Biomarkers Of Angiogenesis Research Articles

Circulating Protein Biomarkers Associated with Heart Failure with Preserved Ejection Fraction

Introduction The prevalence of heart failure with preserved ejection fraction (HFpEF) is increasing. This disease has posed diagnostic and therapeutic challenges; mortality and morbidity remain unacceptably high. Unbiased molecular studies are necessary to identify better diagnostic biomarkers. Hypothesis Large-scale discovery proteomics with a multiplex immunoassay platform will identify novel molecular mechanisms that differentiate HFpEF from patients without heart failure (HF). Methods We performed proteomic analyses (Olink) of 552 proteins on 88 HFpEF cases and 88 no HF controls from individuals referred for cardiac catheterization at Duke University. HFpEF was defined as history of HF, ejection fraction >45% and diastolic dysfunction class ≥1; no-HF controls had no diastolic dysfunction. Univariate logistic regression was used to identify proteins associated with HFpEF; associated proteins at a false discovery rate Results As expected, HFpEF cases were older and had higher BMI, SBP, creatinine and prevalence of DM (p Conclusions Biomarkers of angiogenesis, fibrosis, fatty acid metabolism and inflammation are associated with HFpEF and improve discriminative capabilities on top of clinical factors and NT-proBNP. These findings highlight the importance of these pathways in HFpEF and identify potential novel circulating diagnostic biomarkers.

Mesenchymal Stem Cell Spheroids Embedded in an Injectable Thermosensitive Hydrogel: An In Situ Drug Formation Platform for Accelerated Wound Healing.

The ability of mesenchymal stem cells (MSCs) to enhance cutaneous wound healing has been well established. Extensive expansion of cells to reach sufficient cell numbers for regenerating tissues has always limited cell-based therapies. An ingenious solution to address this challenge is to develop a strategy to increase the immunomodulatory effects of MSCs without expanding them. In this study, we employed a simple characteristic of cells. It was observed that an optimized three-dimensional (3D) MSC culture in spheroid forms significantly improved their paracrine effects. An electrospray (ES) encapsulation apparatus was used to encapsulate individual or 3D spheroid MSCs into microscale alginate beads (microbeads). Furthermore, alginate microbeads were embedded in an injectable thermosensitive hydrogel matrix, which gels at skin temperature. The hydrogel fills and seals the wounds cavities, maintains high humidity at the wound area, absorbs exudate, and fixes microbeads, protecting them from direct contact with the harsh wound environment. In vitro investigations revealed that secretion of interleukin 10 (IL-0) and transforming growth factor β1 (TGF-β1) gene was gradually enhanced, providing a delivery platform for prolonged release of bioactive molecules. In vivo study on full-thickness wounds showed granulation and re-epithelialization, only after 7 days. Moreover, increased expression of α-smooth muscle actin (α-SMA) in the first 14 days after treatment ensured wound contraction. Besides, a gradual decrease in α-SMA secretion resulted in reduced scar formation. Well-organized collagen fibrils and high expression of the angiogenesis biomarker CD31 confirmed the promoting effect of the hydrogel on the wound-healing process. The proposed wound-dressing system would potentially be used in scalable and effective cell-based wound therapies.

Ethanol-Induced Oxidative Stress Modifies Inflammation and Angiogenesis Biomarkers in Retinal Pigment Epithelial Cells (ARPE-19): Role of CYP2E1 and its Inhibition by Antioxidants.

The retinal pigment epithelium (RPE) plays a key role in retinal health, being essential for the protection against reactive oxygen species (ROS). Nevertheless, excessive oxidative stress can induce RPE dysfunction, promoting visual loss. Our aim is to clarify the possible implication of CYP2E1 in ethanol (EtOH)-induced oxidative stress in RPE alterations. Despite the increase in the levels of ROS, measured by fluorescence probes, the RPE cells exposed to the lowest EtOH concentrations were able to maintain cell survival, measured by the Cell Proliferation Kit II (XTT). However, EtOH-induced oxidative stress modified inflammation and angiogenesis biomarkers, analyzed by proteome array, ELISA, qPCR and Western blot. The highest EtOH concentration used stimulated a large increase in ROS levels, upregulating the cytochrome P450-2E1 (CYP2E1) and promoting cell death. The use of antioxidants such as N-acetylcysteine (NAC) and diallyl sulfide (DAS), which is also a CYP2E1 inhibitor, reverted cell death and oxidative stress, modulating also the upstream angiogenesis and inflammation regulators. Because oxidative stress plays a central role in most frequent ocular diseases, the results herein support the proposal that CYP2E1 upregulation could aggravate retinal degeneration, especially in those patients with high baseline oxidative stress levels due to their ocular pathology and should be considered as a risk factor.

Association of Plasma Biomarkers for Angiogenesis and Proteinopathy in Indian Amyotrophic Lateral Sclerosis Patients.

Abstarct Background Amyotrophic lateral sclerosis (ALS) is a rare motor neuron disease with progressive degeneration of motor neurons. Various molecules have been explored to provide the early diagnostic/prognostic tool for ALS without getting much success in the field and miscellaneous reports studied in various population. Objective The study was aimed to see the differential expression of proteins involved in angiogenesis (angiogenin [ANG], vascular endothelial growth factor [VEGF], vascular endothelial growth factor receptor 2 [VEGFR2], etc), proteinopathy (transactive response DNA binding protein-43 [TDP-43] and optineurin [OPTN]), and neuroinflammation (monocyte chemoattractant protein-1[MCP-1]) based on the characteristics of ALS pathology. Though, suitable panel based on protein expression profile can be designed to robust the ALS identification by enhancing the prognostic and diagnostic efficacy for ALS. Methods A total of 89 ALS patients and 98 nonneurological controls were analyzed for the protein expression. Expression of angiogenic (VEGF, VEGFR2, and ANG), neuroinflammation (MCP-1), and proteinopathy (TDP-43 and OPTN) markers were estimated in plasma of the participants. Proteins were normalized with respective value of total protein before employing statistical analysis. Results Analysis has exhibited significantly reduced expression of angiogenic, proteinopathy, and neuroinflammation biomarkers in ALS patients in comparison to controls. Spearman’s correlation analysis has showed the positive correlation to each protein. Conclusion Altered expression of these proteins is indicating the prominent function in ALS pathology which may be interdependent and may have a synergistic role. Hence, a panel of expression can be proposed to diagnose ALS patient which may also suggest the modulation of therapeutic strategy according to expression profile of patient.

THU479 - Prognostic and diagnostic role of angiogenesis biomarkers in hepatocellular carcinoma treated with chemoembolization

THU479 - Prognostic and diagnostic role of angiogenesis biomarkers in hepatocellular carcinoma treated with chemoembolization

Bone-Targeting Liposome-Encapsulated Salvianic Acid A Improves Nonunion Healing Through the Regulation of HDAC3-Mediated Endochondral Ossification.

AimNonunion is a major complication in fracture repair and remains a challenge in orthopaedics and trauma surgery. In this study, we aimed to evaluate the effectiveness of treatment of nonunion with a large radial defect using a bone-targeting liposome-encapsulated salvianic acid A (SAA-BTL)-incorporated collagen sponge and further elucidate whether the effects were closely related to histone deacetylase 3 (HDAC 3)-mediated endochondral ossification in nonunion healing process.MethodsFifteen New Zealand female rabbits were randomly divided into three groups. Segmental radius critical size defects (15 mm) were created via surgery on both the forelimbs of the rabbits. The SAA-BTL/SAA/saline-incorporated collagen sponges were implanted into the defects in the three groups, respectively, for four weeks of treatment. X-ray imaging, micro-computed tomography (CT) analysis, histology, and immunofluorescence analysis (HDAC3, collagen II, VEGFA, and osteocalcin) were performed to determine the effects of the treatments. In addition, a short interfering RNA was applied to induce HDAC3 knockdown in the chondrogenic cell line ATDC5 to investigate the roles of HDAC3 and SAA intervention in endochondral ossification in nonunion healing.ResultsX-ray imaging and micro-CT results revealed that SAA-BTL-incorporated collagen sponges significantly stimulated bone formation in the nonunion defect rabbit model. Furthermore, immunofluorescence double staining and histology analysis confirmed that SAA-BTL significantly increased the expression of P-HDAC3, collagen II, RUNX2, VEGFA, and osteocalcin in vivo; accelerated endochondral ossification turnover from cartilage to bone; and promoted long bone healing of nonunion defects. ATDC5 cells knocked down for HDAC3 showed significantly decreased expression of HDAC3, which resulted in reduced expression of chondrogenesis, osteogenesis, and angiogenesis biomarker genes (Sox9, Col10a1, VEGFA, RUNX2, and Col1a1), and increased expression of extracellular matrix degradation marker (MMP13). SAA treatment reversed these effects in the HDAC3 knockdown cell model.ConclusionSAA-BTL can improve nonunion healing through the regulation of HDAC3-mediated endochondral ossification.

Periconceptional exposure to lopinavir, but not darunavir, impairs decidualization: a potential mechanism leading to poor birth outcomes in HIV-positive pregnancies.

Periconceptional exposure to lopinavir, but not darunavir, impairs decidualization: a potential mechanism leading to poor birth outcomes in HIV-positive pregnancies.

Combination Antioxidant/NSAID Therapies and Oral/Topical Ocular Delivery Modes for Prevention of Oxygen-Induced Retinopathy in a Rat Model.

Given the complexity of oxygen-induced retinopathy (OIR), we tested the hypothesis that combination therapies and modes of administration would synergistically optimize efficacy for prevention of OIR. Newborn rats were exposed to neonatal intermittent hypoxia (IH) from the first day of life (P0) until P14 during which they received: (1) oral glutathione nanoparticles (nGSH) with topical ocular phosphate buffered saline (PBS); (2) nGSH with topical ocular Acuvail (ACV); (3) oral coenzyme Q10 (CoQ10) + ACV; (4) oral omega 3 polyunsaturated fatty acids (n-3 PUFAs) + ACV; (5) CoQ10 + n-3 PUFAs + PBS; or (6) CoQ10 + n-3 PUFAs + ACV. Treated groups raised in room air (RA) served as controls. At P14, pups were placed in RA with no treatment until P21. Retinal vascular pathology, ocular angiogenesis biomarkers, histopathology, and morphometry were determined. All combination treatments in IH resulted in the most beneficial retinal outcomes consistent with suppression of angiogenesis growth factors during reoxygenation/reperfusion and no significant adverse effects on somatic growth. nGSH + PBS also reversed IH-induced retinopathy, but had negative effects on growth. Simultaneously targeting oxidants, inflammation, and poor growth mitigates the damaging effects of neonatal IH on the developing retina. Therapeutic synergy with combination delivery methods enhance individual attributes and simultaneously target multiple pathways involved in complex diseases such as OIR.

Pulsed magnetic field treatment ameliorates the progression of peripheral neuropathy by modulating the neuronal oxidative stress, apoptosis and angiogenesis in a rat model of experimental diabetes

Objective The present study aimed to investigate the possible anti-neuropathic effects of daily pulsed magnetic field treatments (PMF) in streptozotocin (60 mg/kg) induced 4 weeks diabetic (type-1) wistar rats (6–8 months). Materials and methods Body mass, blood glucose and thermal and mechanical sensations were evaluated during the PMF or sham-PMF in diabetic or non-diabetic rats (n = 7/group). After the measurements of motor nerve conduction velocities (MNCV), the levels of several biomarkers for oxidative stress, apoptosis and angiogenesis in spinal cord and sciatic nerve were measured. Results PMF for 4 weeks significantly recovered the MCNV (96.9% and 63.9%) and almost fully (100%) restored to the latency and threshold. PMF also significantly suppressed the diabetes induced enhances in biochemical markers of both neuronal tissues. Conclusions Findings suggested that PMF might prevent the development of functional abnormalities in diabetic rats due to its anti-oxidative, anti-apoptotic and anti-angiogenic actions in neuronal tissues.

P-266 LDH levels as predictors of efficacy in second-line treatment for metastatic gastric cancer: The LINE study

Serum lactate dehydrogenase (LDH) levels are recognized as an indirect biomarker of tumor hypoxia and angiogenesis for several solid tumors. Ramucirumab represents the first molecularly targeted agent proven to be effective in second-line therapy for advanced gastric or gastro-oesophageal junction adenocarcinoma, alone or in combination with chemotherapy. However, little is known so far about potential predictive factors of benefit from antiangiogenic treatment. Thus, we conducted an observational retrospective study aimed at evaluating the possible differential prognostic impact of baseline serum LDH levels in advanced gastric cancer (GC) patients treated or not with ramucirumab in the second-line setting.

Neutrophil extracellular trapping and angiogenesis biomarkers after intravenous or inhalation anaesthesia with or without intravenous lidocaine for breast cancer surgery: a prospective, randomised trial

BackgroundExperimental and, retrospective, clinical data indicate that anaesthetic technique might influence the risk of metastasis after cancer surgery. Neutrophil extracellular trapping (NETosis) is an immunological mechanism strongly linked with increased metastatic risk. Similarly, vascular endothelial growth factor A is linked to angiogenesis implicated in recurrence. Therefore, we investigated the effect of four anaesthetic techniques on NETosis and angiogenic factors expression in women undergoing breast cancer resection. MethodsWomen (n=120) undergoing primary breast tumour resection were randomly assigned to receive one of four anaesthetics: sevoflurane (S), sevoflurane plus i.v. lidocaine (SL), propofol (P), and propofol plus i.v. lidocaine (PL). Venous blood was collected before induction and 20–28 h after operation. Neutrophil myeloperoxidase and citrullinated histone H3, biomarkers of NETosis, and biomarkers of angiogenesis were measured by enzyme-linked immunosorbent assay. ResultsPatient characteristic data and perioperative management did not differ between study groups. The anaesthetic technique including lidocaine decreased expression of citrullinated histone H3 compared with no lidocaine (109 [23] vs 125 [22] ng ml−1, P=0.01 for SL and S and 98 [14] vs 130 [32] mg ml−1, P=0.007, for PL and P, respectively). Similarly, myeloperoxidase was decreased by lidocaine (8.5 [3.4] vs 10.8 [1.8] ng ml−1, P=0.03 for SL and S and 8.6 [3.1] vs 11.6 [2.5] ng ml−1, P=0.01 for PL and P, respectively). Lidocaine also decreased expression of matrix metalloproteinase 3 (MMP3) but not MMP9, whichever anaesthetic was used. Vascular endothelial growth factor A concentrations were not significantly influenced by the anaesthetic technique. ConclusionsI.V. perioperative lidocaine decreased postoperative expression of NETosis and MMP3, regardless of general anaesthetic technique. This supports the hypothesis that i.v. lidocaine during cancer surgery of curative intent might reduce recurrence. Clinical trial registrationNCT02839668.

Intra-carotid arterial transfusion of circulatory-derived autologous endothelial progenitor cells in rodent after ischemic stroke\u2014evaluating the impact of therapeutic time points on prognostic outcomes

BackgroundThis study tested the optimal time point for left intra-carotid arterial (LICA) administration of circulatory-derived autologous endothelial progenitor cells (EPCs) for improving the outcome in rat after acute ischemic stroke (IS).Methods and resultsAdult male SD rats (n = 70) were equally categorized into group 1 (sham-operated control), group 2 (IS), group 3 (IS+EPCs/1.2 × 106 cells/by LICA administration 3 h after IS), group 4 (IS+EPCs/LICA administration post-day-3 IS), group 5 (IS+EPCs/LICA administration post-day-7 IS), group 6 (IS+EPCs/LICA administration post-day-14 IS), and group 7 (IS+EPCs/LICA administration post-day-28 IS). The brain infarct volume (BIV) (at day 60/MRI) was lowest in group 1, highest in group 2, and significantly progressively increased from groups 3 to 7, whereas among the IS animals, the neurological function was significantly preserved in groups 3 to 6 than in groups 2 and 7 post-day-60 IS (all P < 0.0001). By day 60, the endothelial cell markers at protein and cellular levels and number of small vessels exhibited an opposite pattern of BIV among the groups (all P < 0.0001). The protein and cellular levels of inflammation, and protein levels of oxidative stress, autophagy, and apoptosis were highest in group 2, lowest in group 1, and progressively increased from groups 3 to 7 (all P < 0.0001). The angiogenesis biomarkers at protein and cellular levels were significantly progressively increased from groups 1 to 3, then significantly progressively decreased from groups 4 to 7 (all P < 0.0001).ConclusionEarly EPC administration provided better benefits on improving functional/image/molecular-cellular outcomes after acute IS in rat.

90-OR: Inhibition of miRNA-200b Rescues Diabetes-Impaired Angiogenesis

Impaired angiogenic responses to ischemia characterize the vascular complications associated with diabetes. Diabetic foot ulcers in the presence of ischemia are associated with the most severe outcomes, including a higher rate of mortality and lower probability of healing. Specific micro-RNAs (miRNAs) such as miRNA-200b have been shown to negatively regulate angiogenesis in ischemia. Therefore, we sought to investigate miRNA-200b as a target and biomarker of diabetes-impaired angiogenesis. To assess the importance of miRNA-200b in diabetes-impaired angiogenesis, we transfected endothelial cells with anti-miRNA-200b or anti-miRNA-Neg then performed a functional tubulogenesis assay under high glucose and hypoxic conditions. High glucose impaired tubule formation by 23.6% in response to hypoxia when compared to controls (51.9±15.4 vs. 39.7±23.2, P&amp;lt;0.005), this decrease was prevented by anti-miRNA-200b treatment. Furthermore, in an in vivo hind-limb ischemia model, diabetic mice (n=8-11/group) were injected intramuscularly with anti-miRNA-200b or anti-miRNA-Neg at the time of hind-limb ischemia surgery. Diabetes impaired blood flow reperfusion was assessed by laser Doppler perfusion imaging (LDPI) in anti-miRNA-Neg control mice (LDPI: 0.27), and this was rescued by inhibition of miRNA-200b to nondiabetic levels (LDPI: 0.41, P&amp;lt;0.05). To assess the utility of miRNA-200b as a biomarker of delayed healing, plasma miRNA-200b was measured in a rodent excisional wound model. When compared to controls, diabetes elevated plasma miRNA-200b in both unwounded and wounded animals, suggesting a diabetes related change. Whether this change is seen in humans remains to be investigated. In conclusion, this study has identified that miRNA-200b is a potential target of diabetes-impaired angiogenesis as shown in this preclinical model of predominant ischemia in a diabetes setting. Disclosure C. Cannizzo: None. E. Solly: None. L.F. Olaya: None. M. Abdollahi: None. S.S. Sutanto: None. S.M. Twigg: Advisory Panel; Self; Abbott, AstraZeneca, Sanofi. Speaker’s Bureau; Self; Abbott, AstraZeneca, Novo Nordisk Inc., Roche Diabetes Care, Sanofi. C. Bursill: None. J.T. Tan: None. S. McLennan: None.

0044 Association Between Chronotype and Circulating Levels of Interleukin-6 in Colorectal Cancer Patients: Preliminary Results from the ColoCare Study

Abstract Introduction Accumulating evidence suggests that chronotype, i.e., circadian topology of an individual indicating morning or evening type, is associated with inflammation. To date, no study has examined the relationship between chronotype and inflammation in colorectal cancer patients. We investigated the associations between chronotype and inflammatory and angiogenesis biomarkers in colorectal cancer patients. Methods We used pre-surgery serum samples from n=67 newly diagnosed colorectal cancer patients (stage I-IV) recruited at the ColoCare Study site in Heidelberg, Germany. The ColoCare Study is an ongoing, international, multisite, prospective cohort study in colorectal cancer patients. Inflammatory and angiogenesis biomarkers [c-reactive protein (CRP), interleukin (IL)-6, IL-8, monocyte chemoattractant protein-1 (MCP-1), soluble intercellular adhesion molecule-1 (sICAM-1), soluble vascular cell adhesion molecule-1 (sVCAM-1)] were measured at the Huntsman Cancer Institute, USA using the Meso Scale Discovery platform and were log transformed. Chronotype was assessed prior to surgery with the reduced Morningness-Eveningness Questionnaire (rMEQ; scale 4–25; a higher score indicates more morning-type). Patients were dichotomized, based on the median values for rMEQ, into 2 groups: rMEQ-low (score≤16.0; n=35; indicating more evening-type) or rMEQ-high (score&amp;gt;16.0; n=32; indicating more morning-type). Results Using Mann-Whitney U test, we observed that rMEQ-low group (i.e., more evening-type) compared to rMEQ-high group (i.e., more morning-type) had approx. two times significantly higher levels of log transformed IL-6 (mean=2.24 vs. 1.30; U=382.0; Z=-2.23; p=0.03), but not for other inflammatory or angiogenesis biomarkers. This association between chronotype and IL-6 was maintained even after adjusting for age, sex, tumor stage, tumor site, and sleep duration using a generalized estimating equations model (adjusted mean difference=1.10; 95% confidence interval=0.33, 1.88; p=0.01; effect size, Cohen’s d=0.69). Conclusion These preliminary findings suggest that the evening chronotype is associated with increased IL-6 inflammatory biomarker in colorectal cancer patients. Further research is needed to confirm and understand the mechanistic underpinnings of the observed results. Support Funding: NCI U01 CA206110, R01 CA189184, and R01 CA207371.

Potential Circulating Biomarkers of Recurrence after Hepatic Resection or Liver Transplantation in Hepatocellular Carcinoma Patients.

Background: Improving surgical outcomes in hepatocellular carcinoma (HCC) patients would greatly benefit from biomarkers. Angiogenesis and inflammation are hallmarks of HCC progression and therapeutic targets. Methods: We retrospectively evaluated preoperative clinical variables and circulating (plasma) biomarkers of angiogenesis and inflammation in a cohort of HCC patients who underwent liver resection (LR) or transplantation (LT). Biomarker correlation with outcomes—freedom of liver recurrence (FLR), disease-free survival (DFS) and overall survival (OS)—was tested using univariate and multivariate Cox regression analyses. Results: Survival outcomes associated with sVEGFR1, VEGF and VEGF-C in LT patients and with IL-10 in LR patients. Moreover, in LT patients within Milan criteria, higher plasma VEGF and sVEGFR1 were associated with worse outcomes, while in those outside Milan criteria lower plasma VEGF-C associated with better outcomes. Multivariate analysis indicated that adding plasma VEGF or VEGF-C to a predictive model including Milan criteria and AFP improved prediction of DFS and OS (all p < 0.05). Conclusion: Survival outcomes after LR or LT differentially associated with angiogenic and inflammatory biomarkers. High plasma VEGF correlated with poorer prognosis within Milan criteria while low plasma VEGF-C associated with better prognosis outside Milan criteria. These candidate biomarkers should be further validated to improve patient stratification.

Clinicopathological and prognostic significance of nestin expression in patients with breast cancer: a systematic review and meta-analysis

BackgroundNestin has been revealed to promote tumorigenesis, progression, metastasis, and angiogenesis of breast cancer. Although the prognostic and clinicopathological impact of nestin expression on breast cancer patients has been assessed in several independent studies, their results remained conflicting. Therefore, we performed this meta-analysis to elucidate the prognostic and clinicopathological association of nestin expression with breast cancer.MethodsA comprehensive literature search was performed in the electronic databases PubMed, EMBASE, Web of Science, the Cochrane Library, China National Knowledge Infrastructure (CNKI), and the Wangfang Data. The statistical analysis was conducted using Stata 15.0 and Review Manager 5.3.ResultsA total of 15 studies with 6066 breast cancer patients were included in this meta-analysis. Pooled results indicated that positive expression of nestin was significantly associated with reduced breast cancer-specific survival (BCSS, univariate analysis, HR = 2.11, 95% CI [1.79, 2.49], P < 0.00001; multivariate analysis, HR = 1.30, 95% CI [1.06, 1.60], P = 0.01), worse overall survival (OS, univariate analysis, HR = 1.88, 95% CI [1.31, 2.71], P = 0.0007; multivariate analysis, HR = 1.89, 95% CI [1.34, 2.67], P = 0.0003) and poorer recurrence-free survival (univariate analysis, HR = 2.60, 95% CI [1.52, 4.46], P = 0.0005), but not with distant metastasis-free survival in univariate analysis (P > 0.05). In addition, increased nestin expression was correlated with younger age, higher tumor grade, larger tumor size, positive blood vessel invasion and high vascular proliferation index, but not with lymph node metastasis or lymph vessel invasion. Nestin was preferentially expressed in invasive ductal carcinoma, triple-negative breast cancer and basal-like subtypes. Nestin expression was inversely associated with the expression of ER and PR, but not with HER-2. Conversely, nestin expression was positively correlated with the expression of basal-like markers CK5, P-cadherin and EGFR. Moreover, nestin expression was strongly associated with the presence of five basal-like profiles (BLP1-5).ConclusionsThis meta-analysis revealed the prognostic value and clinicopathological significance of nestin expression in breast cancer. Nestin is an independent prognostic factor for worse BCSS and OS of breast cancer patients. Nestin is also a valuable biomarker for unfavorable clinicopathological features and tumor angiogenesis of breast cancer. Therefore, nestin is a promising therapeutic target for malignant breast cancer, especially for TNBC and basal-like phenotype.

Dimethylarginine dimethylaminohydrolase-1 contributes to exercise-induced cardiac angiogenesis in mice.

Dimethylarginine dimethylaminohydrolase-1 (DDAH1) maintains nitric oxide (NO) bioavailability by degrading asymmetric dimethylarginine (ADMA), which is an endogenous inhibitor of nitric oxide synthase (NOS). It has been well established that DDAH1 and exercise play crucial roles in promoting cardiac angiogenesis under pathological conditions. However, the role of DDAH1 in exercise-induced cardiac angiogenesis remains unclear. In this study, we focused on the change in DDAH1 in response to moderate exercise and the underlying mechanism of exercise-induced cardiac angiogenesis. Eight-week-old male DDAH1 global knockout (KO) mice and DDAH1flox/flox mice (wild-type) were randomly divided into sedentary groups (control) and swimming groups (exercise). After eight weeks of swimming at five days per week, all the mice were anesthetized and sacrificed. Histological examination and Western blot analysis were performed. There were low levels of myocardial capillaries in DDAH1 KO mice under control and exercise conditions. Notably, exercise elevated DDAH1 protein expression, as observed by Western blot analysis. The common cardiac angiogenesis biomarkers vascular endothelial growth factor (VEGF) and Caveolin-1 were increased during exercise. A significant difference in VEGF was observed between the DDAH1 KO and wild-type groups. Similarly, increased Caveolin-1 expression was abrogated in DDAH1 KO mice. Furthermore, we tested the R-Ras/AKT/GSK3β signaling pathway to study the underlying molecular mechanism. DDAH1 may regulate the R-Ras/AKT/GSK3β pathway due to distinct protein changes in this pathway in the DDAH1 KO and wild-type groups. Our findings suggest that DDAH1 plays an important role in exercise-induced cardiac angiogenesis by regulating the R-Ras/AKT/GSK3βsignaling pathway.

Effect of Weight Loss Surgery on Biomarkers of Angiogenesis in Obese Patients

BackgroundThe present study aims to clarify the effects of weight loss on biomarkers associated with angiogenesis in patients who underwent laparoscopic sleeve gastrectomy (SG) or adjustable gastric banding (LAGB) in the 12-month follow-up study.Materials and MethodsWe studied 24 obese patients who underwent laparoscopic weight loss surgery, 13 of whom underwent SG and 11 of whom underwent LAGB. We evaluated the circulating level of angiogenesis biomarkers preoperatively and 12 months after surgery.ResultsBefore surgery, the following angiogenic circulating factors were significantly higher than those of healthy subjects: angiopoietin 2 (ANG-2) (p < .05), granulocyte colony-stimulating factor (G-CSF) (p < .05), hepatocyte growth factor (HGF) (p < .01), platelet endothelial cell adhesion molecule (PECAM-1) (p < .01), and vascular endothelial growth factor (VEGF) (p < .05). The following angiogenesis biomarkers decreased significantly after weight loss compared with their baseline values: ANG-2 (p < .05), follistatin (p < .05), HGF (p < .01), PECAM-1 (p < .01), and VEGF (p < .05). There were no significant differences in the circulating levels of angiogenesis biomarkers between individuals who underwent SG and those who underwent LAGB; however, HGF, PECAM-1, and VEGF tended to be lower after SG. %BMI correlated negatively with HGF, PECAM-1, and VEGF. A similar significant negative correlation was found for %WL and %EWL. WHR correlated with PDGF-B and VEGF.ConclusionsWe concluded that weight loss surgery induces the changes of circulating levels of angiogenesis biomarkers in obese patients. The changes in angiogenesis status in obese patients who lost weight after bariatric surgery depended on the amount of weight loss.

PET Imaging of VEGFR with a Novel 64Cu-Labeled Peptide.

Vascular endothelial growth factor receptors (VEGFRs) are well recognized as significant biomarkers of tumor angiogenesis. Herein, we have developed a first-of-its-kind peptide-based VEGFR positron emission tomography (PET) tracer. The novel [64Cu]VEGF125–136 peptide possessed satisfactory radio-characteristics and showed good specificity for the visualization of VEGFR in various mouse models, in which the tumor-specific radioactivity uptake was highly correlated to the VEGFR expression level. Moreover, the tracer showed high tumor uptake (ca. 5.89 %ID/g at 20 min postinjection in B16F10 mice) and excellent pharmacokinetics, achieving the maximum imaging quality within 1 h after injection. These features convey [64Cu]VEGF125–136 as a promising, clinically translatable PET tracer for the imaging of tumor angiogenesis.

Plasma Leucine-Rich \u03b1-2-Glycoprotein 1 Predicts Cardiovascular Disease Risk in End-Stage Renal Disease

Plasma leucine-Rich α-2-glycoprotein 1 (LRG1) is an innovative biomarker for inflammation and angiogenesis. Many adverse pathophysiological changes including inflammation, atherosclerosis, and premature mortality is associated with End-stage renal disease (ESRD). However, whether levels of plasma LRG1 correlate with the co-morbidities of ESRD patients is unknown. Plasma LRG1 and high-sensitivity C-reactive protein (hsCRP) were analyzed by ELISA in 169 hemodialysis patients from the Immunity in ESRD (iESRD) study. Patient demographics and comorbidities at the time of enrollment were recorded. Peripheral blood monocyte and T cell subsets were assessed by multicolor flow cytometry. In the univariate analysis, a higher level of LRG1 was associated with the presence of cardiovascular disease (CVD) and peripheral arterial occlusive disease (PAOD). In multivariate logistic regression models, higher LRG1 tertile was significantly associated with PAOD (odds ratio = 3.49) and CVD (odds ratio = 1.65), but not with coronary artery disease, history of myocardial infarction, or stroke after adjusting for gender, diabetes, hemoglobin, albumin, calcium-phosphate product, and level of hsCRP. In addition, the level of LRG1 had a positive correlation with IL-6, hsCRP, and also more advanced T cell differentiation. The association suggests that LRG1 participates in the progression of atherosclerosis by inducing inflammation. Therefore, the role of LRG1 in coexisting inflammatory response should be further investigated in the pathogenesis of cardiovascular morbidity and mortality in patients with ESRD.