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Biomedical subjects

C Soria

Publications and source records attributed to C Soria.

At least 55 records · Page 3Linked to original sources

Risk factors and outcomes for atherothrombotic disease in French patients: the RIVAGE study. RIsque VAsculaire Group d'Etude.

This prospective observational study was designed to delineate the course of atherosclerotic disease in a representative group of French patients receiving standard medical care and to look for clinical and laboratory factors predictive of recurrent cardiovascular events. The 2416 study patients (75.2% men and 24.8% women) had diagnoses of peripheral arterial disease (stage II or III), ischemic heart disease (stable angina or myocardial infarction), or cerebrovascular disease (transient ischemic attack or stroke); 2004 patients (82.9%) had only one of these diagnoses, and 412 (17.1%) had more than one. Among patients with a given stage of peripheral arterial disease, mean age was older in the women than in the men. Coronary disease and cerebrovascular disease were more severe in the men. During the 18-month follow-up, 408 cardiovascular events were recorded in 380 patients (15.7% of the overall study group). In patients who had a single clinical event at inclusion, subsequent clinical events usually occurred in the same vascular bed. The incidences of coronary and cerebral events were correlated with age and the incidence of peripheral events with smoking status. Fatal events were correlated with age but not with the baseline diagnosis, except for a weak relationship with peripheral arterial disease. In a subset of 411 patients who had laboratory tests, plasma fibrinogen level was the only independent predictor of recurrence for all cardiovascular events; this parameter was more closely correlated with fatal events than with all events.

Aged↗

Carboxymethyl benzylamide dextran blocks angiogenesis of MDA-MB435 breast carcinoma xenografted in fat pad and its lung metastases in nude mice.

We previously showed that carboxymethyl benzylamide dextran (CMDB7) prevents tumor growth and tumor angiogenesis by binding to angiogenic growth factors, thereby preventing them from reaching their receptors on tumor or stromal cells (Bagheri-Yarmand et al. Br. J. Cancer, 78: 111-118, 1998; Bagheri-Yarmand et al. Cell Growth Differ., 9: 497-504, 1998). In this study, CMDB7 inhibited neovessel formation within the fibroblast growth factor 2-enriched matrigel in mice, and its anticancer effect was then tested in a metastatic breast cancer model. Human MDA-MB435 cells were injected into the mammary fat pad of nude mice, and breast tumors developed within 1 week; all of the mice had lung metastases at 12 weeks. CMDB7 treatment (50, 150, or 300 s.c. or 300 i.v. mg/kg/week for 10 weeks) reduced the incidence of lung metastases to 12%. Histological analysis showed markedly less tumor neovascularization in the CMDB7-treated mice. Pulmonary metastasis incidence was strongly dependent on the intratumoral neoangiogenesis in primary tumors.

Adipose Tissue↗

Effects of glucocorticoids and mineralocorticoids on proliferation and maturation of human peripheral blood stem cells.

It has been shown that hematopoietic progenitors can be expanded ex vivo in the presence of various cytokine combinations. Glucocorticoids (GC) are involved in the self-renewal of erythroid progenitors in chicken. To see whether GC have a similar effect on hematopoiesis in humans, CD34(+) peripheral blood stem cells were cultured in serum free medium in the presence of a GC, triamcinolone acetonide. However, our results demonstrate an inhibition of both erythroid and granulocyte-macrophage (GM) proliferation and a modification of erythroid colony morphology. Furthermore, RU38486 (Mifepristone), a potent GC antagonist, was unable to reverse the inhibitory effect of triamcinolone acetonide. We also identified and characterized another steroid subfamily, the mineralocorticoid (MC) subfamily, in human PB CD34(+) cells. The MC, aldosterone, significantly enhanced GM colony formation and diminished the erythroid colony number. Neither of effects were inhibited by ZK91587, an antagonist specific to the MC receptor (MCR). In contrast, ZK91587 reversed the stimulatory effect of deoxycorticosterone on GM colony formation. Cytoplasmic staining for MCR was observed in CD34(+) cells incubated with a polyclonal antiserum raised against human MCR. To our knowledge, this is the first demonstration of the presence of MCR in human PB CD34(+) cells.

Adult↗

Effect of surgical stress on benzodiazepine receptors as a consequence of placebo pellet implantation in rat: an autoradiographic study.

This paper reports modifications in benzodiazepine (BZ) receptors induced by minimally invasive surgery, such as pellet implantation, a widely used surgical process for chronic drug administration. The intrinsic stress induced by this manipulation on BZ receptors was analysed in an autoradiographic saturation study determining the affinity (K(D)) and total number (Bmax) of binding sites of a number of brain areas from the mesencephalon, cerebral cortex, hippocampus, and cerebellum. The radioligand used for the study was [3H]flunitrazepam, which permitted overall characterization of BZ binding sites. Use of the specific BZ1 agonist zolpidem as an inhibitor of this radioligand permitted the direct characterization of subtype 2 (BZ2) and the indirect characterization of subtype 1 receptor (BZ1). Significant increases in Bmax and K(D) values were observed in pellet-implanted animals with respect to those not implanted. The results support the notion of an up-regulation of these receptors, mainly in BZ1 receptors, following sustained desensitization as a result of the surgical stress induced by pellet implantation.

Animals↗

Oncostatin M induces angiogenesis in vitro and in vivo.

Neovascularization of the atherosclerotic plaque is responsible for its weakening and consequently for the complications of vascular disease. Macrophages are a source of growth factors that can modulate angiogenesis. In this study, we analyzed the effect of oncostatin M (OSM) on angiogenesis, as it could be involved in the development of atherosclerosis. The effect of OSM was compared with those of leukemia inhibitory factor (LIF) and interleukin-6 (IL-6). On human dermal microvasculature endothelial cells (HMEC-1s), OSM (22.5 to 112.5 pmol/L) induced a dose-dependent increase in cell proliferation greater than that induced by the classic angiogenic factors vascular endothelial growth factor (VEGF; 543 pmol/L) and basic fibroblast growth factor (bFGF; 1.1 nmol/L). LIF (19 to 475 pmol/L) induced only a 30% increase in cell proliferation, and IL-6 had no effect. Furthermore, in a modified Boyden-chamber model, OSM, LIF, and IL-6 were chemoattractant for HMEC-1s. In a tridimensional gel of fibrin, OSM increased tube formation and tube length, which were already noticeable by day 3. LIF and IL-6 induced a weaker effect that was only obvious by day 10. The angiogenic effect of OSM was also demonstrated in vivo in a rabbit corneal model: OSM was more potent than LIF, the length of the neovessels being longer with OSM than with LIF, whereas IL-6 was without effect. We tested factors that could be involved in the proliferative effect of OSM on HMEC-1s. OSM induced only a slight increase in the urokinase receptor and a 60% increase in VEGF secretion, whereas it does not modify IL-8 secretion or bFGF levels. The effect of OSM seems to depend on endothelial cell origin and cell species: OSM (up to 112.5 pmol/L) did not induce human umbilical vein endothelial cell proliferation and even had a small inhibitory effect (17%) on calf pulmonary artery endothelial cells. In conclusion, OSM induces an angiogenic effect on capillary endothelial cells, which could be, at least in part, implicated in pathological processes such as atherosclerosis or tumor growth.

Capillaries↗

Recruitment of primitive peripheral blood cells: synergism of interleukin 12 with interleukin 6 and stem cell factor.

Interleukin-12 (IL-12), a heterodimeric cytokine with potent biological activity, was evaluated for effects on proliferation of human immature progenitor cells in vitro. In vitro proliferation of 5-FU-resistant CD34+ (G0) peripheral blood stem cells (PBSC) in response to sequential cytokine stimulation was examined in the presence and absence of 100 ng/ml IL-12. PBSC were found to include a subpopulation of cells that were resistant to 25 microg/ml 5-FU and required a combination of IL-12, IL-6 and SCF for the production of morphologically recognizable clonogenic elements at day 14 in semisolid medium. Furthermore, addition of IL-6 soluble receptor (IL-6Rs) to IL-6 and SCF led to a similar recruitment. We also demonstrated a significant production of IL-6Rs by CD34+ cells stimulated by IL-12. We noted that glucocorticoids and aldosterone, a mineralocorticoid, had a positive effect on recruitment, but neither mineralocorticoid nor glucocorticoids induced IL-6Rs production by CD34+ cells. The recruitment mechanism by steroids seemed to be different from that used by IL-12. These results confirm previous findings which showed the involvement of IL-12 on immature PBSCs and suggest that IL-12 might play a key role in early haemopoiesis.

Antigens, CD34↗

Increased expression of u-PA and u-PAR on monocytes by LDL and Lp(a) lipoproteins--consequences for plasmin generation and monocyte adhesion.

Monocyte-derived foam cells figure prominently in rupture-prone regions of atherosclerotic plaque. As urokinase/urokinase-receptor (u-PA/u-PAR) is the trigger of a proteolytic cascade responsible for ECM degradation, we have examined the effect of atherogenic lipoproteins on monocyte surface expression of u-PAR and u-PA. Peripheral blood monocytes, isolated from 10 healthy volunteers, were incubated with 10 to 200 microg/ml of native or oxidised (ox-) atherogenous lipoproteins for 18 h and cell surface expression of u-PA and u-PAR was analysed by flow cytometry. Both LDL and Lp(a) induced a dose-dependent increase in u-PA (1.6-fold increase with 200 microg/ml of ox-LDL) and u-PAR [1.7-fold increase with 200 microg/ml of ox-Lp(a)]. There is a great variability of the response among the donors, some of them remaining non-responders (absence of increase of u-PA or u-PAR) even at 200 microg/ml of lipoproteins. In positive responders, enhanced u-PA/u-PAR is associated with a significant increase of plasmin generation ( .9-fold increase with 200 microg/ml of ox-LDL), as determined by an amidolytic assay. Furthermore, monocyte adhesion to vitronectin and fibrinogen was significantly enhanced by the lipoproteins [respectively 2-fold and 1.7-fold increase with 200 microg/ml of ox-Lp(a)], due to the increase of micro-PAR and ICAM-1, which are receptors for vitronectin and fibrinogen. These data suggest that atherogenous lipoproteins could contribute to the development of atheromatous plaque by increasing monocyte adhesion and trigger plaque weakening by inducing ECM degradation.

Cell Adhesion↗

Abnormal fibrin clot architecture in nephrotic patients is related to hypofibrinolysis: influence of plasma biochemical modifications: a possible mechanism for the high thrombotic tendency?

Porosity, viscoelasticity and morphological properties of plasma fibrin from 16 nephrotic patients and 16 healthy volunteers were compared. Nephrotic patients were characterized by formation of tight and rigid plasma fibrin gels which resulted in a slower rate of fibrin lysis studied either under pressure-driven permeation or diffusional transport of fibrinolytic agents. These latter findings indicated that both abnormal fibrin network conformation and abnormal fibrin fiber structure were involved in hypofibrinolysis. Albumin supplementation up to 40 mg/ml partially restored normal fibrin architecture and increased the rate of fibrinolysis in these patients. Multiparametric analysis showed that nephrotic patients were mainly characterized by a low plasma albumin level (R = -0.85), a low albumin to fibrinogen ratio (R = -0.89) and a high resistance to lysis (R = -0.82). High triglycerides level was the only plasma modification related to the slower fibrin lysis rate (R = -0.54). High fibrin rigidity (G') was the only fibrin parameter simultaneously related to the nephrotic state (R = 0.75) and the lysis resistance (R = -0.71). After eliminating the effects of age, albumin and fibrinogen levels, low fibrin porosity (Ks) and low fiber mass-length ratio (mu) were the main features of the nephrotic state. These findings are discussed in relation to both the pathophysiology of thrombotic complications in nephrotic syndrome and their pharmacological prevention.

Adolescent↗

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↗

A new quantitative D-dimer assay appropriate in emergency: reliability of the assay for pulmonary embolism exclusion diagnosis.

Plasma D-dimers, degradation products of cross-linked fibrin, are elevated in several thrombotic diseases. In the last decade, their measurement has been performed with specific monoclonal antibody based ELISA assay, with a high negative predictive value of such pathologies. However these methods have a low clinical impact since they cannot be used in emergency because they are time consuming and require series. Recently, rapid tests have been proposed with similar accuracy and are feasible for use in emergency conditions. The aim of our study was to evaluate the potential value of a new quantitative rapid assay, based on agglutination of latex microparticles coated with two monoclonal antibodies specific for D-dimers (Liatest D-Di, Diagnostica Stago), in the exclusion diagnosis of pulmonary embolism (PE). Eighty-five consecutive suspected PE patients were included in the study. D-dimer determination was performed with both standard ELISA and Liatest D-Di just before pulmonary scintigraphy. Sixty-nine patients were free of PE and 16 had PE. Our results confirm the excellent sensitivity and negative predictive values of the conventional D-dimer ELISA. Using a cut-off value of 500 ng/ml, the sensitivity and the negative predictive values of Liatest D-Di were 94% and 96%, respectively. Only one case of PE had a D-dimer value at 480 ng/ml, close to the cut-off value. This study demonstrates that the Liatest D-Di assay is sensitive enough to be used as the first step in the assessment of PE. However, the best cut-off value has to be determined to get an exclusion diagnosis with certainty.

Adult↗

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↗

IL-12 indirectly enhances proliferation of 5-FU-treated human hematopoietic peripheral blood CD34+ cells.

Interleukin-12 (IL-12) or natural killer cell stimulatory factor (NKSF), has multiple effects on T lymphocytes and natural killer cells. In this study, the effect of IL-12 on human hematopoiesis was studied by analyzing the growth of CD34+ peripheral blood stem cells (PBSC), in steady state. In the presence of Epo, IL-12 alone or in combination with IL-3 or SCF had no effect on the formation of colonies from CD34+ cells. In culture with Epo, G-CSF, and IL-3, the effect of Flt3-ligand (FL) on CD34+ PBSC was investigated in the presence or absence of IL-12. No additional effect of IL-12 was observed when combined with FL. We evaluated 5-FU-treated human CD34+ PBSC proliferation in cultures with Epo, G-CSF, and IL-3, in the presence or absence of IL-12. No cytokine combination enhanced colony formation from 5-FU-treated CD34+ cells. However, in cultures of 5-FU-treated human CD34+ cells, the most efficient combination was IL-3 + Epo + G-CSF + Accessory cells (CD34-). Furthermore, IL-12 enhanced this colony formation significantly. To investigate whether immature CD34+ cells were responsible for FL or SCF, 5-FU-treated human CD34+ cells were cultured with or without IL-12. Whereas no synergistic effect was observed in combination with IL-12, SCF alone significantly enhanced colony formation. However, the colony number was found to be smaller than with the potent combination of accessory cells in the presence of IL-12. These results indicate that accessory cells, lost in CD34+ cell purification, could be partly responsible for an IL-12 effect on immature human PBSC proliferation.

Adult↗

Regulation of interleukin 3 receptor alpha chain (IL-3R alpha) on human monocytes by interleukin (IL)-4, IL-10, IL-13, and transforming growth factor beta (TGF-beta).

Human interleukin 3 receptor (IL-3R) is constitutively expressed on committed haematopoietic stem cells, where it mediates proliferation and differentiation. This receptor is also expressed by monocytes and may induce functional activation. Interleukin (IL)-4, IL-10, IL-13, and transforming growth factor beta (TGF-beta) have different effects on human monocytes. As IL-3R may be regulated by different cytokines, whether the above-mentioned cytokines were able to modulate the alpha chain of IL-3R (IL-3R alpha) on monocytes was examined. Effects on IL-3R alpha antigen (Ag) expression were analysed by direct immunofluorescence and flow cytometry. Reverse transcription-polymerase chain reaction (RT-PCR) was used to detect variations in IL-3R alpha mRNA expression. IL-10 and TGF-beta were found to downregulate IL-3R alpha Ag. In contrast, IL-4 and IL-13 both caused a dose- and time-dependent increase. A maximum effect was observed at 1 ng/ml of IL-4 for 18 h. Furthermore, in RT-PCR, IL-4 was found to slightly up-regulate IL-3R alpha mRNA expression. These observations suggest that IL-4 and IL-13 play a role in the regulation of IL-3R alpha expression and the effects of cytokines on human monocytes may be mediated, in part, through the regulation of IL-3R.

Antigens↗

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↗

The suppression of fibroblast growth factor 2/fibroblast growth factor 4-dependent tumour angiogenesis and growth by the anti-growth factor activity of dextran derivative (CMDB7).

Our previous studies showed that carboxymethyl benzylamide dextran (CMDB7) blocks basic fibroblast growth factor (FGF-2)-dependent cell proliferation of a human breast epithelial line (HBL100), suggesting its potential role as a potent antiangiogenic substance. The derived cell line (HH9), which was transformed with the hst/FGF4 gene, has been shown to be highly proliferative in vitro and to induce angiogenic tumours in nude mice. We show here that CMDB7 inhibits the mitogenic activities of the conditioned media from HBL 100 and HH9 cells in a dose-dependent manner. When HH9 cells were injected s.c. into nude mice, CMDB7 treatment (300 mg kg(-1) week(-1)) suppressed the tumour take and the tumour growth by about 50% and 80% respectively. Immunohistochemical analysis showed a highly significant decrease, by more than threefold, in the endothelial density of viable tumour regions, together with a significant increase in the necrosis area. This antiangiogenic activity of CMDB7 was further demonstrated by direct inhibition of calf pulmonary artery (CPAE) and human umbilical vein (HUVEC) endothelial cell proliferation and migration in vitro. In addition, we showed that CMDB7 inhibits specifically the mitogenic effects of the growth factors that bind to heparin such as FGF-2, FGF-4, platelet-derived growth factor (PDGF-BB) and transforming growth factor (TGF-beta1), but not those of epidermal growth factor (EGF) and insulin-like growth factor (IGF-1). These results demonstrate that CMDB7 inhibits FGF-2/FGF-4-dependent tumour growth and angiogenesis, most likely by disrupting the autocrine and paracrine effects of growth factors released from the tumour cells.

3T3 Cells↗

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↗