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Biomedical subjects

M Schwab

Publications and source records attributed to M Schwab.

At least 235 records · Page 13Linked to original sources
PubMed1988

Sustained expression of the human protooncogene MYCN rescues rat embryo cells from senescence.

Amplification of the human gene MYCN may play a role in the malignant progression of human neuroblastomas. In pursuit of this possibility, previous studies have shown that the abundant expression of MYCN in cultured cells can elicit several aspects of the transformed phenotype. We now extend those findings by demonstrating that rat embryo cells transfected with MYCN can proliferate for at least 200 generations. Isolation of established cells was dependent on high expression of MYCN and on biological selection to eliminate untransfected cells. The established cells were not tumorigenic in syngeneic rats or athymic mice, failed to grow in soft agar, and required relatively high concentrations of serum for proliferation in culture. Our results show that enhanced expression of MYCN can rescue normal cells from senescence, add to the credentials of MYCN as an authentic protooncogene, and identify an additional biological activity that can be used in the characterization of MYCN.

Animals↗
PubMed1988

Psychotropic effects of corticotropin-releasing hormone stimulation in depressive patients.

Synthetic human corticotropin-releasing hormone (hCRH) was administered as an intravenous bolus (100 micrograms) to 13 patients suffering from endogenous depression and to 12 healthy volunteers. Compared with controls, depressed patients showed a significant amelioration of mood and well-being 2 h after hCRH administration in the rating scales applied ('Befindlichkeits-Skala', 'Eigenschaftswörterliste', 'Kurzskala Stimmung-Aktivierung', Self-Rating Depression Scale, Hamilton Rating Scale for Depression). Based on our preliminary data, a psychotropic effect and at least a mediating function of hCRH regarding pathophysiology and etiopathogenesis of endogenous depressions must be assumed.

Adult↗
PubMed1988

Significance of the cardioprotective effect of prostanoids and indomethacin.

Recent investigations in several organs indicate cytoprotective effects of prostanoids. For further elucidation of this efficacy the investigations dealt with the cardioprotection of prostanoids (iloprost, PGE1) and the cyclooxygenase inhibitor indomethacin under in vivo- and in vitro-conditions. The experiments were carried out in isolated perfused guinea pig hearts and anaesthetized rabbits. Cardiac damage was induced by chemical substances or loading by aortic constriction or ischemia. In isolated perfused hearts iloprost and indomethacin suppressed the toxic effects of carbon tetrachloride, chloroform, benzene, sodium dithionate and phenylethylbarbituric acid, but not the efficacy of quinine sulfate and 2,4-dinitro-phenol. Cardiac loading by aortic stenosis or ischemia induced a decrease of contractility and blood pressure and changes in the myocardial PGI2-biosynthesis. On the other side application of indomethacin, iloprost or PGE1 diminished the cardiac damage and inhibit the myocardial PGI2-formation. The results show that indomethacin and prostanoids have a protective effect in pathophysiological changes or toxic damage of the heart, possibly caused by a stabilization of the cellular membrane.

Alprostadil↗
PubMed1988

Tumorigenicity of SEWA murine cells correlates with degree of c-myc amplification.

Previous studies have shown that cells of the SEWA mouse tumor contain amplified copies of the proto-oncogene c-myc in the aberrant chromosomal structures of double minutes (DMs), homogeneously staining regions (HSRs) and C-bandless chromosomes (CMs). DMs, and to a lesser degree CMs, tend to disappear from the cells grown in vitro and again reappear after transfer back in vivo, as if DNA amplification confers a growth advantage upon the tumor cells. We have now isolated five in vitro clones that exhibit different degrees of c-myc amplification. When we inoculated cells of the different clones into compatible hosts, we found that there was a positive correlation between degree of c-myc amplification, level of c-myc RNA, and tumorigenicity. Our results lend further support to the idea that gene amplification contributes to the higher malignant phenotype, and to progression of tumors.

Animals↗
PubMed1987

Triple non-contiguous injuries of the spine. A report of 2 cases.

Two cases of triple non-contiguous injuries of the spine are presented. Both patients had obvious single level injuries which obscured the associated double lesions. The importance of meticulous clinical and radiological examination of the entire spine is emphasised.

Adult↗
PubMed1987

Expression of N-myc and c-src during the development of fetal human brain.

We studied N-myc RNA by in situ hybridization and S1 nuclease protection analysis in human fetal cerebrum, retina, lung, liver, and placenta during the second trimester. High levels of N-myc RNA were found in the early fetal cerebral germinal layer and the primordial cortex, with lower levels in the intermediate layer. After the twentieth week, N-myc expression declined in the attenuated germinal layer, remained high in the undifferentiated outer cortex, but declined in the differentiating inner cortex, which now expressed c-src. The primitive retina had high levels of N-myc RNA in the inner nuclear and ganglion cell layers between 12 and 21 weeks of fetal age. During this time, c-src RNA increased with fetal age in the ganglion cell layer. Lower levels of N-myc RNA were expressed in some cells of lung and placenta. Thus, appreciable N-myc RNA elevation is present in immature neural cells, disappears with differentiation, and may be unrelated to mitosis since high levels occur in the primordial cortex, which grows by accretion, and not by cell division.

Brain↗
PubMed1987

Effects of intravenous N-acetylprocainamide on hemodynamics and left ventricular function in man.

N-acetylprocainamide (NAPA) is the active metabolite of procainamide currently undergoing evaluation for its antiarrhythmic properties. Its effects on hemodynamic variables and on ventricular function in man are poorly defined. The effects of intravenously administered NAPA (18 mg/kg over 30 minutes; mean plasma level 40.2 +/- 6.2 micrograms/ml) on hemodynamics and left ventricular ejection fraction (LVEF) assessed by radionuclide ventriculography were therefore determined in 14 patients undergoing diagnostic cardiac catheterization. The peak effects of the drug with respect to most measured variables were seen at 30 minutes and were still apparent at 60 minutes. NAPA increased heart rate (3% at 10 minutes; p less than 0.01), decreased mean pulmonary arterial pressure (14%; p less than 0.05) and capillary wedge pressure (27%; p less than 0.01), decreased mean arterial pressure (12%; p less than 0.01), cardiac index (8%; p less than 0.01), LV dp/dtmax (9%; p less than 0.05), and stroke work index (17%; p less than 0.01). The LVEF increased 5% (p less than 0.05). There was a trend for the systemic vascular resistance to decrease, but this did not reach statistical significance. The data show that NAPA exerts relatively weak peripheral arteriolar and venodilator effects associated with a mild reduction in contractility and cardiac output but an increase in LVEF in patients with preserved ventricular function.

Acecainide↗
PubMed1987

Neoplastic transformation by the human gene N-myc.

Amplification and abundant expression of a gene known as N-myc are found frequently in advanced stages of human neuroblastoma and may play a role in the genesis of several malignant human tumors. Previous studies have shown that N-myc can cooperate with a mutant allele of the proto-oncogene c-Ha-ras to transform embryonic rat cells in culture. Here we show that N-myc can also act alone to elicit neoplastic growth of an established line of rat fibroblasts (Rat-1). We used recombinant DNA vectors to express either N-myc or its kindred gene c-myc in transfected cells. Both genes caused morphological transformation, anchorage-independent growth, and tumorigenicity. We noticed two variables that appeared to influence the ability to isolate cells transformed by N-myc and c-myc: the abundance in which the genes were expressed and biological selection to eliminate untransformed cells from the cultures. Our findings sustain the belief that N-myc is an authentic proto-oncogene, lend further credibility to the role of N-myc in the genesis of human tumors, and establish a convenient assay that can be used to explore further the properties of both N-myc and c-myc.

Animals↗
PubMed1986

Antigen presentation in the peripheral nervous system: Schwann cells present endogenous myelin autoantigens to lymphocytes.

Schwann cells (SC) isolated from neonatal rat sciatic nerves are shown to immunogenically present foreign and exogenous autoantigen to antigen-specific syngeneic T line cells in vitro. The antigen-presenting SC express Ia antigens on their membranes upon treatment with interferon gamma and contact with syngeneic T line cells. Monoclonal antibodies against Ia block specific antigen presentation, but not polyclonal mitogenic T cell activation. The antigen-presenting SC bind antibodies specific for astrocytic glial fibrillary acidic protein and may thus be related to the nonmyelinating glia cells of the peripheral nerve. Furthermore, SC isolated from 6-day-old rats activate rat myelin basic protein (MBP)-specific syngeneic T line cells in the absence of exogenous MBP. In contrast, they activate purified protein derivative of tuberculin (PPD)-specific T cells only in the presence of PPD. Since the MBP-specific T line cells are not activated by syngeneic professional antigen-presenting cells in the absence of MBP, endogenous MBP produced in the 6-day-old sciatic nerves appears to be presented by autochthonous SC to the autoreactive T cells.

Animals↗
PubMed1986

Malignant metamorphosis: developmental genes as culprits for oncogenesis in Xiphophorus.

Neoplastic growth is a widespread developmental aberration among multicellular organisms ranging from primitive avertebrates such as coelenterates (Brien, 1961) and annelids (Cooper, 1969) to man. A major goal of the studies concerning neoplasia has been to obtain insight into its cellular and molecular basis, and it has been suggested as early as the beginning of this century that cellular genes are paramount in the etiology of neoplasis. Early support for this idea has been gained by Mendelian strategies applied to a number of experimental systems, such as Xiphophorus. During the last years molecular biology has provided some insight into the genetic mechanisms that might be involved in neoplasia in higher vertebrates, and it has been possible to identify proto-oncogenes as candidates for the agents directing cellular transformation and/or maintainance of the neoplastic state of the cell. The high degree of evolutionary conservation of the proto-oncogenes points to basic functions that these genes normally might have for the cell and at the same time indicates that crucial steps associated with tumorigenesis might take similar pathways in different classes of vertebrates. There are now four main lines of molecular evidence that relate cellular genes to neoplasia: insertional mutagenesis or chromosomal rearrangement that juxtaposes an exogenous or endogenous genetic element which augments gene expression next to a cellular gene, resulting in elevated expression (for review, see Varmus, 1982; Klein, 1983); gene amplification that results in an increase of the copy number and an elevated expression of a particular gene and, to date, has been found in tumors of humans and mice (for overviews, see Schwab et al., 1984; Schwab, 1985; Alitalo and Schwab, 1986); structural alteration of a cellular gene itself which results in the synthesis of an altered protein (Weinberg, 1982; Cooper, 1982); and generation of fusion genes as a result of gene translocation with possibly altered biological activities (for review, see Adams, 1985). It remains to be addressed in future experiments which genetic mechanisms are operative in development of tumors of genetic origin in Xiphophorus.

Animals↗
PubMed1986

Nucleotide sequence of the human N-myc gene.

Human neuroblastomas frequently display amplification and augmented expression of a gene known as N-myc because of its similarity to the protooncogene c-myc. It has therefore been proposed that N-myc is itself a protooncogene, and subsequent tests have shown that N-myc and c-myc have similar biological activities in cell culture. We have now detailed the kinship between N-myc and c-myc by determining the nucleotide sequence of human N-myc and deducing the amino acid sequence of the protein encoded by the gene. The topography of N-myc is strikingly similar to that of c-myc: both genes contain three exons of similar lengths; the coding elements of both genes are located in the second and third exons; and both genes have unusually long 5' untranslated regions in their mRNAs, with features that raise the possibility that expression of the genes may be subject to similar controls of translation. The resemblance between the proteins encoded by N-myc and c-myc sustains previous suspicions that the genes encode related functions.

Amino Acid Sequence↗
PubMed1986

Human proto-oncogene N-myc encodes nuclear proteins that bind DNA.

N-myc is a gene whose amplification has been implicated in the genesis of several malignant human tumors. We have identified two proteins with molecular weights of 65,000 and 67,000 encoded by N-myc. The abundance of these proteins in tumor cells was consonant with the extent of amplification of N-myc. The two proteins apparently arose from the same mRNA, were phosphorylated, were exceptionally unstable, were located in the nucleus of cells, and bound to both single- and double-stranded DNA. These properties suggest that the products of N-myc and of the related proto-oncogene c-myc may have similar biochemical functions and that N-myc may be a regulatory gene. Our findings sustain the view that inordinate expression of N-myc may contribute to the genesis of several different human tumors.

Apudoma↗
PubMed1986

Rearrangement at the 5' end of amplified c-myc in human COLO 320 cells is associated with abnormal transcription.

The proto-oncogene c-myc is amplified in sublines of human COLO 320 cells carrying either homogeneously staining chromosomal regions or double minutes. COLO 320 cells carrying homogeneously staining chromosomal regions have 15 to 20 copies of an apparently normal c-myc allele and 1 to 2 copies of an abnormal c-myc allele lacking exon 1 and express high levels of a normal c-myc mRNA 2.5 kilobases in size. COLO 320 cells carrying double minutes have about 25 copies each of the normal allele and the abnormal allele but express preferentially an abnormal c-myc mRNA 2.2 kilobases in size. Nucleotide sequence analyses revealed that the break point of rearrangement resulting in the loss of exon 1 in the abnormal allele lies within a region frequently rearranged in human and murine B-cell tumors.

Alleles↗
PubMed1986

Detection of N-myc oncogene expression in human neuroblastoma by in situ hybridization and blot analysis: relationship to clinical outcome.

We studied N-myc oncogene expression in 13 human neuroectodermal tumors and one teratoma by in situ hybridization. In four of six neuroblastomas, there was increased N-myc expression (15 to 49% of the cells). Many of the primitive neuroblastic cells had an increase of N-myc RNA not observed in the larger, more differentiated cells. Two neuroblastomas matured to ganglioneuromas; no biopsies performed during this progression expressed increased N-myc RNA. Three ganglioneuroblastomas, two tumors presenting as ganglioneuromas, a cerebral neuroectodermal tumor, a neurofibrosarcoma, and the teratoma did not have increased N-myc expression. The data obtained by in situ hybridization correlated well with data obtained by blot analysis. Neuroblastomas/ganglioneuroblastomas with a favorable course did not have appreciable elevation of N-myc expression over 10 to 77 mo of follow-up; thus N-myc may not be involved in the maintenance of the neoplastic state. However, such tumors with a fatal outcome 2 to 14 mo after diagnosis usually had elevated N-myc expression. These findings suggest a relationship between elevated levels of N-myc RNA and poor prognosis.

Brain Neoplasms↗
PubMed1986

Brain-derived neurotrophic factor supports the survival of cultured rat retinal ganglion cells.

Brain-derived neurotrophic factor (BDNF) is a small, basic protein purified from the mammalian brain that has been shown previously to support the survival of cultured spinal sensory neurons (Barde et al., 1982). In current studies, BDNF was tested for its ability to support the survival of cultured CNS cells isolated from the perinatal rat retina. Both immunofluorescent labeling of Thy-1 and prior retrograde labeling with HRP were used as retinal ganglion cell markers in vitro. With embryonic day (E) 17 retinas, it was found that BDNF allowed the survival of a small subpopulation of neurons (about 7% of the cells plated at this age) identified by the immunofluorescent labeling of Thy-1. No detectable effects were seen when either the total number of cells or the number of tetanus toxin-positive neurons was measured. BDNF also had an effect on cultured neurons retrogradely labeled after HRP injections in the superior colliculi of neonatal rats. The BDNF-responsive population was therefore detected only in retinal cultures with specific markers and identified as consisting of retinal ganglion cells. These cells could be enriched about 80-fold by density gradient centrifugation, and purified ganglion cell cultures were shown to be responsive to BDNF. Whereas with E17 retinas, the number of surviving Thy-1 positive neurons could be kept constant for at least 4 d, the survival of postnatal neurons was only transiently increased by BDNF. We conclude that in the retina, BDNF affects only the survival of ganglion cells in vitro by a direct action on these cells. The results are discussed in terms of target-derived neurotrophic support during development.

Animals↗
PubMed1985

Comparative electrophysiologic profiles of calcium antagonists with particular reference to bepridil.

The calcium antagonist bepridil hydrochloride differs pharmacologically from the conventional agents that block the myocardial slow channel. Its clinical electrophysiologic effects are poorly defined. The effects of 2 mg/kg + 1 mg/kg of intravenously administered bepridil in 10 patients were compared with those of 3 mg/kg + 1 mg/kg in 9 patients undergoing electrophysiologic evaluation of clinical symptoms. The overall effects of the 2 regimens did not differ significantly. The drug reduced the heart rate slightly; it had no effect on the PR interval but significantly lengthened the AH interval by 2 to 10%, HV by 2 to 12% and QTc by 5 to 8%. The most striking effect was the prolongation of the functional (up to 17%, p less than 0.001) and the effective (up to 13%, p less than 0.001) refractory periods of the atrioventricular node with a lengthening of the Wenckebach cycle (up to 17%, p less than 0.001). In contrast to the action of verapamil, bepridil significantly prolonged the ventricular (4 to 7%, p less than 0.01 to p less than 0.001) and the atrial (12 to 19%, p less than 0.05 to p less than 0.001) effective refractory periods. The data indicate that bepridil hydrochloride has a wide spectrum of electrophysiologic activity in man consistent with inhibitory actions on myocardial slow and fast channels and a significant lengthening of cardiac repolarization. These overall effects suggest that the antiarrhythmic profile of the drug is likely to be wider than those of conventional calcium antagonists.

Adult↗