121 research outputs found
Angiogenesis in cancer - general pathways and their therapeutic implications
No full textA vast amount of data shows that angiogenesis has a pivotal role in tumor growth, progression, invasiveness and metastasis. This is a complex process involving essential signaling pathways such as vascular endothelial growth factor (VEGF) and Notch in vasculature, as well as additional players such as bone marrow-derived endothelial progenitor cells. Primary tumor cells, stromal cells and cancer stem cells strongly influence vessel growth in tumors. Better understanding of the role of the different pathways and the crosstalk between different cells during tumor angiogenesis are crucial factors for developing more effective anticancer therapies. Targeting angiogenic factors from the VEGF family has become an effective strategy to inhibit tumor growth and so far the most successful results are seen in metastatic colorectal cancer (CRC), renal cell carcinoma (RCC) and non-small cell lung cancer (NSCLL). Despite the initial enthusiasm, the angiogenesis inhibitors showed only moderate survival benefit as monotherapy, along with a high cost and many side effects. Obviously, other important pathways may affect the angiogenic switch, among them Notch signaling pathway attracted a large interest because its ubiquitous role in carcinogenesis and angiogenesis. Herein we present the basics for VEGF and Notch signaling pathways and current advances of targeting them in antiangiogenic, antitumor therapy
Avian area vasculosa and CAM as rapid in vivo pro-angiogenic and antiangiogenic models.
No full textAngiogenesis, the development of new blood vessels from preexisting ones, is driven by coordinated signaling pathways governed by specific molecules, hemodynamic forces, and endothelial and periendothelial cells. The processes involve adhesion, migration, and survival machinery within the target endothelial and periendothelial cells. Factors that interfere with any of these processes may therefore influence angiogenesis either positively (pro-angiogenesis) or negatively (antiangiogenesis). The avian area vasculosa (AV) and the avian chorioallantoic membrane (CAM) are two useful tools for studying both angiogenesis and antiangiogenesis since they are amenable to both intravascular and topical administration of target, agents, are relatively rapid assays, and can be adapted very easily to study angiogenesis-dependent processes, such as tumor growth. Both models provide a physiological setting that permits investigation of pro-angiogenic and antiangiogenic agent interactions in vivo
Dynamics of the Developing Chick Chorioallantoic Membrane Assessed by Stereology, Allometry, Immunohistochemistry and Molecular Analysis.
No full textThe chick chorioallantoic membrane (CAM) is a widely used model for the study of angiogenesis, tumour growth, as well as drug efficacy. In spite of this, little is known about the developmental alteration from its appearance to the time of hatching. In the current study the CAM has been studied by classical stereology and allometry. Expression levels of selected angiogenesis-related molecules were estimated by RT-PCR and cell dynamics assessed by proliferation and apoptosis assays. Absolute CAM volume increased from a low of 0.47 ± 0.11 cm3 at embryonic day 8 (E8) to a high of 2.05 ± 0.27 cm3 at E18, and then decreased to 1.6 ± 0.47 cm3 at E20. On allometric analysis, three growth phases were identifiable. Between E8-13 (phase I), the CAM grew fastest; moderately in phase II (E13-18) but was regressing in phase III (E18-20). The chorion, the mesenchyme and the allantoic layers grew fastest in phase I, but moderately in phase II. The mesenchyme grew slowly in phase III while the chorion and allantois were regressing. Chorionic cell volume increased fastest in phase I and was regressing in phase III. Chorionic capillaries grew steadily in phase I and II but regressed in phase III. Both the chorion and the allantois grew by intrinsic cell proliferation as well as recruitment of cells from the mesenchyme. Cell proliferation was prominent in the allantois and chorion early during development, declined after E17 and apoptosis started mainly in the chorion from E14. VEGFR2 expression peaked at E11 and declined steadily towards E20, VEGF peaked at E13 and E20 while HIF 1α had a peak at E11 and E20. Studies targeting CAM growth and angiogenesis need to take these growth phases into consideration
SDF-1/CXCR4 signalling is involved in blood vessel growth and remodelling by intussusception.
No full textThe precise mechanisms of SDF-1 (CXCL12) in angiogenesis are not fully elucidated. Recently, we showed that Notch inhibition induces extensive intussusceptive angiogenesis by recruitment of mononuclear cells and it was associated with increased levels of SDF-1 and CXCR4. In the current study, we demonstrated SDF-1 expression in liver sinusoidal vessels of Notch1 knockout mice with regenerative hyperplasia by means of intussusception, but we did not detect any SDF-1 expression in wild-type mice with normal liver vessel structure. In addition, pharmacological inhibition of SDF-1/CXCR4 signalling by AMD3100 perturbs intussusceptive vascular growth and abolishes mononuclear cell recruitment in the chicken area vasculosa. In contrast, treatment with recombinant SDF-1 protein increased microvascular density by 34% through augmentation of pillar number compared to controls. The number of extravasating mononuclear cells was four times higher after SDF-1 application and two times less after blocking this pathway. Bone marrow-derived mononuclear cells (BMDC) were recruited to vessels in response to elevated expression of SDF-1 in endothelial cells. They participated in formation and stabilization of pillars. The current study is the first report to implicate SDF-1/CXCR4 signalling in intussusceptive angiogenesis and further highlights the stabilizing role of BMDC in the formation of pillars during vascular remodelling
Corrosion of concrete structures due to climate change
No full textConcrete is clearly one of the most predominant-used material in both residential and non-residential structures across Europe (Peled and Fishman, 2021). A reinforced concrete (RC) structure is expected to satisfy criteria for serviceability, structural integrity, and stability over its designed operational lifespan, without significant loss of utility or excessive unforeseen maintenance (for general requirements see also EN 1990). Comprehending the degradation mechanisms that impact these structures is essential for accurately estimating their service life and formulating cost-effective maintenance strategies. The main mechanisms responsible for concrete degradation include corrosion caused by carbonation and the presence of chloride ions, freeze-thaw cycles, sulphate attack and erosion due to high-velocity water flow, ice, or wind-blown sand.Integral Design & Managemen
Preliminary Results on October 27, 2004 Vrancea Earthquake - Case Study on Sofia Strong Ground
No full textThe intermediate-depth earthquakes in Vrancea (Romania) are particularly notable in the group of the European earthquakes. The scope of this work is to show preliminary results of the seismic effects of 27, October, 2004 earthquake from the Vrancea seismogenic zone. Particular attention is done on the records registered in Bucharest and Sofia. The study is limited to the question about the level of the ground motions in terms of recorded spectral amplitudes during 2004 Vrancea strong earthquakes. For this purpose we discuss: (1) the strong ground motion records in due to Vrancea strong earthquake, 2004; (2) the regional seismicity and a review of the available recurrence and attenuation relationships; (3) results from the response of one storey building due to scaled record in Sofia.
The results of this study confirm the significant influence of the Vrancea intermediate-depth seismogenic zone on very large territory of Bulgaria and the need to provide realistic seismic input, from Vrancea sources, for the purposes of seismic microzonation.JRC.G.5 - European laboratory for structural assessmen
Generated Accelerograms on the Example of Sofia City for the Purposes of Microzonation
No full textExpected seismic excitation is analyzed along three profiles with length of 14 km, passing through the central part of Sofia city. Accelerograms are simulated for a scenario earthquakes with M=7. A hybrid modelling method is applied, based on the modal summation technique and finite differences scheme. The site amplification is calibrated taking into account the response spectra ratio of 2D to 1D models. As a result accelerograms are generated at intervals of 100 m along the three profiles. The seismic response of reinforced concrete industrial building designed according to the Eurocodes is studied by use of the generated accelerograms. Response characteristics, such as damage index and story drift are calculated. Maps of distribution of the damage index on the area covered by the three profiles are plotted for the considered scenario. The results could be used for the purpose of microzonation.JRC.DG.G.5 - European laboratory for structural assessmen
EUROPEAN UNION HORIZON 2020 SMART CITY APPROACH AND ITS APPLICATION IN THE BULGARIAN CONTEXT
No full textLAMA2 Congenital Muscle Dystrophy: A Novel Pathogenic Mutation in Bulgarian Patient
No full textCongenital muscle dystrophies (CMD) are genetically and clinically heterogeneous hereditary myopathies mainly with autosomal recessive type of inheritance. The most common form worldwide is considered to be merosin-deficient muscle dystrophy type 1A, called MDC1A (due to laminin-α2 defects as a result of LAMA2 gene mutation), accounting for 30-40% of total cases of CMD. The exact molecular and clinical diagnoses, respectively, are a prerequisite for the most effective treatment; sometimes orphan drugs exist for some rare diseases. One of such drugs is Tarix, which was FDA approved and announced in 2016 for treatment of MDC1A. Here we present a patient diagnosed postmortem as having early-onset LAMA2-related muscular dystrophy as a result of mutations in LAMA2, identified by Sanger sequencing in his parents: a novel nonsense mutation c.4452T>A in exon 31, identified in the mother, and a known pathogenic nonsense mutation c.2901C>A in exon 21, detected in the father. The truncating nature of both nonsense mutations made the clinical presentation severe and the outcome fatal. Genetic analysis in such cases of muscle dystrophy is of utmost impact, because it makes the correct diagnosis with at least some specific options for treatment, makes the prognosis depending on the severity of mutation discovered, determines reproductive risk, and offers prophylaxis in the family by means of prenatal or preimplantation diagnostics
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