Structure and inhibitory effects on angiogenesis and tumor development of a new vascular endothelial growth inhibitor

Blocking angiogenesis is an attractive strategy to inhibit tumor growth, invasion, and metastasis. We describe here the structure and the biological action of a new cyclic peptide derived from vascular endothelial growth factor (VEGF). This 17-amino acid molecule designated cyclopeptidic vascular endothelial growth inhibitor (cyclo-VEGI, CBO-P11) encompasses residues 79-93 of VEGF which are involved in the interaction with VEGF receptor-2. In aqueous solution, cyclo-VEGI presents a propensity to adopt a helix conformation that was largely unexpected because only \u3b2-sheet structures or random coil conformations have been observed for macrocyclic peptides. Cyclo-VEGI inhibits binding of iodinated VEGF165 to endothelial cells, endothelial cells proliferation, migration, and signaling induced by VEGF165. This peptide also exhibits anti-angiogenic activity in vivo on the differentiated chicken chorioallantoic membrane. Furthermore, cyclo-VEGI significantly blocks the growth of established intracranial glioma in nude and syngeneic mice and improves survival without side effects. Taken together, these results suggest that cyclo-VEGI is an attractive candidate for the development of novel angiogenesis inhibitor molecules useful for the treatment of cancer and other angiogenesis-related diseases

Magnetic resonance imaging in children: common problems and possible solutions for lung and airways imaging

Pediatric chest MRI is challenging. High-resolution scans of the lungs and airways are compromised by long imaging times, low lung proton density and motion. Low signal is a problem of normal lung. Lung abnormalities commonly cause increased signal intenstities. Among the most important factors for a successful MRI is patient cooperation, so the long acquisition times make patient preparation crucial. Children usually have problems with long breath-holds and with the concept of quiet breathing. Young children are even more challenging because of higher cardiac and respiratory rates giving motion blurring. For these reasons, CT has often been preferred over MRI for chest pediatric imaging. Despite its drawbacks, MRI also has advantages over CT, which justifies its further development and clinical use. The most important advantage is the absence of ionizing radiation, which allows frequent scanning for short- and long-term follow-up studie

Iterative feedback tuning of PID parameters: comparison with classical tuning rules

We apply the Iterative Feedback Tuning (IFT) method to the tuning of PID parameters in applications where the objective is to achieve a fast response to set point changes. We compare the performance of these IFT-tuned PID controllers with the performance achieved by four classical PID tuning schemes that are widely used in industry. Our simulations show that IFT always achieves a performance that is at least as good as that of the classical PID tuning schemes, and often dramatically better: faster settling time and less overshoot. In addition, IFT is also optimal with respect to the presence of noise, whereas the other schemes are designed for noise-free conditions. The IFT method used here is a variant of the initial IFT scheme, in which no weighting is applied to the control error during a time window that corresponds to the transient response, and where the length of this window is progressively reduced. This method was initially proposed in Lequin (CD-ROM of European Control Conference, Paper TH-A-H6, Brussels, Belgium, 1997) and elaborated on in Lequin et al. (Proceedings of the 14th IFAC World Congress, Paper I-3b-08-3, Beijing, People's Republic of China, 1999, pp. 433-437). (C) 2003 Elsevier Science Ltd. All rights reserved

Mapping the heparin-binding site on the 13-14F3 fragment of fibronectin.

Fibronectin, a multifunctional glycoprotein of the extracellular matrix, plays a major role in cell adhesion. Various studies have revealed that the human 13th and 14th fibronectin type III domains (labeled (13)F3 and (14)F3 here) contain a heparin-binding site. Mapping of the heparin-binding sites of (13-14)F3, (13)F3, and (14)F3 by NMR chemical shift perturbation, isothermal titration calorimetry, and molecular modeling show that (13)F3 provides the dominant heparin-binding site and that the residues involved are within the first 29 amino acids of (13)F3. Predictions from earlier biochemical and modeling studies as well as the x-ray structure of (12-14)F3 were tested. It was shown that the positively charged residues that project into the solvent from the ABE face of the triple-stranded beta sheet on (13)F3 are involved in binding, but (14)F3 does not appear to contribute significantly to heparin binding

Chiral \u201cbasket handle\u201d binaphthyl porphyrins: synthesis,catalytic epoxidation and NMR conformational studies

Three \u201cbasket handle\u201d porphyrins have been prepared by condensation of tetrakis-(\u3b1,\u3b2,\u3b1,\u3b2-2-aminophenyl)porphyrin atropoisomer with 1,1\u2032-binaphthyl, 2,2\u2032-dimethoxy, -3,3\u2032-dicarbonylchloride, -3,3\u2032-diacetylchloride and -3,3\u2032-dipropanoylchloride. The epoxidation of styrene with the three iron catalysts, obtained after metalation of the free porphyrins, occurs with good yields and moderate ee up to 54%. These porphyrins showed unexpected conformational differences, as revealed by NMR spectroscopy. In particular, variable temperature NMR studies showed that the methoxy group in one of them undergoes intermediate conformational exchange on the 1H NMR time scale at room temperature. Lowering the temperature to -50 \ub0C revealed the presence of four states in slow exchange on the NMR time scale. These results evidence a dynamic conformational equilibrium of the binaphthyl handles that adopt different, asymmetric positions with respect to the porphyrin plane

MRI-guided definition of cerebrospinal fluid distribution around cranial and sacral nerves : implications for brain tumors and craniospinal irradiation

Background: The SIOPE-Brain Tumor Group recently published a guideline on craniospinal target volume delineation for highly conformal radiotherapy. In order to spare critical structures like e.g., the lens or cochlea, highly conformal techniques can underdose the cerebrospinal fluid (CSF) in the dural reflections around cranial and sacral nerves. The purpose of this study is to generate evidence for CSF extension within the dural sheaths of the cranial and sacral nerves in order to improve accuracy in target volume delineation.Material and methods: Ten healthy volunteers, age 21 till 41 years, underwent an MRI-scan of the skull-base and sacral plexus. To evaluate CSF extension, cT2-weighted images with fat suppression, low signal to noise ratio and little to no motion-related artifacts were used. Two observers measured the extension of CSF from the inner table of the skull for the cranial nerves, and outside the spinal canal for the sacral nerves.Results: CSF extension (mean distance [95% CI]) was visible within the dural sheaths surrounding the majority of the cranial nerves: optic nerve (40 mm [38-42]), trigeminal nerve (16 mm [15-19]), facial-vestibulocochlear nerve (11 mm [11-12]), glossopharyngeal-vagus-accessory nerve (7 mm [7-9]) and hypoglossal nerve (8 mm [7-9]). No CSF was observed outside the spinal canal at sacral level. No significant difference between both observers was measured.Conclusion: This study generates evidence for significant CSF extension outside the inner table of the skull. Despite the vicinity of the lens and cochlea, we therefore recommend the inclusion of both optic nerves and internal auditory canals in the clinical target volume for craniospinal irradiation when using highly conformal delivery techniques

Blood-brain barrier permeability following conventional photon radiotherapy – A systematic review and meta-analysis of clinical and preclinical studies

Radiotherapy (RT) is a cornerstone treatment strategy for brain tumours. Besides cytotoxicity, RT can cause disruption of the blood–brain barrier (BBB), resulting in an increased permeability into the surrounding brain parenchyma. Although this effect is generally acknowledged, it remains unclear how and to what extent different radiation schemes affect BBB integrity. The aim of this systematic review and meta-analysis is to investigate the effect of photon RT regimens on BBB permeability, including its reversibility, in clinical and preclinical studies. We systematically reviewed relevant clinical and preclinical literature in PubMed, Embase, and Cochrane search engines. A total of 69 included studies (20 clinical, 49 preclinical) were qualitatively and quantitatively analysed by meta-analysis and evaluated on key determinants of RT-induced BBB permeability in different disease types and RT protocols. Qualitative data synthesis showed that 35% of the included clinical studies reported BBB disruption following RT, whereas 30% were inconclusive. Interestingly, no compelling differences were observed between studies with different calculated biological effective doses based on the fractionation schemes and cumulative doses; however, increased BBB disruption was noted during patient follow-up after treatment. Qualitative analysis of preclinical studies showed RT BBB disruption in 78% of the included studies, which was significantly confirmed by meta-analysis (p < 0.01). Of note, a high risk of bias, publication bias and a high heterogeneity across the studies was observed. This systematic review and meta-analysis sheds light on the impact of RT protocols on BBB integrity and opens the discussion for integrating this factor in the decision-making process of future RT, with better study of its occurrence and influence on concomitant or adjuvant therapies