High Vascular Endothelial Growth Factor Research Articles

Predicting chemotherapy toxicity in multiple myeloma: the prognostic value of pre-treatment serum cytokine levels of interleukin-6, interleukin-8, monocyte chemoattractant protein-1, and vascular endothelial growth factor

IntroductionMultiple Myeloma (MM), a prevalent hematological malignancy, poses significant treatment challenges due to varied patient responses and toxicities to chemotherapy. This study investigates the predictive value of pretreatment serum levels of interleukin-6 (IL-6), interleukin-8 (IL-8), monocyte chemoattractant protein-1 (MCP-1), and vascular endothelial growth factor (VEGF) for chemotherapy-induced toxicities in newly diagnosed MM patients. We hypothesized that these cytokines, pivotal in the tumor microenvironment, might correlate with the incidence and severity of treatment-related adverse events.MethodsWe conducted a prospective observational study with 81 newly diagnosed MM patients, analyzing serum cytokine levels using the multiplex cytometric bead assay (CBA) flow cytometry method. The study used non-parametric and multivariate analysis to compare cytokine levels with treatment-induced toxicities, including lymphopenia, infections, polyneuropathy, and neutropenia.ResultsOur findings revealed significant associations between cytokine levels and specific toxicities. IL-8 levels were lower in patients with lymphopenia (p=0.0454) and higher in patients with infections (p=0.0009) or polyneuropathy (p=0.0333). VEGF concentrations were notably lower in patients with neutropenia (p=0.0343). IL-8 demonstrated an 81% sensitivity (AUC=0.69; p=0.0015) in identifying infection risk. IL-8 was an independent predictor of lymphopenia (Odds Ratio [OR]=0.26; 95% Confidence Interval [CI]=0.07-0.78; p=0.0167) and infection (OR=4.76; 95% CI=0.07-0.62; p=0.0049). High VEGF levels correlated with a 4-fold increased risk of anemia (OR=4.13; p=0.0414).ConclusionsPre-treatment concentrations of IL-8 and VEGF in serum can predict hematological complications, infections, and polyneuropathy in patients with newly diagnosed MM undergoing chemotherapy. They may serve as simple yet effective biomarkers for detecting infections, lymphopenia, neutropenia, and treatment-related polyneuropathy, aiding in the personalization of chemotherapy regimens and the mitigation of treatment-related risks.

Association of Neurotrophic Factors at Midlife With In Vivo Measures of β-Amyloid and Tau Burden 15 Years Later in Dementia-Free Adults.

Neurotrophic factors (NTFs) play an important role in Alzheimer disease (AD) pathophysiology. Brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF) are important NTFs. However, a direct link of BDNF and VEGF circulating levels with in vivo measures of amyloid-β (Aβ) and tau burden remains to be elucidated. We explored the relationship of BDNF and VEGF serum levels with future brain Aβ and tau pathology in a cohort of cognitively healthy, predominantly middle-aged adults and tested for possible effect modifications by sex and menopausal status. This cross-sectional analysis was conducted using data from the Framingham Heart Study (FHS), a community-based cohort study. The study sample included cognitively healthy participants from the FHS Offspring and Third-generation cohorts. BDNF and VEGF were measured in the third-generation cohort during examination cycles 2 (2005-2008) and 1 (2002-2005), respectively, and in the offspring cohort during examination cycle 7 (1998-2001). Participants underwent 11C-Pittsburgh compound B amyloid and 18F-Flortaucipir tau-PET imaging (2015-2021). Linear regression models were used to assess the relationship of serum BDNF and VEGF levels with regional tau and global Aβ, adjusting for potential confounders. Interactions with sex and menopausal status were additionally tested. The sample included 414 individuals (mean age = 41 ± 9 years; 51% female). Continuous measures of BDNF and VEGF were associated with tau signal in the rhinal region after adjustment for potential confounders (β = -0.15 ± 0.06, p = 0.018 and β = -0.19 ± 0.09, p = 0.043, respectively). High BDNF (≥32,450 pg/mL) and VEGF (≥488 pg/mL) levels were significantly related to lower rhinal tau (β = -0.27 ± 0.11, p = 0.016 and β = -0.40 ± 0.14, p = 0.004, respectively) and inferior temporal tau (β = -0.24 ± 0.11, p = 0.028 and β = -0.26 ± 0.13, p = 0.049, respectively). The BDNF-rhinal tau association was observed only among male individuals. Overall, BDNF and VEGF were not associated with global amyloid; however, high VEGF levels were associated with lower amyloid burden in postmenopausal women (β = -1.96 ± 0.70, p = 0.013, per 1 pg/mL). This study demonstrates a robust association between BDNF and VEGF serum levels with in vivo measures of tau almost 2 decades later. These findings add to mounting evidence from preclinical studies suggesting a role of NTFs as valuable blood biomarkers for AD risk prediction.

DYNAMICS OF VASCULAR ENDOTHELIAL GROWTH FACTOR IN HEMORRHAGIC STROKE DEPENDING ON THE DISEASE SEVERITY

Introduction. The results of experimental studies indicate the growth factors, in particular the vascular endothelial growth factor, around the hematoma already at the beginning of hemorrhagic stroke.
 The aim of the study: to find out the features of vascular endothelial growth factor expression in patients with hemorrhagic stroke depending on the disease severity.
 Research metods. 53 patients with hemorrhagic stroke were examined. The control group - 25 people with hypertension without dyscirculatory disorders of cerebral circulation.
 The level of neurological deficit was assessed using the National Institute of Health Stroke Scale (NIHSS).
 Vascular endothelial growth factor (VEGF) in the blood was determined on the 1st, 5th and 21st days of the acute stroke period by enzyme-linked immunosorbent assay (ELISA) (test kits of the company "Biosourse" (USA)). The research results were analyzed by the method of variational statistics using the program "STATISTICA 6.0" (StatSoft, USA).
 Results and discussion. With a mild degree of severity, the content of VEGF in the blood is significantly lower on the 1st and 5th days of the acute period compared to the control group. This may be one of the factors contributing to the development of a hemorrhagic stroke. An increase in VEGF in the first days of the disease can be a marker of the serious condition of patients with hemorrhagic stroke. VEGF levels on the 5th and 21st days are highest in mild cases, and lowest in severe cases. The increased synthesis of VEGF in case of a mild stroke indicates a more adequate response of the endothelium to damage.
 Conclusions. A marker of a mild hemorrhagic stroke can be low VEGF levels in the first days of the disease and their significant increase at the end of the previous period. High VEGF in the blood at the beginning of the disease, and relatively lower indicators (compared to a mild course) at the end of the previous period are associated with the severe condition of patients with hemorrhagic stroke.

Whole brain morphologic features improve the predictive accuracy of IDH status and VEGF expression levels in gliomas.

Glioma is a systemic disease that can induce micro and macro alternations of whole brain. Isocitrate dehydrogenase and vascular endothelial growth factor are proven prognostic markers and antiangiogenic therapy targets in glioma. The aim of this study was to determine the ability of whole brain morphologic features and radiomics to predict isocitrate dehydrogenase status and vascular endothelial growth factor expression levels. This study recruited 80 glioma patients with isocitrate dehydrogenase wildtype and high vascular endothelial growth factor expression levels, and 102 patients with isocitrate dehydrogenase mutation and low vascular endothelial growth factor expression levels. Virtual brain grafting, combined with Freesurfer, was used to compute morphologic features including cortical thickness, LGI, and subcortical volume in glioma patient. Radiomics features were extracted from multiregional tumor. Pycaret was used to construct the machine learning pipeline. Among the radiomics models, the whole tumor model achieved the best performance (accuracy 0.80, Area Under the Curve 0.86), while, after incorporating whole brain morphologic features, the model had a superior predictive performance (accuracy 0.82, Area Under the Curve 0.88). The features contributed most in predicting model including the right caudate volume, left middle temporal cortical thickness, first-order statistics, shape, and gray-level cooccurrence matrix. Pycaret, based on morphologic features, combined with radiomics, yielded highest accuracy in predicting isocitrate dehydrogenase mutation and vascular endothelial growth factor levels, indicating that morphologic abnormalities induced by glioma were associated with tumor biology.

Neuropilin-1 and placental growth factor as prognostic factors in metastatic breast cancer

BackgroundAngiogenesis is crucial for tumor development, progression, and metastasizing. The most important regulator of angiogenesis is the vascular endothelial growth factor (VEGF) family, which is involved in multiple pathways in tumor microenvironment. The objective of this study was to investigate the prognostic value of the VEGF family in patients treated for metastatic breast cancer. The emphasis was on neuropilin-1 (NRP-1) and placental growth factor (PlGF).Materials and methodsAn analysis of eight members of the VEGF family was performed using baseline plasma samples of 65 patients treated for metastatic HER2 negative breast cancer in a phase II first-line bevacizumab plus chemotherapy trial. The patients were divided into two groups, high or low, according to the median for each VEGF family member. Progression-free survival (PFS) and overall survival (OS) were determined for each VEGF family member.ResultsThe patients with low plasma levels of NRP-1 and PlGF had a longer OS than those with high plasma levels [multivariable adjusted hazard ratios (HRs) 2.54 (95% confidence interval (CI) 1.11–5.82, p = 0.02) and 3.11 (95% CI 1.30–7.47, p = 0.01), respectively]. The patients with low levels of both NRP-1 and PlGF had a remarkably long OS with HR of 6.24, (95% CI 1.97–19.76, p = 0.002). In addition, high baseline NRP-1 level was associated with a significantly shorter PFS [multivariable adjusted HR 2.90 (95% CI 1.02–8.28, p = 0.04)] than that in the low-level group, and a high baseline vascular endothelial growth factor receptor-2 level was associated with a longer PFS [multivariable adjusted HR 0.43 (95% CI 0.19–0.98, p = 0.04)].ConclusionEspecially NRP-1 and PlGF have prognostic potential in metastatic breast cancer patients treated with a bevacizumab-taxane combination. Patients with low plasma levels of NRP-1 or PlGF have longer OS than patients with high levels. Patients with both low NRP-1 and PlGF levels appear to have excellent long-term survival.Trial registrationClinicalTrials.gov identifier: NCT00979641, registration date 18/09/2009. The regional Ethics Committee: R08142M, registration date 18/11/2008.

Long-term day-by-day tracking of microvascular networks sprouting in fibrin gels: From detailed morphological analyses to general growth rules.

Understanding and controlling of the evolution of sprouting vascular networks remains one of the basic challenges in tissue engineering. Previous studies on the vascularization dynamics have typically focused only on the phase of intense growth and often lacked spatial control over the initial cell arrangement. Here, we perform long-term day-by-day analysis of tens of isolated microvasculatures sprouting from endothelial cell-coated spherical beads embedded in an external fibrin gel. We systematically study the topological evolution of the sprouting networks over their whole lifespan, i.e., for at least 14 days. We develop a custom image analysis toolkit and quantify (i) the overall length and area of the sprouts, (ii) the distributions of segment lengths and branching angles, and (iii) the average number of branch generations-a measure of network complexity. We show that higher concentrations of vascular endothelial growth factor (VEGF) lead to earlier sprouting and more branched networks, yet without significantly affecting the speed of growth of individual sprouts. We find that the mean branching angle is weakly dependent on VEGF and typically in the range of 60°-75°, suggesting that, by comparison with the available diffusion-limited growth models, the bifurcating tips tend to follow local VEGF gradients. At high VEGF concentrations, we observe exponential distributions of segment lengths, which signify purely stochastic branching. Our results-due to their high statistical relevance-may serve as a benchmark for predictive models, while our new image analysis toolkit, offering unique features and high speed of operation, could be exploited in future angiogenic drug tests.

Prospective Observational Study of Ramucirumab Plus Docetaxel After Combined Chemoimmunotherapy in Patients With Non-Small-Cell Lung Cancer.

A history of pre-administration of immune checkpoint inhibitors has been reported to be associated with good outcomes of ramucirumab (RAM) plus docetaxel (DOC) combination therapy for advanced non-small-cell lung cancer (NSCLC). However, existing knowledge on the clinical significance of RAM and DOC following combined chemoimmunotherapy is limited. Therefore, we evaluated the efficacy and safety of RAM plus DOC therapy after combined chemoimmunotherapy and attempted to identify the predictors of its outcomes. This multicenter, prospective study investigated the efficacy and safety of RAM plus DOC after combined chemoimmunotherapy. The primary endpoint was progression-free survival (PFS). Secondary endpoints were the objective response rate (ORR), disease control rate (DCR), overall survival (OS), and incidence of adverse events. An exploratory analysis measured serum cytokine levels at the start of treatment. Overall, 44 patients were enrolled from 10 Japanese institutions between April 2020 and June 2022. The median PFS and OS were 6.3 and 22.6 months, respectively. Furthermore, the ORR and DCR were 36.4% and 72.7%, respectively. The high vascular endothelial growth factor D (VEGF-D) group had a significantly shorter PFS and OS. A combination of high VEGF-A and low VEGF-D levels was associated with a longer PFS. Our results showed that RAM plus DOC after combined chemoimmunotherapy might be an effective and relatively feasible second-line treatment for patients with advanced NSCLC in a real-world setting.

RORα inhibits gastric cancer proliferation through attenuating G6PD and PFKFB3 induced glycolytic activity

BackgroundGlycolysis is critical for harvesting abundant energy to maintain the tumor microenvironment in malignant tumors. Retinoic acid-related orphan receptor α (RORα) has been identified as a circadian gene. However, the association of glycolysis with RORα in regulating gastric cancer (GC) proliferation remains poorly understood.MethodsBioinformatic analysis and retrospective study were utilized to explore the role of RORα in cell cycle and glycolysis in GC. The mechanisms were performed in vitro and in vivo including colony formation, Cell Counting Kit-8 (CCK-8), Epithelial- mesenchymal transition (EMT) and subcutaneous tumors of mice model assays. The key drives between RORα and glycolysis were verified through western blot and chip assays. Moreover, we constructed models of high proliferation and high glucose environments to verify a negative feedback and chemoresistance through a series of functional experiments in vitro and in vivo.ResultsRORα was found to be involved in the cell cycle and glycolysis through a gene set enrichment analysis (GSEA) algorithm. GC patients with low RORα expression were not only associated with high circulating tumor cells (CTC) and high vascular endothelial growth factor (VEGF) levels. However, it also presented a positive correlation with the standard uptake value (SUV) level. Moreover, the SUVmax levels showed a positive linear relation with CTC and VEGF levels. In addition, RORα expression levels were associated with glucose 6 phosphate dehydrogenase (G6PD) and phosphofructokinase-2/fructose-2,6-bisphosphatase (PFKFB3) expression levels, and GC patients with low RORα and high G6PD or low RORα and high PFKFB3 expression patterns had poorest disease-free survival (DFS). Functionally, RORα deletion promoted GC proliferation and drove glycolysis in vitro and in vivo. These phenomena were reversed by the RORα activator SR1078. Moreover, RORα deletion promoted GC proliferation through attenuating G6PD and PFKFB3 induced glycolytic activity in vitro and in vivo. Mechanistically, RORα was recruited to the G6PD and PFKFB3 promoters to modulate their transcription. Next, high proliferation and high glucose inhibited RORα expression, which indicated that negative feedback exists in GC. Moreover, RORα deletion improved fluorouracil chemoresistance through inhibition of glucose uptake.ConclusionRORα might be a novel biomarker and therapeutic target for GC through attenuating glycolysis.

Serum Vitamin D Levels and Vascular Endothelial Growth Factor in Patients with Type 2 Diabetes Mellitus: A Cross-sectional Study

Introduction: Diabetes Mellitus (DM) is the most common noncommunicable disease and the fifth leading cause of death worldwide. Recent research has demonstrated that low Vitamin D levels and high Vascular Endothelial Growth Factor (VEGF) in middle-aged and elderly populations represent a risk factor for Type 2 Diabetes Mellitus (T2DM). Aim: To estimate the Vitamin D and VEGF levels in study subjects with T2DM and healthy controls and to correlate the Vitamin D level and VEGF with HbA1c % in study subjects with T2DM. Materials and Methods: A cross-sectional study was undertaken from October 2014 to November 2016 at the Department of Medicine in collaboration with the Department of Biochemistry, Bangalore Medical College and Research Institute, Bangalore. The study included 50 T2DM subjects on oral hypoglycaemic agents for five years and 50 age and sexmatched healthy controls selected randomly from the general population. In all the study subjects, Random Blood Glucose (RBG), LFT, Renal Function Test (RFT), HBA1c, serum Vitamin D, and serum VEGF were estimated. Student t-test and Chisquare/Fisher-Exact test were used to find the significance of study parameters between cases and controls. Multivariate logistic regression analysis was done to assess the risk factors for DM. Results: The mean age of the cases was 50.9±9.7 years and of controls was 49.76±7.7 years. Among the 50 cases, 19 (38%) were men and 31 (62%) were women. Among the 50 controls, 27 (54%) were men and 23 (46%) were women. The mean Body Mass Index (BMI) among cases was 27.21±4.59 and in controls was 24.82±2.63 (p-value=0.0016). The mean serum 25(OH) Vitamin D levels in cases were 11.39±3.32 ng/mL and in controls were 28.06±11.14 ng/mL (p-value <0.001). The mean serum VEGF levels in cases were 97.52±16.96 pg/mL and in controls were 56.37±17.74 pg/mL (p-value <0.001). Conclusion: The present study found that subjects with T2DM have lower serum 25(OH) Vitamin D levels and higher serum VEGF levels than those without T2DM. Serum Vitamin D decreases and serum VEGF-A levels increase with increasing HbA1c%, correlating with vascular complications.

Novel CO2-encapsulated Pluronic F127 hydrogel for the treatment of Achilles tendon injury

Nonsurgical treatment and surgical repairment of injured Achilles tendons seldom restore the wounded tendon to its original elasticity and stiffness. Therefore, we hypothesized that the surgically repaired Achilles tendon can achieve satisfactory regeneration by applying multi-drug encapsulated hydrogels. In this study, a novel bupivacaine-eluting carbon dioxide-encapsulated Pluronic F127 hydrogel (BC-hydrogel) was developed for the treatment of Achilles tendon injuries. The rheological properties of BC-hydrogel were measured. A high-performance liquid chromatography assay was used to assess the release characteristics of bupivacaine in both in vitro and in vivo settings. Furthermore, the effectiveness of BC-hydrogel in treating torn tendons was examined in a rat model, and histological analyses were conducted. Evidently, the degradable hydrogels continuously eluted bupivacaine for more than 14 days. The animal study results revealed that the BC-hydrogel improved the post-surgery mobility of the animals compared with pristine hydrogels. Histological assay results demonstrated a significant reaction to high vascular endothelial growth factor in the surrounding tissues and expression of collagen I within the repaired tendon. This demonstrates the potential of this novel BC-hydrogel as an effective treatment method for Achilles tendon injuries.

The possible dual role of Ang-2 in the prognosis of pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) features a dense desmoplastic stroma, which raises the intratumoral interstitial pressure leading to vascular collapse and hypoxia, inducing angiogenesis. Vascular growth factors, such as vascular endothelial growth factor (VEGF) and angiopoietin-2 (Ang-2), increase in PDAC. A high VEGF and a high circulating Ang-2 associate with shorter survival in PDAC. In addition to the circulatory Ang-2, PDAC endothelial and epithelial cells express Ang-2. No correlation between tumor epithelial nor endothelial cell Ang-2 expression and survival has been published. We aimed to examine Ang-2 expression and survival. This study comprised PDAC surgical patients at Helsinki University Hospital in 2000–2013. Ang-2 immunohistochemistry staining was completed on 168 PDAC patient samples. Circulating Ang-2 levels were measured using ELISA in the sera of 196 patients. Ang-2 levels were assessed against clinical data and patient outcomes. A low tumor epithelial Ang-2 expression predicted shorter disease-specific survival (DSS) compared with a high expression (p = 0.003). A high serum Ang-2 associated with shorter DSS compared with a low circulating Ang-2 (p = 0.016). Ang-2 seemingly plays a dual role in PDAC survival. Further studies are needed to determine the mechanisms causing tumor cell Ang-2 expression and its positive association with survival.

Serum VEGF levels as a predictor of recurrence in patients with advanced‑stage esophageal squamous cell carcinoma following curative esophagectomy followed by chemotherapy or concurrent radiotherapy.

The present study evaluated serum levels of vascular endothelial growth factor (VEGF) as a predictor of recurrence in patients with advanced-stage esophageal squamous cell carcinoma (ESCC) following curative esophagectomy followed by chemotherapy or concurrent radiotherapy. Patients with locally advanced resectable ESCC underwent R0 esophagectomy followed by chemotherapy or concurrent radiotherapy as an adjuvant. Serum VEGF levels in 173 patients, including 57 patients with recurrent disease, and 183 healthy controls were determined using a Luminex assay. The results demonstrated that the serum VEGF levels were significantly higher in 57 patients with locally advanced resectable ESCC at recurrence compared with the levels at pre-treatment (P<0.001). The patients with recurrence exhibited significantly higher serum VEGF levels during chemotherapy or concurrent radiotherapy than patients with no recurrence (P<0.05). Patients with low serum VEGF levels had a significantly longer survival time than those with high serum VEGF levels prior to treatment (P<0.01). The median survival times were 70 and 25 months in patients with locally advanced resectable ESCC with serum VEGF levels <161.75 and ≥161.75 pg/ml following treatment, respectively (P<0.01). Compared with patients with VEGF levels <147 pg/ml following treatment, patients with locally advanced resectable ESCC with VEGF levels ≥147 pg/ml had a significantly higher risk of recurrence (P<0.01). Patients with low serum VEGF levels (<147 pg/ml) had significantly higher recurrence-free survival rates than those with high serum VEGF levels (≥147 pg/ml) following treatment (P<0.01). The findings of the present study demonstrate that serum VEGF levels are a potential predictor of recurrence and of the treatment outcomes of chemotherapy or concurrent radiotherapy in patients with locally advanced resectable ESCC.

VEGFR-2 adhesive nanoprobes reveal early diabetic retinopathy in vivo

Diabetic retinopathy (DR) is a debilitating organ manifestation of diabetes. Absent of early diagnosis and intervention, vision tends to drastically and irreversibly decline. Previously, we showed higher vascular endothelial growth factor receptor 2 (VEGFR-2) expression in diabetic microvessels, and the suitability of this molecule as a biomarker for early DR diagnosis. However, a hurdle to translation remained generation of biodegradable nanoprobes that are sufficiently bright for in vivo detection. Here, an adhesive fluorescent nanoprobe with high brightness was developed using biodegradable materials. To achieve that, a fluorophore with bulky hydrophobic groups was encapsulated in the nanoparticles to minimize fluorophore π-π stacking, which diminishes brightness at higher loading contents. The nanoprobe selectively targeted the VEGFR-2 under dynamic flow conditions. Upon systemic injection, the nanoprobes adhered in the retinal microvessels of diabetic mice and were visualized as bright spots in live retinal microscopy. Histology validated the in vivo results and showed binding of the nanoprobes to the microvascular endothelium and firmly adhering leukocytes. Leukocytes were found laden with nanoprobes, indicating the potential for payload transport across the blood-retinal barrier. Our results establish the translational potential of these newly generated nanoprobes in early diagnosis of DR.

High VEGF Concentrations Accelerate Human Trabecular Meshwork Fibrosis in a TAZ-Dependent Manner.

We aimed to investigate the effects of different concentrations of vascular endothelial growth factor (VEGF) on the extracellular matrix (ECM) and fibrotic proteins in human trabecular meshwork (TM) cells. We also explored how the Yes-associated protein (YAP)/transcriptional co-activator with PDZ-binding motif (TAZ) signaling pathway modulates VEGF-induced fibrosis. We determined cross-linked actin network (CLAN) formation using TM cells. Changes in fibrotic and ECM protein expression were determined. High VEGF concentrations (10 and 30 ng/mL) increased TAZ and decreased p-TAZ/TAZ expression in TM cells. Western blotting and real-time PCR revealed no YAP expression changes. Fibrotic and ECM protein expression decreased at low VEGF concentrations (1 and 10 ρg/mL) and significantly increased at high VEGF concentrations (10 and 30 ng/mL). CLAN formation increased in TM cells treated with high VEGF concentrations. Moreover, TAZ inhibition by verteporfin (1 μM) rescued TM cells from high-VEGF-concentration-induced fibrosis. Low VEGF concentrations reduced fibrotic changes, whereas high VEGF concentrations accelerated fibrosis and CLAN formations in TM cells in a TAZ-dependent manner. These findings reflect the dose-dependent influences of VEGF on TM cells. Moreover, TAZ inhibition might be a therapeutic target for VEGF-induced TM dysfunction.

The effects of cream-based Triticum vulgare with and without therapeutic ultrasound on excisional wound healing in diabetic rats

Purpose The purpose of the current study was to evaluate the effect of Triticum vulgare (TVE) alone or combined with therapeutic ultrasound (TUS) on wound healing in a diabetic rat model. Materials and Methods A total of 72 male Wistar rats were randomly divided into four groups: Group Control, wounded rats without treatment; Group TUS, wounded rats with TUS application; Group TVE, wounded rats treated with TVE; and Group TVE + TUS, wounded rats treated with TVE + TUS. Wound healing was assessed using wound area calculation and thermographic, biochemical, histopathologic, immunohistochemical, and immunofluorescence analyses on post-wounding days 7, 14, and 21. Results On day 21, the wound surface area was significantly decreased in Group TVE + TUS (0.18 ± 0.07 cm2) compared to the other groups (p < 0.001). A significant increase in wound area temperature was recorded on days 7, 14, and 21 in all groups compared to day 0 (p < 0.001). On day 21, Group TVE + TUS (35.4 ± 0.2 °C) had the most significantly highest wound area temperature compared to the other groups (p < 0.001). The highest histopathological scores were recorded in Group TVE + TUS on days 7, 14, and 21 (p = 0.04). The highest vascular endothelial growth factor expression was observed in Group TVE + TUS (82.53 ± 1.98) on day 7 (p = 0.03). Conclusion In conclusion, treatment with a combination of TVE and TUS effectively enhanced wound healing in diabetic rats compared with other treatment groups.

Predictive value of serum HIF-1α and VEGF for arrhythmia in acute coronary syndrome patients.

Percutaneous coronary intervention (PCI) has been widely used in the alleviation of myocardial ischemia in patients with acute coronary syndrome (ACS). However, the incidence of reperfusion arrhythmia (RA) after PCI is high, which seriously affects the prognosis of ACS patients. Therefore, this study aimed to study the predictive value of serum HIF-1α and VEGF levels before PCI for RA in ACS patients post PCI. A total of 200 ACS patients who underwent PCI were selected and divided into those with RA after PCI (RA, n = 93) and those without RA after PCI (non-RA, n = 107) according to Lown grade. Spearman correlation analysis was applied for the relationship between serum hypoxia inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF) levels and Lown grade. Patients with RA after PCI tended to have higher levels of creatine kinase muscle and brain isoenzyme (CK-MB), serum HIF-1α and VEGF before surgery. Low left ventricular ejection fraction (LVEF), high CK-MB, high serum VEGF and HIF-1α were risk factors for RA in ACS patients within 24 h after PCI. Receiver operating characteristic (ROC) analysis revealed that serum HIF-1α and VEGF levels could predict RA in ACS patients after PCI, and the combined detection could increase the sensitivity of single HIF-1α detection and the specificity of single VEGF detection. Lown grade was positively correlated with the serum HIF-1α and VEGF concentrations. In conclusion, serum HIF-1α and VEGF levels before PCI are risk factors for the occurrence of RA in ACS patients after PCI, and have certain predictive values for the occurrence of RA in ACS patients after PCI.

Immunostaining for VEGF and Decorin Predicts Poor Survival and Recurrence in Canine Soft Tissue Sarcoma

The aim of this study was to investigate whether using immunohistochemistry to detect the angiogenic proteins vascular endothelial growth factor (VEGF) and decorin can help predict the risk of local recurrence of, or death from, canine soft tissue sarcoma (STS). VEGF and decorin were detected using validated immunohistochemical methods on 100 formalin-fixed paraffin-embedded samples of canine STS. The tumours had been resected previously, with clinical outcome determined by questionnaire. Each slide was assessed by light microscopy and the pattern of immunostaining with VEGF and decorin determined. Patterns of immunostaining were then analysed to detect associations with outcome measures of local recurrence and tumour-related death. High VEGF immunostaining was significantly (p < 0.001) associated with both increased local recurrence and reduced survival time. The distribution of decorin immunostaining within the tumour was significantly associated with survival time (p = 0.04) and local tumour recurrence (p = 0.02). When VEGF and decorin scores were combined, STS with both high VEGF and low decorin immunostaining were more likely to recur or cause patient death (p < 0.001). The results of this study suggest that immunostaining of VEGF and decorin may help predict the risk of local recurrence of canine STS.

Clinicopathologic significance of the delta-like ligand 4, vascular endothelial growth factor, and hypoxia-inducible factor-2α in gallbladder cancer.

Gallbladder cancer (GBC) is usually detected in advanced stages with a low 5-year survival rate. Delta-like ligand 4 (DLL4), vascular endothelial growth factor (VEGF), and hypoxia-inducible factor-2alpha (HIF2α) have been studied for their role in tumorigenesis and potential for therapeutic target, and multiple clinical trials of the agents targeting them are ongoing. We investigated the expression of these markers in surgically resected GBC and tried to reveal their association with the clinicopathologic features, mutual correlation of their expression, and prognosis of the GBC patients by their expression. We constructed the tissue microarray blocks of 99 surgically resected GBC specimens and performed immunohistochemistry of DLL4, VEGF, and HIF2α. We used the quantitative digital image analysis to evaluate DLL4 and VEGF expression, while the expression of HIF2α was scored manually. The expression of VEGF and HIF2α showed a significant trend with tumor differentiation (p= .028 and p= .006, respectively). We found that the high DLL4 and VEGF expression were significantly correlated with lymph node metastasis (p= .047, both). The expression of VEGF and HIF2α were significantly correlated (p < .001). The GBC patients with low HIF2α expression showed shorter recurrence-free survival than those with high HIF2α expression. This study suggested the possibility of the usage of DLL4 and VEGF to predict the lymph node metastasis and the possibility of VEGF and HIF2α to predict the expression level mutually. Further studies may be needed to validate our study results and eventually accelerate the introduction of the targeted therapy in GBC.

Reprogramming of VEGF-mediated extracellular matrix changes through autocrine signaling

ABSTRACT Vascular endothelial growth factor (VEGF) plays key roles in angiogenesis, vasculogenesis, and wound healing. In cancers, including triple negative breast cancer (TNBC), VEGF has been associated with increased invasion and metastasis, processes that require cancer cells to traverse through the extracellular matrix (ECM) and establish angiogenesis at distant sites. To further understand the role of VEGF in modifying the ECM, we characterized VEGF-mediated changes in the ECM of tumors derived from TNBC MDA-MB-231 cells engineered to overexpress VEGF. We established that increased VEGF expression by these cells resulted in tumors with reduced collagen 1 (Col1) fibers, fibronectin, and hyaluronan. Molecular characterization of tumors identified an increase of MMP1, uPAR, and LOX, and a decrease of MMP2, and ADAMTS1. α-SMA, a marker of cancer associated fibroblasts (CAFs), increased, and FAP-α, a marker of a subset of CAFs associated with immune suppression, decreased with VEGF overexpression. Analysis of human data from The Cancer Genome Atlas Program confirmed mRNA differences for several molecules when comparing TNBC with high and low VEGF expression. We additionally characterized enzymatic changes induced by VEGF overexpression in three different cancer cell lines that clearly identified autocrine-mediated changes, specifically uPAR, in these enzymes. Unlike the increase of Col1 fibers and fibronectin mediated by VEGF during wound healing, in the TNBC model, VEGF significantly reduced key protein components of the ECM. These results further expand our understanding of the role of VEGF in cancer progression and identify potential ECM-related targets to disrupt this progression.

Low Serum Vascular Endothelial Growth Factor Level Predicts Adverse Outcomes in Neonates with Respiratory Distress Syndrome

Objective: Preterm neonates are susceptible to neonatal respiratory distress syndrome (NRDS). Lower levels of cord blood vascular endothelial growth factor (VEGF) are implicated in NRDS. This study aims to explore whether the serum VEGF level has prognostic values on neonates with respiratory distress syndrome (RDS). Methods: A total of 80 infants diagnosed with NRDS were enrolled, with 70 preterm neonates without NRDS as controls. Cord blood samples before treatment and venous blood samples after treatment were collected and clinical information was recorded. The serum VEGF level was measured using enzyme-linked immunosorbent assay kits. Receiver operating characteristic (ROC) curve was used to evaluate whether serum VEGF is a biomarker of NRDS. Newborns were followed up for 1 month to collect survival information. The influence of VEGF levels on overall survival was analyzed using the Kaplan-Meier method. The univariate and multivariate Cox regression models were adopted to assess the prognostic factor of NRDS. Results: VEGF level was decreased in sera of neonates with RDS. The area under the ROC curve of VEGF level in distinguishing neonates with RDS from neonates without RDS was 0.949, with a cutoff value of 39.72 (87.50% sensitivity, 87.14% specificity). Serum VEGF was a biomarker of NRDS. Neonates with RDS with high VEGF levels had longer periods of survival than those with low VEGF levels. NRDS grade and VEGF level were independent prognostic factors affecting the overall survival of neonates with RDS. Conclusion: Decreased serum VEGF level in RDS neonates can predict the poor prognosis of NRDS, and VEGF level might be an independent prognostic factor for the overall survival of RDS neonates. Clinical Trial Registration No. 201901A.