Enhanced Platelet Activation Mediates the Accelerated Angiogenic Switch in Mice Lacking Histidine-Rich Glycoprotein

BACKGROUND: The heparin-binding plasma protein histidine-rich glycoprotein (HRG; alternatively, HRGP/HPRG) can suppress tumor angiogenesis and growth in vitro and in vivo. Mice lacking the HRG gene are viable and fertile, but have an enhanced coagulation resulting in decreased bleeding times. In addition, the angiogenic switch is significantly enhanced in HRG-deficient mice. METHODOLOGY/PRINCIPAL FINDINGS: To address whether HRG deficiency affects tumor development, we have crossed HRG knockout mice with the RIP1-Tag2 mouse, a well established orthotopic model of multistage carcinogenesis. RIP1-Tag2 HRG(-/-) mice display significantly larger tumor volume compared to their RIP1-Tag2 HRG(+/+) littermates, supporting a role for HRG as an endogenous regulator of tumor growth. In the present study we also demonstrate that platelet activation is increased in mice lacking HRG. To address whether this elevated platelet activation contributes to the increased pathological angiogenesis in HRG-deficient mice, they were rendered thrombocytopenic before the onset of the angiogenic switch by injection of the anti-platelet antibody GP1bα. Interestingly, this treatment suppressed the increase in angiogenic neoplasias seen in HRG knockout mice. However, if GP1bα treatment was initiated at a later stage, after the onset of the angiogenic switch, no suppression of tumor growth was detected in HRG-deficient mice. CONCLUSIONS: Our data show that increased platelet activation mediates the accelerated angiogenic switch in HRG-deficient mice. Moreover, we conclude that platelets play a crucial role in the early stages of tumor development but are of less significance for tumor growth once angiogenesis has been initiated

Dimethylarginine dimethylaminohydrolase I enhances tumour growth and angiogenesis

Angiogenesis is a prerequisite for tumour progression and is highly regulated by growth factors and cytokines a number of which also stimulate the production of nitric oxide. Asymmetric dimethylarginine is an endogenous inhibitor of nitric oxide synthesis. Asymmetric dimethylarginine is metabolised by dimethylarginine dimethylaminohydrolase. To study the effect of dimethylarginine dimethylaminohydrolase on tumour growth and vascular development, the rat C6 glioma cell line was manipulated to overexpress the rat gene for dimethylarginine dimethylaminohydrolase I. Enhanced expression of dimethylarginine dimethylaminohydrolase I increased nitric oxide synthesis (as indicated by a two-fold increase in the production of cGMP), expression and secretion of vascular endothelial cell growth factor, and induced angiogenesis in vitro. Tumours derived from these cells grew more rapidly in vivo than cells with normal dimethylarginine dimethylaminohydrolase I expression. Immunohistochemical and magnetic resonance imaging measurements were consistent with increased tumour vascular development. Furthermore, dimethylarginine dimethylaminohydrolase activity was detected in a series of human tumours. This data demonstrates that dimethylarginine dimethylaminohydrolase plays a pivotal role in tumour growth and the development of the tumour vasculature by regulating the concentration of nitric oxide and altering vascular endothelial cell growth factor production

A molecular clamp ensures allosteric coordination of peptidyltransfer and ligand binding to the ribosomal A-site

Although the ribosome is mainly comprised of rRNA and many of its critical functions occur through RNA–RNA interactions, distinct domains of ribosomal proteins also participate in switching the ribosome between different conformational/functional states. Prior studies demonstrated that two extended domains of ribosomal protein L3 form an allosteric switch between the pre- and post-translocational states. Missing was an explanation for how the movements of these domains are communicated among the ribosome's functional centers. Here, a third domain of L3 called the basic thumb, that protrudes roughly perpendicular from the W-finger and is nestled in the center of a cagelike structure formed by elements from three separate domains of the large subunit rRNA is investigated. Mutagenesis of basically charged amino acids of the basic thumb to alanines followed by detailed analyses suggests that it acts as a molecular clamp, playing a role in allosterically communicating the ribosome's tRNA occupancy status to the elongation factor binding region and the peptidyltransferase center, facilitating coordination of their functions through the elongation cycle. The observation that these mutations affected translational fidelity, virus propagation and cell growth demonstrates how small structural changes at the atomic scale can propagate outward to broadly impact the biology of cell

The role of tumour-derived iNOS in tumour progression and angiogenesis

BACKGROUND: Progressive tumour growth is dependent on the development of a functional tumour vasculature and highly regulated by growth factors and cytokines. Nitric oxide (NO) is a free radical, produced both by tumour and host cells, and functions as a signalling molecule downstream of several angiogenic factors. Both pro-and antitumourigenic properties have been attributed to NO. METHODS: The expression of the inducible isoform of NO synthase (iNOS) was knocked down in the C6 glioma cell line using constitutive expression of antisense RNA, and the effect of tumour-derived NO on tumour progression and angiogenesis was investigated. RESULTS: Tumours in which iNOS expression was decreased displayed significantly reduced growth rates compared with tumours derived from parental C6 cells. Quantitative non-invasive magnetic resonance imaging and fluorescence microscopy of tumour uptake of Hoechst 33342, and haematoxylin and eosin staining, revealed significantly impaired vascular development and function in antisense iNOS tumours compared with control in vivo, primarily associated with the more necrotic tumour core. Decreased iNOS expression had no effect on tumour VEGF expression. CONCLUSION: Nitric oxide derived from tumour iNOS is an important modulator of tumour progression and angiogenesis in C6 gliomas and further supports the therapeutic strategy of inhibiting iNOS for the treatment of cancer. British Journal of Cancer (2011) 104, 83-90. doi:10.1038/sj.bjc.6606034 www.bjcancer.com Published online 7 December 2010 (C) 2011 Cancer Research U

Systematic Experimental Evaluation Of Three-Dimensional Boundary Elements Method

204 σ.Στη συγκεκριμένη διπλωματική εργασία πραγματοποιήθηκαν υπολογιστικές δοκιμές, για διάφορες γεωμετριές ελικων, με τη χρήση του κώδικα 3-διαστατης ροής Unsteady του καθηγητή Ε.Μ.Π Γεράσιμου Πολίτη. Αναλυτικά οι Γεωμετρίες που ελέγχθηκαν ήταν σε πλέγμα 2010 (20 chordwise & 10 spanwise) και σε πλέγμα 3015 (30 chordwise & 15 spanwise) Κρατήσαμε σταθερό το λόγο της εκτεταμένης επιφάνειας ΑΕ/Α0 = 0,7 Επιλέξαμε 3-πτερες έλικες με 2 διαφορετικές διακριτοποιήσεις ενω οι 4-πτερες και 5-πτερες είναι ολες με την ίδια διακριτοποίηση (πλεγμα 2010) H περιοχή της wagenigen είναι απο P/D=0.5 έως P/D=1.4 Επιλέξαμε 3 τιμές του P/D που περίπου θα σαρώνουν όλη την περιοχή μεταβολής του λόγου βήματος της σειράς. Συγκρίνουμε pressure με Morino αλλα στην περίπτωση των Pressure κάνουμε και αλλαγή παραμέτρων που σχετίζονται με την γεωμετρία της λωρίδας kutta Για το θέμα του πως επιλέχθηκαν οι παράμετροι, επιλέχθηκαν γιατι πριν απο αυτή την παρουσίαση έγιναν διερευνητικά τρεξίματα με προηγούμενα development του κώδικα . Development 36 & 39 οι οποίες οδηγησαν στα αποτελέσματα που περιλαμβάνονται στον πίνακα.In this thesis computational tests took place for various propeller geometries, using the 3-dimensional Flow Code “Unsteady” of Professor of NTUA Gerasimos Politis. Details of the geometries were tested in a grid 2010 (20 chordwise & 10 spanwise) grid and 3015 (30 chordwise & 15 spanwise) We kept constant the ratio of extended surface AE/A0 = 0.7 We chose 3-blade propellers with 2 different discretization while the 4-5-feathers and feathers are all the same discretization (mesh2010) The wagenigen region is from P / D = 0.5 to P / D = 1.4 We chose 3 values of P / D that will sweep around the entire region change speech pitch range. Compare with pressure Morino but in the case of Pressure we change parameters related to the geometry of the strip kutta On the issue of how the parameters were selected to this presentation were probing runs with previous development codes. Development 36 & 39 which led to the resultslisted in the table.Γεώργιος-Αλέξανδρος Δ. Συνετό