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Biomedical subjects

A Fishman

Publications and source records attributed to A Fishman.

At least 19 recordsLinked to original sources
PubMed2006

Impaired migration of trophoblast cells caused by simvastatin is associated with decreased membrane IGF-I receptor, MMP2 activity and HSP27 expression.

BACKGROUND: Statins inhibit 3-hydroxy-3-methylglutaryl coenzyme-A reductase, the rate-limiting enzyme of the mevalonate pathway, and are used successfully in the treatment of hypercholesterolaemia. Statins are contraindicated during pregnancy. Lately, we have shown that simvastatin has adverse affects on human first trimester placental explants' proliferation and migration. The objective of the present study was to investigate the molecules involved in mediating simvastatin's effect on trophoblast cell migration. We hypothesized that simvastatin attenuates insuline-like growth factor-I (IGF-I) receptor expression (involved in trophoblast motility), matrix metalloproteinase (MMP) activities, and heat shock protein 27 (HSP27) levels (whose mRNA is actively transcribed during trophoblast differentiation) in trophoblast cells thus consequently effecting their migration. METHODS: Human placental explants were cultured above a matrigel with/without simvastatin (10 microM) for 5 days. In this model, trophoblast migrates from the villi into the matrigel. Western-blot and immunohistochemistry served for analysing HSP27 expression. Immunohistochemistry was used for assessing IGF-I receptor localization. MMPs activity was assayed by gel zymography. RESULTS: Simvastatin reduced IGF-I receptor membranal expression, MMP2 activity and HSP27 expression in trophoblast cells (P < 0.05). CONCLUSIONS: The inhibitory effect of simvastatin on trophoblast cell migration is associated with a significant decrease in the tested molecules, which probably contributes to the impaired migration.

Blotting, Western↗
PubMed2006

Aromatase inhibitors reverse tamoxifen induced endometrial ultrasonographic changes in postmenopausal breast cancer patients.

OBJECTIVE: Aromatase inhibitors may decrease endometrial thickness in breast cancer patients previously having short-term tamoxifen treatment. There is a necessity to find out if aromatase inhibitors can also decrease endometrial thickness in patients previously treated with long-term tamoxifen treatment. METHODS: Prospective comparison of the last ultrasonographic endometrial thickness measurement taken before discontinuation of long-term tamoxifen treatment in 36 postmenopausal breast cancer patients, with further measurements, performed following aromatase inhibitors administration. RESULTS: There was a significant decrement of endometrial thickness, following 36.2 +/- 16.8 months of tamoxifen treatment, from a mean value of 9.1 +/- 5.8 mm, measured at the last ultrasonographic measurement performed before discontinuation of tamoxifen treatment, down to a mean value of 6.0 +/- 5.0 mm, measured following 5.8 +/- 5.8 months of aromatase inhibitors therapy (P = 0.001). A second ultrasonographic measurement performed in 8 patients following of additional 7.5 +/- 4.0 months of aromatase inhibitors treatment revealed further decrement of mean endometrial thickness to 4.8 +/- 2.1 mm (P = 0.002 compared to baseline). In 28 patients (77.8%), endometrial thickness was reduced following the administration of aromatase inhibitors, in four patients (11.1%) there was no change in endometrial thickness and four (11.1%) patients demonstrated an increase of endometrial thickness. CONCLUSIONS: Aromatase inhibitors may reverse endometrial thickening induced by long-term tamoxifen treatment in postmenopausal breast cancer patients.

Antineoplastic Agents, Hormonal↗
PubMed2006

Infertility, ovulation induction treatments and the incidence of breast cancer--a historical prospective cohort of Israeli women.

CONTEXT: Ovulation induction drugs may be associated with increased breast cancer risk. Results so far have been inconclusive. OBJECTIVE: To evaluate the association between infertility, exposure to ovulation induction drugs and the incidence of breast cancer. DESIGN: Historical prospective cohort and nested case-control study. SETTING: Institutional practice PATIENTS: About 5,788 women attending five infertility centers in Israel between 1964 and 1984. INTENTION: Abstracting of medical records and telephone interviews. MAIN OUTCOME MEASURE: Breast cancer incidence was determined through linkage with the National Cancer Registry database. Standardized incidence ratios (SIRs) and 95% confidence intervals were computed by comparing the observed to the expected cancer rates in the general population. In addition, a nested case-control study within the cohort was performed with interviews of breast cancer cases and two matched controls. RESULTS: The study cohort included 120,895 women years of follow-up. Compared to 115.2 expected breast cancer cases, 131 cases were observed (SIR = 1.1; 95% CI 0.9-1.4). Risk for breast cancer was significantly higher for women treated with clomiphene citrate (SIR = 1.4; 95% CI 1.0-1.8). Similar results were noted when comparisons were carried out between treated and untreated women, and when multivariate models were applied. In the nested case-control study, higher cycle index (OR = 2.2; 95% CI 1.0-4.8) and treatment with clomiphene citrate (OR=2.7; 95% CI 1.3-5.7) were associated with higher risk for breast cancer. CONCLUSION: Infertility and usage of infertility drugs in general are not associated with increased risk for breast cancer. However, for infertile women treated with clomiphene citrate, breast cancer risk is elevated.

Adult↗
PubMed2006

High incidence of BRCA1-2 germline mutations, previous breast cancer and familial cancer history in Jewish patients with uterine serous papillary carcinoma.

OBJECTIVE: To test the carrier status of the three germline founder mutations in Jewish patients with uterine serous papillary carcinoma (USPC) and to evaluate its association to their personal and familial cancer records. METHODS: Retrospective analysis of histologically confirmed USPC Jewish patients diagnosed between April 1, 1997 and December 31, 2003. All cases were genetically tested for the three BRCA1-2 founder germline mutations (185delAG and 5382insC in BRCA1 and 6174delT in BRCA2). The analysis was performed on genomic DNA extracted from whole blood or paraffin embedded normal tissue of these patients, employing PCR amplification of target sequences and differential digestion with restriction enzymes. The carrier frequency was compared to the known population frequency of these mutations. RESULTS: The study group comprised 22 Jewish patients with USPC diagnosed within this timeframe. The mean age was 71.8 years (range 56-79). FIGO surgical stage distribution revealed 59% at stages III-IV. Seven USPC patients (32%) with a previous diagnosis of breast cancer were identified. Familial cancer history was recorded in 23% of the patients (four with breast cancer and one with ovarian cancer). DNA analysis revealed six BRCA1-2 germline mutation carriers (27%) as follows: three with BRCA2-6174delT, two with BRCA1-185delAG, and one with BRCA1-5382insC mutation. Three of the carriers had a previous diagnosis of breast cancer. Four carriers had familial cancer history in first-degree relative (three with breast cancer and one with ovarian cancer). CONCLUSIONS: The high rate of BRCA germline mutations in USPC patients observed in the present study, coupled with the strong personal and familial cancer history as well as the histological and clinical resemblance to the ovarian cancer, may indicate that USPC is a part or an expression of the hereditary breast-ovarian cancer syndrome. This option may have implications in our clinical recommendations for non-affected BRCA1-2 carriers.

Aged↗
PubMed2005

A multicenter study of CA 125 level as a predictor of non-optimal primary cytoreduction of advanced epithelial ovarian cancer.

AIMS: To provide a large database of pre-operative CA 125 levels which may predict inappropriate cytoreductive surgery in patients with advanced epithelial ovarian cancer. METHODS: A multicenter review of the records of 424 patients with FIGO stage III and IV epithelial ovarian cancer of patients who underwent primary cytoreductive surgery was performed. The validity of pre-operative CA 125 level measurement as a single predictor of the possibility to achieve only suboptimal cytoreduction was evaluated by calculating the sensitivity and the specificity of various cut-off values. The relative importance of different cut-off values in achieving the best predictive validity was assessed by a receiver operating characteristics (ROC) curve. RESULTS: Optimal cytoreduction (largest diameter of residual tumour < or =1 cm) was achieved in 242 patients. The median CA 125 level in optimally cytoreduced patients was lower than in those patients suboptimally debulked (304 vs 863 U/mL; p<0.001). The area under the ROC curve was 0.65 (95% confidence interval, 0.60-0.71) and the CA 125 threshold derived from the ROC was 400 U/mL. The accuracy of the test at this level was 62%. CONCLUSIONS: The clinical applicability of the ROC derived CA 125 threshold is limited. The data accrued in the study provides a basis for decision-making regarding the place of primary surgery various CA 125 levels.

Biomarkers, Tumor↗
PubMed2005

ICSI outcome in patients with transient azoospermia with initially motile or immotile sperm in the ejaculate.

BACKGROUND: In patients with transient azoospermia, few sperm may be found in the ejaculate. We investigated the outcome of ICSI in patients with transient azoospermia. METHODS: Records of patients with transient azoospermia referred during a 42 month period were reviewed. If only immotile sperm were found, the sample was incubated with 30% human serum albumin (HSA) before motility re-assessment. If still immotile, mechanical assessment of sperm viability was utilized. Study groups were: (A) motile sperm; (B) motility achieved by HSA; (C) no motility, but viability assessed by a mechanical technique; and (D) control group with sperm counts from 1 to 5 x 10(6)/ml. There were 57 couples (cycles) in the study group and 43 couples (cycles) in the control group. RESULTS: Age, days of stimulation and endometrial thickness were comparable among groups. In 29.8% of the cycles, only immotile sperm were found. Fertilization and cleavage rates were higher in groups A and D than in groups B and C. Clinical pregnancy rate/cycle and live birth rate/cycle were not different among groups. No congenital malformations were found in newborns. CONCLUSION: Fertilization and cleavage rates were lower in patients with initially immotile sperm compared with those with initially motile sperm and oligoasthenoteratozoospermia patients. Clinical pregnancy and viable pregnancy rates were not statistically different among groups, although when only immotile sperm were present both clinical pregnancy and live birth rate were lower in comparison with cycles with motile sperm.

Ejaculation↗
PubMed2005

Simvastatin has deleterious effects on human first trimester placental explants.

BACKGROUND: Statins inhibit 3-hydroxy-3-methylglutaryl coenzyme-A reductase (HMG-CoA reductase), the rate-limiting enzyme of the mevalonate pathway, and have been used successfully in the treatment of hypercholesterolaemia. Animal models have provided evidence for the teratogenic effects of statins on pregnancy outcome. Thus statins are contraindicated during pregnancy. However, conflicting data are available from inadvertent use of statins in human pregnancy. Therefore we decided to explore the effects of simvastatin on the placenta in an in vitro human placental model. METHODS: Human first trimester placental explants that were grown on matrigel were exposed to medium supplemented with simvastatin. Migration of extravillous trophoblast cells was assessed by visual observation. Proliferative and apoptotic events of the trophoblast cells were assesed by immunohistochemical examination using anti-Ki67 and anti-activated caspase-3 antibodies respectively. Hormone levels were measured. RESULTS: Simvastatin sharply inhibited migration of extravillous trophoblast cells from the villi to the matrigel (P < 0.05). Moreover, simvastatin inhibited half of the proliferative events in the villi (P < 0.05) and increased apoptosis of cytotrophoblast cells compared to control. Moreover, simvastatin significantly decreased secretion of progesterone from the placental explants (P < 0.01). CONCLUSION: Simvastatin adversely affects human first trimester trophoblast.

Apoptosis↗
PubMed2005

The effect of 6-mercaptopurine on early human placental explants.

BACKGROUND: 6-mercaptopurine (6-MP) is an antineoplastic and immunosuppressive drug. Recently, more women have received this drug during pregnancy. Animal studies have shown that 6-MP has deleterious effects on the fetus, while human data include prematurity, intrauterine growth restriction, low birth weight and malformations that occur especially when the drug is administered in the first trimester of pregnancy. OBJECTIVES: To study the effects of 6-MP on cellular functions of human trophoblast explants. METHODS: Human placental explants (5.5-9 weeks gestational age), that were grown on matrigel, were exposed to medium containing 6-MP for 5 days. Medium alone served as control. Extravillous trophoblast (EVT) cell migration assessment was performed by visual observation. Analysis of proliferating events of the trophoblast cells was assessed by immunohistochemical examination. Apoptosis was analyzed by Tunnel procedure and by anti-caspase 3 staining and hormone level by enzyme-linked immunosorbent assay. RESULTS: 6-MP inhibited migration of EVT cells from the villi to the matrigel with a lower proliferation rate and increased apoptosis of cytotrophoblast cells compared to controls. However, no significant effect of 6-MP on hormone levels was observed. CONCLUSIONS: 6-MP inhibited migration and proliferation of trophoblast cells in first-trimester human placental explant culture.

Antimetabolites, Antineoplastic↗
PubMed2004

Three-dimensional first trimester fetal volumetry: comparison with crown rump length.

BACKGROUND: Ultrasonographic volumetry measurements of human fetus have become possible using three-dimensional ultrasound systems. OBJECTIVE: To evaluate the weekly increase of fetal volume during the first trimester of normal pregnancies compared to the crown rump length and creating a first trimester fetal volume nomogram. METHODS: Crown rump length and three-dimensional ultrasonographic volumetry measurements performed on 72 first trimester fetuses using virtual organ computer aided analysis (VOCAL). RESULTS: A significant direct correlation (r = 0.939) was found between the calculated fetal volumes and crown rump lengths. A 6-12 weeks gestation fetal volume nomogram was proposed. CONCLUSION: Fetal volume database in the first trimester may serve as a reference table for diagnosis of early pregnancy failure.

Anthropometry↗
PubMed2004

The value of sonohysterography in the prediction of endometrial pathologies in asymptomatic postmenopausal breast cancer tamoxifen-treated patients.

BACKGROUND: The study evaluated the efficacy of sonohysterography in identifying endometrial pathologies in asymptomatic postmenopausal tamoxifen (TAM)-treated patients by evaluating its performance characteristics. MATERIALS AND METHODS: Multiple assessments of sonohysterography evaluations of intrauterine mass diameter were evaluated by logistic regression analysis based on overall 85 patients (who had transvaginal ultrasonographic endometrial thickness of >/=8 mm) followed by hysteroscopy and endometrial histological findings. Performance characteristics were calculated with correlation to the endometrial histological findings. RESULTS: The mean endometrial thickness was 14.6 +/- 6.2 mm, and the mean intrauterine mass diameter detected by SIS was 11.6 +/- 10.4 mm. There was a gradual decrease in sensitivity and gradual increase in specificity of the SIS studies with the increase in intrauterine mass diameter. False-negative and false-positive of SIS were 2.4% and 8.2%, respectively. ROC curve analysis of intrauterine mass revealed 5 mm as the best accurate cutoff value for the diagnosis of endometrial pathologies, with a sensitivity of 74.1%, specificity of 93.0%, and positive predictive value of 88.3% and negative predictive value of 84.2%. The risk of endometrial pathology was elevated by 1.37-fold, with any additional millimeter of diameter of the intrauterine mass. The mean diameter of the intrauterine mass gradually increased the greater the severity of the histological findings. CONCLUSIONS: Sonohysterography improves the accuracy of diagnosis of intrauterine mass in asymptomatic postmenopausal tamoxifen-treated patients. The size of the intrauterine mass correlates with the severity of the endometrial pathology.

Aged↗
PubMed2004

The value of transvaginal ultrasonography in the prediction of endometrial pathologies in asymptomatic postmenopausal breast cancer tamoxifen-treated patients.

OBJECTIVE: There is no established ultrasonographic endometrial cutoff value for the diagnosis of endometrial pathologies in asymptomatic postmenopausal tamoxifen (TAM)-treated patients. We attempted to seek the most accurate cutoff value. MATERIALS AND METHODS: Multiple ultrasonographic cutoff points were evaluated by logistic regression analysis based on 279 patients who had transvaginal ultrasonographic examinations followed by endometrial histopathological analysis. Performance characteristics were calculated with correlation to the endometrial histological findings. We also calculated how many endometrial pathologies could have been left undiagnosed and the number of endometrial samplings, with different cutoff values, which could have been avoided. RESULTS: There was a gradual increase in specificity and a gradual decrease in sensitivity of the ultrasonographic studies with the increase of endometrial thickness. More overall and more various endometrial pathologies were identified with the increase in cutoff values. The best cutoff value appeared to be 15 mm (sensitivity 37.9%, specificity 87.2%, positive predictive value 63.0%, and negative predictive value 70.2%). However, by avoiding performance endometrial sampling up to this cutoff value, 62.2% endometrial pathologies including 48 endometrial polyps, one case of endometrial hyperplasia with atypia, and one case of endometrial cancer may have been left undiagnosed. At the same time, endometrial sampling in 78.5% of cases may have been avoided. CONCLUSION: In asymptomatic postmenopausal breast cancer tamoxifen-treated patients, the use of wider ultrasonographic endometrial cutoff values could be associated not only with the performance of fewer endometrial samplings, but also with a higher possibility of endometrial pathologies, including endometrial cancers, being left undiagnosed.

Antineoplastic Agents, Hormonal↗
PubMed2003

Application of comparative genomic hybridization technique for detection of chromosomal aberrations in benign cystic teratoma.

Benign cystic teratoma, also known as dermoid cyst, is the most common of all ovarian neoplasms accounting for 10%-20% of all ovarian cysts. Most have a normal 46,XX karyotype. Less than 2% can undergo malignant transformation. By using the comparative genomic hybridization technique on nine benign ovarian cysts we were able to show two cases with chromosomal aberrations not seen before in dermoid cysts but known to be involved in malignant ovarian tumors. We speculate that these are the tumors carrying the potential for malignant transformation.

Adult↗
PubMed2002

Effect of BRCA mutations on the length of survival in epithelial ovarian tumors.

PURPOSE: To study the role of BRCA mutations in ovarian cancer survival. PATIENTS AND METHODS: Blood samples and specimens of ovarian tumors (whenever blood samples were not available) at the time of the primary surgery were obtained in the course of a nationwide case-control study of women with ovarian cancer in Israel. The three common BRCA mutations in Israel (185delAG, 5382insC, and 6174delT) were analyzed with a multiplex polymerase chain reaction to amplify the exons containing the three mutations using fluor-labeled primers in a single reaction. Because each mutation is a small insertion or deletion, they can be detected as length polymorphisms. Patients were followed for up to 5 years (range, 20 to 64 months). Statistical analysis was performed using the Kaplan-Meier method and the log-rank test. Stepwise Cox regression analysis was used for determination of independent prognostic factors. RESULTS: This report is based on 896 blood or tumor specimens analyzed for the presence of the BRCA mutations. Of these, 234 women (26.1%) were found to be positive. A significant difference in survival pattern was found between BRCA1/BRCA2 carriers and noncarriers among the women with invasive ovarian cancer (median survival, 53.4 months v. 37.8 months; 3-year survival, 65.8% v. 51.9%, respectively). These differences were independent of age at diagnosis or stage of the disease. CONCLUSION: Our data indicate that the survival of patients with ovarian cancer is affected by BRCA germline mutation, at least in the early years after diagnosis.

Case-Control Studies↗
PubMed2001

A two-step enzymatic resolution process for large-scale production of (S)- and (R)-ethyl-3-hydroxybutyrate.

An efficient two-step enzymatic process for production of (R)- and (S)-ethyl-3-hydroxybutyrate (HEB), two important chiral intermediates for the pharmaceutical market, was developed and scaled-up to a multikilogram scale. Both enantiomers were obtained at 99% chemical purity and over 96% enantiomeric excess, with a total process yield of 73%. The first reaction involved a solvent-free acetylation of racemic HEB with vinylacetate for the production of (S)-HEB. In the second reaction, (R)-enriched ethyl-3-acetoxybutyrate (AEB) was subjected to alcoholysis with ethanol to derive optically pure (R)-HEB. Immobilized Candida antarctica lipase B (CALB) was employed in both stages, with high productivity and selectivity. The type of butyric acid ester influenced the enantioselectivity of the enzyme. Thus, extending the ester alkyl chain from ethyl to octyl resulted in a decrease in enantiomeric excess, whereas using bulky groups such as benzyl or t-butyl, improved the enantioselectivity of the enzyme. A stirred reactor was found unsuitable for large-scale production due to attrition of the enzyme particles and, therefore, a batchwise loop reactor system was used for bench-scale production. The immobilized enzyme was confined to a column and the reactants were circulated through the enzyme bed until the targeted conversion was reached. The desired products were separated from the reaction mixture in each of the two stages by fractional distillation. The main features of the process are the exclusion of solvent (thus ensuring high process throughput), and the use of the same enzyme for both the acetylation and the alcoholysis steps. Kilogram quantities of (S)-HEB and (R)-HEB were effectively prepared using this unit, which can be easily scaled-up to produce industrial quantities.

Acetylation↗
PubMed2001

Parity, oral contraceptives, and the risk of ovarian cancer among carriers and noncarriers of a BRCA1 or BRCA2 mutation.

BACKGROUND: Multiparity and the use of oral contraceptives reduce the risk of ovarian cancer, but their effects on this risk in women with a BRCA1 or BRCA2 mutation are unclear. METHODS: We conducted a population-based case-control study of ovarian cancer among Jewish women in Israel. Women were tested for the two founder mutations in BRCA1 and the one founder mutation in BRCA2 that are known to be common among Jews. We estimated the effects of parity and oral-contraceptive use on the risk of ovarian cancer in carriers and noncarriers in separate analyses that included all control women, who did not have ovarian cancer. RESULTS: Of 751 controls who underwent mutation analysis, 13 (1.7 percent) had a BRCA1 or BRCA2 mutation, whereas 244 of 840 women with ovarian cancer (29.0 percent) had a BRCA1 or BRCA2 mutation. Overall, each additional birth and each additional year of use of oral contraceptives were found to lower the risk of ovarian cancer, as expected. Additional births were protective in separate analyses of carriers and noncarriers, but oral-contraceptive use appeared to reduce the risk only in noncarriers; among carriers, the reduction in the odds of ovarian cancer was 12 percent per birth (95 percent confidence interval, 2.3 to 21 percent) and 0.2 percent per year of oral-contraceptive use (-4.9 to 5.0 percent). CONCLUSIONS: The risk of ovarian cancer among carriers of a BRCA1 or BRCA2 mutation decreases with each birth but not with increased duration of use of oral contraceptives. These data suggest that it is premature to use oral contraceptives for the chemoprevention of ovarian cancer in carriers of such mutations.

Adult↗
PubMed2001

Primary serous papillary carcinoma of the peritoneum: CT findings.

AIM: To describe the computed tomography (CT) findings of primary serous papillary carcinoma of the peritoneum. MATERIAL AND METHODS: The clinical data and imaging studies of 36 women aged 37-85 years with primary papillary serous carcinoma of the peritoneum were retrospectively evaluated. Twenty-seven patients presented with general abdominal complaints; all had elevated levels of CA-125. Thirty-two women were post-menopausal, four had had bilateral salpingo-oophorectomy. RESULTS: The most common findings on pre-operative abdominal CT, performed in 30 patients, were a variable amount of ascites (n = 29), omental involvement (n = 28), irregular parietal peritoneum thickening (n = 22) and mural thickening of the sigmoid colon (n = 10). Thoracic findings included enlarged cardiophrenic nodes (n = 15) and pleural effusion (n = 11). Six patients had unilateral or bilateral adnexal masses of soft tissue density, which proved to be surface serous papillary carcinoma. CONCLUSION: Diffuse peritoneal disease on CT in patients with normal-sized ovaries or following bilateral salpingo-oophorectomy, with elevated level of serum CA-125, but without an identifiable primary tumour, should suggest the diagnosis of primary serous papillary carcinoma of the peritoneum. Associated adnexal masses or focal bowel wall thickening may be seen, representing surface involvement by this tumour.

Adult↗