Assessment of serum angiogenic factors as a diagnostic aid for small bowel angiodysplasia in patients with obscure gastrointestinal bleeding and anaemia

To assess the use of serum levels of angiopoietin-1 (Ang1), Ang2 and tumor necrosis factor-α (TNFα) as predictive factors for small bowel angiodysplasia (SBA). METHODSSerum samples were collected from patients undergoing capsule endoscopy for any cause of obscure gastrointestinal bleeding (OGIB) or anaemia. Based on small bowel findings patients were divided into 3 groups: (1) SBA; (2) other bleeding causes; and (3) normal, according to diagnosis. Using ELISA technique we measured serum levels of Ang1, Ang2 and TNFα and compared mean and median levels between the groups based on small bowel diagnosis. Using receiver operator curve analysis we determined whether any of the factors were predictive of SBA. RESULTSSerum samples were collected from a total of 120 patients undergoing capsule endoscopy for OGIB or anaemia: 40 with SBA, 40 with other causes of small bowel bleeding, and 40 with normal small bowel findings. Mean and median serum levels were measured and compared between groups; patients with SBA had significantly higher median serum levels of Ang2 (3759 pg/mL) compared to both other groups, with no significant differences in levels of Ang1 or TNFα based on diagnosis. There were no differences in Ang2 levels between the other bleeding causes (2261 pg/mL) and normal (2620 pg/mL) groups. Using Receiver Operator Curve analysis, an Ang2 level of > 2600 pg/mL was found to be predictive of SBA, with an area under the curve of 0.7. Neither Ang1 or TNFα were useful as predictive markers. CONCLUSIONElevations in serum Ang2 are specific for SBA and not driven by other causes of bleeding and anaemia. Further work will determine whether Ang2 is useful as a diagnostic or prognostic marker for SBA.

Shared changes in angiogenic factors across gastrointestinal vascular conditions:A pilot study

BACKGROUND Neovascularisation is common to a variety of gastrointestinal(GI)disorders with differing aetiologies and presentations;usually affecting adults above 60 years.Shared angiogenic factors modulated by disease specific elements could be a common denominator and represent novel diagnostic and therapeutic targets.As yet,assessment of angiogenic factors across several GI vascular disorders associated with recurrent bleeding and anaemia has not been reported.AIM To assess serum levels of angiogenic factors in several intestinal vascular disorders.METHODS A case control study was performed in Tallaght University Hospital in patients with endoscopically proven small bowel angiodysplasia(SBA),portal hypertensive gastropathy(PHG),gastric antral vascular ectasia(GAVE)and nonbleeding,non-anaemic controls.Using enzyme-linked immunosorbent assay,concentrations of Angiopoietin 1(Ang-1),Ang-2 and vascular endothelial growth factor(VEGF)were measured from 2 serum tubes of blood following informed consent.The relative expression of Ang-1 and Ang-2 and Ang-1/2 ratio was calculated and compared between groups.Statistical analysis was applied using a t-test,and a P value of<0.05 was considered significant.RESULTS To date 44 samples were tested:10 SBA,11 PHG,8 GAVE and 15 controls.Mean age 60(range 20-85)years and 20(45%)were males.Controls were significantly younger(49 years vs 66 years,P=0.0005).There was no difference in VEGF levels between the groups(P=0.6).SBA,PHG and GAVE Ang-1 levels were similar and were significantly lower than controls,(P=0.0002,95%CI:241 to 701).Ang-2 levels were statistically higher in PHG and GAVE groups compared to controls(P= 0.01, 95%CI: 77.8 to 668) and as a result, also had a lower Ang-1/2 ratioscompared to controls. While SBA Ang-2 levels were higher than controls, this didnot reach statistical significance. Neither age nor haemoglobin level, which wassimilar between disease groups, could explain the difference. In addition, themedian Ang-1/Ang-2 ratio for all patients was found to be significantly lowercompared to controls, 8 vs 28 respectively, P = 0.001, 95%CI: -27.55 to -7.12.CONCLUSIONOur novel pilot study suggests common alterations in Ang-1 and Ang-2 levelsacross several GI vascular disorders. Differences in Ang-1/Ang-2 ratios amongvascular disorders compared to controls suggest disease-specific modulation.

Role of angiogenesis and angiogenic factors in acute and chronic wound healing

Angiogenesis plays a crucial role in wound healing by forming new blood vessels from preexisting vessels by invading the wound clot and organizing into a microvascular network throughout the granulation tissue.This dynamic process is highly regulated by signals from both serum and the surrounding extracellular matrix environment.Vascular endothelial growth factor,angiopoietin,fibroblast growth factor and transforming growth factor-beta are among the potent angiogenic cytokines in wound angiogenesis.Specific endothelial cell ECM receptors are critical for morphogenetic changes in blood vessels during wound repair.In particular integrin(αvβ3)receptors for fibrin and fibronectin,appear to be required for wound angiogenesis:αvβ3 is focally expressed at the tips of angiogenic capillary sprouts invading the wound clot,and any functional inhibitors ofαvβ3 such as monoclonal antibodies,cyclic RGD peptide antagonists,and peptidomimetics rapidly inhibit granulation tissue formation.In spite of clear knowledge about influence of many angiogenic factors on wound healing,little progress has been made in defining the source of these factors,the regulatory events involved in wound angiogenesis and in the clinical use of angiogenic stimulants to promote repair.

Regulation and function of angiogenic factors in chronic lymphocytic leukemia

Progression of chronic lymphocytic leukemia(CLL)is determined by the localization of malignant cells in lymphoid tissues,where they receive growth and survival signals.CLL cells produce angiogenic factors that are regulated by internal and external stimuli and whose levels vary according to the clinical stage of the disease.Stromal cellular and molecular components in CLL niches disturb the balance of pro-and antiangiogenic molecules in CLL cells and induce an angiogenic switch.Additionally,CLL cells also influence the behavior of microenvironmental cells,inducing endothelial cell proliferation and increasing the angiogenic capacity of macrophages,neutrophils,and other cells present in CLL niches.As a result of these reciprocal functional interactions,bone marrow angiogenesis is frequently increased in CLL and has been proposed as a prognostic marker in early disease.Besides their role in regulating angiogenesis,angiogenic factors are also involved in CLL cell migration and survival,all contributing to disease progression.Angiogenic factors,particularly vascular endothelial growth factor,have therefore been attractive therapeutic targets in CLL and many clinical trials were established in the past years.However,the results of these trials reveal that anti-angiogenic therapies alone are not as efficient as expected and should rather be used in combination with other treatments.

Growth factors for therapeutic angiogenesis in hypercholesterolemic erectile dysfunction

The past decade has seen an explosion of new information on the physiology of penile erection, and pathophysiology of erectile dysfunction （ED）. Hypercholesterolemia is a chronic condition that can lead to degeneration in the vasculature bed and can result in ED if the penile vasculature is involved. Angiogenesis is the growth of new blood vessels from preexisting vasculature. Therapeutic angiogenesis seeks to harness the mechanisms of vascular growth to treat disorders of inadequate tissue perfusion, such as coronary artery disease and ED. There have been tremendous changes in the field of therapeutic angiogenesis over the past decade, and there is much promise for the future. Initial preclinical work with cytokine growth factor delivery resulted in a great deal of enthusiasm for the treatment of ischemic heart and/or peripheral vascular disease, though clinical studies have not achieved similar success. With an increased understanding of the complex mechanisms involved in angiogenesis, novel therapies which target multiple different angiogenic pathways are also being developed and tested. The penis is a convenient tissue target for gene therapy because of its external location and accessibility, the ubiquity of endothelial lined spaces, and low level of blood flow, especially in the flaccid state. Therapeutic angiogenesis is an exciting field that continues to evolve. This review will focus on the development of growth factors for hypercholesterolemic ED, the use of various growth factors for ED therapy, their routes of delivery, and the results in animal studies.

Tumor angiogenesis and anti-angiogenic therapy

Anti-angiogenic drugs(AADs),which mainly target the vascular endothelial growth factor-A signaling pathway,have become a therapeutic option for cancer patients for two decades.During this period,tremendous clinical experience of anti-angiogenic therapy has been acquired,new AADs have been developed,and the clinical indications for AAD treatment of various cancers have been expanded using monotherapy and combination therapy.However,improvements in the therapeutic outcomes of clinically available AADs and the development of more effective next-generation AADs are still urgently required.This review aims to provide historical and perspective views on tumor angiogenesis to allow readers to gain mechanistic insights and learn new therapeutic development.We revisit the history of concept initiation and AAD discovery,and summarize the up-to-date clinical translation of anti-angiogenic cancer therapy in this field.

Novel hepatocellular carcinoma molecules with prognostic and therapeutic potentials

Hepatocellular carcinoma(HCC), the predominant form of primary liver cancer, is the sixth most common cancer worldwide and the third leading cause of cancerrelated death. The difficulty to diagnose early cancer stages, the aggressive behaviors of HCC, and the poor effectiveness of therapeutic treatments, represent the reasons for the quite similar deaths per year and incidence number. Considering the fact that the diagnosis of HCC typically occurs in the advanced stages of the disease when the therapeutic options have only modest efficacy, the possibility to identify early diagnostic markers could be of significant benefit. So far, a large number of biomarkers have been associated to HCC progression and aggressiveness, but many of them turned out not to be of practical utility. This is the reason why active investigations are ongoing in this field. Given the huge amount of published works aimed at the identification of HCC biomarkers, in this review we mainly focused on the data published in the last year, with particular attention to the role of(1) molecular and biochemical cellular markers;(2) micro-interfering RNAs;(3) epigenetic variations; and(4) tumor stroma. It is worth mentioning that a significant number of the HCC markers described in the present review may be utilized also as targets for novel therapeutic approaches, indicating the tight relation between diagnosis and therapy. In conclusion, we believe that integrated researches among the different lines of investigation indicated above should represent the winning strategies to identify effective HCC markers and therapeutic targets.

EXPRESSION OF BASIC FIBROBLAST GROWTH FACTOR,TRANSFORMING GROWTH FACTOR β_1 AND THEIRRECEPTORS IN OSTEOSARCOMA AND ITSRELATIONSHIP TO ANGIOGENESIS

Objective: To investigate the expression ofangiogenic factors, basic fibroblast growth factor (bFGF)and transforming growth factor (TGF)-β1 inosteosarcoma, its association with neovascularizationand prognosis. Methods: The expression of bFGF, TGFβ1 and their receptors, as well as intratumoralmicrovcssel count (MVD) were studied in 80osteosarcomas by immunohistochemical staining andmorphometry. The relationship between the angiogenicfactors expression and prognosis was evaluated by amultivariate analysis using Cox proportion hazardmodel. Results: Among 80 cases of osteosarcoma, 46cases were positive for bFGFlbFGFr (57.5%), and 31cases for TGF-β1/ TGF-β (RI)(38.8%) respectively. TheMVD and bFGF, TGF-β1, were important indicators topredict the prognosis of patients with osteosarconla bythe Cox proportion hazard model analysis. Conclusioll:The angiogenic factors bFGF and TGF-β1 are involvedin the angiogenesis of osteosarcoma, and theangiogenesis inf'luences the prognosis. Also they may beuseful in the evaluation of the prognosis of patients withosteosarcoma.

Therapeutic neovascularization promoted by injectable hydrogels

The aim of therapeutic neovascularization is to repair ischemic tissues via formation of new blood vessels by delivery of angiogenic growth factors,stem cells or expansion of pre-existing cells.For efficient neovascularization,controlled release of growth factors is particularly necessary since bolus injection of molecules generally lead to a poor outcome due to inadequate retention within the injured site.In this regard,injectable hydrogels,made of natural,synthetic or hybrid biomaterials,have become a promising solution for efficient delivery of angiogenic factors or stem and progenitor cells for in situ tissue repair,regeneration and neovascularization.This review article will broadly discuss the state-of-the-art in the development of injectable hydrogels from natural and synthetic precursors,and their applications in ischemic tissue repair and wound healing.We will cover a wide range of in vitro and in vivo studies in testing the functionalities of the engineered injectable hydrogels in promoting tissue repair and neovascularization.We will also discuss some of the injectable hydrogels that exhibit self-healing properties by promoting neovascularization without the presence of angiogenic factors.