PLGF) and Norrie disease protein (NDP). METHODS: An oxygen glucose deprivation (OGD) model involved cells cultured in DMEM containing 1% O2, 94% N2 and 0 g/L glucose. High intraocular pressure (HIOP)-induced retinal ischemia was created by increasing IOP to 120 mmHg for 60 min in Wistar rats. The methods included electroretinogram (ERG), histopathology, MTT assay and biochemistry. RESULTS: When compared with cells cultured in DMEM containing DMSO (DMSO+DMEM), cells subjected to OGD and pre-administrated with DMSO (DMSO+OGD) showed a significant reduction in the cell viability and NDP expression. Moreover, cells that received OGD and 1 h pre-administration of 0.1 µM moscatilin (Pre-OGD Mos 0.1 µM) showed a significant counteraction of the OGD-induced decreased cell viability. Furthermore, compared with the DMSO+OGD group (44.54 ± 3.15%), there was significant elevated NDP levels in the Pre-OGD Mos 0.1 µM group (108.38 ± 29.33%). Additionally, there were significant ischemic alterations, namely reduced ERG b-wave, less numerous retinal ganglion cells, decreased inner retinal thickness, and reduced/enhanced amacrine's ChAT/Müller's GFAP or vimentin immunolabelings. Moreover, there were significantly increased protein levels of HIF-1α, VEGF, PKM2, RBP2 and, particularly, PLGF (pg/ml; Sham vs. Vehicle: 15.11 ± 1.58 vs. 39.53 ± 5.25). These ischemic effects were significantly altered when 1.0 g/Kg/day DNL (DNL1.0 + I/R or I/R+ DNL1.0) was applied before and/or after ischemia, but not vehicle (Vehicle+I/R). Of novelty and significance, the DNL1.0 action mechanism appears to be similar to that of the anti-PLGF Eylea [PLGF (pg/ml); DNL1.0 vs. Eylea+I/R: 19.93 ± 2.24 vs. 6.44 ± 0.60]. CONCLUSIONS: DNL and moscatilin are able to protect against retinal ischemic/hypoxic changes respectively by downregulating PLGF and upregulating NDP. Progression of developmental retinal vascular disorders such as Norrie disease due to persistent ischemia/hypoxia might be thus prevented.

Cardioprotective activity of placental growth factor combined with oral supplementation of l-arginine in a rat model of acute myocardial infarction.

OBJECTIVE: Exogenous administration of placental growth factor (PlGF) stimulates angiogenesis and improves ventricular remodeling after acute myocardial infarction (AMI), and supplementation with l-arginine ameliorates endothelial function. The objective of the present study was to compare the cardioprotective effects of combination therapy of PlGF and l-arginine with those of direct administration of PlGF alone in a rat model of AMI. MATERIALS AND METHODS: Fifty male Sprague Dawley rats were randomly divided into five groups: sham group, normal saline group, l-arginine group, PlGF group, and combination group (PlGF + l-arginine). An AMI rat model was established by ligation of the left anterior descending of coronary arteries. After 4 weeks of postligation treatment, cardiac function, scar area, angiogenesis and arteriogenesis, myocardial endothelial nitric oxide synthase (eNOS) and collagen I protein content, and plasma concentration of brain natriuretic peptide (BNP) were studied. Echocardiography, Masson's staining, immunohistochemical analyses, Western blot, and enzyme-linked immunosorbent assay were performed. RESULTS: Left ventricular ejection fraction (LVEF), left ventricular fraction shortening (LVFS), and capillary and arteriole densities were higher in the PlGF group than in the normal saline group (P<0.01). Scar area, collagen I protein content, and plasma concentration of BNP were decreased in the PlGF group (P<0.01). Myocardial eNOS protein level was elevated in the l-arginine group and PlGF + l-arginine group (P<0.01). Compared with the PlGF group, LVEF, LVFS, myocardial eNOS, and capillary and arteriole densities were higher in the combination group (P<0.01). Scar area, content of collagen I protein, and plasma concentration of BNP were reduced in the combination group (P<0.01). CONCLUSION: Exogenous administration of PlGF stimulates angiogenesis and improves cardiac function. l-arginine increases the expression of the eNOS protein. PlGF and l-arginine have a more pronounced, synergistic protective effect on myocardial protection compared with that of exogenous PlGF therapy alone.

Efficient inhibition of growth of metastatic cancer cells after resection of primary colorectal cancer by soluble Flt-1.

Removal of primary tumors often leads to increases in growth of metastatic tumor cells. Thus, development of an efficient treatment to inhibit the growth of metastatic tumor cells after resection of primary tumors appears to be critical for cancer therapy. Here, we reported that administration of a Chinese medicine Shiquandabutao (SQDBT) after removal of the primary cancer significantly inhibited the growth of metastatic cancer cells in mouse liver. Further analyses showed that the effect of SQDBT resulted from one of its main component, Siwutang (SWT), rather than from another main component, Sijunzitang (SJZT). Moreover, we found that the soluble Flt-1 from SWT neutralized the increased placental growth factor (PLGF) secreted by the metastatic cancer cells after primary cancer resection and subsequently inhibited the cancer neovascularization to suppress the metastatic cancer growth. Thus, our study reveals an essential role of SQDBT in inhibiting the growth of metastatic cancer after removal of primary cancer and further highlights PLGF as a potential target for metastatic cancer treatment.

Placental growth factor in cancer.

INTRODUCTION: Placental growth factor (PLGF) belongs to the VEGF family, which among the three VEGF receptors binds exclusively to VEGFR1, present on various cell types. Isoform PLGF-2 also binds the neuropilin co-receptors. PLGF is dispensable for development and health but has a prominent role in pathology including cancer. This has triggered the question whether PLGF targeting might offer an alternative to current antiangiogenesis therapy, which encounters problems of refractoriness and acquired resistance. AREAS COVERED: This article reviews the available literature on the characteristics of PLGF, its role(s) in cancer and the findings on PLGF inhibition in preclinical models with attention to as yet unresolved questions and summarizes data from initial clinical trials. EXPERT OPINION: Preclinical studies show that inhibition of PLGF, either by genetic inhibition or by pharmacological blockade using distinct independently generated anti-PLGF antibodies, slows down tumor growth and metastasis and even induces regression of pre-existing medulloblastoma, the most frequent brain cancer in children. These promising preclinical findings, together with the acceptable safety profile of anti-PLGF administration in Phase I clinical trials, have attracted attention to PLGF as a potential target for therapy.

Antioxidant and antiangiogenic activity of Astronium graveolens Jacq. leaves.

Angiogenesis is involved in many physiological and pathological conditions. Natural compounds with antioxidant activity have also been reported to possess potent antiangiogenic properties by regulating angiogenesis modulators such as vascular endothelial growth factor (VEGF). Based on this, we screened the antioxidant and antiangiogenic activities of Astronium graveolens leaf extracts by a DPPH test and a competitive enzyme-linked immunosorbent assay, respectively. MeOH extract expressed a significant free radical-scavenging activity (EC50 = 37.65 µg/mL) and it was able to inhibit the interaction between placental growth factor (PlGF) (placental growth factor), a VEGF family member, and its receptor Flt-1 by more than 50% at 1 mg/mL. 1,2,3,4,6-Penta-O-galloyl-d-glucopyranose, 6 is the most active compound of the extract. It exhibited a high potency in scavenging DPPH (EC50 = 2.16 µg/mL) and reduced by 58% the PlGF/Flt-1 interaction at a concentration of 50 µM. Moreover, the known compounds (1-6) have been isolated for the first time in A. graveolens.

Maternal soluble fms-like tyrosine kinase-1, placental growth factor, plasminogen activator inhibitor-2, and folate concentrations and early fetal size: the Generation R study.

OBJECTIVE: Fetal growth is dependent on adequate development of the placenta. Impaired angiogenesis and vasculogenesis in early pregnancy compromises placental and embryonic development. The proteins soluble fms-like tyrosine kinase (sFlt)-1, placental growth factor (PlGF), and plasminogen activator inhibitor (PAI)-2, and the B vitamin folate are determinants of placental development. This study aims to identify associations between these maternal biomarkers and early fetal size. STUDY DESIGN: From a prospective birth cohort study in The Netherlands, 1491 pregnant women were selected for this study. At a mean gestational age (GA) of 12.4 weeks (SD 0.8) maternal venous blood samples were obtained to determine the concentrations of sFlt-1, PlGF, PAI-2, and folate. Early fetal size was assessed with measurement of the crown-to-rump length (CRL) at a mean of 12.4 weeks' GA (SD 0.8). Analyses were performed using multivariable linear regression analyses with the biomarkers (continuous, quintiles) as regressors and CRL as main outcome measure. RESULTS: Linear trend analysis showed positive associations between maternal sFlt-1 (P < .001), PlGF (P = .042), PAI-2 (P < .001), and folate (P = .039) and CRL. These associations were independent of GA, maternal age, height, body mass index, ethnicity, fetal sex, parity, educational level, smoking, and folic acid supplement use (folate not adjusted). CONCLUSION: sFlt-1, PlGF, PAI-2, and folate are positively associated with first-trimester fetal size.