Relationship between fibroblast growth factor in plasma and carotid plaque neovascularization: a pilot study.

Background: Unstable atherosclerotic carotid plaques with intraplaque neovascularization (IPN) carry a substantial risk for ischemic stroke. Conventional ultrasound methods fall short in detecting IPN, where superb microvascular imaging (SMI) has emerged as a promising tool for both visualizing and quantification. High levels of fibroblast growth factor 23 (FGF-23) have, in observational studies, been suggested as related to cardiovascular morbidity and mortality. The association of FGF-23 to atherosclerotic carotid plaque instability remains relatively unexplored. Methods: A cohort of twenty-nine patients with ≥50% atherosclerotic carotid stenosis underwent conventional carotid ultrasound, SMI, and blood tests, including measurement of FGF-23 in plasma. Nineteen patients were characterized as symptomatic and ten as asymptomatic. Results: Our major findings were: i) Higher FGF-23 levels were strongly correlated with increased SMI-assessed IPN. ii) Neo-vessel count recorded by quantitative SMI was positively correlated to increased FGF-23 levels, but not with basic FGF levels. (iii) In contrast, traditional risk factors for plaque instability exhibited no noteworthy associations with SMI-assessed IPN or with FGF-23 levels. Conclusion: This pilot study suggest the potential of FGF-23 as a valuable marker for neovascularization and atherosclerotic carotid plaque instability as a risk factor for ischemic stroke. Further research involving larger cohorts and prospective data is necessary to understand FGF-23's role in this context comprehensively.

Inflammatory biomarkers, angiogenesis and lymphangiogenesis in epicardial adipose tissue correlate with coronary artery disease.

In this study, we explored the relationship between inflammatory adipokine levels and coronary artery disease (CAD). We collected subcutaneous adipose tissues(SAT), pericardial adipose tissues(PAT), and epicardial adipose tissues (EAT) and serum samples from 26 inpatients with CAD undergone coronary artery bypass grafting and 20 control inpatients without CAD. Serum inflammatory adipokines were measured by ELISA. Quantitative real-time PCR and western blot were used to measure gene and protein expression. Adipocyte morphology was assessed by H&E staining. Immunohistochemistry and immunofluorescence were used to measure endothelial and inflammatory markers. Serum pro- and anti-inflammatory adipokine levels were higher and lower, respectively, in the CAD group than those in the control group (P < 0.05). In CAD, the pro-inflammatory adipokine levels via ELISA in EAT and PAT were elevated. Pro-inflammatory adipokine mRNA expression was increased, while anti-inflammatory adipokine mRNA expression decreased, in CAD relative to NCAD in EAT and PAT rather than SAT. In EAT, adipocyte area and macrophage-specific staining were lower, while lymphatic vessel marker expression was higher in CAD. Additionally, the endothelial marker expression in EAT was higher than PAT in CAD. The three tissue types had different blood vessel amounts in CAD. The regulation and imbalance expression of the novel biomarkers, including inflammatory adipokine, macrophage infiltration, angiogenesis, and lymphangiogenesis in EAT and PAT, may be related to the pathogenesis of CAD. The serum levels of inflammatory adipokines may correlate to CAD, which requires large sample size studies to get further validation before clinic practice.

The Effect of Hypoxia Inducible Factor -1 Alpha and Vascular Endothelial Growth Factor Level in Type 2 Diabetes Microvascular Complications and Development.

Background: Angiogenesis in diabetic patients is often caused by hyperglycemia induced by hypoxia. Objective: The aim of this study was to analyze the serum level of Hypoxia Inducible Factor -1α (HIF-1α) and Vascular Endothelial Growth Factor (VEGF) between March until Desember 2020. Methods: This is a cross-sectional analytic methods, 135 patients with Type 2 Diabetes 48 samples with Microvascular complication and 87 samples with non-microvascular complication were recruited from the various primary health care centers in Medan city and surrounding areas in North Sumatera. VEGF levels and HIF-1α tested were done with ELISA methods in the laboratory of Medical Faculty, Universitas Sumatera Utara. Statistical analysis was performed using the IBM SPSS Statistics version 24. The significance level was set up to 0.005. Results: The median HIF-1 levels in patients with microvascular complications were lower than those without microvascular complications, with a range of HIF-1α values in non-complicated samples (0.02-13.96) ng/ml and a range of HIF-1α values in vascular complications (0.52- 8.87) mg/dL. There was a significant difference in HIF-1α levels in patients with Type-2 DM with complications compared to those without complications (p<0.05). Median VEGF levels were higher in complicated Type-2 DM. There was no difference in VEGF levels in patients with Type-2 DM with complications compared to those without complications (p > 0.005). Conclusion: HIF-1α and VEGF levels showed the development in vascularity. With the higher level of HIF-1α, an increase in VEGF levels were found, indicating the angiogenesis is occurring. Although complications have not yet occurred, it is predicted that high VEGF values will cause vascular complications in the future.

Longitudinal Dynamics of Coagulation and Angiogenesis Markers in Cancer Patients During and After Chemotherapy.

Hemostatic parameters have been investigated as molecular determinants of tumor progression. To analyze the dynamics of microparticle-associated tissue factor activity (MPTF), tissue factor antigen (TF-Ag), and angiopоietin-2 (ANG-2) in cancer patients before, during, and after active treatment and to explore their potential as biomarkers for metastatic occurrence and death. Blood for the analysis of MPTF, TF-Ag, ANG-2, and conventional hemostatic tests was sampled in 111 patients with various cancers at 4 consecutive visits: before first chemotherapy cycle, after 3 courses, at the sixth course, and 3 months after chemotherapy cessation. Patients were followed up until metastatic progression/death or the end of the study. MPTF did not change during chemotherapy, but increased significantly after treatment cessation. Total TF-Ag and ANG-2 decreased throughout active treatment. Significant drop of their levels was observed 3 months post therapy cessation. Progressive disease was significantly associated with higher pre-chemotherapy TF-Ag and fibrinogen. Elevated baseline levels of fibrinogen were associated with increased risk of shortened progression free survival. Cessation of chemotherapy is associated with significant change of hemostatic parameters. Pre-chemotherapy levels of TF-Ag and fibrinogen may be informative of disease state and prognosis.

Plasma Lipid Profiling Contributes to Untangle the Complexity of Moyamoya Arteriopathy.

Moyamoya arteriopathy (MA) is a rare cerebrovascular disorder characterized by ischemic/hemorrhagic strokes. The pathophysiology is unknown. A deregulation of vasculogenic/angiogenic/inflammatory pathways has been hypothesized as a possible pathophysiological mechanism. Since lipids are implicated in modulating neo-vascularization/angiogenesis and inflammation, their deregulation is potentially involved in MA. Our aim is to evaluate angiogenic/vasculogenic/inflammatory proteins and lipid profile in plasma of MA patients and control subjects (healthy donors HD or subjects with atherosclerotic cerebrovascular disease ACVD). Angiogenic and inflammatory protein levels were measured by ELISA and a complete lipidomic analysis was performed on plasma by mass spectrometry. ELISA showed a significant decrease for MMP-9 released in plasma of MA. The untargeted lipidomic analysis showed a cumulative depletion of lipid asset in plasma of MA as compared to HD. Specifically, a decrease in membrane complex glycosphingolipids peripherally circulating in MA plasma with respect to HD was observed, likely suggestive of cerebral cellular recruitment. The quantitative targeted approach demonstrated an increase in free sphingoid bases, likely associated with a deregulated angiogenesis. Our findings indicate that lipid signature could play a central role in MA and that a detailed biomarker profile may contribute to untangle the complex, and still obscure, pathogenesis of MA.

Plasma Metabolomics of Intermediate and Neovascular Age-Related Macular Degeneration Patients.

To characterize metabolites and metabolic pathways altered in intermediate and neovascular age-related macular degeneration (IAMD and NVAMD), high resolution untargeted metabolomics was performed via liquid chromatography-mass spectrometry on plasma samples obtained from 91 IAMD patients, 100 NVAMD patients, and 195 controls. Plasma metabolite levels were compared between: AMD patients and controls, IAMD patients and controls, and NVAMD and IAMD patients. Partial least-squares discriminant analysis and linear regression were used to identify discriminatory metabolites. Pathway analysis was performed to determine metabolic pathways altered in AMD. Among the comparisons, we identified 435 unique discriminatory metabolic features. Using computational methods and tandem mass spectrometry, we identified 11 metabolic features whose molecular identities had been previously verified and confirmed the molecular identities of three additional discriminatory features. Included among the discriminatory metabolites were acylcarnitines, phospholipids, amino acids, and steroid metabolites. Pathway analysis revealed that lipid, amino acid, and vitamin metabolism pathways were altered in NVAMD, IAMD, or AMD in general, including the carnitine shuttle pathway which was significantly altered in all comparisons. Finally, few discriminatory features were identified between IAMD patients and controls, suggesting that plasma metabolic profiles of IAMD patients are more similar to controls than to NVAMD patients.

Correlation between serum uric acid levels and carotid plaque neovascularisation assessed by contrast-enhanced ultrasound.

AIM: To investigate the potential impact of serum uric acid (SUA) levels on the grade of intraplaque neovascularisation (IPN) at contrast-enhanced ultrasound (CEUS). MATERIAL AND METHODS: The study screened 212 patients with carotid atherosclerotic plaques using conventional ultrasound, and the patients then underwent CEUS. Based on the distribution of contrast medium microbubbles in the plaque, patients were split into three groups: 60 patients regarded as grade 0-1 (group A), 81 patients as grade 2 (group B), and 71 patients as grade 3 (group C), and SUA levels were measured on the second day after CEUS. RESULTS: The frequencies of stroke were statistically different between the three groups (p<0.05). In grades 0, 1, 2, and 3, SUA levels ranged from 236.92 ± 72.75, 276.46 ± 67.31, 283.93 ± 53.85, and 384.49 ± 79.80 µmol/l, respectively. Spearman's analysis showed that the visual grade of IPN at CEUS correlated linearly with the SUA level (r=0.551, p<0.01). The difference in SUA levels between different sexes was statistically significant (p<0.05), and the differences in plaque echogenicity and diastolic blood pressure (DBP) between the three groups were also statistically significant (all p<0.05). CONCLUSIONS: SUA levels correlate positively with the visual grade of IPN at CEUS, which may promote plaque vulnerability. The present results may further help to optimise therapy for vulnerable plaque and improve stroke risk stratification strategies.

Anti-Fibrotic and Anti-Angiogenic Activities of Osbeckia octandra Leaf Extracts in Thioacetamide-Induced Experimental Liver Cirrhosis.

Chronic liver inflammation has become a major global health concern. In the absence of clinical surrogate markers to diagnose inflammatory liver disease, the intervention with effective drugs in modern medicine tends to be late. In Sri Lanka, traditional medical practitioners prescribe herbal preparations from Osbeckia octandra for the prevention and treatment of liver disorders. To test the efficacy of such treatments, we have administered thioacetamide (TAA) to male Wistar rats to induce chronic liver damage (disease control; DC) and examined how various leaf extracts: crude leaf suspension (CLS), boiled leaf extract (BLE), sonicated leaf extract (SLE), methanol leaf extract (MLE) and hexane leaf extract (HLE) of O. octandra ameliorate TAA-induced liver disease. The CLS, BLE and SLE treatments in cirrhotic rats significantly attenuated disease-related changes, such as liver weight and hepato-enzymes. The mRNA levels of Tnf-α were significantly decreased by 3.6, 10 and 3.9 times in CLS, BLE and SLE compared to DC. The same treatments resulted in significantly lower (19.5, 4.2 and 2.4 times) α-Sma levels compared to DC. In addition, Tgf-ß1 and Vegf-R2 mRNA expressions were significantly lower with the treatments. Moreover, BLE expressed a strong anti-angiogenic effect. We conclude that CLS, BLE and SLE from O. octandra have potent hepatic anti-fibrotic effects in TAA-induced liver cirrhosis.

A Novel Nomogram for Individually Predicting of Vascular Invasion in Gastric Cancer.

PURPOSE: Vascular invasion (VI) is associated with recurrence and is an indicator of poor prognosis in gastric cancer (GC). Pre-operative identification of VI may guide the selection of the optimal surgical approach and assess the requirement for neoadjuvant therapy. METHODS: A total of 271 patients were retrospectively collected and randomly allocated into the training and validation datasets. The least absolute shrinkage and selection operator regression model was used to select potentially relevant features, and multivariable logistic regression analysis was used to develop the nomogram. RESULTS: The nomogram consisted of pre-operative serum complement C3 levels, duration of symptoms, pre-operative computed tomography stage, abdominal distension and undifferentiated carcinoma. The nomogram provided good calibration for both the training and the validation set, with area under the curve values of 0.792 and 0.774. Decision curve analysis revealed that the nomogram was clinically useful. CONCLUSION: The present study constructed a nomogram for the pre-operative prediction of VI in patients with GC. The nomogram may aid the identification of high-risk patients and aid the optimization of pre-operative decision-making.

Apelin promotes blood and lymph vessel formation and the growth of melanoma lung metastasis.

Apelin, a ligand of the APJ receptor, is overexpressed in several human cancers and plays an important role in tumor angiogenesis and growth in various experimental systems. We investigated the role of apelin signaling in the malignant behavior of cutaneous melanoma. Murine B16 and human A375 melanoma cell lines were stably transfected with apelin encoding or control vectors. Apelin overexpression significantly increased melanoma cell migration and invasion in vitro, but it had no impact on its proliferation. In our in vivo experiments, apelin significantly increased the number and size of lung metastases of murine melanoma cells. Melanoma cell proliferation rates and lymph and blood microvessel densities were significantly higher in the apelin-overexpressing pulmonary metastases. APJ inhibition by the competitive APJ antagonist MM54 significantly attenuated the in vivo pro-tumorigenic effects of apelin. Additionally, we detected significantly elevated circulating apelin and VEGF levels in patients with melanoma compared to healthy controls. Our results show that apelin promotes blood and lymphatic vascularization and the growth of pulmonary metastases of skin melanoma. Further studies are warranted to validate apelin signaling as a new potential therapeutic target in this malignancy.

Platelets as messengers of early-stage cancer.

Platelets have an important role in tumor angiogenesis, growth, and metastasis. The reciprocal interaction between cancer and platelets results in changes of several platelet characteristics. It is becoming clear that analysis of these platelet features could offer a new strategy in the search for biomarkers of cancer. Here, we review the human studies in which platelet characteristics (e.g., count, volume, protein, and mRNA content) are investigated in early-stage cancer. The main focus of this paper is to evaluate which platelet features are suitable for the development of a blood test that could detect cancer in its early stages.

Relationship between carotid intraplaque neovascularization and haemoglobin A1c in diabetic patients.

INTRODUCTION: We aimed to evaluate the characteristics of carotid artery plaques and the relationship between intraplaque neovascularization (IPN) and hemoglobin A1c (HbA1c) in patients of <60 years old with diabetes mellitus (DM) by comparison with diabetes ≥60 years of age. METHODS: One-hundred-and-one patients with DM were studied into two groups: those <60 and those ≥60 years of age. All the patients underwent standard carotid ultrasonography and contrast-enhanced ultrasonography, which we used to evaluate IPN. RESULTS: Diabetic complications were present in 41 of 50 patients (82 %) in the <60-year-old group, of whom 17 (34 %) had diabetes-related vascular complications. Of the 47 plaques in the <60-year-old group, six (13 %) had IPN Grade 0, 16 (34 %) had IPN Grade 1, and 25 (53 %) had IPN Grade 2. The AUC and RAUC of the plaque in the <60-year-old group were significantly higher than those of the ≥60-year-old group (P = 0.012 and 0.031, respectively). There were also differences in the AUC, RAUC and semi-quantitative grades between patients with and without diabetic macrovasculopathy and diabetic peripheral artery disease (all P < 0.05). The AUC, RAUC and semi-quantitative grading of IPN positively correlated with blood glucose and HbA1c (P < 0.05). CONCLUSION: IPN is more common in DM patients who are younger, and have higher blood glucose and HbA1c concentrations, and these plaques are more vulnerable.

Tocilizumab (TCZ) Decreases Angiogenesis in Rheumatoid Arthritis Through Its Regulatory Effect on miR-146a-5p and EMMPRIN/CD147.

Background: Angiogenesis is a major contributor to the development of inflammation during Rheumatoid arthritis (RA), as the vascularization of the pannus provides nutrients and oxygen for the infiltrating immune cells and proliferating synoviocytes. Tocilizumab (TCZ) is an anti-IL-6 receptor antibody that is used in the treatment of RA patients, and has been shown to exert anti-inflammatory effects. However, its effects on angiogenesis are not fully elucidated, and the molecular mechanisms regulating this effect are unknown. Methods: We evaluated the concentrations of several pro- and anti-angiogenic factors and the expression levels of several microRNA molecules that are associated with RA and angiogenesis in serum samples obtained from 40 RA patients, before and 4 months after the initiation of TCZ treatment. Additionally, we used an in vitro co-culture system of fibroblasts (the HT1080 cell line) and monocytes (the U937 cell line) to explore the mechanisms of TCZ action. Results: Serum samples from RA patients treated with TCZ exhibited reduced circulating levels of EMMPRIN/CD147, enhanced expression of circulating miR-146a-5p and miR-150-5p, and reduced the angiogenic potential as was manifested by the lower number of tube-like structures that were formed by EaHy926 endothelial cell line. In vitro, the accumulation in the supernatants of the pro-angiogenic factors EMMPRIN, VEGF and MMP-9 was increased by co-culturing the HT1080 fibroblasts and the U937 monocytes, while the accumulation of the anti-angiogenic factor thrombospondin-1 (Tsp-1) and the expression levels of miR-146a-5p were reduced. Transfection of HT1080 cells with the miR-146a-5p mimic, decreased the accumulation of EMMPRIN, VEGF and MMP-9. When we neutralized EMMPRIN with a blocking antibody, the supernatants derived from these co-cultures displayed reduced migration, proliferation and tube formation in the functional assays. Conclusions: Our findings implicate miR-146a-5p in the regulation of EMMPRIN and propose that TCZ affects angiogenesis through its effects on EMMPRIN and miR-146a-5p.

Long non-coding RNA MEG3 inhibits neovascularization in diabetic retinopathy by regulating microRNA miR-6720-5p and cytochrome B5 reductase 2.

Diabetic retinopathy (DR) is a major cause of vision loss in working and elderly populations. long non-coding RNA (LncRNA) MEG3 is thought to have some effect on DR, but the exact mechanism remains to be clarified. The expression levels of lncRNA MEG3, miR-6720-5p, and cytochrome B5 reductase 2 (CYB5R2) in human retinal microvascular endothelial cells (hRMECs) were detected by quantitative reverse transcription polymerase chain reaction (qRT-PCR). 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), transwell migration, and tube formation assays were used to determine the cell viability, migration, and tube formation ability of hRMECs, respectively. The interaction of MEG3, miR-6720-5p, and CYB5R2 was detected and explored by a luciferase assay. The expression of MEG3 and CYB5R2 was upregulated and that of miR-6720-5p was downregulated in patients with DR and hRMECs treated with high glucose. Knocking down MEG3 or CYB5R2 promoted proliferation, migration, and neovascularization in hRMECs. The intervention of miR-6720-5p reversed the effect of MEG3 knockdown on hRMEC function, and this effect was eliminated by silencing CYB5R2. Therefore, MEG3 acted as a sponge to suppress miR-6720-5p and regulate the expression of CYB5R2, thereby inhibiting DR neovascularization.

Interleukin-9 serves as a key link between systemic inflammation and angiogenesis in psoriasis.

BACKGROUND: Psoriasis is a T helper cell-mediated chronic immune-mediated inflammatory disease affecting mainly the skin, although systemic pathological effects are also observed. Cytokine-mediated interaction between T lymphocytes and keratinocytes lead to excessive proliferation of keratinocytes, which in turn leads to formation of a proinflammatory milieu and finally to psoriatic plaque formation. AIM: To measure interleukin (IL)-9, IL-17 and vascular endothelial growth factor (VEGF) levels in patients with psoriasis compared with controls, and to evaluate the effect of methotrexate (MTX) monotherapy on the aforesaid cytokine levels in psoriasis. METHODS: This cohort study included 54 patients with psoriasis and 54 age- and sex-matched healthy controls (HCs). IL-9, IL-17 and VEGF levels were measured by using commercially available ELISA kits. Patients with psoriasis who were on MTX monotherapy were followed up for a period of 3 months. RESULTS: Patients with psoriasis had increased levels of IL-9, IL-17 and VEGF at baseline, compared with the HC group. After 3 months of MTX monotherapy, Psoriasis Area Severity Index (PASI), Dermatology Life Quality Index (DLQI) and levels of cytokines (IL-9, IL-17 and VEGF) were significantly decreased compared with baseline. PASI and DLQI at baseline also showed a positive correlation with IL-9, IL-17 and VEGF. CONCLUSION: Our results suggest the existence of a proinflammatory milieu in psoriasis, with increased levels of IL-9, IL-17 and the proangiogenic growth factor VEGF, showing an increasing trend with increasing disease severity and impaired quality of life (QoL). MTX treatment helps to reduce levels of IL-9, IL-17 and VEGF, thereby limiting disease progression and improving QoL in psoriasis.

Umbilical cord plasma-derived exosomes from preeclamptic women induce vascular dysfunction by targeting HMGCS1 in endothelial cells.

Hypertension is one of the major clinical manifestations of preeclampsia. Vascular dysfunction is crucial for the occurrence and progression of hypertension. Exosomes are emerging as mediators of intercellular communication and can participate in angiogenesis. In this study, we hypothesize that umbilical cord plasma-derived exosomes from preeclamptic women (PE-uexo) impair vascular development by regulating endothelial cells. Here, umbilical cord plasma samples from women with normal pregnancies and matched preeclamptic patients were used to isolate circulating exosomes. Proliferation, Transwell and tube formation assays indicated that PE-uexo impaired the angiogenesis of human umbilical vein endothelial cells (HUVECs). On the basis of microarray analysis of HUVECs treated with PE-uexo or exosomes from women with normal pregnancies, we showed that the expression of 3-hydroxy-3-methylglutaryl-CoA synthase 1 (HMGCS1) was decreased in the PE-uexo-treated HUVECs. Furthermore, downregulation of HMGCS1 in HUVECs attenuated the proliferation and migration of these cells. Interestingly, HMGCS1 was decreased in P0 HUVECs from preeclamptic pregnancies compared with normotensive pregnancies. Together, these observations suggest that PE-uexo disrupts normal function in vascular endothelial cells by targeting HMGCS1, which may result in vascular disorders in the offspring.

Pretreatment to Posttreatment Hypoxia Inducible Factor-1α Ratios as a Potentially Predictive Marker for First-Line Treatment in Nonsmall Cell Lung Cancer Patients without Known Driver Mutations.

Background: Hypoxia inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF) are key angiogenic regulatory factors. The aim of this study was to identify the most useful prognostic angiogenic factors in advanced nonsmall cell lung cancer (NSCLC) without known driver gene mutations. Methods: Eligible patients were pathologically confirmed to have advanced NSCLC without known driver mutations. All patients were treated with standard first-line chemotherapy ± bevacizumab. Serum concentrations of HIF-1α, VEGF, sVEGFR1, sVEGFR2, and endostatin were measured via enzyme-linked immunosorbent assays (ELISAs) prior to and after two cycles of treatment. Area under the curve (AUC) and optimal cutoff values were calculated by receiver operator characteristic curve (ROC) analyses. The parameters that predicted survival were evaluated by univariate and multivariate Cox proportional hazard analyses. Results: A total of 47 patients were included in this study. HIF-1α levels decreased significantly after treatment in the nonprogressing (partial response/stable disease) patient group (707.94 vs. 355.53 pg/mL, p = 0.002), but increased levels were seen in patients with progressive disease, however, the extent of change did not reach significance (173.70 vs. 416.34 pg/mL, p = 0.078). An HIF-1α ratio of 1.18 was chosen as the best point to predict treatment response through ROC analyses. Via univariate and multivariate analyses, we found that patients with a HIF-1α ratio ≥1.18 after treatment were significantly more likely to have a prolonged progression-free survival (PFS, HR 0.303, 95% CI: 0.153-0.603, p = 0.001) and overall survival (OS, HR 0.436, 95% CI: 0.153-0.603, p = 0.025). Conclusions: We identified the pretreatment to posttreatment HIF-1α ratio as a promising predictor for PFS and OS in NSCLC patients without known driver mutations.

Analysis of novel serum markers of fibrosis and angiogenesis in patients with alcoholic liver cirrhosis.

INTRODUCTION: Alcohol consumption causes acute and chronic liver injury. The clinical forms of alcohol liver disease (ALD) include steatosis, hepatitis, cirrhosis, and hepatocellular carcinoma (HCC) associated with liver cirrhosis. OBJECTIVE: The aim of the study was to determine the levels of novel markers of fibrogenesis and angiogenesis in patients with alcoholic liver cirrhosis. Serum levels of angiopoietin-like peptide 4 (ANGPTL-4), asialoglycoprotein receptor 1 (ASGP-R1), and S100 calcium-binding protein A8 (S100A8) were assessed. Levels of hyaluronic acid (Hyal) and collagen IV (Coll IV) werealso determined at various stages of alcoholic liver cirrhosis. MATERIAL AND METHODS: The study group consisted of 72 patients with alcoholic liver cirrhosis, while the control group included 22 healthy subjects without a history of alcohol abuse. The degree of liver cirrhosis was evaluated according to the Pugh-Child criteria (Pugh-Child score). Based on thse scores, patients were assigned to one of three groups: Pugh-Child (P-Ch) A - 21 with stage A, P-Ch B - 23 with stage B and P-Ch C - 28 with stage C liver cirrhosis. Serum levels of markers were determined using ELISA. RESULTS: The study findings demonstrated higher levels of ANGPTL-4, ASGP-R1, S100A, hyaluronic acid and serum collagen IV in the group of patients with alcoholic liver cirrhosis, compared to the control group. Furthermore, their levels increased with the progression of alcoholic liver cirrhosis. CONCLUSIONS: The biomarkers analysed in the study may be useful for diagnosis and prognosis in patients with alcoholic liver cirrhosis.

Recent Advances in Experimental Models of Breast Cancer Exosome Secretion, Characterization and Function.

Breast cancer (BC) is responsible for 15% of all the cancer deaths among women in the USA. The tumor microenvironment (TME) has the potential to act as a driver of breast cancer progression and metastasis. The TME is composed of stromal cells within an extracellular matrix and soluble cytokines, chemokines and extracellular vesicles and nanoparticles that actively influence cell behavior. Extracellular vesicles include exosomes, microvesicles and large oncosomes that orchestrate fundamental processes during tumor progression through direct interaction with target cells. Long before tumor cell spread to future metastatic sites, tumor-secreted exosomes enter the circulation and establish distant pre-metastatic niches, hospitable and permissive milieus for metastatic colonization. Emerging evidence suggests that breast cancer exosomes promote tumor progression and metastasis by inducing vascular leakiness, angiogenesis, invasion, immunomodulation and chemoresistance. Exosomes are found in almost all physiological fluids including plasma, urine, saliva, and breast milk, providing a valuable resource for the development of non-invasive cancer biomarkers. Here, we review work on the role of exosomes in breast cancer progression and metastasis, and describe the most recent advances in models of exosome secretion, isolation, characterization and functional analysis. We highlight the potential applications of plasma-derived exosomes as predictive biomarkers for breast cancer diagnosis, prognosis and therapy monitoring. We finally describe the therapeutic approaches of exosomes in breast cancer.

The Prognostic Value of Circulating VEGF-A Level in Patients With Hepatocellular Cancer.

BACKGROUND: Neovascularization plays a crucial pathogenic role in tumor development and vascular endothelial growth factor (VEGF-A) is a key signaling element that drives angiogenesis, thereby facilitating hepatocellular cancer (HCC) growth and metastasis. We aimed to define the relationship between serum VEGF-A levels and clinical outcomes in a cohort of Turkish patients with HCC. METHODS: We enrolled and prospectively followed 84 patients with HCC in our study. Serum VEGF-A levels were measured and we assessed the association between VEGF-A levels and clinical features. RESULTS: Forty-eight patients had cirrhosis while 35 patients were noncirrhotic. Serum VEGF-A levels were significantly lower in HCC patients with cirrhosis compared to non-cirrhotic HCC patients (p = 0.03).In terms of viral hepatitis subtype, 36 (%42.8) of patients were hepatitis B virus (HBV) positive and 8 (%9.5) of patients were hepatitis C virus (HCV) positive. Patients with serum VEGF-A levels ≥100 pg/mL had significantly lower OS rates than patients with serum VEGF-A level <100 pg/mL (p = 0.01). The OS rates were 5.8 and 14.2 months, respectively (p = 0.02). The median OS was 7.38 months (95% CI: 5.89-13.79 months). We observed a significant relationship between serum VEGF-A level and tumor size. Patients with tumor size ≤ 5cm had lower VEGF-A levels than patients with VEGF-A levels <5 cm. The VEGF-A levels were 132.7 and 342.1 pg/mL, respectively (p < 0.001). The median follow-up was 32 months. CONCLUSIONS: Serum VEGF-A level, a biological marker of angiogenesis, is an independent predictor of survival in patients with HCC. Serum VEGF-A levels may be utilized to predict response to treatment targeting serum VEGF-A in patients with HCC.