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E Friedman

Publications and source records attributed to E Friedman.

At least 361 records · Page 20Linked to original sources
PubMed1989

Tyrosine phosphorylation of a Mr 63,000 protein induced by an endogenous mitogen in human colon carcinoma cells, but not in normal colonocytes.

Transformation of normal human colonocytes makes them sensitive to new mitogenic signals. Long-chain diglycerides (LCDGs) found in the human colon are mitogens selective for colon tumor cells, inducing mitogenesis in premalignant cells from each of 13 adenomas and in malignant cells from two of four carcinomas, but having no mitogenic effects on normal colonocytes (E. Friedman, P. Isaksson, J. Rafter, B. Marian, S. Winawer, and H. Newmark, Cancer Res., 49:544-548, 1989). Parallel to this biological activity pattern, LCDGs induce protein phosphorylation only in adenomas and carcinomas. Immunoblotting with an anti-phosphotyrosine monoclonal antibody demonstrated that the LCDG dimyristin, at concentrations found within the body, induced a 6-fold increase of tyrosine phosphorylation of an Mr 63,000 protein found in the particulate fraction of colon carcinoma cells. Tyrosine phosphorylation was maximal 0.5 min after addition of the LCDG, then fell, but remained elevated 40% over constitutive levels for at least 6 h. The Mr 63,000 tyrosine phosphoprotein was found in each of four colon carcinoma cell lines and an adenoma, but not in normal colonocytes, suggesting that the tyrosine kinase is activated only in tumor cells. Constitutive levels of the Mr 63,000 substrate were enhanced 2-fold by incubation of cells for 20 h with sodium orthovanadate, a tyrosine phosphatase inhibitor. This result suggested that carcinoma cells continually phosphorylate and dephosphorylate this tyrosine kinase substrate during growth. Thus, the colon tumor cell mitogen, dimyristin, utilizes a signal transduction pathway, containing the Mr 63,000 tyrosine kinase substrate, which is already in use during cell growth, possibly by other mitogens or growth factors.

Carcinoma↗
PubMed1989

Clonality of parathyroid tumors in familial multiple endocrine neoplasia type 1.

Familial multiple endocrine neoplasia type 1 (MEN-1) is characterized by tumors of the parathyroids, endocrine pancreas, and anterior pituitary. Since the gene associated with MEN-1, located on chromosome 11 (11q13), may normally inhibit tumor proliferation, tumors could arise from inactivation of one or both of the alleles. However, parathyroid tumors in patients with MEN-1 have been considered to result from polyclonal hyperplasia. Using genetic probes, we tested parathyroid tumors for a monoclonal component, represented by a loss of alleles at any of eight loci along chromosome 11. Ten of 16 tumors from 14 patients with familial MEN-1 had losses of alleles from chromosome 11. Tumors with losses were larger than those without (1.6 vs. 0.2 g; P less than 0.002), suggesting that a monoclonal adenoma may develop after a phase of polyclonal hyperplasia. In 7 of 10 tumors, the subregion of loss was less than the full length of chromosome 11 but always included one copy of the MEN-1 locus. Of 34 sporadic adenomas from patients without MEN-1, 9 showed similar allelic losses in chromosome 11; in 7 the losses included the apparent MEN-1 locus. We conclude that many "hyperplastic" parathyroid tumors in familial MEN-1 are in fact monoclonal and may progress or even begin to develop by inactivation of the MEN-1 gene (at 11q13) in a precursor cell. Some sporadic adenomas have allelic losses on chromosome 11, which may also involve the MEN-1 gene.

Adenoma↗
PubMed1989

Heterogeneity in the response of familial polyposis epithelial cells and adenomas to increasing levels of calcium in vitro.

A biomarker of increased risk for colon cancer is abnormally high proliferation of colonic epithelial cells. The authors developed an in vitro assay that measures the ability of human colonic epithelial cells that are in progressive stages of abnormal development to respond to direct application of calcium as the chloride in tissue culture medium. Incorporation of 3H-thymidine and autoradiography in situ was employed to measure the number of proliferating cells cultured at 0.1 mM CaCl2, the optimum level for growth, and 2.2 to 5 mM, both levels achievable in the colonic lumen. Abnormal cell proliferation was reduced in biopsies from 13 of 14 patients without familial polyposis but at increased risk for colon cancer because of previous colonic neoplasms or familial association; in cells from three of four asymptomatic individuals in familial polyposis families at risk for that disease; and in cells of three of ten patients symptomatic with familial polyposis. Growth of tubular adenoma cells from two of seven familial polyposis patients was also inhibited by calcium. Growth inhibition was not observed in more advanced colon tumors including eight adenomas, either villotubular or villous, and five carcinomas. These findings indicate heterogeneity within the familial polyposis phenotype for the normal cellular response to growth inhibition by calcium, and a further loss of response to calcium as these cells progress toward malignancy.

Adenoma↗
PubMed1989

Fecal diglycerides as selective endogenous mitogens for premalignant and malignant human colonic epithelial cells.

Diglycerides (DGs) have been found in fecal extracts at concentrations which induce mitogenesis of adenoma and some carcinoma cells but not normal cells in primary culture. DGs containing stearic, oleic, palmitic, and myristic acid side chains were found in fecal extracts from each of eight subjects. Synthetic 1,2-DGs, containing the fatty acids found in endogenous fecal DGs, induced mitogenesis in cultures of premalignant cells from each of 13 adenomas, covering all histological classes, and in cultures from two of four carcinomas. The potent adenoma mitogen, dimyristin, had no mitogenic activity on cultures of normal colonic epithelial cells from seven different subjects. These results suggest DGs may act as endogenous mitogens in the development of human colon cancer. The extent of adenoma mitogenesis was correlated with the chain length of the saturated R-groups: 16 greater than 14 greater than 12 greater than 10 greater than 8 much greater than 18. DGs with oleic acid residues, C18:1, were among the most active, while substitution of even one fatty acid residue with a stearic acid residue, C18:0, reduced or eliminated mitogenic activity. Dimyristin also induced enhanced levels of urokinase secretion from carcinoma cells, in parallel to the phorbol ester tumor promoter, 12-O-tetradecanoylphorbol-13-acetate. These results imply that DGs found in the colon induce a selective growth of benign colonic tumors and some carcinomas, and may enhance the invasive capacity of carcinomas, while leaving normal cells unaffected.

Adenoma↗
PubMed1989

Detection and surveillance of colorectal cancer.

Colorectal cancer is the second most common cause of cancer in the United States. The overall mortality rate approaches 60%. However, the detection of early lesions results in a mortality rate of 20% or less. Therefore, if improvement in survival is to occur, increased efforts need to be focused not only on primary prevention but also on early detection of malignant lesions and the eradication of potentially malignant lesions. There is no universal consensus as to how this can be accomplished. The purpose of this article is to serve as a guideline, providing a practical basis for improving early detection and management of colorectal cancer and its precursors.

Adult↗
PubMed1989

Thiazide-induced hyponatremia. Reproducibility by single dose rechallenge and an analysis of pathogenesis.

STUDY OBJECTIVE: To determine whether a single-dose of thiazide administered to patients with previous thiazide-induced hyponatremia will cause hyponatremia and, if so, to analyze its pathogenesis. DESIGN: Prospective controlled study comparing patients with previous thiazide-induced hyponatremia with two control groups. PATIENTS AND CONTROLS: Eleven patients with thiazide-induced (Kaluril [hydrochlorothiazide, 50 mg; amiloride, 5 mg]) hyponatremia of less than 130 mmol/L at least 1 week before the study. Two groups of controls: 10 young healthy volunteers and 11 elderly hypertensive patients previously treated uneventfully with thiazide. INTERVENTIONS: Administration of a single dose of hydrochlorothiazide, 50 mg, and amiloride, 5 mg. MEASUREMENTS: Blood pressure, pulse rate, body weight, serum urea, creatinine, sodium, potassium, magnesium, osmolality, plasma antidiuretic hormone, renin, aldosterone and also urinary sodium, potassium, osmolality, and cyclic adenosine monophosphate (cAMP) before and 6 to 8, 12, and 24 hours after drug administration. RESULTS: Within 6 to 8 hours serum sodium decreased in patients, young controls, and elderly controls by 5.5 +/- 1.1 (mean +/- SE), 1.2 +/- 0.4, and 1.8 +/- 0.9 mmol/L, respectively (Py less than 0.001 [patients versus young controls], Pe = 0.017 [patients versus elderly controls]). Serum osmolality decreased in patients, young controls, and elderly controls by 14.9 +/- 2.6, 2.8 +/- 1.6, and 6.6 +/- 1.5 mmol/kg, respectively (Py less than 0.001, Pe = 0.012). All patients and only one control subject reached osmolality of less than 280 mmol/kg. At 6 to 8 hours all patients gained weight (0.85 +/- 0.13 kg) whereas young and elderly controls lost weight (0.47 +/- 0.23 and 0.45 +/- 0.2 kg, respectively) (Py much less than 0.001, Pe much less than 0.001). Patients' responses to the drug did not differ from both control groups regarding sodium and potassium urinary excretion, osmolar and free water clearance, and antidiuretic hormone blood levels. Water restriction in one patient attenuated serum sodium reduction. CONCLUSIONS: Use of a single-dose of a thiazide diuretic may predict the development of hyponatremia. Increased body weight apparently due to polydipsia may play a major role in the pathogenesis of thiazide-induced hyponatremia.

Adult↗
PubMed1989

Colonic epithelial cell proliferation in responders and nonresponders to supplemental dietary calcium.

Supplemental dietary calcium decreased and normalized hyperproliferation of colonic epithelial cells in individuals in familial colon cancer kindreds, measured by rates and patterns of [3H]thymidine labeling of epithelial cells in colonic crypts. In whole colonic crypts hyperproliferation was decreased to lower levels in over one-half of the subjects individually studied during the course of the calcium supplementation regimen. The remaining familial colon cancer subjects did not show reductions in cell proliferation measured over the whole crypt. However, when their cell-labeling data were analyzed in regions of the colonic crypt, the size of the proliferative compartment decreased and contracted towards the crypt base after calcium, a pattern typical of individuals at decreased risk for colonic cancer. This contraction of the proliferative region of the crypts occurred through decreased cell labeling in the two crypt compartments closest to the luminal surface and increased cell labeling in the second crypt compartment nearest to the base of the crypt. Following in vitro exposure of colonic epithelial cells to increasing physiological amounts of calcium, cell proliferation in familial colon cancer subjects decreased uniformly and greater heterogeneity in responsiveness was observed in cells from individuals with familial polyposis.

Adenomatous Polyposis Coli↗
PubMed1989

Lithium inhibition of protein kinase C activation-induced serotonin release.

The effect of lithium on protein kinase C (PKC) stimulation-induced serotonin and norepinephrine release facilitation was examined in [3H]5-HT and [3H]NE preloaded superfused rat brain slices. The facilitation of K+-evoked [3H]5-HT release elicited by the active phorbol esters PMA and PDBu was inhibited by 4 mM but not by 1 mM in vitro lithium. In experiments performed in cortical, hippocampal and hypothalamic slices obtained from animals treated for 3 weeks with lithium-containing diet, PMA-induced facilitation of K+-elicited [3H]5-HT release was found to be inhibited by the treatment (serum lithium less than 1 mEq/l). Basal [3H]5-HT efflux, which was enhanced by PMA in control animals, was also inhibited by lithium treatment. In parietal cortical slices, PMA elicited increase in K+-evoked [3H]NE release was prevented in slices taken from lithium-treated (3 weeks) animals. Lithium treatment did not affect the activity and distribution of protein kinase C in cortical tissue. However, 3 weeks of treatment reduced the PMA-induced translocation of the enzyme. These results suggest that lithium treatment interferes with serotonin and norepinephrine release facilitation which results from the stimulation of PKC by phorbol esters. These actions of the ion may be mediated by its ability to inhibit PMA induced PKC translocation.

Animals↗
PubMed1989

Increased scleral rigidity and age-related macular degeneration.

The coefficient of scleral rigidity of the eyes of 29 patients with age-related macular degeneration (ARMD) was significantly higher than the rigidity of 25 control patients, frequency matched for age. The data suggest that an increased scleral rigidity may be a significant risk factor for the development of the disorder.

Aged↗
PubMed1989

Comparison of the computed structures for the phosphate-binding loop of the p21 protein containing the oncogenic site Gly 12 with the X-ray crystallographic structures for this region in the p21 protein and EFtu. A model for the structure of the p21 protein in its oncogenic form.

The GTP-binding p21 protein encoded by the ras-oncogene can be activated to cause malignant transformation of cells by substitution of a single amino acid at critical positions along the polypeptide chain. Substitution of any non-cyclic L-amino acid for Gly 12 in the normal protein results in a transforming protein. This substitution occurs in a hydrophobic sequence (residues 6-15) which is known to be involved in binding the phosphate moities of GTP (and GDP). We find, using conformational energy calculations, that the 6-15 segment of the normal protein (with Gly 12) adopts structures that contain a bend at residues 11 and 12 with the Gly in the D* conformation, not allowed energetically for L-amino acids. Substitution of non-cyclic L-amino acids for Gly 12 results in shifting this bend to residues 12 and 13. We show that many computed structures for the Gly 12-containing phosphate binding loop, segment 9-15, are superimposable on the corresponding segment of the recently determined X-ray crystallographic structure for residues 1-171 of the p21 protein. All such structures contain bends at residues 11 and 12 and most of these contain Gly 12 in the C* or D* conformational state. Other computed conformations for the 9-15 segment were superimposable on the structure of the corresponding 18-23 segment of EFtu, the bacterial chain elongation factor having structural similarities to the p21 protein in the phosphate-binding regions. This segment contains a Val residue where a Gly occurs in the p21 protein. As previously predicted, all of these superimposable conformations contain a bend at positions 12 and 13, not 11 and 12. If these structures that are superimposable on EFtu are introduced into the p21 protein structure, bad contacts occur between the sidechain of the residue (here Val) at position 12 and another phosphate binding loop region around position 61. These bad contacts between the two segments can be removed by changing the conformation of the 61 region in the p21 protein to the corresponding position of the homologous region in EFtu. In this new conformation, a large site becomes available for the binding of phosphate residues. In addition, such phenomena as autophosphorylation of the p21 protein by GTP can be explained with this new model structure for the activated protein which cannot be explained by the structure for the non-activated protein.

Cell Transformation, Neoplastic↗
PubMed1989

Elevated platelet MAO is related to impulsivity in disruptive behavior disorders.

Platelet monoamine oxidase (MAO) activity was measured in 32 drug-free prepubertal boys with externalizing symptoms of disruptive behavior disorders and 47 boys with no DSM-III-R diagnoses, and correlated to questionnaire and laboratory performance measures of impulsivity. A subgroup of boys with high MAO activity exhibited significantly poorer performance (i.e., more impulsivity) than a subgroup of low MAO activity on laboratory tasks requiring response inhibition. High MAO patients were more impulsive than high MAO controls on some performance tasks and elevated platelet MAO was unrelated to personality questionnaire measures of impulsivity or to patient status. These data suggest that biological markers such as MAO activity may correlate better with performance than clinical questionnaire measures. Abnormally high platelet MAO activity may not be sufficient to produce externalizing symptoms in children, perhaps interacting with an underlying behavioral dimension of impulsivity.

Attention Deficit Disorder with Hyperactivity↗
PubMed1989

The effect of exogenous lymphokines on immunoglobulin production and lymphocyte proliferation in renal transplant patients.

Peripheral blood mononuclear cells from stable long-term kidney transplant patients were activated in vitro by Staphylococcus Aureus Cowan I (SAC) (a B cell mitogen). The effect of exogenous interleukin 2 and/or B cell growth factor (BCGF) on these cells was measured by 3H-thymidine incorporation and immunoglobulin production. Both proliferation and Ig production were lower in SAC-activated cells from transplanted patients compared to controls (P less than 0.01). BCGF significantly enhanced blastogenesis (P less than 0.01) and Ig production (P less than 0.01) in SAC-treated cells from either patients or controls; however, the SAC- and BCGF-treated cells of transplant patients did not reach normal proliferation or immunoglobulin production values (P less than 0.001, P less than 0.01, respectively). The addition of IL-2 to SAC-activated cells also increased proliferation and Ig production both in controls (P less than 0.05) and patients (P less than 0.005). However, cells from transplant patients treated with SAC and IL-2 did not reach the normal levels of proliferation or immunoglobulin production (P less than 0.05 for both). IL-2 did not enhance the increase of immunoglobulin production brought about by BCGF. SAC-activated B cells from transplant patients do not proliferate normally and do not produce normal amounts of Ig. The addition of IL-2 and BCGF results in a partial but subnormal improvement in both proliferation and Ig production. We conclude that the B cell abnormality in transplant patients may be due to lack of T cell lymphokines and an intrinsic B cell defect. These results suggest that the administration of exogenous lymphokines to transplant patients with B cell dysfunction may be clinically useful.

Adult↗