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EN
Angiogenesis, the formation of new capillaries from pre-existing vascular network, plays an important role in physiological and pathological processes such as embryonic development, wound healing, and development of atherosclerosis. Extension of the circulatory network is also considered to be one the most important factors during cancerogenesis. Inhibition of angiogenesis may lead to inhibition of tumor growth whereas stimulation may improve wound healing. Research achievements suggest the use of plants and their extracts as potential therapeutic agents with pro- or antiangiogenic activity. Since the anticancer and antiangiogenic properties of many phytomedicines have been amply reviewed elsewhere this paper will focus on the treatment of vascular insufficiency in wound healing. Globally accepted herbal drugs are thought to be safe and effective, however, there is a need for more evidence-based confirmation in controlled and validated trials. Among the most frequently studied proangiogenic phytochemicals are ginsenosides from Panax ginseng, beta-sitosterol from Aloe vera, calycosin from Radix Astragali, and extracts from Hippophae rhamnoides L. and Angelica sinensis.
EN
I Chair and Department of Gynecological Oncology and Gynecology is a specialist research center providing help in diagnostics and treatment of gynecological malignancies. The research work is focused on the processes of angiogenesis and lymphangiogenesis. Development of blood and lymphatic vessels is subject to research in a wide range of malignancies, including ovarian cancer, endometrial cancer and uterine sarcomas. Angiogenesis in malignancies of the female genital tract is investigated by using some modern 3D sonography that uses high-definition blood flow imaging. Ovarian Tumors and Early Ovarian Cancer Detection unit was established in 2002 and since that time more than 3500 patients with difficult to diagnose tumors have been consulted and treated in the Department. Ovarian cancer immunology studies are the second leading research fiekld in the 1st Chair Department of Gynecological Oncology and Gynecology. The Department is well equipped with diagnostic devices as well as a scientific laboratory. This allows for studies in the fields of imaging of masses, their immunology, biochemistry and molecular biology. Understanding immunological response in patients with ovarian cancer is the key to develop new, effective therapies, including immunological vaccines. In this area we are cooperating with prominent international research centers: Department of Surgery, University of Michigan and Department of Microbiology and Immunology, University of Arkansas. Results of our research are published in both Polish and international journals specializing in fields of gynecology, oncology, immunology and basic science.
EN
We investigated the feasibility of a novel therapeutic approach to treat neoplastic diseases in mice. This novel strategy consists in delivering a protein (angiostatin) with strong antiangiogenic properties, followed by administration of the interleukin 12 gene that is strongly immunomodulatory and has also some antiangiogenic effects. When angiostatin-mediated antiangiogenic therapy was used in combination with intratumor delivery of the IL-12 gene (a strategy much safer than IL-12 protein administration), this produced a synergistic therapeutic effect.
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EN
Recently, significant attention has been paid to the possibility of thwarting cancer progression by inhibition of neoangiogenesis (formation of new blood vessels) in growing tumors. Although general mechanisms of angiogenesis have been elucidated, virtually nothing is known about the effects of low doses of ionizing radiation on pro-angiogenic properties of endothelial cells. In the present study, we evaluated the effects of a low (0.2 Gy), intermediate (1 Gy), and high (4 Gy) doses of X-rays on a few angiogenesis-related parameters of isolated murine endothelial cells. We show here that 24 to 48 hours after irradiation with 0.2 Gy the cell proliferation was inhibited to a similar extent as after the exposure to 1 Gy. Also, adhesion of the 0.2 Gy-irradiated cells to both gelatin and MatrigelŽ was inhibited 24 hours post-exposure, whereas irradiation with 1 or 4 Gy resulted in the increased adhesion of the cells to these substrata. Similar effects were observed during the "wound" migration assay. Finally, 24 hours after exposure of the cells to 0.2 Gy of X-rays, the surface expression of the â3 integrin subunit was down-regulated, whereas irradiations with 1 and 4 Gy of X-rays resulted in the significantly elevated expression of this subunit. These results indicate that proliferating endothelial cells are sensitive in vitro to relatively low doses of ionizing radiation
EN
Manipulation of angiogenesis in vivo is an example of successful gene therapy strategies. Overexpression of angiogenic genes like VEGF, FGF or PDGF causes new vessel formation and improves the clinical state of patients. Gene therapy is a very promising procedure but requires large amounts of pharmaceutical-grade plasmid DNA. In this regard we have constructed a bicistronic plasmid DNA vector encoding two proangiogenic factors, VEGF165 and FGF-2. The construct (pVIF) contains the internal ribosome entry site (IRES) of the encephalomyocarditis virus (ECMV) which permits both genes to be translated from a single bicistronic mRNA. The IRES sequence allows for a high efficiency of gene expression in vivo. The pVIF vector was characterized in vitro and in vivo. In vivo angiogenesis studies showed that the bicistronic vector encoding two proangiogenic factors induces the formation of new vessels significantly more than pVEGF165 or pFGF-2 alone. In our opinion the combined proangiogenic approach with VEGF165 and FGF-2 is more powerful and efficient than single gene therapy. We also postulate that IRES sequence can serve as a useful device improving efficiency of gene therapy.
EN
Tumor endothelial cells are actively involved in the neovascularization processes that accompany tumor growth. Their easy accessibility for systemically applied therapeutics makes them interesting targets for therapeutic intervention. Especially for drug targeting-based therapeutics that often consist of macromolecular moieties, the tumor endothelium is considered a much better target than the tumor cells located behind the vascular wall barrier. In this review, the general principles underlying the development and choices in the development of vascular drug-targeting strategies are discussed. An overview of target epitopes identified in the past two decades is followed by a summary of those strategies that directly or indirectly induced tumor blood flow blockade in vivo. The demonstrated therapeutic success in pre-clinical animal models in debulking large tumor masses and inhibiting tumor outgrowth warrant further development of these therapeutic approaches. Yet, more effort should be put in studies in which the efficacy of different effector activities aimed at the same target, of one effector activity aimed at different targets, and of multiple target strategies are be compared. Combining these data with proper inventories on the molecular basis of tumor endothelial heterogeneity in general will make possible the development of tumor vascular drug-targeting strategies towards clinical application.
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Content available GPU enhanced simulation of angiogenesis
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EN
In the paper we present the use of graphic processor units to accelerate the most time-consuming stages of a simulation of angiogenesis and tumor growth. By the use of advanced CUDA mechanisms such as shared memory, textures and atomic operations, we managed to speed up the CUDA kernels by a factor of 57x. However, in our simulation we used the GPU as a co-processor and data from CPU was copied back and forth in each phase. It decreased the speedup of rewritten stages by 40%. We showed that the performance of the entire simulation can be improved by a factor of 10 up to 20.
EN
Magnetic resonance imaging study is currently the reference method for the detection and diagnosis of the central nervous system tumors. A large number of tumors, especially high-grade, has a higher water content in the cells, which results in prolongation of MRI T1 and T2 what appearance as increased signal intensity in in T2-weighted images and the reduction in T1-weighted images. MRI can be performed with administration of contrast agent, which shortens T1 and increases signal on T1-weighted sequences. This allows to identify areas of increased angiogenesis), which is the exponent of the cancer malignancy degree and its biological activity. Obtained MRI images are analyzed and evaluated by a radiologist and a clinician. Most of the time it is the "by the eye" analysis, which is based on the MRI image evaluation by the generally accepted radiological standards. However, this method is relatively inaccurate. which in turn can bring to the wrong diagnosis of the disease and implementation or even lack of implementation of appropriate treatment. More and more researches are conducted in this area, but developed methods are usually very complicated and difficult to carry out by the "layman" which is the clinician. That is why the attempt is made, to develop a simple and clear algorithm for MRI image analysis in patients with the central nervous system tumors, allowing for quick and objective evaluation of magnetic resonance imaging study.
PL
Badanie metodą rezonansu magnetycznego jest aktualnie metodą referencyjną przy wykrywaniu i diagnozowaniu nowotworów centralnego układu nerwowego. Duża część nowotworów, zwłaszcza o wysokim stopniu złośliwości, charakteryzuje się większą zawartością wody w komórkach, co w badaniu MRI skutkuje wydłużeniem T1 i T2, uwidocznionym jako nasilenie sygnału w obrazach T2-zależnych oraz jego obniżeniem w obrazach T1-zależnych. MRI można przeprowadzić z podaniem środka kontrastowego, co powoduje skrócenie czasu T1 i podniesienie
EN
Angiogenesis, i.e. formation of new blood vessels out of pre-existing capillaries, is essential to the development of tumour vasculature. The discovery of specific antiangiogenic inhibitors has important therapeutic implications for the development of novel cancer treatments. Vasostatin, the N-terminal domain of calreticulin, is a potent endogenous inhibitor of angiogenesis and tumour growth. In our study, using B16(F10) murine melanoma model and electroporation we attempted intramuscular transfer of human vasostatin gene. The gene therapy was combined with antiangiogenic drug dosing schedule of a known chemotherapeutic (cyclophosphamide). The combination of vasostatin gene therapy and cyclophosphamide administration improved therapeutic effects in melanoma tumours. We observed both significant inhibition of tumour growth and extended survival of treated mice. To our knowledge, this is one of the first reports showing antitumour efficacy of electroporation-mediated vasostatin gene therapy combined with antiangiogenic chemotherapy.
EN
The hydrazine derivatives of benzopyrones remain an unexplored group of chemical compounds. This preliminary study investigates the influence of A-5, CH-3 and K-2 derivatives at concentrations of 1, 10, 100 nM and 1 μM on selected biochemical factors of a melanoma cell line WM-115, with regard to their potential angiogenic properties. The studied compounds were found to influence cell proliferation, as well as total protein, bFGF and FGFR1 concentration.
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Content available remote Carbon monoxide - a "new" gaseous modulator of gene expression.
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EN
Carbon monoxide (CO) is an odorless, tasteless and colorless gas which is generated by heme oxygenase enzymes (HOs). HOs degrade heme releasing equimolar amounts of CO, iron and biliverdin, which is subsequently reduced to bilirubin. CO shares many properties with nitric oxide (NO), an established cellular messenger. Both CO and NO are involved in neural transmission and modulation of blood vessel function, including their relaxation and inhibition of platelet aggregation. CO, like NO, binds to heme proteins, although CO binds only ferrous (FeII) heme, whereas NO binds both ferrous and ferric (FeIII). CO enhances the activity of guanylate cyclase although it is less potent than NO. In contrast, CO inhibits other heme proteins, such as catalase or cytochrome P450. The effects of CO on gene expression can be thus varied, depending on the cellular microenvironment and the metabolic pathway being influenced. In this review the regulation of gene expression by HO/CO in the cardiovascular system is discussed. Recent data, derived also from our studies, indicate that HO/CO are significant modulators of inflammatory reactions, influencing the underlying processes such as cell proliferation and production of cytokines and growth factors.
EN
Manipulation of angiogenesis in vivo is an example of successful gene therapy strate­gies. Overexpression of angiogenic genes like VEGF, FGF or PDGF causes new vessel formation and improves the clinical state of patients. Gene therapy is a very promis­ing procedure but requires large amounts of pharmaceutical-grade plasmid DNA. In this regard we have constructed a bicistronic plasmid DNA vector encoding two proangiogenic factors, VEGF165 and FGF-2. The construct (pVIF) contains the inter­nal ribosome entry site (IRES) of the encephalomyocarditis virus (ECMV) which per­mits both genes to be translated from a single bicistronic mRNA. The IRES sequence allows for a high efficiency of gene expression in vivo. The pVIF vector was character­ized in vitro and in vivo. In vivo angiogenesis studies showed that the bicistronic vec­tor encoding two proangiogenic factors induces the formation of new vessels signifi­cantly more than pVEGF165 or pFGF-2 alone. In our opinion the combined pro- angiogenic approach with VEGF165 and FGF-2 is more powerful and efficient than single gene therapy. We also postulate that IRES sequence can serve as a useful device improving efficiency of gene therapy.
EN
Peroxisome proliferator-activated receptors-γ (PPARγ) are ligand-inducible transcription factors of the nuclear hormone receptor superfamily. We examined the effect of PPARγ activation on the generation of vascular endothelial growth factor (VEGF), one of the major angiogenic agents. Rat vascular smooth muscle cells (VSMC) and murine macrophages RAW264.7 were incubated for 24 h with PPARγ activators: prostaglandin J2 and ciglitazone. PPARγ were expressed in VSMC and RAW cells and their activity was upregulated in the presence of PGJ2 and ciglitazone. Incubation of the cells with PPARγ activators significantly augmented the release of VEGF protein into the media, both in resting and in IL-1β- or LPS-stimulated cultures. The higher protein generation was connected with the increased expression of mRNA and transcriptional activation of VEGF promoter. We conclude that the activation of PPARγ upregulates the generation of VEGF and may be involved in the regulation of angiogenesis.
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