Placental Growth Factor Expression Research Articles

Status of alternative angiogenic pathways in glioblastoma resected under and after bevacizumab treatment

Glioblastoma multiforme (GBM) acquires resistance to bevacizumab (Bev) treatment. Bev affects angiogenic factors other than vascular endothelial growth factor (VEGF), which are poorly understood. We investigated changes in angiogenic factors under and after Bev therapy, including angiopoietin-1 (ANGPT1), angiopoietin-2 (ANGPT2), placental growth factor (PLGF), fibroblast growth factor 2, and ephrin A2 (EphA2). Fifty-four GBM tissues, including 28 specimens from 14 cases as paired specimens from the same patient obtained in three settings: initial tumor resection (naïve Bev), tumors resected following Bev therapy (effective Bev), and recurrent tumors after Bev therapy (refractory Bev). Immunohistochemistry assessed their expressions in tumor vessels and its correlation with recurrent MRI patterns. PLGF expression was higher in the effective Bev group than in the naïve Bev group (p = 0.024) and remained high in the refractory Bev group. ANGPT2 and EphA2 expressions were higher in the refractory Bev group than in the naïve Bev group (p = 0.047 and 0.028, respectively). PLGF expression was higher in the refractory Bev group compared with the naïve Bev group for paired specimens (p = 0.036). PLGF was more abundant in T2 diffuse/circumscribe patterns (p = 0.046). This is the first study to evaluate angiogenic factors other than VEGF during effective and refractory Bev therapy in patient-derived specimens.

10005-ANGI-1 REGULATION OF ALTERNATIVE ANGIOGENIC FACTORS IN BEVACIZUMAB THERAPY FOR GLIOBLASTOMA

Abstract The elucidation of the mechanism of action and resistance is imperative to overcome resistance to Bev and develop a more effective therapy. This study aims to investigate the status and change of alternative angiogenic factors regarding Bev usage using human specimens. The present study used 54 glioblastoma tissues obtained at 3 different settings: tumors of initial resection (naive Bev group), tumors resected following Bev therapy (effective Bev group), and recurrent tumors after Bev therapy (refractory/autopsied Bev group). Importantly, naive Bev-refractory Bev of 22 specimens in 11 cases (including 4 autopsy specimens and 7 salvage surgery specimens) were obtained as paired specimens from the same patient. The expression of alternative angiogenic factors including basic fibroblast growth factor (bFGF), placental growth factor (PlGF), Angiopoietin1 (Ang-1), Angiopoietin2(Ang-2) and EphrinA2 were investigated via immunohistochemistry. PlGF expression was higher in the effective group than in the Naive group (p=0.048), and Ang-2 (0.047) and EphA2 (p=0.028) were higher in the relapse group than in the Naive group. Interestingly, in paired specimens, PlGF expression was higher in the refractory group than in the Naive group (p=0.036). This suggests that angiogenic factors other than VEGF are involved in recurrence. We provide the first clinicopathological evidence of the status of alternative angiogenic pathway after the Bev usage. These in situ observations will help to optimize therapy.

Effects of sirtuin 1 deficiency on trophoblasts and its implications in the pathogenesis of pre-eclampsia

Background Sirtuin 1 (SIRT1) is mainly localised in syncytiotrophoblasts and cytotrophoblasts, and is involved in pregnancy regulation. However, data on the association between SIRT1 and pre-eclampsia (PE) remains limited. This study aimed to investigate the role of SIRT1 in PE pathophysiology. Methods Placental SIRT1 expression, as well as serum SIRT1, placental growth factor (PlGF), and soluble FMS-like tyrosine kinase 1 (sFlt-1) levels, were measured using quantitative real-time polymerase chain reaction (qRT-PCR), western blotting, and enzyme-linked immunosorbent assays in 40 healthy pregnant women (NP group) and 40 women with severe PE (PE group). Additionally, the effects of SIRT1 on the migration, invasion, PlGF, and sFlt-1 secretion of HTR-8/SVneo cells were analysed. Results SIRT1 expression was significantly reduced in the placenta of patients with severe PE compared with that in healthy pregnant women. Compared with the NP group, serum SIRT1 and PlGF expression was significantly lower in the PE group; however, the expression of serum sFlt-1 was significantly higher in the PE group. Correlation analysis showed that in the PE group, placental SIRT1 protein levels positively correlated with serum PlGF levels (r = 0.468, P = .002) and negatively correlated with serum sFlt-1 levels (r = −0.542, P < .001). Cells with downregulated SIRT1 had a significantly shorter migration distance and a prominently reduced number of invasive cells compared with the corresponding negative control group, suggesting that SIRT1 deficiency may inhibit the migration and invasive ability of HTR-8/SVneo cells. The opposite results were observed after transfection with lentivirus overexpressing SIRT1. Compared with the corresponding controls, cells with downregulated SIRT1 had significantly reduced PlGF levels and significantly increased sFlt-1 levels in the cell culture supernatants, whereas SIRT1 overexpression produced the opposite results. Conclusions SIRT1 deficiency may contribute to the pathogenesis of pre-eclampsia by reducing trophoblastic migration, invasion, and PlGF secretion and increasing sFlt-1 secretion.

Expression of placental growth factor, neuropilin-1, and neuropilin-2 in primary pterygium tissue.

The aim of this study was to evaluate the expression of placental growth factor (PLGF), neuropilin-1 (NP-1), and neuropilin-2 (NP-2) molecules in primary pterygium tissue compared with normal conjunctival tissue. The records of 42 patients who underwent excision surgery with autografts for primary pterygium (pterygium group) and 20 patients who underwent conjunctival nevus excision surgery (control group) in the same period were reviewed retrospectively. The samples obtained from the pterygium tissues in the pterygium group and the clean conjunctival tissues adjacent to the nevus in the control group were collected from the archive. Immunohistochemical stains of the primary antibodies-1/100 diluted PLGF, NP-1, and NP-2 (Abcam Cambridge Science Park, UK)-were applied to all groups. Staining intensities and the percentage of positive cells in epithelial, endothelial, stromal, and inflammatory cells were analyzed by an experienced pathologist. The positivity rates of PLGF and NP-2 expression in epithelial, endothelial, stromal, and inflammatory cells were found to be higher in the pterygium group than in the control group (PLGF: p < 0.001, p < 0.001, p = 0.001, and p < 0.001, respectively; NP-2: p < 0.001 for all). Staining intensities for PLGF and NP-2 were higher in the pterygium group than in the control group (PLGF: p < 0.001, p < 0.001, p = 0.005, and p < 0.001, respectively; NP-2: p < 0.001, p < 0.001, p = 0.001, and p < 0.001, respectively). However, no significant differences were found in any cell type in terms of NP-1 expression positivity rates (p = 0.730, p = 0.121, p = 0.524, and p = 0.624, respectively) or staining intensity (p = 0.716, p = 0.147, p = 0.147, and p = 0.780, respectively). PLGF and NP-2 levels were found to be higher in pterygium tissue, while there was no difference in NP-1. These results indicate the possible roles of NP-2 and PLGF in primary pterygium.

Preliminary investigation of the anti‐colon cancer activity of cucurbitacin C from cucumber: A network pharmacological study and experimental validation

AbstractColon cancer (CC) is a prevalent malignant tumor of the gastrointestinal tract and ranks among the leading causes of death in cancer patients worldwide. Cucurbitacin, a group of tetracyclic triterpenoids widely found in Cucurbitaceae plants, exhibits diverse pharmacological activities. However, the pharmacological activity of cucurbitacin C (CuC), a cucurbitacin derivative exclusively present in cucumbers, remains unclear. To investigate CuC's action targets and potential targets for CC, we utilized a database to obtain relevant information. Additionally, we identified differentially expressed genes in CC patients from The Cancer Genome Atlas and discovered 64 crossover targets formed through the intersection of drug‐disease targets. Through the construction of a protein‐protein interaction network, we identified 20 central genes. Enrichment analysis revealed that the cross‐targets were significantly enriched in four signaling pathways, namely, the PI3K‐Akt, Ras, MAPK, and IL‐17 signaling pathways. Correlation and expression analysis of the enriched central genes led to the identification of 7 key targets, among which matrix metalloproteinases (MMP)‐1, MMP‐3, and MMP‐13 demonstrated a significant association with poor prognosis in patients. Furthermore, we validated the network pharmacology results with in vitro and in vivo experiments. CuC can effectively inhibit the proliferation and migration of HCT‐116. CuC also can suppress the colon tumor growth in vivo, while reducing the expression of placental growth factor, MMP‐1, MMP‐3, MMP‐9, and MMP‐13 both in vitro and in vivo, consistent with the predicted results. Together, our results demonstrated that CuC holds promise as a potential agent for CC treatment.

Плацентарні фактори у вагітних з ізольованими вадами серця в плода

The placenta, as a unique and transient organ in humans, ensures the development and protection of the fetus, the expression of angiogenic and antiangiogenic factors and their receptors. The integrity of the fetoplacental endothelial barrier is critical for the development of fetal organs, especially the cardiovascular system. Placental growth factor (PLGF) regulates the morphologic and functional development of the uteroplacental vasculature and can vary with gestational age and in various pathologic conditions of the pregnant woman. Since there is a differential expression of PLGF and soluble form of fms-like tyrosine kinase (sFlt-1) at different gestational ages and their competitive interaction, it is advisable to study their level in the blood of a pregnant woman as indicators of regulation of the placental vascular system in pathological conditions of the woman and fetus. Purpose - to determine the levels of placental factors, namely PLGF and sFlt-1, in the serum of pregnant women with isolated congenital heart disease (CHD) in the fetus to increase the effectiveness of diagnostics and the ability to predict heart diseases. Materials and methods. The work was based on a prospective clinical study of a hospital sample, using the case-control study method, with the evaluation of some clinical and laboratory data in 30 pregnant women with isolated fetal CHD (study group) and 60 pregnant women with a healthy fetus (control group). In order to minimize the influence of various risk factors for fetal heart disease, the criteria for selecting pregnant women with non-syndromic forms of CHD and the control group were defined. Clinical, laboratory and statistical methods were used in the study. The level of angiogenesis indicators in blood serum of pregnant women of both groups was determined by enzyme-linked immunosorbent assay in units of pg/ml in the third trimester of pregnancy. The statistical analysis was carried out using the R software package. ROC analysis and AUC (area under the ROC curve) were used for quantitative interpretation. Differences with p&lt;0.05 were considered statistically significant. Results. According to the results of the study, the age of the women in the study group ranged from 17 to 39 years with a mean of 28.36±5.12, and the age of the women in the control group was 29.63±5.39 (p=0.239). The mean gestational age of women in the study group at enrollment was 28.26±8.45 weeks. The mean PLGF level was 93.73±77.32 pg/mL in the study group and 198.63±168.27 pg/mL in the control group (p=0.002). The average level of sFlt-1 in the blood serum of the women in the study group was 9779.44±5407.53 pg/ml, while in the pregnant women in the control group it was 3124.6±1624.53 (p&lt;0.001). The sFlt/PlGF ratio was 180.9±151.1 in the study group and 15.76±14.7 in the control group (p&lt;0.001). Conclusions. The obtained results in the form of a decrease of the placental growth factor in the blood of pregnant women with congenital heart defects in the fetus and an increase of the antiangiogenic factor in this group in the III trimester compared to a healthy fetus indicate a violation of angiogenesis in the fetoplacental system. Analysis of data on the age of pregnant women of both groups did not reveal a statistically significant difference between them. Due to the usage of multifactor logistic regression model, was created the CHD “risk calculator” which, using the placental factors of the pregnant woman, calculates the probability of the occurrence of a heart defect in fetus. The study was conducted in accordance with the tenets of the Declaration of Helsinki. The local ethics committee approved the study protocol for all participants. Informed consent was obtained from patients. No conflict of interests was declared by the author.

Oleuropein attenuates placental growth factor expression by regulating oxidative stress and apoptosis in acrylamide hepatotoxicity

The liver is susceptible to toxic effects, as it is the main site of acrylamide biotransformation and detoxification. Researchers have claimed that placental growth factor (PlGF) and its pathway are potentially involved in numerous diseases, including liver fibrosis and angiogenesis. Oleuropein is a natural phenolic compound with potent antioxidant effects. The purpose of this study was to examine the role of PlGF and the potential protection provided by oleuropein in acrylamide hepatotoxicity. Wistar albino rats were assigned into control, acrylamide (ACR) (5 mg/kg), oleuropein (OLE) (4.2 mg/kg), and ACR+OLE groups. Acrylamide and oleuropein were administered for 21 days. The control group received only physiological saline. Liver tissues were evaluated histologically and immunohistochemically. Histological examinations revealed significant enlargement of the sinusoidal vessels and abundant hepatocytes with pyknotic nuclei in the ACR group. Acrylamide toxicity resulted in elevated PlGF, accumulation of 8-hydroxydeoxyguanosine (8-OHdG), and increased Caspase-3 immunoreactivity in the liver. Oleuropein treatment reduced the increased expression of PlGF, 8-OHdG, and Caspase-3 against these deleterious effects observed in the ACR group. A positive correlation was observed between PlGF levels as well as oxidative stress and apoptosis markers in acrylamide toxicity. Oleuropein probably counteracted this mechanism by exhibiting antioxidant activity.

Expression of placental growth factor and a disintegrin and metalloprotease with a thrombospondin type motifs 1-4-8 during the three trimesters of rat pregnancy at the maternal-fetal interface.

The functional roles of the a disintegrin and metalloprotease with a thrombospondin type motifs (ADAMTS) gene family in reproductive physiology, reproductive organs developments and adult reproductive health are still under investigation. The expression of the anti-angiogenic proteases ADAMTS-1, ADAMTS-4 and ADAMTS-8 in placental angiogenesis at various stages of pregnancy also remains unclear. The purpose of this study was therefore to determine the localization and expression of the ADAMTS-1, ADAMTS-4 and ADAMTS-8 proteins during the three stages of pregnancy in rats. Maternal-fetal tissue samples were collected on Days 5, 12 and 19 of each trimester, corresponding to the first, second and third trimesters. The expression of placental growth factor (PlGF) and ADAMTS-1, ADAMTS-4 and ADAMTS-8 at the maternal-fetal interface was examined using immunohistochemistry and western blot at three distinct phases of pregnancy. ADAMTS-1, ADAMTS-4 and ADAMTS-8 were detected in all three trimesters of pregnancy. The relative amount of PIGF increased in the first trimester and decreased significantly in the third trimester (p < 0.05). The expression of ADAMTS-1 and ADAMTS-4 was significantly higher in the second (p < 0.05) and third trimesters (p < 0.01) compared to the first trimester. However, no statistically significant change was observed in ADAMTS-8 expression between trimesters. The ADAMTS exhibiting the highest expression during the first trimester was ADAMTS8. These findings indicate that the expression of ADAMTS-1, ADAMTS-4 and ADAMTS-8 in the three different stages of rat pregnancy may be involved in the modulation of decidualization, morphogenesis and angiogenesis. Periodic changes in ADAMTS expression are thought to be regulated by gonadal steroids.

PlGF/FLT-1 deficiency leads to reduced STAT3-C/EBPβ signaling and aberrant polarization in decidual macrophages during early spontaneous abortion.

Dysregulated macrophage polarization (excessive M1-like or limited M2-like macrophages) in the early decidua contributes to allogeneic fetal rejection and thus early spontaneous abortion. However, the modulators of M1/M2 balance at the early maternal-fetal interface remain mostly unknown. First-trimester decidual tissues were collected from normal pregnant women undergoing elective pregnancy terminations and patients with spontaneous abortion. We measured the expression of placental growth factor (PlGF) and Fms-like-tyrosine-kinase receptor 1 (FLT-1), and characterized the profiles of macrophages in decidua. Notably, we investigated the effect of recombinant human PlGF (rhPlGF) on decidual macrophages (dMφs) from normal pregnancy and revealed the underlying mechanisms both in vitro and in vivo. The downregulated expression of PlGF/ FLT-1 may result in spontaneous abortion by inducing the M1-like deviation of macrophages in human early decidua. Moreover, the CBA/J×DBA/2 abortion-prone mice displayed a lower FLT-1 expression in uterine macrophages than did CBA/J×BALB/c control pregnant mice. In in vitro models, rhPlGF treatment was found to drive the M2-like polarization of dMφs via the STAT3/CEBPB signaling pathway. These findings were further supported by a higher embryo resorption rate and uterine macrophage dysfunction in Pgf knockout mice, in addition to the reduced STAT3 transcription and C/EBPβ expression in uterine macrophages. PlGF plays a key role in early pregnancy maintenance by skewing dMφs toward an M2-like phenotype via the FLT-1-STAT3-C/EBPβ signaling pathway. Excitingly, our results highlight a rationale that PlGF is a promising target to prevent early spontaneous abortion.

Association of Low Placental Growth Factor Gene Expression with Maternal and Neonatal Outcomes in Type 1 Diabetes: A Single Center, Cross-Sectional Study

Objective : The placental growth factor (PlGF) plays a crucial role in early and late pregnancy placental development. Pregestational type 1 diabetes (T1D) is a pregnancy complication that may lead to serious fetomaternal complications. Our study analyzed the association between placental PlGF mRNA expression and metabolic control, fetal weight and development in women with T1D. Materials and methods : A cross-sectional study on 65 pregnant women with T1D in singleton pregnancies admitted to the tertiary-level perinatal care unit. The study examined associations between the placental mRNA-PlGF gene expression measured with quantitative real-time PC and markers of maternal metabolism in the third trimester. The expression was also compared across maternal subgroups stratified according to the birth weight (small- vs. appropriate- vs. large-for-gestational age; SGA, AGA, LGA, respectively) and the following neonatal outcomes: mode of delivery, Apgar score and pH in the umbilical vessels. Results : Placental PlGF mRNA expression was significantly lower in SGA than in AGA and LGA patients (0.60 ± 0.34 vs. 0.63 ± 0.54 vs. 1.02 ± 0.15, respectively, p &lt; 0.05). In the SGA group, the expression of the PlGF-mRNA correlated positively with maternal 3 rd trimester BMI (r = 0.49, p = 0.04), pH and BE cord blood values, and maternal 3 rd trimester mean BP. There was no correlation between 3 rd -trimester glycated hemoglobin and mean blood glucose levels (MBG) and PlGF expression. Conclusions : Our data suggest that lower PlGF mRNA expression may predict neonatal outcomes in women with T1D giving birth to SGA newborns.

Alzheimer’s Amyloid β Peptide Induces Angiogenesis in an Alzheimer’s Disease Model Mouse through Placental Growth Factor and Angiopoietin 2 Expressions

Increased angiogenesis, especially the pathological type, has been documented in Alzheimer's disease (AD) brains, and it is considered to be activated due to a vascular dysfunction-mediated hypoxic condition. To understand the role of the amyloid β (Aβ) peptide in angiogenesis, we analyzed its effects on the brains of young APP transgenic AD model mice. Immunostaining results revealed that Aβ was mainly localized intracellularly, with very few immunopositive vessels, and there was no extracellular deposition at this age. Solanum tuberosum lectin staining demonstrated that compared to their wild-type littermates, the vessel number was only increased in the cortex of J20 mice. CD105 staining also showed an increased number of new vessels in the cortex, some of which were partially positive for collagen4. Real-time PCR results demonstrated that placental growth factor (PlGF) and angiopoietin 2 (AngII) mRNA were increased in both the cortex and hippocampus of J20 mice compared to their wild-type littermates. However, vascular endothelial growth factor (VEGF) mRNA did not change. Immunofluorescence staining confirmed the increased expression of PlGF and AngII in the cortex of the J20 mice. Neuronal cells were positive for PlGF and AngII. Treatment of a neural stem cell line (NMW7) with synthetic Aβ1-42 directly increased the expression of PlGF and AngII, at mRNA levels, and AngII at protein levels. Thus, these pilot data indicate that pathological angiogenesis exists in AD brains due to the direct effects of early Aβ accumulation, suggesting that the Aβ peptide regulates angiogenesis through PlGF and AngII expression.

Are Altered Expression of Vascular Endothelial Growth Factor and Placental Growth Factor Associated with Placental Angiogenesis in Recurrent Pregnancy Loss?

Are Altered Expression of Vascular Endothelial Growth Factor and Placental Growth Factor Associated with Placental Angiogenesis in Recurrent Pregnancy Loss?

Designing and Developing Enzyme-Linked Immunosorbent Assay Sandwich Kit for Measuring Placental Growth Factor Concentration.

Placental growth factor (PlGF) is an angiogenic factor belonging to vascular endothelial growth factor family. This factor is mainly expressed in the placenta and have important role in blood supply to embryonic tissues and fetal. According to accumulated data after 10th week of gestational age the expression of PlGF is increased. The peak of this factor is seen in the 30th week of pregnancy. The abnormal expression of PlGF have been seen in some diseases such as preeclampsia, eclampsia, cancer, and atherosclerotic lesions. Preeclampsia is a pregnancy complication characterized by high blood pressure and signs of damage to another organ system, most often the liver and kidneys. As noted the level of PlGF decreased in preeclampsia is, therefore, timely and accurate measurement of this factor could help in diagnosing preeclampsia. In this study, we worked on development of sandwich enzyme-linked immunosorbent assay (ELISA) kit for measurement of PlGF, to this end, bivalent single-domain monoclonal antibody with high affinity binding was used as detection antibody and rabbit polyclonal antibody with strong signal to PlGF was used as capture antibody. Both types of antibodies were produced in the laboratory. Therefore, this study showed that the designed kit can measure PlGF up to 7.5 pg/mL. Intra-assay accuracy was <10% and interassay accuracy was <15%. The ELISA sandwich kit had the appropriate sensitivity and accuracy in measuring human PlGF.

CircRNA Uxs1/miR-335-5p/PGF axis regulates choroidal neovascularization via the mTOR/p70 S6k pathway

Age-related macular degeneration (AMD) is one of the leading causes of irreversible blindness in the elderly population. Neovascular AMD is the late stage, characterized by choroidal neovascularization (CNV). Non-coding RNAs have been implicated in CNV; however, the role of circular RNAs (circRNAs) has not yet been elucidated. Herein, we comprehensively investigated circRNA profiles in laser-induced CNV mouse models and patient specimens. A novel circRNA, circRNA Uxs1, was identified, and its function in CNV regulation was investigated in the present study. CircRNA Uxs1 was consistently upregulated in CNV patient specimens and CNV mouse models. Knockdown of circRNA Uxs1 interrupted the tube formation, migration, and proliferation of endothelial cells in vitro. Silencing circRNA Uxs1 in vivo alleviated neovascularization formation, as shown by the decreased size of laser spots. Mechanistically, circRNA Uxs1 functioned by binding to miR-335-5p, which further upregulated the expression of placental growth factor (PGF) gene and activated the mammalian target of rapamycin/p70 S6 Kinase (mTOR/p70 S6k) pathway. By subretinal injections of adeno-associated virus (AAV), we demonstrated the anti-angiogenic function of circRNA Uxs1 knockdown in vivo. In conclusion, circRNA Uxs1 promoted CNV by sponging miR-335-5p, which stimulated PGF expression and subsequently activated the mTOR/p70 S6k pathway. Therefore, circRNA Uxs1 may serve as a promising therapeutic target for CNV.

Apolipoprotein A1 suppresses the hypoxia-induced angiogenesis of human retinal endothelial cells by targeting PlGF.

To investigate the anti-angiogenic effect of apolipoprotein A1 (apoA1) on primary human retinal vascular endothelial cells (HRECs) and explore the possible mechanism. The primary HRECs were transfected with apoA1-GFP recombinant lentiviral and were compared with cells undergoing transfection with empty lentiviral vectors. Hypoxia chambers were used to simulate the anoxic environment of cells under pathological condition. The concentrations of secreted vascular endothelial growth factor (VEGF) and placental growth factor (PlGF) were measured by enzyme-linked immunosorbent assay (ELISA). Cell migration ability was detected by wound healing assay. The sprouting of HRECs was determined by tube formation assay. The protein levels of extracellular signal regulated kinase 1/2 (ERK1/2) and phosphorylated ERK1/2 (p-ERK1/2) were measured by Western blot. Overexpressed apoA1 in hypoxia-induced HRECs significantly suppressed PlGF (0.67±0.10 folds, P=0.007). Overexpressed apoA1 also attenuated hypoxia-induced cell migration (0.32±0.11 folds, P<0.0001), tube formation (0.66±0.01 folds, P<0.0001) and the phosphorylation levels of ERK (0.6±0.11 folds, P=0.025). Pretreatment of mitogen-activated protein kinase kinase (MEK) inhibitor (U0126) further reduced the PlGF and angiogenesis in hypoxia-induced HRECs. ApoA1 inhibits the angiogenesis at least in part by inactivating ERK1/2 in hypoxia-induced HRECs. Moreover, apoA1 suppresses the PlGF expression, which selectively associated with pathological angiogenesis.

Expression of Concern: Maternal Smoking History Enhances the Expression of Placental Growth Factor in Invasive Trophoblasts at Early Gestation Despite Cessation of Smoking.

Expression of Concern: Maternal Smoking History Enhances the Expression of Placental Growth Factor in Invasive Trophoblasts at Early Gestation Despite Cessation of Smoking.

Whole blood transcript and protein abundance of the vascular endothelial growth factor family relate to cognitive performance

The vascular endothelial growth factor (VEGF) family of genes has been implicated in the clinical development of Alzheimer's Disease (AD). A previous study identified associations between gene expression of VEGF family members in the prefrontal cortex and cognitive performance and AD pathology. This study explored if those associations were also observed in the blood. Consistent with previous observations in brain tissue, higher blood gene expression of placental growth factor (PGF) was associated with a faster rate of memory decline (p=0.04). Higher protein abundance of FMS-related receptor tyrosine kinase 4 (FLT4) in blood was associated with biomarker levels indicative of lower amyloid and tau pathology, opposite the direction observed in brain. Also, higher gene expression of VEGFB in blood was associated with better baseline memory (p=0.008). Notably, we observed that higher gene expression of VEGFB in blood was associated with lower expression of VEGFB in the brain (r=-0.19, p=0.02). Together, these results suggest that the VEGFB, FLT4, and PGF alterations in the AD brain may be detectable in the blood compartment.

Inhibition of triple negative breast cancer-associated inflammation and progression by N- acylethanolamine acid amide hydrolase (NAAA)

Triple-negative breast cancer (TNBC) is associated with high mortality due to the high expression of pro-inflammatory cytokines and lack of targeted therapies. N-acylethanolamine acid amidase (NAAA) is an N-terminal cysteine hydrolase that promotes inflammatory responses through the deactivation of Palmitoylethanolamide (PEA), an endogenous bioactive lipid mediator. Here, we examined NAAA expression in TNBC cells (MDA-MB-231 and MDA-MB-BrM2 cells) and the effects of NAAA inhibition on TNBC tumor growth, using a selective NAAA inhibitor AM11095 (IC50 = 20 nM). TNBC cells expressed elevated levels of full-length and splice mRNAs naaa variants. TNBC cells also express the N-acyl ethanol amides and elevated levels of the two fatty acid cores arachidonic (AA) and docosahexaenoic (DHA). PEA or AM11095 inhibited the secretion of IL-6 and IL-8, reduced the activation of the NF-kB pathway, decreased the expression of VEGF and Placental growth factor (PLGF) in TNBCs, and inhibited tumor cell migration in vitro. Using cellular magnetic resonance imaging (MRI), body images of mice administered with human MDA-MB-BrM2 cells treated with AM11095 showed a significant decrease in tumor numbers with a lower volume of tumors and increased mice survival. Mice untreated or treated with vehicle control showed a high number of tumors with high volumes in multiple organs. Thus, NAAA inhibition may constitute a potential therapeutic approach in the management of TNBC-associated inflammation and tumor growth.

Reduced expression in preterm birth of sFLT-1 and PlGF with a high sFLT-1/PlGF ratio in extracellular vesicles suggests a potential biomarker.

Preterm birth may have a pathological impact on intrauterine development of the fetal brain, resulting in developmental disabilities. In this study, we examine the expression of soluble Fms-like tyrosine kinase 1 (sFLT-1) and placental growth factor (PlGF), which is one of the vascular endothelial growth factors (VEGFs), as these play a key role in angiogenesis; in particular, we examine their effect on the sFLT-1/PlGF ratio in cases of preterm birth as compared to typical pregnancies. Enzyme-linked immunosorbent assay was performed on samples of maternal-derived plasma and extracellular vesicles-exosomes (EVs-EXs) isolated at the third trimester, consisting of 17 samples from cases of preterm birth and 38 control cases. Our results showed that both sFLT-1 (P=0.0014) and PlGF (P=0.0032) were significantly downregulated in cases of preterm birth compared to controls, while the sFLT-1/PIGF ratio was significantly (P=0.0008) increased in EVs-EXs, but not in maternal plasma. Our results suggest that this reduced expression of sFLT-1 and PlGF with an elevated sFLT-1/PlGF ratio in EVs-EXs may represent a potential biomarker for prediction of PTB.

MPC-1 IMMUNOHISTOLOGICAL COMPREHENSIVE ANALYSIS OF ANGIOGENIC FACTORS OTHER THAN VEGF IN GLIOBLASTOMAS IN RELATION TO THE USE OF BEVACIZUMAB

Abstract To date, few clinical observations have been reported for changes of alternative angiogenic factors (other than vascular endothelial growth factor [VEGF]) in human gliomas under bevacizumab (Bev). The elucidation of the mechanism of action and resistance is imperative to overcome resistance to Bev and develop a more effective therapy. This study aims to investigate the status and change of alternative angiogenic factors regarding Bev usage.The present study used 56 glioblastoma tissues obtained at 3 different settings: tumors of initial resection (naive Bev group), tumors resected following Bev therapy (effective Bev group), and recurrent tumors after Bev therapy (refractory/autopsied Bev group). The expression of alternative angiogenic factors including basic fibroblast growth factor (bFGF), placental growth factor (PlGF), Angiopoietin1 (Ang-1), Angiopoietin2(Ang-2) and EphrinA2 were investigated via immunohistochemistry. In large tumor vasculature (diameter &amp;gt;15μm), the expression of PlGF was significantly higher in the effective Bev group than naive Bev group. The expression of Ang-2 was persistently suppressed in the refractory/autopsied Bev group. In microtumor vasculature (diameter &amp;lt;15μm), the expression of Ang-2 was higher in the effective group than naive Bev group. The status of PlGF was similar among these three groups.We provide the first clinicopathological evidence of the status of alternative angiogenic pathway after the Bev usage. These in situ observations will help to optimize therapy.