On completely homogeneous c-spaces.

In this paper we determine completely homogeneous c-spaces. Various properties of completely homogeneous c-spaces are discussed. Relation between completely homogeneous c-space and hereditary homogeneous c-space is studied. Completely homogeneous connective spaces are also characterised.

Aurora B kinase inhibitor AZD1152: determinants of action and ability to enhance chemotherapeutics effectiveness in pancreatic and colon cancer.

BACKGROUND: AZD1152, the prodrug for AZD1152-hydroxyquinazoline pyrazol anilide (HQPA), is a selective inhibitor of Aurora B kinase activity. Preclinical evaluation of AZD1152 has been reported in several human cancer models. The potentiality of this compound in combination therapy warrants further investigation in solid tumours. EXPERIMENTAL DESIGN: This study explored the effects of AZD1152-HQPA in colon and pancreatic tumour cells. The antitumour properties of AZD1152, either as single agent or in combination with chemotherapeutics, were evaluated in each study model. The efficacy and the toxicity of AZD1152 alone and in combination with gemcitabine were validated in pancreatic tumour xenograft model. RESULTS: AZD1152-HQPA treatment resulted in a dramatic increase of chromosome number, modification of cell cycle and induction of apoptosis. The most effective combination was that with chemotherapeutics given soon after AZD1152 in both tumour cell types. The effectiveness of the sequential schedule of AZD1152 with gemcitabine was confirmed in nude mice bearing MiaPaCa-2 tumours, showing inhibition of tumour volumes and delaying of tumour growth after the interruption of the treatments. Here we show that AZD1152-HQPA enhances oxaliplatin and gemcitabine effectiveness in colon and pancreatic cancer, respectively. First, we provide advances into administration schedules and dosing regimens for the combination treatment in in vivo pancreatic tumour.

An effector region in Eps8 is responsible for the activation of the Rac-specific GEF activity of Sos-1 and for the proper localization of the Rac-based actin-polymerizing machine.

Genetic and biochemical evidence demonstrated that Eps8 is involved in the routing of signals from Ras to Rac. This is achieved through the formation of a tricomplex consisting of Eps8-E3b1-Sos-1, which is endowed with Rac guanine nucleotide exchange activity. The catalytic subunit of this complex is represented by Sos-1, a bifunctional molecule capable of catalyzing guanine nucleotide exchange on Ras and Rac. The mechanism by which Sos-1 activity is specifically directed toward Rac remains to be established. Here, by performing a structure-function analysis we show that the Eps8 output function resides in an effector region located within its COOH terminus. This effector region, when separated from the holoprotein, activates Rac and acts as a potent inducer of actin polymerization. In addition, it binds to Sos-1 and is able to induce Rac-specific, Sos-1-dependent guanine nucleotide exchange activity. Finally, the Eps8 effector region mediates a direct interaction of Eps8 with F-actin, dictating Eps8 cellular localization. We propose a model whereby the engagement of Eps8 in a tricomplex with E3b1 and Sos-1 facilitates the interaction of Eps8 with Sos-1 and the consequent activation of an Sos-1 Rac-specific catalytic ability. In this complex, determinants of Eps8 are responsible for the proper localization of the Rac-activating machine to sites of actin remodeling.

Effect of polydeoxyribonucleotides on human fibroblasts in primary culture.

The effects of a mixture of oligo- and polydeoxyribonucleotides (PDRN) on the growth and protein secretion of cultured human skin fibroblasts were investigated. Both intact and DNAase-digested PDRN stimulated cell proliferation to a similar extent. When cultured fibroblasts were incubated with radioactive amino acids in the presence of intact or digested PDRN the incorporation of the tracer into secreted proteins increased significantly. This stimulation appears to be specific for certain protein components, including fibronectin. These results are interpreted assuming that PDRN and the nucleotides and nucleosides resulting from its degradation, can act as signal transducers or, alternatively, can be internalized and utilized to provide purine and pyrimidine rings for the salvage pathways.

Hyaluronidase-injectable microparticles intended for the treatment of extravasation.

Hyaluronidase is a protein whose enzymatic activity is successfully employed in extravasation therapy. Taking into account that several proteins (e.g. gelatin and albumin) have been employed as natural polymers for the preparation of microspheres, this work approaches a comprehensive investigation on hyaluronidase injectable microparticles. The goals are either to obtain a sustained release preparation of hyaluronidase or to use the enzyme as drug carrier. Microspheres have been prepared using a water-in-oil emulsification technique, and they have been crosslinked either by thermal or chemical means. Results show that hyaluronidase microspheres with good morphological characteristics can be obtained by this preparation method. Manufacturing variables influence the enzymatic activity of the microspheres, which can be highly preserved under mild experimental conditions. Moreover, the suitability of this enzyme as a microparticulate drug carrier has been shown by the successful encapsulation of hydrocortisone sodium succinate.

Role of decorin on in vitro fibrillogenesis of type I collagen.

Tendon and corneal decorins are differently iduronated dermatan sulphate/proteoglycan (DS/PG) and the biochemical parameter that differentiates type I collagens is the hydroxylysine glycoside content. We have examined the effect of tendon and corneal decorins on the individual phases (tlag, dA/dt) of differently glycosylated type I collagens fibril formation, at molar ratios PG:collagen monomer ranging from 0.15:1 to 0.45:1. The results obtained indicate that decorins exert a different effect on the individual phases of fibril formation, correlated to the degree of glycosylation of collagen: at the same PG:collagen ratio the fibril formation of highly glycosylated corneal collagen is more efficiently inhibited than that of the poorly glycosylated one (tendon). Moreover tendon and corneal decorins exert a higher control on the fibrillogenesis of homologous collagen with respect to the heterologous one. These data suggest a possible tissue-specificity of the interaction decorin/type I collagen correlated to the structure of the PG and collagen present in extracellular matrices.

Structural heterogeneity of dermatan sulfate chains: correlation with heparin cofactor II activating properties.

To obtain dermatan sulfate (DS) with different structural characteristics and biological properties we isolated three groups of chains from a bovine mucosal DS preparation, differently iduronated and sulfated. The selected DS chains were characterized by their total charge values, electrophoretic mobility, susceptibility to Chondroitinase AC II treatment and disaccharide composition of Chondroitinase ABC digests. Besides the major IdoUA-->GalNac-4-SO4 sequences, two DS fractions (s-DS 1.75 M and f-DS 1.75 M) contained more than 10% disulfated disaccharides sequences and the third DS fraction (s-DS 1.5 M) contained only 4% disulfated disaccharides. Chondroitinase AC II treatment indicated that both the electrophoretically retarded forms (s-DS) are iduronic acid rich, as they were only minimally degraded to disaccharides/oligosaccharides. The ability of DS crude preparation to activate the heparin cofactor II (HCII) mediated inhibition of thrombin depends on the relative amount of highly active DS chains; this activity is related to the overall charge of DS chains and particularly with the content of IdoUA-2-SO4-->GalNAc-4-SO4 and UA-->GalNAc-4,6-di-SO4 disaccharides.