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J Soria

Publications and source records attributed to J Soria.

At least 55 records · Page 3Linked to original sources
PubMed1999

Fibrinogen Bastia (gamma 318 Asp-->Tyr) a novel abnormal fibrinogen characterized by defective fibrin polymerization.

A new congenital dysfibrinogen, Fibrinogen Bastia, was discovered in a 20-year-old woman with no clinical symptoms. The plasma thrombin-clotting time was severely prolonged. The functional plasma fibrinogen concentration was low (0.2 mg/ml), whereas the immunological concentration was normal (2.9 mg/ml). Purified fibrinogen Bastia displayed a markedly prolonged thrombin-clotting time related to a delayed thrombin-induced fibrin polymerization. Both the thrombin-clotting time and the fibrin polymerization were partially corrected by the addition of calcium ions. The anomaly of fibrinogen Bastia was found to be located in the gamma-chain since by SDS-PAGE performed according to the method of Laemmli two gamma-chains were detected, one normal and one with an apparently lower molecular weight. Furthermore, analysis of plasmin degradation products demonstrated that calcium ions only partially protect fibrinogen Bastia gamma-chain against plasmin digestion, suggesting that the anomaly is located in the C-terminal part of the gamma-chain. Sequence analysis of PCR-amplified genomic DNA fragments of the propositus demonstrated a single base substitution (G-->T) in the exon VIII of the gamma chain gene, resulting in the amino acid substitution 318 Asp (GAC)-->Tyr (TAC). The PCR clones were recloned and 50% of them contained the mutation, indicating that the patient was heterozygous. These data indicate that residue Asp 318 is important for normal fibrin polymerization and the protective effect of calcium ions against plasmin degradation of the C-terminal part of the gamma-chain.

Adult↗
PubMed1998

Angiostatin gene transfer: inhibition of tumor growth in vivo by blockage of endothelial cell proliferation associated with a mitosis arrest.

The antitumoral effects that follow the local delivery of the N-terminal fragment of human plasminogen (angiostatin K3) have been studied in two xenograft murine models. Angiostatin delivery was achieved by a defective adenovirus expressing a secretable angiostatin K3 molecule from the cytomegalovirus promoter (AdK3). In in vitro studies, AdK3 selectively inhibited endothelial cell proliferation and disrupted the G2/M transition induced by M-phase-promoting factors. AdK3-infected endothelial cells showed a marked mitosis arrest that correlated with the down-regulation of the M-phase phosphoproteins. A single intratumoral injection of AdK3 into preestablished rat C6 glioma or human MDA-MB-231 breast carcinoma grown in athymic mice was followed by a significant arrest of tumor growth, which was associated with a suppression of neovascularization within and at the vicinity of the tumors. AdK3 therapy also induced a 10-fold increase in apoptotic tumor cells as compared with a control adenovirus. Furthermore, we showed that systemic injection of AdK3 delayed C6 tumor establishment and growth, confirming that angiostatin can function in a paracrin manner. Our data support the concept that targeted antiangiogenesis, using adenovirus-mediated gene transfer, represents a promising alternative strategy for delivering antiangiogenic factors as their bolus injections present unsolved pharmacological problems.

Adenoviridae↗
PubMed1998

Endothelial metalloprotease-disintegrin protein (ADAM) is implicated in angiogenesis in vitro.

Recently two metalloproteinase, disintegrin, cysteine proteins (MDCs), also called ADAMs were identified on endothelial cells. However the role of these ADAMs are not defined on these cells. In order to elucidate whether ADAMs associated with endothelial cells could be involved in angiogenesis, we have tested the effect of an inhibitor of ADAM (GL 129471) in models of angiogenesis in vitro. Our results showed that GL 129471 inhibited endothelial cell migration and adhesion and increased the number of cells in the G2/M phase leading to an inhibition of cell proliferation. The effects of GL 129471 are not mimicked by the endogenous matrix metalloproteinase inhibitor TIMP-2. These data suggest that ADAMs may play important role in angiogenesis and could provide a new target for inhibition of angiogenesis in cancers.

Journal Article↗
PubMed1998

Adenovirus-mediated delivery of a uPA/uPAR antagonist suppresses angiogenesis-dependent tumor growth and dissemination in mice.

AdmATF is a recombinant adenovirus encoding a secreted version of the amino-terminal fragment (ATF) of murine urokinase (uPA). This defective adenovirus was used in three murine models to assess the antitumoral effects associated with local or systemic delivery of ATF, a broad cell invasion inhibitor that antagonizes uPA binding to its cell surface receptor (uPAR). A single intratumoral injection of AdmATF into pre-established MDA-MB-231 human breast xenografts grown in athymic mice, or into pre-established C57/BL6 syngeneic Lewis lung carcinoma resulted in a specific arrest of tumor growth. Neovascularization within and at the vicinity of the injection site was also suppressed, suggesting that AdmATF inhibited primary tumor growth by targeting angiogenesis. AdmATF also interfered with tumor cell establishment at distant sites: (1) lung dissemination of Lewis lung carcinoma cells was significantly reduced following intratumoral injection at the primary site; and (2) systemic administration of AdmATF inhibited subsequent liver metastasis in a LS174T human colon carcinoma xenograft model. These data outline the potential of using a recombinant adenovirus directing the secretion of an antagonist of cell-associated uPA for cancer gene therapy.

Adenoviridae↗
PubMed1998

Regulation of the uPAR/uPA system expressed on monocytes by the deactivating cytokines, IL-4, IL-10 and IL-13: consequences on cell adhesion to vitronectin and fibrinogen.

Urokinase (uPA) and its receptor (uPAR) have been proposed to be involved in monocyte migration by inducing degradation of matrix proteins. In addition, uPAR is also implicated in cell adhesion to the vascular wall. The adhesive function of uPAR depends on a direct interaction with vitronectin which is increased by uPA and by modification of cell surface integrin (such as CD11b-CD18) when associated to uPAR. In this study we analysed the role of three deactivating cytokines, IL-4, IL-10 and IL-13, on the surface expression of uPA, uPAR and CD11b by monocytes and their consequences on monocyte adhesion to immobilized fibrinogen and vitronectin. IL-10 induced a decrease in uPA and CD11b after 18 h incubation and a delayed decrease in uPAR which was only significant after 48 h incubation. These results may explain the decrease in monocyte adhesion, which was observed after an 18 h incubation with IL-10, on immobilized vitronectin and fibrinogen. In contrast, IL-4 and IL-13 induced a decrease in uPAR after 18 h and a significant increase in uPA both in the cell lysates and at the cell surface, as well as an increase in cell surface associated CD11b. These cytokines did not modify cell adhesiveness to vitronectin or fibrinogen despite the increase in CD11b-CD18. This could be due to the decrease in uPAR because CD11b-CD18/uPAR forms a cell adhesion complex. In addition, the increase in uPA induced by IL-4 could counterbalance the direct interaction of uPAR with vitronectin. The increase in uPA suggests that IL-4 and IL-13 could induce plaque fissuring by monocytes, whereas IL-10 may induce protection against matrix protein degradation by decreasing uPA.

Cell Adhesion↗
PubMed1998

Fatal myelofibrosis following fludarabine administration in a patient with indolent lymphoma.

We report a case of fulminant myelofibrosis after administration of fludarabine in a patient diagnosed as having refractory low-grade lymphoma, progressing fatally. Myelofibrosis in the setting of an indolent lymphoma is very rare; this fact, and the short period between drug administration and fibrosis suggest an etiopathogenic link, although this potential and severe adverse effect of fludarabine has not been previously reported in the literature.

Antimetabolites, Antineoplastic↗
PubMed1997

Hyaluronectin blocks the stimulatory effect of hyaluronan-derived fragments on endothelial cells during angiogenesis in vitro.

Hyaluronic acid (HA) is a glycosaminoglycan of the extracellular matrix. Its fragmentation by the hyaluronidase, secreted by tumor cells, facilitates tumor invasion and the HA degradation products generated stimulate angiogenesis. We report here that the HA-binding protein hyaluronectin (HN) inhibits the stimulatory effect of HA-derived fragments on the proliferation and migration of endothelial cells in vitro, and hampers the organization of endothelial cells into capillary-like structures. Since HN strongly inhibits endothelial cell adhesion to immobilized HA, it is postulated that HN acts by impairing the binding to endothelial cells of HA fragments generated by hyaluronidase, thereby neutralizing the effect of HA degradation products on angiogenesis. Our results reveal a new mechanism by which the angiogenesis induced by HA fragments is modulated by HN.

Animals↗
PubMed1997

Defective cell migration in an ovarian cancer cell line is associated with impaired urokinase-induced tyrosine phosphorylation.

The urokinase receptor (u-PAR), a protein anchored to cell membrane by a glycosyl phosphatidylinositol, plays a central role in cancer cell invasion and metastasis by binding urokinase plasminogen activator (u-PA), thereby facilitating plasminogen activation. Plasmin can promote cell migration either directly or by activating metalloproteinases that degrade some of the components of the extra cellular matrix. However, the IGR-OV1-Adria cell line contains the u-PAR but does not migrate even in the presence of exogenous u-PA, although the parental IGR-OV1 cell line migrates normally in the presence of u-PA. We therefore investigated the role of cell signalling for u-PA induced cell locomotion. We show that cell migration induced by u-PA-u-PAR complex is always associated with tyrosine kinase activation for the following reasons: (1) the blockade of the u-PAR by a chimeric molecule (albumin-ATF) inhibits not only the u-PA-induced cell migration, but also the signalling in IGR-OV1 line; (2) the binding of u-PA to u-PAR on non-migrating IGR-OV1-Adria cells was not associated with tyrosine kinase activation; (3) the inhibition of tyrosine kinase also blocked cell migration of IGR-OV1. Therefore tyrosine kinase activation seems to be essential for the u-PA-induced cell locomotion possibly by the formation of a complex u-PAR-u-PA with a protein whose transmembrane domain can ensure cell signalling. Thus, IGR-OV1 and IGR-OV1-Adria cell lines represent a good model for the analysis of the mechanism of u-PA-u-PAR-induced cell locomotion.

Blotting, Western↗
PubMed1997

Adaptation of esophageal mucosa to acid- and pepsin-induced damage: role of nitric oxide and epidermal growth factor.

To study whether the esophageal mucosa was able to elicit mucosal adaptation, we induced esophageal damage by perfusing acidified pepsin in rabbits. Mucosal adaptation was induced by preexposing the esophageal mucosa to a mild irritant (acidified saline) for 60 min prior to acidified pepsin (strong irritant). Macroscopic and microscopic esophageal injury, cell proliferation, and mucosal barrier function (H+, K+, hemoglobin flux rates) were studied. Preexposure of the esophageal mucosa to acidified saline significantly decreased both the mucosal damage and the mucosal barrier dysfunction induced by acidified pepsin. The development of this phenomenon was nondependent on cell proliferation. Concomitant treatment with either the nitric oxide synthase inhibitor, N(G)-nitro-L-arginine, or the perfusion of immunospecific EGF-receptor antibodies or tyrphostin-25, an inhibitor of the tyrosine kinase activities ligated to the intracytoplasmatic domain of the EGF receptor, during the preexposure period completely reversed the protection induced by acid. We conclude that the rabbit esophageal mucosa shows mucosal adaptation to acid and pepsin. The development of this phenomenon is fast, not dependent on cell proliferation, and dependent, at least in part, on nitric oxide and EGF-receptor-mediated mechanisms.

Adaptation, Physiological↗
PubMed1996

The relationship between the fibrinogen D domain self-association/cross-linking site (gammaXL) and the fibrinogen Dusart abnormality (Aalpha R554C-albumin): clues to thrombophilia in the "Dusart syndrome".

Cross-linking of fibrinogen at its COOH-terminal gamma chain cross-linking site occurs in the presence of factor XIIIa due to self-association at a constitutive D domain site ("gammaXL"). We investigated the contribution of COOH-terminal regions of fibrinogen Aalpha chains to the gammaXL site by comparing the gamma chain cross-linking rate of intact fibrinogen (fraction I-2) with that of plasma fraction I-9, plasmic fraction I-9D, and plasmic fragment D1, which lack COOH-terminal Aalpha chain regions comprising approximately 100, approximately 390, and 413 residues, respectively. The cross-linking rates were I-2 > I-9 > 1-9D = D1, and indicated that the terminal 100 or more Aalpha chain residues enhance gammaXL site association. Fibrinogen Dusart, whose structural abnormality is in the COOH-terminal "alphaC" region of its Aalpha chain (Aalpha R554C-albumin), is associated with thrombophilia ("Dusart Syndrome"), and is characterized functionally by defective fibrin polymerization and clot structure, and reduced plasminogen binding and tPA-induced fibrinolysis. In the presence of XIIIa, the Dusart fibrinogen gamma chain cross-linking rate was about twice that of normal, but was normalized in proteolytic fibrinogen derivatives lacking the Aalpha chain abnormality, as was reduced plasminogen binding. Electron microscopy showed that albumin-bound Dusart fibrinogen "alphaC" regions were located in the vicinity of D domains, rather than at their expected tethered location near the fibrinogen E domain. In addition, there was considerable fibrinogen aggregation that was attributable to increased intermolecular COOH-terminal Aalpha chain associations promoted by untethered Dusart fibrinogen aC domains. We conclude that enhanced Dusart fibrinogen self-assembly is mediated through its abnormal alphaC domains, leads to increased gammaXL self-association and gamma chain cross-linking potential, and contributes to the thrombophilia that characterizes the "Dusart Syndrome."

Dextrans↗
PubMed1996

Blockage of urokinase receptor reduces in vitro the motility and the deformability of endothelial cells.

The binding of urokinase (u-PA) to its cell surface receptor (u-PAR) is critical for tumor cell invasion. Here, we report that the distribution of this binding by a u-PAR antagonist ATF-HSA inhibits in vitro the motility of endothelial cells in a dose-dependent manner. This inhibition was also observed when the cells were first stimulated with potent angiogenic factors, including bFGF or VEGF. [3H]thymidine incorporation assay demonstrated that ATF-HSA did not affect the cell proliferation. ATF-HSA was more potent than plasmin inhibitors, suggesting that it exerts its effects not solely by inhibiting the remodeling of the extracellular matrix. In fact, analysis of the cell shape change during migration revealed for the first time that its effect is related to a decrease in cell deformability. These results suggest that u-PAR antagonist may be a new approach to control angiogenesis.

Aprotinin↗
PubMed1996

Fibrinogen binding and platelet retention: relationship with the thrombogenicity of catheters.

One of the major problems in the use of catheters is their thrombogenicity, since the embolization of clots near the central nervous system or the coronary arteries can cause permanent damage. In this work we have compared the in vivo thrombogenicity of four different angiography catheters and their in vitro activation of fibrinogen binding and platelet retention. The thrombogenicity of catheters has been evaluated in angiographic conditions by kinetic evaluation of the reduction of blood flow rate through the catheters. The binding of adhesive proteins (fibrinogen and von Willebrand factor [vWF] was studied in vitro using a direct-ELISA technique after circulation of anticoagulated whole blood through sections of catheters. The retention of platelets was studied in vitro using 111Indium-labelled platelets. Fibrinogen binding and platelet retention both seem to be good predictors of catheter thrombogenicity, fibrinogen being the better of the two. The most thrombogenic material has the highest fibrinogen and platelet retention rate. This study also confirms the inefficiency of albumin precoating for the prevention of fibrinogen deposition. The determination of fibrinogen deposition by direct-ELISA technique and platelet retention rate is very useful for preclinical testing of catheters.

Biocompatible Materials↗
PubMed1996

Fibrinogen Dusart: electron microscopy of molecules, fibers and clots, and viscoelastic properties of clots.

Ultrastructural perturbations resulting from defects in polymerization of fibrinogen Dusart, a congenital dysfibrinogenemia with the amino acid substitution A alpha 554 arginine to cysteine, were investigated by a variety of electron microscope studies. Polymerization of this mutant fibrinogen on addition of thrombin is impaired, producing clots with decreased porosity and increased resistance to fibrinolysis, resulting in thrombotic complications in the family members with this dysfibrinogenemia. Electron microscopy of rotary-shadowed individual molecules revealed that, in contrast to control fibrinogen, most of the alpha C domains of fibrinogen or fibrin Dusart appeared to be free-swimming appendages that do not exhibit intra- or intermolecular interactions either with each other or with the central domains. The location of albumin on the alpha C domains was demonstrated by electron microscopy using anti-albumin antibodies. Electron microscopy of negatively contrasted fibrin Dusart fibers indicated that they were less ordered than control fibers and had additional mass visible. Electron microscopy of freeze-dried, unidirectionally shadowed fibers showed that they were twisted with a shorter pitch. Scanning electron microscopy revealed that intact clots were made up of thin fibers with many branch points and very small pore sizes. The viscoelastic properties of Dusart fibrin clots measured with a torsion pendulum indicated a marked increase in stiffness consistent with the structural observations.

Biomechanical Phenomena↗
PubMed1996

Down-regulation of fibrinogen biosynthesis by IL-4, IL-10 and IL-13.

High levels of fibrinogen are recognized as an important vascular risk factor; however, it is not known if the increase of plasma fibrinogen is directly responsible for this risk, or is only a marker of vascular inflammation. To support this second hypothesis, Oncostatin M (OSM) is a potent stimulator of fibrinogen biosynthesis and induces smooth muscle cell proliferation. In the same way, we analysed whether interleukin-4 (IL-4), interleukin-10 (IL-10) or interleukin-13 (IL-13), which protect vessel walls from monocytes injuries leading to atherosclerosis, could influence fibrinogen biosynthesis. The two levels of regulation of fibrinogen biosynthesis were tested: firstly, the direct effect of these cytokines on fibrinogen production by the hepatoma cell line Hep G2, and secondly their effect on the secretion of hepatocyte stimulating factor (HSF) activity in the supernatant of lipopolysaccharide (LPS)-activated monocytes. IL-4 and IL-13 added to Hep G2 cells down-regulated both the increase of fibrinogen secretion induced by IL-6 and fibrinogen mRNA levels, this effect being more pronounced when Hep G2 were preincubated with the two cytokines before IL-6 addition. The effect of IL-10 was evidenced only on mRNA expression. IL-10 and IL-13 dose-dependently decrease HSF activity secreted by LPS-activated monocytes, whereas IL-4 had no effect. However, the three cytokines decreased HSF activity when monocytes were incubated with the cytokines before LPS activation. The effects of these cytokines on HSF activity are related to variations of IL-6 and OSM secretion. Our data strengthen the hypothesis that the fibrinogen level is a marker of vascular disease, since cytokines which have a protective vascular effect down-regulate fibrinogen production.

Animals↗
PubMed1996

Regulation of fibrinogen biosynthesis by cytokines, consequences on the vascular risk.

High level of fibrinogen in plasma is recognised as an important vascular risk factor. However, it is not known if the increase in fibrinogen is directly responsible for the vascular risk or is a marker of vascular inflammation. Our data strengthen the hypothesis that the fibrinogen level is a marker of vascular disease, since a parallel effect of cytokines on fibrinogen biosynthesis and on vascular injury was noted. Among the cytokines which induce the synthesis of fibrinogen, oncostatin M (OSM) is the most potent cytokine synthesised by activated monocytes for inducing fibrinogen synthesis by Hep G2 cells (human hepatoma cell line). Interestingly at the same concentrations needed for fibrinogen biosynthesis, OSM induces smooth muscle cell proliferation. In contrast, the cytokines IL-4, IL-10 and IL-13 which have a protective effect against vascular injury leading to atherosclerosis, dose dependently down regulate the biosynthesis of fibrinogen. This was due to both a decrease of IL-6 induced fibrinogen synthesis by hepatocytes, evidenced by a decrease in fibrinogen secretion in the medium and beta chain mRNA expression and to an inhibition of production of the hepatocyte-stimulating activity for fibrinogen biosynthesis (HSF) by LPS-activated monocytes. Noteworthingly, IL-10 induces a significant decrease of the production of OSM by LPS-activated monocytes. In situ activation of monocytes by cytokines in the vessel wall could also contribute to the deposition of fibrin(ogen) derivatives, identified as pathogenic factor.

Arteriosclerosis↗
PubMed1996

Constitutional delay in growth and puberty: a comparison of final height achieved between treated and untreated children.

Constitutional delay in growth and puberty (CDGP) is one of the principal causes of consultation due to short height. Frequently familial short stature is associated with the CDGP. The predicted final height is reached in the majority of the cases but some individuals do not achieve their target height. Poor growth, especially during the pubertal years, as well as a short or growth delayed mother are some of the negative factors for final outcome. Some prepubertal children show a transient diminished GH secretion that normalizes during puberty. Therapy with hGH or oxandrolone increases growth velocity but does not ameliorate final height. The psychosocial situation of the children is the most important condition to treat with testosterone, estrogens or oxandrolone. In view of the results hGH should not be administered routinely to these cases. It remains open which children could benefit from hGH therapy.

Body Height↗