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1.
Automatic Parallel Detection of Neovascularization from Retinal Images Using Ensemble of Extreme Learning Machine.
Huang, H, Ma, H, Qian, W
Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual International Conference. 2019;:4712-4716
Abstract
Retinopathy screening is a non-invasive method to collect retinal images and neovascularization detection from retinal images plays a significant role on the identification and classification of diabetes retinopathy. In this paper, an automatic parallel detection framework for neovascularization with color retinal images using ensemble of extreme learning machine is proposed. The framework employs two Map-Reduce Jobs to extract features and trains Extreme Learning Machine models. Ensemble methods such as bagging, subspace partitioning and cross validating are used to increase the accuracy. The framework is evaluated with retinal images from MESSIDOR database. Experimental results show the framework can improve the detection accuracy, as well as speedup the processing time to 22 times on average.
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Vascular endothelial growth factor: An important molecular target of curcumin.
Saberi-Karimian, M, Katsiki, N, Caraglia, M, Boccellino, M, Majeed, M, Sahebkar, A
Critical reviews in food science and nutrition. 2019;(2):299-312
Abstract
The discovery of Vascular Endothelial Growth Factor (VEGF), the key modulator of angiogenesis, has triggered intensive research on anti-angiogenic therapeutic modalities. Although several clinical studies have validated anti-VEGF therapeutics, with few of them approved by the U.S. Food and Drug Administration (FDA), anti-angiogenic therapy is still in its infancy. Phytochemicals are compounds that have several metabolic and health benefits. Curcumin, the yellow pigment derived from turmeric (Curcuma longa L.) rhizomes, has a wide range of pharmaceutical properties. It has also been shown to inhibit VEGF by several studies. In this review, we elaborate the effect of curcumin on VEGF and angiogenesis and its therapeutic application.
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3.
Potential molecular mechanisms underlying the effect of arsenic on angiogenesis.
Zhang, J, Zhang, Y, Wang, W, Zhang, Z
Archives of pharmacal research. 2019;(11):962-976
Abstract
Arsenic is a potent chemotherapeutic drug that is applied as a treatment for cancer; it exerts its functions through multiple pathways, including angiogenesis inhibition. As angiogenesis is a critical component of the progression of many diseases, arsenic is a feasible treatment option for patients with other angiogenic diseases, including rheumatoid arthritis and psoriasis, among others. However, arsenic is also a well-known carcinogen, demonstrating a pro-angiogenesis effect. This review will focus on the dual effects of arsenic on neovascularization and the relevant mechanisms underlying these effects, aiming to provide a rational understanding of arsenic treatment. In particular, we expect to provide a comprehensive overview of the current knowledge of the mechanisms by which arsenic influences angiogenesis.
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4.
Role of angiogenesis in adenomyosis-associated abnormal uterine bleeding and subfertility: a systematic review.
Harmsen, MJ, Wong, CFC, Mijatovic, V, Griffioen, AW, Groenman, F, Hehenkamp, WJK, Huirne, JAF
Human reproduction update. 2019;(5):647-671
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Abstract
BACKGROUND Adenomyosis commonly occurs with abnormal uterine bleeding (AUB) and is associated with subfertility and a higher miscarriage rate. Recent evidence showed abnormal vascularization in the endometrium in patients with adenomyosis, suggesting a role of angiogenesis in the pathophysiology of AUB and subfertility in adenomyosis and providing a possible treatment target. OBJECTIVE AND RATIONALE We hypothesized that the level of abnormal vascularization and expression of angiogenic markers is increased in the ectopic and eutopic endometrium of adenomyosis patients in comparison with the endometrium of control patients. This was investigated through a search of the literature. SEARCH METHODS A systematic search was performed in PubMed and Embase until February 2019. Combinations of terms for angiogenesis and adenomyosis were applied as well as AUB, subfertility or anti-angiogenic therapy. The main search was limited to clinical studies carried out on premenopausal women. Original research articles focusing on markers of angiogenesis in the endometrium of patients with adenomyosis were included. Studies in which no comparison was made to control patients or which were not published in a peer-reviewed journal were excluded. A second search was performed to explore the therapeutic potential of targeting angiogenesis in adenomyosis. This search also included preclinical studies. OUTCOMES A total of 20 articles out of 1669 hits met our selection criteria. The mean vascular density (MVD) was studied by quantification of CD31, CD34, von Willebrand Factor (vWF) or factor-VIII-antibody-stained microvessels in seven studies. All these studies reported a significantly increased MVD in ectopic endometrium, and out of the six articles that took it into account, four studies reported a significantly increased MVD in eutopic endometrium compared with control endometrium. Five articles showed a significantly higher vascular endothelial growth factor expression in ectopic endometrium and three articles in eutopic endometrium compared with control endometrium. The vascular and pro-angiogenic markers α-smooth muscle actin, endoglin, S100A13, vimentin, matrix metalloproteinases (MMPs), nuclear factor (NF)-kB, tissue factor (TF), DJ-1, phosphorylated mammalian target of rapamycin, activin A, folli- and myostatin, CD41, SLIT, roundabout 1 (ROBO1), cyclooxygenase-2, lysophosphatidic acid (LPA) 1,4-5, phospho signal transducer and activator of transcription 3 (pSTAT3), interleukin (IL)-6, IL-22 and transforming growth factor-β1 were increased in ectopic endometrium, and the markers S100A13, MMP-2 and -9, TF, follistatin, myostatin, ROBO1, LPA1 and 4-5, pSTAT3, IL-6 and IL-22 were increased in eutopic endometrium, compared with control endometrium. The anti-angiogenic markers E-cadherin, eukaryotic translation initiation factor 3 subunit and gene associated with retinoic-interferon-induced mortality 19 were decreased in ectopic endometrium and IL-10 in eutopic endometrium, compared with control endometrium. The staining level of vWF and two pro-angiogenic markers (NF-κB nuclear p65 and TF) correlated with AUB in patients with adenomyosis. We found no studies that investigated the possible relationship between markers of angiogenesis and subfertility in adenomyosis patients. Nine articles reported on direct or indirect targeting of angiogenesis in adenomyosis-either by testing hormonal therapy or herbal compounds in clinical studies or by testing angiogenesis inhibitors in preclinical studies. However, there are no clinical studies on the effectiveness of such therapy for adenomyosis-related AUB or subfertility. WIDER IMPLICATIONS The results are in agreement with our hypothesis that increased angiogenesis is present in the endometrium of patients with adenomyosis compared with the endometrium of control patients. It is likely that increased angiogenesis leads to fragile and more permeable vessels resulting in adenomyosis-related AUB and possibly subfertility. While this association has not sufficiently been studied yet, our results encourage future studies to investigate the exact role of angiogenesis in the etiology of adenomyosis and related AUB or subfertility in women with adenomyosis in order to design curative or preventive therapeutic strategies.
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5.
Annexin A2 (ANX A2): An emerging biomarker and potential therapeutic target for aggressive cancers.
Sharma, MC
International journal of cancer. 2019;(9):2074-2081
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Abstract
ANX A2 is an important member of annexin family of proteins expressed on surface of endothelial cells (ECs), macrophages, mononuclear cells and various types of cancer cells. It exhibits high affinity binding for calcium (Ca++ ) and phospholipids. ANX A2 plays an important role in many biological processes such as endocytosis, exocytosis, autophagy, cell-cell communications and biochemical activation of plasminogen. On the cell surface ANX A2 organizes the assembly of plasminogen (PLG) and tissue plasminogen activator (tPA) for efficient conversion of PLG to plasmin, a serine protease. Proteolytic activity of plasmin is required for activation of inactive pro-metalloproteases (pro-MMPs) and latent growth factors for their biological actions. These activation steps are critical for degradation of extracellular matrix (ECM) and basement proteins (BM) for cancer cell invasion and metastasis. Increased expression of ANX A2 protein/gene has been correlated with invasion and metastasis in a variety of human cancers. Moreover, clinical studies have positively correlated ANX A2 protein expression with aggressive cancers and with resistance to anticancer drugs, shorter disease-free survival (DFS), and worse overall survival (OS). The mechanism(s) by which ANX A2 regulates cancer invasion and metastasis are beginning to emerge. Investigators used various technologies to target ANX A2 in preclinical model of human cancers and demonstrated exciting results. In this review article, we analyzed existing literature concurrent with our own findings and provided a critical overview of ANX A2-dependent mechanism(s) of cancer invasion and metastasis.
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Isolation of Human Endothelial Cells from Normal Colon and Colorectal Carcinoma - An Improved Protocol.
Naschberger, E, Regensburger, D, Tenkerian, C, Langheinrich, M, Engel, FB, Geppert, C, Hartmann, A, Grützmann, R, Schellerer, VS, Stürzl, M
Journal of visualized experiments : JoVE. 2018;(134)
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Abstract
Primary cells isolated from human carcinomas are valuable tools to identify pathogenic mechanisms contributing to disease development and progression. In particular, endothelial cells (EC) constituting the inner surface of vessels, directly participate in oxygen delivery, nutrient supply, and removal of waste products to and from tumors, and are thereby prominently involved in the constitution of the tumor microenvironment (TME). Tumor endothelial cells (TECs) can be used as cellular biosensors of the intratumoral microenvironment established by communication between tumor and stromal cells. TECs also serve as targets of therapy. Accordingly, in culture these cells allow studies on mechanisms of response or resistance to anti-angiogenic treatment. Recently, it was found that TECs isolated from human colorectal carcinoma (CRC) exhibit memory-like effects based on the specific TME they were derived from. Moreover, these TECs actively contribute to the establishment of a specific TME by the secretion of different factors. For example, TECs in a prognostically favorable Th1-TME secrete the anti-angiogenic tumor-suppressive factor secreted protein, acidic and rich in cysteine-like 1 (SPARCL1). SPARCL1 regulates vessel homeostasis and inhibits tumor cell proliferation and migration. Hence, cultures of pure, viable TECs isolated from human solid tumors are a valuable tool for functional studies on the role of the vascular system in tumorigenesis. Here, a new up-to-date protocol for the isolation of primary EC from the normal colon as well as CRC is described. The technique is based on mechanical and enzymatic tissue digestion, immunolabeling, and fluorescence activated cell sorting (FACS)-sorting of triple-positive cells (CD31, VE-cadherin, CD105). With this protocol, viable TEC or normal endothelial cell (NEC) cultures could be isolated from colon tissues with a success rate of 62.12% when subjected to FACS-sorting (41 pure EC cultures from 66 tissue samples). Accordingly, this protocol provides a robust approach to isolate human EC cultures from normal colon and CRC.
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Multiple modes of action of eribulin mesylate: Emerging data and clinical implications.
Cortes, J, Schöffski, P, Littlefield, BA
Cancer treatment reviews. 2018;:190-198
Abstract
Eribulin mesylate (eribulin) is a synthetic analogue of the marine-sponge natural product halichondrin B. Eribulin exhibits potent antiproliferative activities against a variety of human cancer cell types in vitro and in vivo, and is used for the treatment of certain patients with advanced breast cancer or liposarcoma who are refractory to other treatments. The antiproliferative effects of eribulin have long been attributed to its antimitotic activities. Unlike other microtubule-targeting agents, eribulin inhibits microtubule polymerization through specific plus end binding, thus interfering with microtubule dynamic instability. Non-mitotic effects of eribulin on tumor biology have also been established in laboratory settings including: tumor vasculature remodeling, increased vascular perfusion, reduced hypoxia, and phenotypic changes involving reversal of epithelial-to-mesenchymal transition (EMT), resulting in reduced capacities for migration, invasion, and seeding lung metastases in experimental models. Preclinical data suggest that increased perfusion following eribulin treatment improves delivery of subsequent drugs. Supporting evidence for eribulin's non-mitotic effects in the clinical setting include increased tumor oxygen saturation, reduced hypoxia, phenotype changes consistent with EMT reversal, and genotype changes consistent with shifts from nonendocrine-responsive, luminal B, to endocrine-responsive, luminal A, breast cancer subtypes. Finally, potential biomarkers for eribulin response have been established based on tumor-phenotype and gene-expression profiles. Overall, preclinical and clinical data support both antimitotic and non-mitotic mechanisms of eribulin that may underlie the survival benefit observed in various clinical trials.
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Anti-angiogenic drug scheduling optimisation with application to colorectal cancer.
Sturrock, M, Miller, IS, Kang, G, Hannis Arba'ie, N, O'Farrell, AC, Barat, A, Marston, G, Coletta, PL, Byrne, AT, Prehn, JH
Scientific reports. 2018;(1):11182
Abstract
Bevacizumab (bvz) is a first choice anti-angiogenic drug in oncology and is primarily administered in combination with chemotherapy. It has been hypothesized that anti-angiogenic drugs enhance efficacy of cytotoxic drugs by "normalizing" abnormal tumor vessels and improving drug penetration. Nevertheless, the clinical relevance of this phenomenon is still unclear with several studies over recent years suggesting an opposing relationship. Herein, we sought to develop a new computational tool to interrogate anti-angiogenic drug scheduling with particular application in the setting of colorectal cancer (CRC). Specifically, we have employed a mathematical model of vascular tumour growth which interrogates the impact of anti-angiogenic treatment and chemotherapeutic treatment on tumour volume. Model predictions were validated using CRC xenografts which underwent treatment with a clinically relevant combinatorial anti-angiogenic regimen. Bayesian model selection revealed the most appropriate term for capturing the effect of treatments on the tumour size, and provided insights into a switch-like dependence of FOLFOX delivery on the tumour vasculature. Our experimental data and mathematical model suggest that delivering chemotherapy prior to bvz may be optimal in the colorectal cancer setting.
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Bromophenol curcumin analog BCA-5 exerts an antiangiogenic effect through the HIF-1α/VEGF/Akt signaling pathway in human umbilical vein endothelial cells.
Guo, C, Wang, L, Jiang, B, Shi, D
Anti-cancer drugs. 2018;(10):965-974
Abstract
The bromophenol curcumin analog 1,5-bis(3-bromo-4, 5-dimethoxyphenyl) penta-1, 4-dien-3-one (BCA-5) was assayed for antiangiogenic activity. Tandem mass tag labeling and liquid chromatography-tandem mass spectrometry were used to quantify the dynamic changes in the human umbilical vein endothelial cell (HUVEC) proteome. Functional annotation showed that BCA-5 might inhibit compounds related to the extracellular matrix, compounds that possess cytoskeletal protein-binding activity, and compounds that interact with cell motility-related enzymes, indicating antiangiogenic potential. In-vitro experiments have shown that BCA-5 inhibited HUVEC proliferation and induced HUVEC apoptosis. BCA-5 inhibited HUVEC migration, invasion, and tubular formation. BCA-5 decreased the phosphorylation of Akt and endothelial nitric oxide synthase; it also reduced the expression of hypoxia-inducible factor-1α and vascular endothelial cell growth factor in a dose-dependent manner. These results suggest that BCA-5 has antiangiogenic properties and should be considered a potent antiangiogenesis drug for the treatment of cancer.
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CLEC14a-HSP70-1A interaction regulates HSP70-1A-induced angiogenesis.
Jang, J, Kim, MR, Kim, TK, Lee, WR, Kim, JH, Heo, K, Lee, S
Scientific reports. 2017;(1):10666
Abstract
CLEC14a (C-type lectin domain family 14 member) is a tumor endothelial cell marker protein that is known to play an important role in tumor angiogenesis, but the basic molecular mechanisms underlying this function have not yet been clearly elucidated. In this study, using various proteomic tools, we isolated a 70-kDa protein that interacts with the C-type lectin-like domain of CLEC14a (CLEC14a-CTLD) and identified it as heat shock protein 70-1A (HSP70-1A). Co-immunoprecipitation showed that HSP70-1A and CLEC14a interact on endothelial cells. In vitro binding analyses identified that HSP70-1A specifically associates with the region between amino acids 43 and 69 of CLEC14a-CTLD. Competitive blocking experiments indicated that this interacting region of CLEC14a-CTLD significantly inhibits HSP70-1A-induced extracellular signal-regulated kinase (ERK) phosphorylation and endothelial tube formation by directly inhibiting CLEC14a-CTLD-mediated endothelial cell-cell contacts. Our data suggest that the specific interaction of HSP70-1A with CLEC14a may play a critical role in HSP70-1A-induced angiogenesis and that the HSP70-1A-interacting region of CLEC14a-CTLD may be a useful tool for inhibiting HSP70-1A-induced angiogenesis.