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Biomedical subjects

E Friedman

Publications and source records attributed to E Friedman.

At least 253 records · Page 14Linked to original sources
PubMed1994

Evidence for a distinct D1-like dopamine receptor that couples to activation of phosphoinositide metabolism in brain.

Dopamine and the D1 receptor agonist SKF 38393 activate the phospholipase C-mediated hydrolysis of phosphoinositides in brain slices. This action is selectively inhibited by SCH-23390, thus suggesting its mediation through the dopamine D1 receptor. To determine if the dopamine receptor that mediates phosphoinositide hydrolysis is the adenylyl cyclase-linked D1 receptor or a different subtype of the dopamine D1 receptor, 20 benzazepine compounds that were previously characterized as selective dopamine D1 receptor agonists were tested for stimulation of phosphoinositide hydrolysis in rat striatal slices and for activation of adenylyl cyclase in rat striatal membranes. The compounds displayed a range of potencies and efficacies in stimulating adenylyl cyclase or phosphoinositide hydrolysis. Compounds such as SKF 81427 and SKF 38393 were as efficacious as dopamine in stimulating phosphoinositide hydrolysis, whereas other compounds, including SKF 85174 and SKF 86284, although showing high efficacy in stimulating cyclic AMP, failed to stimulate inositol phosphate formation. There was no correlation between the potencies (r = 0.016; p > 0.95) or efficacies (r = -0.294; p > 0.24) of the tested compounds in stimulating cyclic AMP formation and phosphoinositide hydrolysis. These observations indicate that the D1-like dopamine receptor that mediates phosphoinositide hydrolysis is pharmacologically distinct from the classic D1 receptor that is coupled to stimulation of cyclic AMP formation.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1994

Inhibition of dopamine agonist-induced phosphoinositide hydrolysis by concomitant stimulation of cyclic AMP formation in brain slices.

We examined the effects of cyclic AMP on dopamine receptor-coupled activation of phosphoinositide hydrolysis in rat striatal slices. Forskolin, dibutyryl cyclic AMP, and the protein kinase A activator Sp-cyclic adenosine monophosphothioate (Sp-cAMPS) significantly inhibited inositol phosphate formation stimulated by the dopamine D1 receptor agonist SKF 38393. Conversely, the protein kinase A antagonist Rp-cyclic adenosine monophosphothioate (Rp-cAMPS) dose-dependently potentiated the SKF 38393 effect. In the presence of 200 microM Rp-cAMPS, the dose-response curves of the dopamine D1 receptor agonists SKF 38393 and fenoldopam were shifted to the left and maximal agonist responses were markedly increased. The agonist EC50 values, however, were not significantly altered by protein kinase A inhibition. Neither Sp-cAMPS nor Rp-cAMPS significantly affected basal inositol phosphate accumulation. These findings demonstrate that dopaminergic stimulation of phosphoinositide hydrolysis is inhibited by elevations in intracellular cyclic AMP. Dopamine receptor agonists that stimulate adenylyl cyclase could suppress their activation of phosphoinositide hydrolysis by concomitantly stimulating the formation of cyclic AMP in striatal tissue. The interaction between dopamine D1 receptor-stimulated elevations in cyclic AMP and dopaminergic stimulation of inositol phosphate formation suggests a cellular colocalization of these dopamine-coupled transduction pathways in at least some cells of the rat striatum.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1994

Platelet-activating factor: diminished acetylcholine release from rat brain slices is mediated by a Gi protein.

The effect of platelet-activating factor (PAF) on neurotransmitter release from rat brain slices prelabeled with [3H]acetylcholine ([3H]ACh), [3H]norepinephrine ([3H]NE), or [3H]serotonin ([3H]5-HT) was studied. PAF inhibited K+ depolarization-induced [3H]ACh release in slices of brain cortex and hippocampus by up to 59% at 10 nM but did not inhibit [3H]ACh release in striatal slices. PAF did not affect 5-HT or NE release from cortical brain slices. The inhibition of K(+)-evoked [3H]ACh release induced by PAF was prevented by pretreating tissues with several structurally different PAF receptor antagonists. The effect of PAF was reversible and was not affected by pretreating brain slices with tetrodotoxin. PAF-induced inhibition of [3H]ACh release was blocked 90 +/- 3 and 86 +/- 2% by pertussis toxin and by anti-G alpha i1/2 antiserum incorporated into cortical synaptosomes, respectively. The results suggest that PAF inhibits depolarization-induced ACh release in brain slices via a G alpha i1/2 protein-mediated action and that PAF may serve as a neuromodulator of brain cholinergic system.

Acetylcholine↗
PubMed1994

The phospholipase C beta 3 gene located in the MEN1 region shows loss of expression in endocrine tumours.

Oncogenesis of tumours related to multiple endocrine neoplasia type 1 (MEN1) is associated with somatic deletions involving the MEN1 locus, suggesting inactivation of a tumour suppressor gene in this region. Identification of meiotic cross-overs in MEN1 families has placed the MEN1 locus centromeric of D11S807. An extended deletion mapping was performed in 27 primary parathyroid tumours, and identified D11S427 as the closest centromeric flanking marker. Through physical mapping using newly isolated cDNA clones, we estimated the distance between the flanking markers D11S807 and D11S427 to be less than 900 kb. One of these cDNA clones showed expression of a 4.4 kb message in multiple tissues, including those affected in MEN1, while in five endocrine tumours no transcript was detected. Sequence characterization showed that this gene encodes for the phospholipase C beta 3, a key enzyme in signal transduction.

Blotting, Northern↗
PubMed1994

Can the uptake of breast screening by Asian women be increased? A randomized controlled trial of a linkworker intervention.

This study investigates the effectiveness of a linkworker intervention, giving encouragement and explanations about breast screening, on the subsequent attendance for screening by 'Asian' women. The control group received no visits. The study population comprised all women with Asian names, from a batch of general practices where high proportions of patients were Asian, who were invited for screening. It was found that 59 per cent of the intervention group could be contacted by linkworkers. No difference in attendance was found between the intervention and control groups (49 per cent and 47 per cent). Twenty-five per cent of women were permanently or temporarily not resident at the invitation address. Attendance for screening was related to length of stay in the United Kingdom. This type of intervention was not a successful strategy for promoting uptake by Asian women, and indicates that it is essential to evaluate rigorously projects with such objectives.

Aged↗
PubMed1994

Normal structural dopamine type 2 receptor gene in prolactin-secreting and other pituitary tumors.

Dopamine, acting via its specific receptor (DRD2) in the anterior pituitary, tonically inhibits pituitary prolactin secretion and lactotroph proliferation. In addition, dopamine agonist therapy for pituitary prolactinomas results in reduction of prolactin secretion and tumor regression. These observations lead to the speculation that functional dopamine uncoupling may release lactotrophs from the inhibitory effects of dopamine and contribute to the development of prolactin (PRL)-secreting pituitary tumors. We hypothesized that such an uncoupling may occur by inactivating mutation(s) of the DRD2. To test our hypothesis, we examined 79 pituitary tumors, mostly prolactinomas and mixed GH/PRL-secreting, for mutations in the coding exons of the DRD2 gene. We used the polymerase chain reaction and analyzed the fragments for migration abnormalities on denaturing gradient gel electrophoresis, complemented by direct DNA sequencing. No mutations were demonstrated, and all migration abnormalities detected by denaturing gradient gel electrophoresis were due to polymorphisms within the DRD2 gene. In addition, allelic losses in the multiple endocrine neoplasia type 1 region in 11q13 could not be demonstrated in all five informative prolactinomas. We conclude that mutations in the DRD2 gene do not occur in PRL or GH/PRL-secreting pituitary tumors and that allelic loss of 11q13 is uncommon in prolactinomas.

Base Sequence↗
PubMed1994

The role of nm23 in transforming growth factor beta 1-mediated adherence and growth arrest.

nm23 has properties of a metastasis suppressor gene and also has been implicated in the control of response to transforming growth factor beta 1 (TGF beta 1) by studies in melanoma cells. In this report, we have examined the role of nm23 in two HT29 colon carcinoma sublines at different stages in tumor progression with different responses to TGF beta 1: the HD3 subline, which shows TGF beta 1-induced growth arrest and differentiation; and the more invasive and tumorigenic U9 subline, which induces tumors 7-fold as large as those induced by HD3 cells with one-half the latency. Analysis by semiquantitative reverse transcription-polymerase chain reaction showed that antisense phosphorothiolated oligonucleotides to the nm23 initiation site (nm23 AS oligos) decreased nm23 mRNA levels 2-8-fold in HD3 and U9 cells when normalized to beta-actin mRNA levels. However, a role for nm23 in TGF beta 1-mediated responses could only be found in HD3 cells. nm23 AS oligos inhibited the differentiation property of cell adherence over 90% in HD3 cells, and this loss of adherence could be partially blocked by concurrent treatment with TGF beta 1. In contrast, U9 cell adherence was not detectably altered by nm23 AS oligos, whether added in the presence or absence of TGF beta 1. The TGF beta 1-induced inhibition of HD3 cell proliferation was blocked by nm23 AS oligos, whereas the TGF beta 1-induced proliferation of U9 cells was unaffected by nm23 AS oligos.(ABSTRACT TRUNCATED AT 250 WORDS)

Base Sequence↗
PubMed1994

Localization and identification of the multiple endocrine neoplasia type 1 disease gene.

The familial and genetic nature of multiple endocrine neoplasia type 1 (MEN 1) syndrome was first pointed out by Wermer in 1954, who suggested that an autosomal dominant gene with high penetrance controls the trait. The clinical picture is variable, depending mainly on which glands are involved and whether the tumors hypersecrete symptom-causing hormones. The most frequent endocrinopathies are hyperparathyroidism, pancreatic-duodenal, and pituitary tumors. Other tumors are also seen more frequently than in the general population, e.g., adrenocortical and thyroid tumors, carcinoids, lipomas, and pinealomas.

Chromosome Mapping↗
PubMed1994

Increases in guanine nucleotide binding to striatal G proteins is associated with dopamine receptor supersensitivity.

The role of the regulatory guanine nucleotide binding proteins (G proteins) in the development of dopamine (DA) receptor supersensitivity was studied in striatal membranes from reserpine treated rats. [alpha-32P]GTP labeled two striatal proteins with molecular masses of 45 and 40 kD. These proteins were previously identified as alpha subunits of Gs and Gi/Go, respectively. Seven days of reserpine treatment caused a 43% increase in steady-state basal [alpha-32P]GTP binding to striatal G alpha s. Basal [alpha-32P]GTP binding to the 40-kD protein band was unchanged by reserpine treatment. Incubation of membranes with DA stimulated [alpha-32P]GTP binding to both protein bands. Although 10 microM DA stimulated guanine nucleotide binding to G alpha s and G alpha i/o in control tissue by 317% and 236%, respectively, the increases in [alpha-32P]GTP binding in the reserpine-treated animals were 482% (P < .01) and 366% (P < .01), respectively. A single injection of reserpine did not alter basal or DA-stimulated [alpha-32P]GTP binding. Repeated reserpine treatment also enhanced serotonin-induced stimulation of [alpha-32P]GTP binding to striatal G alpha i/o but not to G alpha s. However, carbachol-stimulated binding was unaffected by the treatment Reserpine treatment did not change membrane G alpha s, G alpha i/1/2 or G alpha o levels, as assessed by immunoblotting or by toxin-catalyzed ADP ribosylation. These results suggest that increases in both basal and receptor-mediated activations of G proteins are associated with the development of reserpine-induced striatal DA receptor supersensitivity. (ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

The capacity for growth stimulation by TGF beta 1 seen only in advanced colon cancers cannot be ascribed to mutations in APC, DCC, p53 or ras.

Human colon cancer development is associated with the accumulation of mutations and deletions in the suppressor genes DCC, APC and p53 and mutations in the dominant oncogene K-ras, with loss of wild type alleles. In earlier studies we had observed that about half of the resected human colon cancers placed into primary culture were growth stimulated by TGF beta 1. This group included the more advanced cancers which were either poorly differentiated primary-site cancers or metastases. In contract, the more differentiated colon cancers were inhibited or unaffected by TGF beta 1, indicating that a switch in response to TGF beta 1 occurs during colon cancer progression. Different sublines of the HT29 colon carcinoma cell line model the resected cancers, responding to TGF beta 1 by proliferation, inhibition or no growth modulation. The current study shows that while the poorly differentiated, TGF beta 1-stimulated sublines are most tumorigenic, all the sublines have the same spectrum of mutations: truncating mutations in both APC (adenomatous polyposis coli) alleles, no activated ras genes, mutated and thus overexpressed p53, and very low expression of DCC compared to normal colon cells. Genes other than the four already implicated in colon carcinoma evolution are responsible for the mitogenic response to TGF beta 1 found in the more advanced cancers.

Base Sequence↗
PubMed1994

Colon carcinoma cells switch their response to transforming growth factor beta 1 with tumor progression.

Transforming growth factor beta 1 (TGF-beta 1) switches from an inhibitor of tumor cell growth to a stimulator of growth and invasion during human colon carcinoma progression. We originally observed that metastatic colon carcinoma cells in primary culture responded to TGF-beta 1 by proliferation, whereas moderate to well-differentiated primary site colon carcinomas were growth inhibited by TGF-beta 1 (P. Schroy et al., Cancer Res., 50: 261-265, 1990). We then cloned several colon carcinoma cell lines which modeled these responses to TGF-beta 1 and expressed TGF-beta 1 (M. M. Hafez et al., Cell Growth & Differ., 1: 617-626, 1990; 3: 753-762, 1992). Two of these colon carcinoma cell lines, U9 and HD3, which activate approximately equal amounts of TGF-beta 1 and express equal amounts of TGF-beta receptors, are now used to compare the effects of TGF-beta 1 in modulating invasive behavior. The U9 cell line exhibits autocrine-positive growth regulation in vitro by TGF-beta 1, whereas the HD3 cell line shows the opposite response, autocrine-negative regulation. Blocking endogenous TGF-beta 1 with isotype-specific antibody inhibited U9 cell growth because autocrine TGF-beta 1 acts as a mitogen for U9 cells. In contrast, antibody to TGF-beta 1 stimulated HD3 cell proliferation because autocrine TGF-beta 1 inhibits growth of these cells. U9 cells were 13-fold more invasive in vitro through a collagen I layer than HD3 cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Signal transduction through extracellular signal-regulated kinase-like pp57 blocked in differentiated colon carcinoma cells having low levels of c-src kinase.

Basic fibroblast growth factor (FGF) induced a rapid increase in tyrosine phosphorylation of a 57-kDa cytoplasmic protein with functional myelin basic protein kinase activity and antigenic properties common to mitogen-activated kinases or extracellular signal-regulated kinases. Basic and acidic FGFs and the diacylglycerol diolein used the same signal transduction pathway to activate pp57. These FGFs, like diolein (Lee, H., Ghose-Dastidar, J., Winawer, S., and Friedman, E. (1993) J. Biol. Chem., 268, 5255-5263), increased the cellular concentration of long-chain diacylglycerols within the same short time period as they increased pp57 tyrosine phosphorylation. Both FGF and diolein increased phosphorylation of pp57 on the same V8 protease-generated fragments, suggesting a common pathway for the phosphorylation of pp57. FGF-induced signal transduction through pp57 mitogen-activated kinase led to cell growth in two undifferentiated colon carcinoma cell lines. In contrast, basic FGF neither increased tyrosine phosphorylation of pp57 nor increased cell growth in two colon goblet cell differentiated lines derived from the same parental line as the undifferentiated cells. Both goblet cell lines exhibited levels of protein-tyrosine kinase activity about one-fifth that of the undifferentiated lines. The decrease in tyrosine kinase activity was not due to down-regulation of FGF receptors or their tyrosine kinase activities. c-src kinase-specific activity was decreased 4-5-fold in both goblet cell lines, suggesting a role for c-src in pp57-mediated signal transduction.

CSK Tyrosine-Protein Kinase↗
PubMed1993

Managed care: where will your hospital fit in?

Despite unfulfilled predictions in the past, managed care has in recent years become a major form of health care delivery and financing, and could become the dominant form within a relatively short time. How will hospitals fit into a rapidly changing, managed care-driven delivery scenario? Beginning on page 18, Hospitals Contributing Editor Emily Friedman analyzes the current--and future--implications for the hospital field.

Data Collection↗