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Biomedical subjects

E Friedman

Publications and source records attributed to E Friedman.

At least 127 records · Page 7Linked to original sources
PubMed1999

Lack of the predominant BRCA1 and BRCA2 mutations in Jewish ovarian carcinoma patients who previously underwent ovulation induction.

The objective of the present investigation was to assess the presence of BRCA mutations in ovarian carcinoma patients who were previously treated with fertility drugs. The presence of the predominant Jewish BRCA1 and BRCA2 mutations in archival paraffin-embedded tumor tissue of four Jewish women with ovarian carcinoma who previously underwent ovulation induction with clomiphene citrate, was determined. None of the tissues contained the mutations examined. This preliminary finding does not support the assumption that the presence of BRCA1 and BRCA2 mutations in some infertility patients treated by fertility drugs could explain the subsequent development of epithelial ovarian cancer in these women.

Adult↗
PubMed1999

Differential responsiveness to autocrine and exogenous transforming growth factor (TGF) beta1 in cells with nonfunctional TGF-beta receptor type III.

The two major intestinal epithelial cell lineages are columnar fluid-absorbing cells and mucin-producing goblet cells. High levels of transforming growth factor (TGF) beta1 are found surrounding postmitotic cells in the colonic crypt, suggesting that TGF-beta1 mediates the maturation and growth inhibition of both epithelial cell types. However, we now show that the injection of recombinant TGF-beta1 into mice leads to an enrichment of goblet cells, indicating that these normal epithelial cells are resistant to TGF-beta1. In support of this interpretation, each of two independently isolated cell lines modeling normal colon goblet cells was also growth resistant to exogenous TGF-beta1 but made levels of TGF-beta receptor (TbetaR) I, TbetaRII, and TbetaIII mRNA and protein equal to those made by two TGF-beta1-sensitive cell lines. No mutations were found in the alk5 or alk2 forms of TbetaRI or in TbetaRII; these receptors were found on the cell surface, although they could not bind 125I-labeled TGF-beta1. TbetaRIII binds TGF-beta1, concentrates it, and presents it to TbetaRII. The major TbetaRIII form, betaglycan, did not undergo normal posttranslational modification in either of the goblet cell lines and could not bind 125I-labeled TGF-beta1; thus, it was nonfunctional. TGF-beta resistance was overcome by raising TGF-beta1 levels 100-fold, at which point TbetaRII could bind TGF-beta1. Signaling initiated by these higher TGF-beta1 levels was blocked by the expression of dominant negative TbetaRII, demonstrating that TbetaRII and TbetaRI were functional. Cells resistant to exogenous TGF-beta1 maintained functional cell surface TbetaRI and TbetaRII to mediate responses to autocrine TGF-beta1, which controlled the maturation of the adhesion protein integrin beta1. Expression of dominant negative TbetaRII in goblet cells greatly inhibited the conversion of the beta1 integrin from its precursor to its mature form. Thus, in normal intestinal epithelial goblet cells, TbetaRI and TbetaRII can respond to autocrine but not exogenous TGF-beta without the participation of TbetaRIII. Absorptive epithelial cells are growth inhibited by TGF-beta1 both in vivo and in vitro; therefore, the loss of functional TbetaRIIIs on goblet cells allows differential regulation of the two major intestinal epithelial cell types.

Activin Receptors, Type I↗
PubMed1998

Cost effectiveness of shortening screening interval or extending age range of NHS breast screening programme: computer simulation study.

OBJECTIVE: To compare the cost effectiveness of two possible modifications to the current UK screening programme: shortening the screening interval from three to two years and extending the age of invitation to a final screen from 64 to 69. DESIGN: Computer simulation model which first simulates life histories for women in the absence of a screening programme for breast cancer and then assesses how these life histories would be changed by introducing different screening policies. The model was informed by screening and cost data from the NHS breast screening programme. SETTING: North West region of England. MAIN OUTCOME MEASURES: Numbers of deaths prevented, life years gained, and costs. RESULTS: Compared with the current breast screening programme both modifications would increase the number of deaths prevented and the number of life years saved. The current screening policy costs 2522 pounds per life year gained; extending the age range of the programme would cost 2612 pounds and shortening the interval 2709 pounds per life year gained. The marginal cost per life year gained of extending the age range of the screening programme is 2990 pounds and of shortening the screening interval is 3545 pounds. CONCLUSIONS: If the budget for the NHS breast screening programme were to allow for two more invitations per woman, substantial mortality reductions would follow from extending the age range screened or reducing the screening interval. The difference between the two policies is so small that either could be chosen.

Age Factors↗
PubMed1998

Rates of Jewish ancestral mutations in BRCA1 and BRCA2 in borderline ovarian tumors.

BACKGROUND: Germline mutations in the BRCA1 and BRCA2 genes are known to be associated with an increased risk of breast and epithelial ovarian cancers. Two specific mutations, 185delAG-BRCA1 and 6174delT-BRCA2, have been detected in a substantial proportion (20%-60%) of unselected Ashkenazi Jewish patients--i.e., Jewish patients of Eastern/Northern European descent--with invasive ovarian cancer and in a measurable proportion (2%) of the general Ashkenazi Jewish population. However, uncertainty exists concerning the heritable basis of borderline ovarian tumors and whether these tumors represent an early form of ultimately invasive disease. To gain insight into these issues, we determined the rates of 185delAG-BRCA1 and 6174delT-BRCA2 mutations in patients with borderline ovarian tumors. METHODS: Analysis of 185delAG-BRCA1 and 6174delT-BRCA2 germline mutations was performed by use of a heteroduplex formation assay in samples from 46 consecutive patients with borderline ovarian tumors and 59 consecutive patients with invasive epithelial ovarian cancers. Forty-eight samples were also analyzed by restriction enzyme analysis for the presence of the 5382insC-BRCA1 mutation, a mutation detected in 2.2% of Ashkenazi Jewish patients with breast, but not ovarian, cancer. RESULTS: One (2.2%) of the 46 patient with borderline tumors was identified as a carrier of the 185delAG-BRCA1 mutation, and no patients were found to carry the 6174delT-BRCA2 mutation. Nineteen (32%) of the 59 patients with invasive ovarian cancer were found to carry one of these two mutations; 17 carried 185delAG-BRCA1 and two carried 6174delT-BRCA2 (chi2 test with continuity correction, P = .00028). None of the patients analyzed for 5382insC-BRCA1 were found to carry the mutation. In one high-risk family that included 185delAG-BRCA1 carriers, a single patient with stage IIIc borderline ovarian tumor did not carry the mutation. CONCLUSIONS: Invasive epithelial and borderline ovarian tumors appear to differ in their genetic predisposition and in the molecular mechanisms underlying their genesis.

Female↗
PubMed1998

Prenatal cocaine exposure alters signal transduction in the brain D1 dopamine receptor system.

Cocaine use during pregnancy may result in persistent behavioral abnormalities in the newborn. Animal studies show behavioral and neurochemical alterations in offspring that were exposed to cocaine prenatally. The monoamine neurons, including those containing dopamine, appear and become operational prenatally and mature during early postnatal life. It is therefore conceivable that exposure to cocaine during gestation may critically affect normal development and subsequently cause protracted postnatal neurochemical and behavioral changes. The data we obtained demonstrate that prenatal exposure to cocaine in the rabbit impairs signal transduction via the D1 but not the D2 dopamine receptor system. This is reflected in impaired dopamine-stimulated [35S]GTP gamma S binding to G alpha S without affecting binding of the nucleotide to G alpha I in both cortex and striatum of rabbit offspring. This selective reduction in D1 dopamine receptor-mediated activation of Gs protein increased in severity as the dose of cocaine administered to the pregnant dams was increased. Maximal impairment was observed after treatment with two daily injections of 3 mg/kg of cocaine HC1. The reduction in dopamine-stimulated GTP binding to G alpha s did not result from a decrease in concentration of membrane G alpha s protein or D1 dopamine receptors. The data also indicate that in utero cocaine exposure causes persistent uncoupling of the D1 dopamine receptors from their associated Gs protein which appears as early as gestational day 22 and persists to postnatal day 100. The reduction in D1 dopamine receptor-mediated signal transduction may be mediated by post-translational modifications of the D1 dopamine receptor or of Gs alpha such as phosphorylation, which result in altered coupling between these membrane components. The resultant attenuated D1 dopamine receptor-mediated signaling may ultimately underlie both long-lasting behavioral dysfunction and morphologic changes which are associated with prenatal cocaine exposure in the rabbit.

Animals↗
PubMed1998

[Experience at Sheba Hospital in oncogenetic counseling and genetic testing of women with a high risk for breast and ovarian cancer].

There is inherited predisposition to breast and ovarian cancer in 5-10% of all women with these diseases. Germline mutations in BRCA1 and BRCA2 presumably account for most of the genetically susceptible individuals. We summarize 2 years of experience in counseling and testing for inherited predisposition to these cancers. 597 women (from 320 families) have been evaluated since August 1995. 242 were evaluated for inherited predisposition to breast and ovarian cancer. One-third had clear-cut evidence of familial background. 74 families were of Ashkenazi origin; the age range of breast cancer was 30-35, of ovarian cancer 40-45. In 80% of families other cancers were also noted in first degree family members, including lung, colon, and prostate cancer and leukemia. Genetic testing revealed that 45% of affected and 25% of unaffected women were carriers of a mutation in BRCA1 or BRCA2: 67/90 185delAG (BRCA1), 12/90 6174delT (BRCA2), and 4/90 of 5382insC (BRCA1). In addition, a novel mutation in exon 11 of BRCA1 was detected, carried by 7/90 women. The experience gained in oncogenetic counseling and genetic testing for inherited cancer predisposition will eventually enable determining an optimal, rational therapeutic regimen in carriers of mutations.

Adult↗
PubMed1998

Effect of Fenoterol on PAF-induced lung edema in isolated and perfused rabbit lungs.

We have studied the effects of fenoterol on PAF-induced response in pulmonary circulation. We used 28 isolated and perfused rabbit lungs preparations: eight control preparations (CP), four vehicles preparations (VP), eight PAF preparations (PP) with two doses of PAF, one called low dose (LD = 0.5 microg/kg of weight) and the other high dose (HD = 1 microg/kg of weight) and eight Fenoterol preparations (FP) which we administered 0.05 mg of Fenoterol for 15 min, followed by a LD and HD of PAF. FP prevented elevation of pulmonary artery pressure (Ppa) as compared to PP, at LD of PAF: 12.615 (CI 95%: 8.57-20.885) versus 83.705 (CI 95%: 50.55-114.3) cm of water; and at HD of PAF: 19.38 (CI 95%: 11.235-28.94) versus 205.1 (CI 95%: 141.3-271) cm of water respectively. FP prevented the increase in fluid filtration rate (FFR) observed in PP at both doses of PAF LD: 0.765 (CI 95%: 0.07-3.385) versus 0.01 (CI 95%: -0.05-0.005) g/min; HD: 5.515 (CI 95%: 2.425-8.865) versus 0.03 (CI 95%: 0-0.33) g/min. Our results suggest that PAF has a vasoconstrictor effect that produces lung edema and this effect is inhibited by fenoterol.

Adrenergic beta-Agonists↗
PubMed1998

Immunohistochemical analysis of rasGTPase activating protein (rasGAP) in prostate cancer.

The ras protooncogene plays a key role in the signal transduction cascade of activated growth factors, and is known to be activated or overexpressed in multiple tumor types, including prostate cancer. rasGTPase activating protein (rasGAP), a major downregulator of ras activity, has been shown to be underexpressed in human trophoblastic tumors, and presumably acts as a tumor suppressor gene product in these neoplasms. To assess the role that rasGAP plays in the development of prostate cancer, we performed immunohistochemical analyses with anti rasGAP antibodies of 125 human prostate tumors from Israel. Staining results were correlated with Gleason grade. In the majority of tumors (99/125-79%) there was either no staining or the tumor and surrounding benign glands had a similar pattern of staining. In up to 16% of the tumors, cytoplasmic, tumor-specific loss of expression was noted, presumably indicative of the role of rasGAP as a tumor suppressor gene. Unexpectedly, in up to 21% of the tumors, nuclear staining was demonstrated, and in about 20% of these, there was an accompanying loss of expression in the non neoplastic cytoplasm. Neither cytoplasmic nor nuclear staining correlated with Gleason grade. These findings of nuclear staining by anti-rasGAP are intriguing, since it is the first time that nuclear translocation of rasGAP is demonstrated, which might indicate that in this subset of tumors, rasGAP acts as a direct acting oncogene. The data indicate that rasGAP may play a dual regulatory role in prostate proliferation and that nuclear expression of it may be associated with malignant transformation of these cells.

Adenocarcinoma↗
PubMed1998

An identical novel mutation in BRCA1 and a common haplotype in familial ovarian cancer in non-Ashkenazi Jews.

Unique germline mutations in BRCA1 and BRCA2 account for inherited predisposition to breast and ovarian cancer in high-risk families. In Jewish high-risk individuals of Ashkenazi (east European) descent, three predominant mutations, 185delAG and 5382insC (BRCA1) and 6174delT (BRCA2), seem to account for a substantial portion of germline mutations, and two of these mutations (185delAG and 6174delT) are also found at about 1% each in the general Jewish-Ashkenazi population. We identified a novel BRCA1 mutation in two Jewish-non-Ashkenazi families with ovarian cancer: a thymidine to guanidine alteration at position 3053, resulting in substitution of tyrosine at codon 1017 for a stop codon (Tyr1017Ter). The mutation was first detected by protein truncation test (PTT) and confirmed by sequencing and a modified restriction digest assay. Allelotyping of mutation carriers using intragenic BRCA1 markers revealed that the haplotype was identical in these seemingly unrelated families. No mutation carrier was found among 118 unselected Jewish individuals of Iranian origin. Our findings suggest that this novel mutation should be incorporated into the panel of mutations analysed in high-risk families of the appropriate ethnic background, and that the repertoire of BRCA1 mutations in Jewish high-risk families may be limited, regardless of ethnic origin.

Adult↗
PubMed1998

Involvement of platelet-activating factor in cell death induced under ischemia/postischemia-like conditions in an immortalized hippocampal cell line.

The involvement of platelet-activating factor (PAF) in cell damage induced by ischemia/postischemia-like conditions was studied in a hippocampus-derived cell line, HN33.11. Cells exposed to N2-saturated glucose-free HEPES-buffered saline (ischemia) for 5 h followed by 18 h of incubation in serum-free control medium (postischemia reincubation) remained 67.4 +/- 2.4% viable in comparison with sham-treated cells. Analysis of DNA fragmentation in combination with Hoechst 33258 staining indicates that apoptosis is the dominant mode of cell death in the present model. PAF level during 10 h of ischemia was unchanged. However, an increase in PAF accumulation was found early during the reincubation period that followed 5 h of ischemia. Peak PAF concentrations were noted at 2 h after initiation of reincubation and rapidly declined to control level after 7 h of reincubation. Consistent with a role of PAF in mediating cell death under ischemia/postischemia reincubation in this model, the PAF antagonist BN 50739 exerted a dose-dependent protective effect. Maximal protection (85.7 +/- 5.4%) of the cells from ischemia/reincubation-induced cell damage was achieved at 0.1 microM BN 50739. The PAF antagonist lacked any protective effect against ischemia-induced cell death. On the other hand, the addition of the stable PAF analogue 1-O-hexadecyl-2-N-methylcarbamyl-sn-glycero-3-phosphocholine (MC-PAF) at the onset of ischemia potentiated ischemia/reincubation-induced apoptosis--an effect that was blocked by BN 50739. Pretreatment of HN33.11 cells with the Ca2+ chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N,N-tetraacetic acid acetoxymethyl ester (BAPTA-AM) also provided a protective effect against ischemia/reincubation-induced cell damage. BAPTA-AM increased cell viability by 50%. Pretreatment with BAPTA-AM also decreased ischemia/reincubation-induced PAF accumulation in HN33.11 cells. The results suggest that PAF, acting via a PAF receptor, is at least in part mediating apoptosis under ischemia/postischemia-like conditions in HN33.11 cells.

Azepines↗
PubMed1998

Characterization of the phosphoinositide-linked dopamine receptor in a mouse hippocampal-neuroblastoma hybrid cell line.

Previous studies have established that dopamine (DA) can stimulate phosphoinositide (PI) metabolism in the CNS and in the periphery. The present study summarizes our attempt to find a cell line that expresses this dopaminergic system. We describe that the stable clonal HN33.11 cell line, established by fusion of mouse hippocampal cells with neuroblastoma cells (N18TG2) that originate from A/J mouse, natively expresses the D1 DA receptor system that couples to PI hydrolysis. In this cell line, 500 microM DA or SKF38393 produced 43 and 75% increases in inositol phosphate (IP) accumulations, respectively. In contrast, noradrenaline or 5-hydroxytryptamine did not affect IP accumulations. The formation of IP that was stimulated by DA or SKF38393 was selectively blocked by the D1 DA receptor antagonist SCH23390 with IC50 values of 13 and 16 microM. This response was not mediated by the D1A DA receptor and was cyclic AMP-independent, as HN33.11 cells did not express this receptor, and DA or SKF38393 was unable to stimulate the formation of cyclic AMP. In Ca2+-free/100 microM EGTA medium, basal IP level was reduced by 31.5%, but SKF38393-stimulated PI hydrolysis was not affected. SKF38393-stimulated IP accumulation was also not affected by pertussis toxin (PTX) treatment (200 ng/ml), suggesting that this dopaminergic response is mediated by PTX-insensitive G proteins. Co-immunoprecipitation studies indicated that in membranes of HN33.11 cells, D1-like binding sites are coupled to G alpha(q) protein. Blockade of SKF38393-induced PI hydrolysis with antiserum against phospholipase C (PLC) isozymes, performed in permeabilized cells, as well as co-immunoprecipitation studies implicate PLCbeta3 and PLCbeta4 in this dopaminergically mediated PI hydrolysis cascade. The results indicate that HN33.11 cells express a D1-like DA receptor that couples to PLCbeta3/4 via G alpha(q) protein. These cells may therefore be a useful model system for investigating this receptor system.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1998

The 185delAG BRCA1 mutation originated before the dispersion of Jews in the diaspora and is not limited to Ashkenazim.

The 185delAG mutation in BRCA1 is detected in Ashkenazi Jews both in familial breast and ovarian cancer and in the general population. All tested Ashkenazi mutation carriers share the same allelic pattern at the BRCA1 locus. Our previous study showed that this 'Ashkenazi' mutation also occurs in Iraqi Jews with a similar allelic pattern. We extended our analysis to other non-Ashkenazi subsets: 354 of Moroccan origin, 200 Yemenites and 150 Iranian Jews. Heteroduplex analysis complemented by direct DNA sequencing of abnormally migrating bands were employed. Four of Moroccan origin (1. 1%) and none of the Yemenites or Iranians was a carrier of the 185delAG mutation. BRCA1 allelic patterns were determined for four of these individuals and for 12 additional non-Ashkenazi 185delAG mutation carriers who had breast/ovarian cancer. Six non-Ashkenazi individuals shared the common 'Ashkenazi haplotype', four had a closely related pattern, and the rest ( n = 6) displayed a distinct BRCA1 allelic pattern. We conclude that the 185delAG BRCA1 mutation occurs in some non-Ashkenazi populations at rates comparable with that of Ashkenazim. The majority of Jewish 185delAG mutation carriers have a common allelic pattern, supporting the founder effect notion, but dating the mutation's origin to an earlier date than currently estimated. However, the different allelic pattern at the BRCA1 locus even in some Jewish mutation carriers, might suggest that the mutation arose independently.

Adult↗
PubMed1998

Effect of aging on A1-adenosine receptor-mediated inhibition of norepinephrine release in the rat heart.

Adenosine inhibits norepinephrine (NE) release from cardiac adrenergic nerves and reduces the postsynaptic beta-adrenergic mediated actions of NE, leading to decreased myocardial force of contraction. The actions of adenosine are mediated by pre- and postsynaptic adenosine A1 receptors (A1-AdoR). We reported that adenosine inhibition of postsynaptic beta-adrenergic receptor-mediated cyclic adenosine monophosphate (cAMP) production declines with age in male F344 rat hearts. In this study, cardiac synaptosomes, isolated intact adrenergic nerve terminals, were used to examine the effect of age on adenosine inhibition of NE release. Cardiac synaptosomes were prepared from the hearts of 6- and 24-month-old male F344 rats, loaded with [3H]NE, and placed in a superfusion system. [3H]NE release was induced by high [K+] exposure in the presence of varying concentrations of adenosine or the specific A1-AdoR agonist, N6-p-sulfophenyladenosine (SPA). [3H]NE release was significantly reduced in old rats compared with young rats. Inhibition of [3H]NE release by adenosine and SPA was significantly greater in young rats compared with old rats. The A1-AdoR antagonist, 8-(p-sulfophenyl)-theophylline, blocked the actions of adenosine on [3H]NE release, and the specific adenosine A2-receptor agonist, cyclopropylcarboxamidoadenosine, had no effect on [3H]NE release. Our data suggest that presynaptic A1-AdoR-mediated inhibition of NE release in the rat heart declines with age.

Adenosine↗