Biomedical subjects

C Seidel

Publications and source records attributed to C Seidel.

At least 37 records · Page 2Linked to original sources

PubMed2000

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is an inhibitor of autoimmune inflammation and cell cycle progression.

The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis of tumor cells but not normal cells; its role in normal nontransformed tissues is unknown. We report here that chronic blockade of TRAIL in mice exacerbated autoimmune arthritis, and that intraarticular TRAIL gene transfer ameliorated the disease. In vivo, TRAIL blockade led to profound hyperproliferation of synovial cells and arthritogenic lymphocytes and heightened the production of cytokines and autoantibodies. In vitro, TRAIL inhibited DNA synthesis and prevented cell cycle progression of lymphocytes. Interestingly, TRAIL had no effect on apoptosis of inflammatory cells either in vivo or in vitro. Thus, unlike other members of the tumor necrosis factor superfamily, TRAIL is a prototype inhibitor protein that inhibits autoimmune inflammation by blocking cell cycle progression.

Animals↗

PubMed2000

Serum syndecan-1: a new independent prognostic marker in multiple myeloma.

Serum samples drawn at diagnosis from 174 myeloma patients were analyzed for the presence of the heparan [corrected] sulfate proteoglycan, syndecan-1. Syndecan-1 was elevated in 79% of patients (median, 643 units/mL) compared with 40 healthy controls (median, 128 units/mL), P <.0001. Serum syndecan-1 correlated with the following: serum creatinine, secretion of urine M-component over the course of 24 hours, soluble interleukin-6 (IL-6) receptor, C-terminal telopeptide of type I collagen, beta(2)-microglobulin, percentage of plasma cells in the bone marrow, disease stage, and serum M-component concentration. In order to evaluate syndecan-1 as a prognostic marker in multiple myeloma, it was entered into a multivariate Cox regression model. Data from 138 patients were available for this analysis. As a continuous variable, syndecan-1 was an independent prognostic parameter in addition to serum beta(2)-microglobulin and World Health Organization performance status. When syndecan-1 was dichotomized by the best cutoff (66th percentile, 1170 units/mL), the survival difference between the groups was highly significant: "high" syndecan-1 group had a median survival of 20 months, and the "low" syndecan-1 group had a median of 44 months (P <.0001). We conclude that syndecan-1 is a new independent prognostic parameter in multiple myeloma, and its role in prognostic classification systems should be further investigated. (Blood. 2000;95:388-392)

Biomarkers↗

PubMed2000

Expression of urokinase plasminogen activator and the urokinase plasminogen activator receptor in myeloma cells.

Binding of urokinase (uPA) to its receptor (uPAR; CD87) focuses proteolytic activity on the cell surface and this system is of importance in malignant matrix degradation and tumour invasion. By immunocytochemistry and flow cytometry, we found that primary myeloma cells and myeloma cell lines expressed uPA and uPAR. Soluble uPA was present in cell line supernatants and lysates in low concentrations. In cell lines, uPA and uPAR were located both on the cell surface and intracellularly, but the expression of both proteins was low. Higher levels of uPAR was detected on the cell surface of primary myeloma cells. When primary myeloma cells were gated by CD45 expression, stronger expression was found on immature CD45+ cells than on mature CD45-/dim cells. Finally, both myeloma cell lines and primary cells were able to cleave a uPA-specific substrate showing that the uPA system is functionally active. We conclude that myeloma cells are able to produce uPA and uPAR. This opens up a possible role of the uPA system in myeloma cell invasion and in the proteolytic digestion of bone matrix.

Flow Cytometry↗

PubMed2000

GnRH antagonist cetrorelix prevents sexual maturation of peripubertal male rats.

UNLABELLED: Gonadotropin releasing-hormone (GnRH) analogues contain amino acid substitutions of the native decapeptide. Depending on the substitutions, the analogues have GnRH agonistic or antagonistic properties. GnRH agonists are the established treatment in cases of central precocious puberty caused by premature activation of the hypothalamic GnRH pulse generator. Much less data exist on the use of GnRH antagonists to influence the onset of puberty. Using the GnRH antagonist cetrorelix we conducted a 5 day treatment of peripubertal male rats (cetrorelix group n=12, 100 microg/d intraperitoneally injected; placebo n=10, NaCl 0.9% intraperitoneally injected) from postnatal day 32 to 36 and decapitated on postnatal day 37 to investigate the effects on pubertal development, serum gonadotropin and testosterone levels as well as the GnRH release from explanted hypothalami. A control group of 5 male rats was added for hypothalamus superfusion experiments on day 25. We observed no progress of testicular development in the cetrorelix group. Cetrorelix injected rats had lower testicular weights (531+/-13 versus controls 819+/-25 mg, mean+/-SEM, p<0.0001). 12 h after the last injection testosterone levels were in the castrate range (serum testosterone, median controls: 1.7 ng/ml, median cetrorelix <0.30 ng/ml, p<0.001), and they showed lower serum LH and FSH compared to the same age placebo group. After decapitation the preoptic mediobasal hypothalamic area (POA/MBH) was dissected from 5 randomly selected rats from each treatment group and the release rates of GnRH were determined in superfusion experiments: The hypothalamic GnRH secretion was comparable in the CET and the same age placebo rats but significantly higher than in the 25 day old control group. CONCLUSION: The GnRH antagonist cetrorelix inhibits the pituitary-gonadal axis in peripubertal male rats and may be effective in treating central precocious puberty in males.

Animals↗

PubMed2000

Comparative analysis of different puberty inhibiting mechanisms of two GnRH agonists and the GnRH antagonist cetrorelix using a female rat model.

GnRH agonists are the established treatment of precocious puberty caused by premature stimulation of gonadotropin secretion. It has been reported that after an initial stimulation ("flare-up") they reduce LH secretion by desensitization of pituitary GnRH receptors. Little has been published about the use of GnRH antagonists such as cetrorelix to control the onset of puberty and whether they are potentially advantageous compared with GnRH agonists. We conducted two multigroup experiments (12 and 10 d, respectively) treating prepubertal/peripubertal female rats with either the GnRH agonist triptorelin or buserelin and compared them with rats treated with the GnRH antagonist cetrorelix and controls to assess the effects on pubertal progress and serum hormones. In the second experiment, the effects of buserelin and cetrorelix on gene expression of the GnRH receptor, LH-beta, FSH-beta, and the alpha subunit genes in the pituitary were also investigated. Cetrorelix, triptorelin, and buserelin retarded the onset of puberty as determined by delayed vaginal opening, lower ovarian weights, and lower serum estradiol levels. However, although LH and FSH levels were stimulated by both agonists, they were inhibited by cetrorelix. In the cetrorelix versus buserelin experiment, pituitary gene expression of the GnRH receptor and LH-beta subunit were significantly lower in cetrorelix treated rats compared with controls whereas buserelin had little effect. Expression of FSH-beta and alpha subunit were stimulated by buserelin but not by cetrorelix. Even though all three of these GnRH analogues inhibited gonadal development and delayed the onset of puberty, the GnRH agonists had stimulating and inhibiting effects on the pituitary-gonadal axis whereas cetrorelix exerted only inhibiting effects. We conclude from this female rat model that cetrorelix may offer advantages for a more controlled medical treatment of precocious puberty compared with GnRH agonist treatment.

Animals↗

PubMed2000

Nitric oxide and cGMP influence axonogenesis of antennal pioneer neurons.

The grasshopper embryo has been used as a convenient system with which to investigate mechanisms of axonal navigation and pathway formation at the level of individual nerve cells. Here, we focus on the developing antenna of the grasshopper embryo (Schistocerca gregaria) where two siblings of pioneer neurons establish the first two axonal pathways to the CNS. Using immunocytochemistry we detected nitric oxide (NO)-induced synthesis of cGMP in the pioneer neurons of the embryonic antenna. A potential source of NO are NADPH-diaphorase-stained epithelial cells close to the basal lamina. To investigate the role of the NO/cGMP signaling system during pathfinding, we examined the pattern of outgrowing pioneer neurons in embryo culture. Pharmacological inhibition of soluble guanylyl cyclase (sGC) and of NO synthase (NOS) resulted in an abnormal pattern of pathway formation in the antenna. Axonogenesis of both pairs of pioneers was inhibited when specific NOS or sGC inhibitors were added to the culture medium; the observed effects include the loss axon emergence as well as retardation of outgrowth, such that growth cones do not reach the CNS. The addition of membrane-permeant cGMP or a direct activator of the sGC enzyme to the culture medium completely rescued the phenotype resulting from the block of NO/cGMP signaling. These results indicate that NO/cGMP signaling is involved in axonal elongation of pioneer neurons in the antenna of the grasshopper.

Animals↗

PubMed1999

Hepatocyte growth factor (HGF) induces interleukin-11 secretion from osteoblasts: a possible role for HGF in myeloma-associated osteolytic bone disease.

Multiple myeloma is associated with unbalanced bone remodeling causing lytic bone lesions. Interleukin-11 (IL-11) promotes osteoclast formation and inhibits osteoblast activity and may, thus, be one factor involved in cancer-induced bone destruction. We have previously shown that myeloma cells produce hepatocyte growth factor (HGF). We now report that HGF induces IL-11 secretion from human osteoblast-like cells and from the osteosarcoma cell lines Saos-2 and HOS. In coculture experiments, both the myeloma cell line JJN-3 and primary myeloma cells from 3 patients induced IL-11 secretion from osteoblasts, whereas no induction was observed with the non-HGF producing myeloma cell line OH-2. Enhanced IL-11 induction was observed with physical contact between osteoblasts and myeloma cells as compared with experiments in which contact was prohibited by tissue inserts. Anti-HGF serum strongly reduced the myeloma cell-induced IL-11 secretion. Furthermore, we show that JJN-3 cells express HGF on the cell-surface. Removal of surface-bound HGF on JJN-3 cells reduced IL-11 production induced in cocultures. Transforming growth factor beta1 and IL-1 potentiated the effect of HGF on IL-11 secretion, whereas an additive effect was observed with tumor necrosis factor. Thus, myeloma-derived HGF can influence the bone marrow environment both as a soluble and a surface-bound factor. Furthermore, HGF emerges as a possible factor involved in myeloma bone disease by its ability to induce IL-11.

Hepatocyte Growth Factor↗

PubMed1999

Antigenic heterogeneity of the hepatitis C virus NS4 protein as modeled with synthetic peptides.

The effect of sequence heterogeneity on the immunologic properties of two strong antigenic regions of the hepatitis C virus (HCV) NS4 protein was studied by using a set of 443 overlapping 20-mer synthetic peptides. One antigenic region comprising the cleavage site between NS4a and NS4b (region 5-1-1) was modeled with peptides derived from 73 different known sequences, representing HCV genotypes 1-6. The other antigenic region, designated region 59 and located at the C-terminus of the NS4b protein, was modeled with peptides from 7 known sequences representing genotypes 1-3. All peptides were tested for antigenic reactivity by enzyme immunoassay with a panel of anti-HCV-positive serum specimens representing genotypes 1-5. The data demonstrated that immunoreactive peptides fell into two groups. One group, represented by N-terminal peptides, demonstrated genotype-independent immunoreactivity; the other group, from the central part of region 5-1-1, showed strict genotype specificity. Nineteen peptides from the genotype-independent group strongly immunoreacted with a wide range of serum samples containing antibodies to all 5 HCV genotypes. Twenty-five peptides from the genotype-specific group were found to strongly react with serum containing antibodies only to the genotype from which the peptides were derived. Similar to the N-terminal part of region 5-1-1, peptides derived from region 59 did not show genotype-specific immunoreactivity. Some peptides derived from the central part of region 59 showed very strong and broad antigenic reactivity. Thus, after examining two antigenic regions of the NS4 protein, we identified short sequences that can be used for the efficient detection of either genotype-independent or genotype-specific HCV antibodies.

Amino Acid Sequence↗

PubMed1999

Hepatocyte growth factor in serum after injection of unfractionated and low molecular weight heparin in healthy individuals.

Soluble heparin displaces the cytokine hepatocyte growth factor (HGF) from heparan sulphate proteoglycans on the cell surface and in the extracellular matrix into the circulation. We examined serum HGF elevation after heparin injections, and whether there is a difference between unfractionated heparin (UH) and low molecular weight heparin (LMWH) in their ability to increase serum HGF. 20 healthy individuals were randomized to a single injection of intravenous or subcutaneous UH or LMWH. There was a significant increase in HGF from pretreatment values. This HGF was bioactive. When these preparations were compared on the basis of their serum concentrations (anti-factor Xa activity or molar concentrations), the increase in HGF was greater in individuals receiving UH than LMWH. When UH or LMWH were administered over a 5 d period, the increase in HGF, as well as the difference between treatments to induce HGF, remained stable throughout the treatment. In five patients treated with continuous intravenous heparin infusion HGF was increased throughout the treatment period of 5-7 d. In summary, the rise in bioactive HGF after heparin treatment was stable during continued treatment. UH was more potent in inducing HGF increase than LMWH, both after a single injection and after several days of treatment.

Adolescent↗

PubMed1999

Prognostic evaluation in multiple myeloma: an analysis of the impact of new prognostic factors.

We have analysed the prognostic information for survival of presenting features in an unselected series of 394 myeloma patients. 15 variables with significant prognostic information were identified, among these were some not previously or only recently reported: serum levels of hepatocyte growth factor (HGF), interleukin-6 (IL-6), C-terminal cross-linked telopeptide of collagen I (ICTP) and soluble interleukin-6 receptor (sIL-6R). In a multivariate Cox analysis six variables were significantly and independently associated with poor survival: high age, low W.H.O.-performance status (PS), high serum levels of calcium, beta-2-microglobulin (beta-2M), IL-6 and sIL-6R. A risk score formed to predict survival for each percentile of the patient population allowed an efficient separation of prognostic groups. The discriminating power of the model compared favourably with three other previously published staging systems applied to the study population. Exclusion of IL-6 and sIL-6R from the model only marginally decreased the efficacy of the separation. The predictive value of some variables (sIL-6R, beta-2M and W.H.O.-PS) decreased significantly over time. We conclude that formation of a risk score based on independent variables is an efficient way to separate prognostic groups, that the contribution of new and not easily available parameters should be thoroughly evaluated before inclusion in prognostic models for clinical use and that the predictive value of parameters may decrease over time.

Humans↗

PubMed1999

Apoptosis, proliferation and NF-kappaB activation induced by agonistic Fas antibodies in the human myeloma cell line OH-2: amplification of Fas-mediated apoptosis by tumor necrosis factor.

Tumor necrosis factor (TNF) is known to be a growth factor for several myeloma cell lines. However, in the presence of the agonistic Fas antibody CH 11, TNF enhanced the level of apoptosis in cultures of the human myeloma cell line OH-2. This pro-apoptotic effect of TNF was explained at least in part by a TNF-mediated enhancement of Fas expression. TNF induces proliferation of OH-2 by activating nuclear transcription factor kappa-B (NF-kappaB). The proliferative effect of TNF on OH-2 cells was abrogated by CH11, but this was not caused by an inhibition of the translocation of NF-kappaB. On the contrary, CH11 could by itself activate NF-kappaB in OH-2 cells, and in the presence of an inhibitor of caspase-1 induce proliferation of the cells. The relationship between stimulation of TNF receptors and Fas and the level of NF-kappaB activation was also examined in three other myeloma cell lines. RPMI-8226 cells showed NF-kappaB activation by TNF, but contrary to OH-2, not by CH11. Unstimulated U-266 and JJN-3 cells had high levels of activated NF-kappaB. This shows that NFkappa-B is either constitutively activated or inducible in myeloma cells. Modulation of Fas expression and inhibition of NF-kappaB activation can potentially be of therapeutic importance in multiple myeloma.

Antibodies↗

PubMed1999

Elevated serum concentrations of hepatocyte growth factor in acute myelocytic leukaemia.

Serum concentrations of hepatocyte growth factor (HGF) were measured in 60 patients suffering from acute myelocytic leukaemia (AML). At the time of diagnosis elevated HGF concentrations (> 1.25 ng/ml) were found in 28% of the patients. HGF levels correlated with the presence of disseminated intravascular coagulation (DIC), levels of lysozyme, creatinine, peripheral blood blast counts and lactic dehydrogenase. In the group of patients with high HGF (>1.25 ng/ml) we found a tendency towards an increased early mortality; 41% of them died within 15 d from diagnosis, as opposed to 5% of the patients with normal HGF (log rank test p=0.07). DIC-related bleeding or thrombosis contributed to this early mortality. In responders, HGF levels normalized after treatment. HGF levels are low in neutropenia and neutropenic infections.

Biomarkers, Tumor↗

PubMed1999

The role of hepatocyte growth factor and its receptor c-Met in multiple myeloma and other blood malignancies.

The cytokine hepatocyte growth factor (HGF) and its receptor c-Met are a ligand-receptor pair with important functions in a communicative interplay between HGF-producing, mesenchymal cells and c-Met-expressing target cells. HGF is cytoprotective and causes regeneration of parenchyma after tissue damage in several organs. The receptor c-Met was first characterized as an oncogene product being responsible for the transformation of an osteosarcoma cell line. HGF or c-Met is overexpressed in several human cancers, including various carcinomas. Some cells of hematopoietic origin also seem to be capable of c-Met expression, but the precise role of HGF in normal hematopoiesis is yet to be determined. In blood malignancies like acute myelogenous leukemia and, notably, multiple myeloma, HGF is overproduced and has implications for the prognosis of the patients. Biological significance of HGF overexpression in multiple myeloma is discussed and is likely to include effects on bone turnover and angiogenesis.

Hematologic Neoplasms↗

PubMed1998

Characterization of a linear epitope in the nonstructural region 4 of hepatitis C virus with reactivity to seroconversion antibodies.

Mapping and possible diagnostic meaning of a highly conserved, linear NS4 epitope (NS4/3), located outside the C100-3 antigen within the carboxyl terminal proportion of the NS4 region, with major immunoreactivity with specimens of patients with HCV infection from various geographic origins is described. Transient, acute-phase IgM anti-HCV NS4/3 was detected coincidentally or earlier than active IgG anti-HCV NS4/3 response with four well-characterized seroconversion panels. GenBank alignment studies identified patch homologies between the NS4/3 sequence and a number of non-HCV proteins, which may explain part of the cross-reactivity of the NS4/3 epitope. Some of the "false positive reactivities" of the NS4/3 epitope with asymptomatic blood donors, not being confirmed with FDA-approved anti-HCV assays without the NS4/3 epitope, may be explained by recognition of very early seroconversion antibodies.

Amino Acid Sequence↗

PubMed1998

Identification of carbohydrate deficient transferrin forms by MALDI-TOF mass spectrometry and lectin ELISABiochim Biophys Acta 1998 Aug 24;1381(3):356.

Transferrin was isolated from sera of patients with severe alcohol abuse and from control sera by affinity chromatography using an immobilized polyclonal antibody from sheep, followed by gel filtration. The purified transferrin was then separated by MonoQ chromatography. Compared to the controls, sera from heavy alcohol consumers showed two additional transferrin peaks, eluting earlier than the three main transferrin forms present in all sera. Further analysis of the isolated transferrin forms by matrix assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF-MS) and enzyme linked immunosorbent assay with different digoxigenylated lectins (lectin ELISA) revealed that the main carbohydrate deficient transferrin (CDT) forms are lacking either one or both of the N-Glycan chains.

Alcoholism↗

PubMed1998

Elevated serum concentrations of hepatocyte growth factor in patients with multiple myeloma. The Nordic Myeloma Study Group.

Serum from 398 myeloma patients at diagnosis and serial samples from 29 patients were analysed for hepatocyte growth factor (HGF). HGF was elevated at diagnosis in 43% of myeloma patients compared with healthy controls (median 1.00 ng/mL and 0.44 ng/mL, respectively; P < .00001). In the group with elevated HGF levels 46% of the patients reached plateau phase, as compared with 60% of the patients with low HGF levels (P = .005), and the median survival time was 21 and 32 months, respectively (P = .002). In a univariate Cox regression analysis, HGF was a significant predictor of mortality (P = .02). In the subgroup of patients with beta 2-microglobulin levels less than or equal to 6 mg/L, high versus low HGF was a prognostic factor when a multivariate Cox regression analysis was performed. In serial samples HGF was higher at the time of diagnosis and relapse (median 0.57 ng/mL and 0.52 ng/mL, respectively; P = .0018) than at response (median 0.24 ng/mL, P = .008). We conclude that HGF may be a useful follow-up parameter in myeloma patients. Measurement of HGF may identify a group of patients with poor response to melphalan-prednisone treatment and short survival. HGF was a prognostic factor in patients with high levels of beta 2-microglobulin.

Adult↗

PubMed1998

Role of hepatocyte growth factor and its receptor c-met in multiple myeloma.

Multiple myeloma is characterised by the clonal expansion of malignant plasma cells. Recently, we reported that a new cytokine, hepatocyte growth factor (HGF), and its receptor c-met are related to this disease. Here we review the observations that associate HGF with myeloma. Malignant plasma cells produce HGF and express the receptor c-met. Many patients have elevated HGF levels, which is unfavourable both in terms of survival and response to treatment. Possible biological roles of HGF in this disease are discussed, with special focus on bone homeostasis and its binding to heparan sulphate proteoglycans.

Bone Diseases↗

PubMed1997

Colocalization of NADPH-diaphorase and GABA-immunoreactivity in the olfactory and visual system of the locust.

Nitric oxide synthesizing neurons of the locust CNS have been identified by NADPH-diaphorase staining. However, the conventional transmitters of these neurons are unknown. Here we use double labelling for NADPH-diaphorase and GABA-immunofluorescence on sections of the brain to investigate a potential coexpression of both markers. The antennal lobe is innervated by a cluster of about 45-50 NADPH-diaphorase positive local interneurons which express GABA-immunofluorescence. The mushroom bodies are a higher order olfactory center which receive an extrinsic innervation from GABA-immunoreactive and NADPH-diaphorase positive fiber systems. Each optic lobe contains about 4500 GABA-immunoreactive cell bodies. In the visual system, identifiable GABA-immunoreactive neurons arborize in the external plexiform layer of the lamina, in several strata of the medulla, and in the lobula complex. A survey of all NADPH-diaphorase positive cell groups detected a colocalization of GABA-immunoreactivity in a small subpopulation of somata along the anterior rim of the medulla. These cytochemical findings suggest that nitric oxide may be a characteristic cotransmitter of GABAergic circuits of the antennal lobe, while in mushroom bodies and the visual system the majority of nitric oxide and GABA releasing neurons are distinct populations.

Animals↗