Preparation of Poly(D,L-Lactide/Glycolide) Nanoparticles of Controlled Particle Size Distribution: Application of Experimental Designs

This study investigates the use of the solvent evaporation method for preparing acid and glycolic acid-based copolymer nanoparticles. Initially, appropriate technological and formulation factors for elaboration of polymeric particles were selected by screening. Most favourable results were obtained using polyvinyl alcohol as a dispersing agent and a high pressure homogenizer to reduce the droplet size of the emulsion initially formed. On the basis of the conclusion thus drawn, a composite rotational experimental design was employed to evaluate the joint influence of three formulation variables (phase volume ratio of the emulsion formed, polymer concentration and homogenization pressure) on the micromeritic properties of the suspension finally obtained (mean particle size, coefficient of variation and polydispersity of the particle size distribution). Analysis of variance corresponding to the experimental design, showed a significant influence of the volume phase ratio and the polymer concentration on the mean particle size and the coefficient of variation, whereas the polydispersity is also affected by the homogenization pressure. Considering this information, a 3² experimental factorial design was then selected to investigate the possible interaction between the phase volume ratio and the concentration of polyvinyl alcohol in the aqueous phase. Analysis of variance and subsequent sequencial regression analysis evidenced last hypothesis providing the way to determine the experimental conditions required to achieve a specific particle size distribution.     

Synthesis and Cell Growth Inhibitory Activity of Six Non-glycosaminoglycan-Type Heparin-Analogue Trisaccharides

The design and synthesis of heparin mimetics with high anticancer activity but no anticoagulant activity is an important task in medicinal chemistry. Herein, we present the efficient synthesis of five Glc-GlcA-Glc-sequenced and one Glc-IdoA-Glc-sequenced non-glycosaminoglycan, heparin-related trisaccharides with various sulfation/sulfonylation and methylation patterns. The cell growth inhibitory effects of the compounds were tested against four cancerous human cell lines and two non-cancerous cell lines. Two d -glucuronate-containing tetra-O-sulfated, partially methylated trisaccharides displayed remarkable and selective inhibitory effects on the growth of ovary carcinoma (A2780) and melanoma (WM35) cells. Methyl substituents on the glucuronide unit proved to be detrimental, whereas acetyl substituents were beneficial to the cytostatic activity of the sulfated derivatives.     

Synthesis of gonadotropin-releasing hormone III analogs. Structure-antitumor activity relationships

Following the observation that the activity of gonadotropin-releasing hormone III (GnRH-III) in the suppression of growth of MDA-MB-231 and MCF-7 breast cancer cells surpasses that of GnRH and other analogs thereof, analogs of GnRH-III were synthesized to investigate the structural basis for the improved antitumor activity. Compounds synthesized include analogs with changes in the central sequence in which GnRH-III differs from GnRH and in the C- and N-terminal regions. The results indicate that a salt bridge between Asp6 and Lys8 stabilizes the active conformation of GnRH-III and show the importance of the Trp7. Replacement of the C-terminal Gly-NH2 with D-Ala-NH2 was not well tolerated, but replacement with ethylamide was. Replacement of pGlu1 with Ac-D-Trp appears to have a significantly deleterious effect on a unique conformation of GnRH-III which is responsible for its binding to the receptors on cancer cell lines and the resultant antitumor activity.     

Defensins purified from human granulocytes bind C1q and activate the classical complement pathway like the transmembrane glycoprotein gp41 of HIV-1

BACKGROUND: We previously reported the isolation of aptamer irreversible inhibitors of human neutrophil elastase. We now report on the application of aptamer technology to the field of diagnostic imaging. RESULTS: The enzyme elastase has been reported to bind to the surface of activated neutrophils. Using a fluorescent flow cytometry assay, we showed that an aptamer inhibitor of elastase also binds preferentially to activated neutrophils. We then tested the ability of the aptamer to image inflammation in vivo in a rat reverse passive Arthus reaction model. The aptamer achieved a peak target-to-background (T/B) ratio of 4.3 +/- 0.6 in 2 hours. IgG, which is used clinically to image inflammation, took a longer time to achieve a lower T/B: 3.1 +/- 0.1 at 3 hours. The difference in T/B values is due to the faster clearance of the aptamer signal from the blood pool. CONCLUSIONS: It is feasible to apply aptamer ligands for use in diagnostic imaging, where they may offer significant advantages over monoclonal antibodies and other reagents.     

Structure-activity relationship studies of novel somatostatin analogs with antitumor activity

A series of new somatostatin analogs were synthesized in order to study the relative importance of specific substitutions in relation to selectivity between their endocrine and antitumor effects. Substitutions were carried out in all positions, except for Lys in position 5. Peptides were tested for their ability to inhibit in vitro and in vivo GH release, proliferation of the MCF 7 breast carcinoma cell line and tyrosine kinase activity in the HT 29 human colon carcinoma cell line. Selective biological activity was achieved in GH release and antitumor activity by the different amino acid substitutions. One of the analogs, with a five-residue ring (D-Phe-Cys-Tyr-D-Trp-Lys-Cys-Thr-NH2, TT-232), was unique. It had no GH release inhibitory activity, but did have strong tyrosine kinase inhibitory and antiproliferative effects.     

Molecular biology of thyroid diseases

Recent developments in molecular biology and the accessibility of techniques for clinical research have led to a better understanding of the background of common thyroid diseases. The cloning and sequencing of the thyroid stimulating hormone receptor, thyroid peroxidase and thyroglobulin, and the characterization of the protein-DNA interaction during thyroid hormone action, as well as the discovery of intracellular signal transduction pathways were the most important steps which resulted in new diagnostic and therapeutic approaches. New explanations of thyroid autoimmune processes are being investigated.     

High-Speed,SAD Based Wavefront Sensor Architecture Implementation on FPGA

Wavefront aberrations caused by turbulent or rapidly changing media can considerably degrade the performance of an imaging system. To dynamically compensate these wavefront distortions adaptive optics is applied. We developed an affordable adaptive optic system which combines CMOS sensor and Liquid Crystal on Silicon (LCOS) display technology with the Field Programmable Gate Arrays (FPGA) devices parallel computing capabilities. A high-speed, accurate wavefront sensor is an elemental part of an adaptive optic system. In the paper, an efficient FPGA implementation of the Sum of Absolute Differences (SAD) algorithm, which accomplishes the correlation-based wavefront sensing, is introduced. This architecture was implemented on a Spartan-3 FPGA which is capable of real-time (>500 fps) measuring the incoming wavefront.     

Iron deficiency anemia caused by an arteriovenous malformation in the distal ileum

The case of a young woman with chronic iron deficiency anemia is described. Her consequent guaiac-positive stool suggested a gastrointestinal bleeding behind her anemia. The use of the conventional diagnostic techniques did not result in a definitive diagnosis. The source of the hemorrhage was later detected by the aid of selective mesenteric arteriography as an unusual form of arteriovenous malformations localized to the small intestine. 20 months passed since the resection of the affected intestinal segment. During this period of close follow up no clinical signs of recurrent gastrointestinal hemorrhage was observed. The authors briefly review the relevant literature.