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S M Cohen

Publications and source records attributed to S M Cohen.

At least 73 records · Page 4Linked to original sources
PubMed1999

Immunohistochemical analysis of uroplakins, urothelial specific proteins, in ovarian Brenner tumors, normal tissues, and benign and neoplastic lesions of the female genital tract.

Uroplakins are the characteristic integral membrane proteins in terminally differentiated, superficial urothelial asymmetric unit membrane. Brenner tumors of the ovary and Walthard cell nests of Fallopian tubes have been considered to represent urothelial differentiation in the female genital tract, but no definitive differentiation marker has been demonstrated supporting such a conclusion. An immunohistochemical analysis was performed to assess the expression of uroplakins in these lesions as well as in various benign and neoplastic lesions and normal tissues of the female genital tract. Focal expression of uroplakins was observed on the luminal surface of ovarian Brenner tumor cells forming microcysts in all 5 cases examined. In contrast, uroplakins were slightly expressed in only 1 of 12 cases of Walthard cell nests, even in the presence of microcyst formation. Uroplakins were not expressed in other benign or malignant lesions or normal tissues of the female genital tract. These results support the hypothesis that the Brenner tumor and possibly Walthard cell nests represent urothelial (transitional cell) differentiation.

Brenner Tumor↗
PubMed1999

Notch signaling is not sufficient to define the affinity boundary between dorsal and ventral compartments.

The developing limbs of Drosophila are subdivided into distinct cells populations known as compartments. Short-range interaction between cells in adjacent compartments induces expression of signaling molecules at the compartment boundaries. In addition to serving as the sources of long-range signals, compartment boundaries prevent mixing of the adjacent cell populations. One model for boundary formation proposes that affinity differences between compartments are defined autonomously as one aspect of compartment-specific cell identity. An alternative is that the affinity boundary depends on signaling between compartments. Here, we present evidence that the dorsal selector gene apterous plays a role in establishing the dorsoventral affinity boundary that is independent of Notch-mediated signaling between dorsal and ventral cells.

Animals↗
PubMed1999

Regulation of LIM homeodomain activity in vivo: a tetramer of dLDB and apterous confers activity and capacity for regulation by dLMO.

Dorsal-ventral axis formation in the Drosophila wing depends on the activity of the LIM homeodomain transcription factor Apterous and its cofactor, dLDB/Chip. We present evidence that Apterous activity depends on the formation of a LIM homeodomain dimer bridged by a dimer of cofactor. We show that Apterous activity levels are regulated in vivo by dLMO, an antagonist of homodimer formation. Making use of a constitutively active form of Apterous and dominant-negative forms of Apterous and dLDB/Chip, we show that the normal function of dLMO is to downregulate Apterous activity and that the dLMO mutant phenotype is due to excess Apterous activity. These findings may point to a general mechanism for regulation of LIM homeodomain protein activity.

Animals↗
PubMed1999

Simultaneous multigate spectral Doppler imaging of the umbilical artery and placental vessels: novel ultrasound technology.

OBJECTIVE: To establish gestational age-specific nomograms of pulsatility indices in the umbilical artery and chorionic and intraplacental vessels, using novel ultrasound technology. STUDY DESIGN: A prospective, cross-sectional study of 160 healthy singleton pregnancies between 18 and 33 weeks of gestation. MEASUREMENTS: Using simultaneous multigate spectral Doppler imaging specialized hardware and software, we measured the flow velocity waveforms of the umbilical artery, chorionic and intraplacental vessels. Computerized automatic mapping calculated the pulsatility indices in regions of interest. RESULTS: Data were adequately obtained for 160 fetuses. The pulsatility index values in the three sites measured decreased with advancing gestational age; the correlation coefficients r = -0.74, r = -0.67 and r = -0.68 for the umbilical artery, chorionic and intraplacental vessels, respectively, were found to be highly statistically significant (p < 0.0001). CONCLUSION: Simultaneous multigate spectral Doppler imaging provides simultaneous measurements of the velocity waveforms in the umbilical artery, chorionic and intraplacental vessels, and is a feasible and reproducible method of obtaining these data. The normal data presented may facilitate early detection of flow disturbances in the fetoplacental circulation.

Adult↗
PubMed1999

Placental blood flow measured by simultaneous multigate spectral Doppler imaging in pregnancies complicated by placental vascular abnormalities.

OBJECTIVE: To evaluate the role of placental blood flow measurements by simultaneous multigate spectral Doppler imaging in pregnancies complicated by intrauterine growth restriction (IUGR), and for early detection of placental vascular abnormalities in high- and low-risk pregnancies. METHODS: To assess the sensitivity and specificity of abnormal placental blood flow in detecting IUGR, we followed 22 women whose pregnancies were complicated by IUGR at 28-34 weeks' gestation, and compared the findings with those obtained in 22 matched controls. We defined placental blood flow impedance as abnormal when 10% of placental pulsatility index (PI) measurements were greater than, or equal to, the mean umbilical artery PI (placental PI/umbilical PI > or = 1). To determine the predictive value of abnormal placental blood flow measurement for identifying developing uteroplacental insufficiency, we examined an unselected group of 100 low- and high-risk patients at 20-22 weeks' gestation. We correlated the Doppler findings with the development of pre-eclampsia, IUGR, placental abruption, oligohydramnios and the presence of persistent late decelerations during labor. RESULTS: Placental blood flow determination was more sensitive than umbilical artery blood flow in detecting abnormal umbilical-placental flow impedances as manifested by the presence of IUGR. Of the 100 mixed high- and low-risk patients examined at 20-22 weeks, 32 had abnormal placental blood flow. Of these, 19 (59.4%) subsequently developed pathologies associated with placental vascular disease. Of the 68 patients with normal placental blood flow, only six (8.8%) developed such pathologies. The sensitivity was 76% (19/25), with positive predictive value 59.4% (19/32); the specificity was 82.7% (62/75), with negative predictive value 91.2% (62/68). CONCLUSIONS: Abnormal intraplacental blood flow at 28-34 weeks' gestation is strongly associated with IUGR. In addition, it has moderate positive and negative predictive values for identifying subsequent development of uteroplacental vascular abnormalities.

Adult↗
PubMed1999

Effects of dietary dimethylarsinic acid on the urine and urothelium of rats.

Dimethylarsinic acid (DMA), fed to rats for 2 years, produced bladder hyperplasia and tumors at doses of 40 and 100 p.p.m., more in females than males. No urothelial proliferation was seen in mice. Our objectives were to investigate the mode of action of bladder tumor formation, evaluate the dose-response and the role of diet and to determine if the urothelial effects were reversible. The study included groups of female F344 rats fed DMA in Purina 5002 diet at doses of 0, 2, 10, 40 or 100 p.p.m. for 10 weeks; two groups of females fed DMA (0 and 100 p.p.m.) in Altromin 1321 for 10 weeks; two groups of males fed DMA (0 and 100 p.p.m.) in Purina 5002 for 10 weeks; a female high-dose recovery group (100 p.p.m. in Purina 5002 diet for 10 weeks followed by control diet for 10 weeks); and two female groups (0 and 100 p.p.m.) in Purina diet for 20 weeks. Urothelial toxicity and hyperplasia were detected by light and scanning electron microscopy (SEM), and the bromodeoxyuridine labeling index was increased in the female 40 and 100 p.p.m. groups. The effects were less in males, but were similar in females fed DMA in Altromin 1321. SEM detected no abnormal urinary solids related to treatment in any group. Urinary calcium was increased in the females fed 40 and 100 p.p.m. in Purina diet, despite overall urinary dilution. Calcification was increased in kidneys of female rats fed Purina diet. The urothelial effects of DMA were reversible. The findings support a non-DNA reactive mechanism for DMA rat bladder carcinogenicity related to urothelial toxicity and regeneration. The toxicity is probably not due to urinary solids. The toxicity and regeneration are produced in a dose-responsive manner in female rats, are greater in female than in male rats, and are reversible.

Animals↗
PubMed1999

The premature removal of tissue expanders in breast reconstruction.

The role of tissue expanders in breast reconstruction is well established. Little information exists, however, regarding the incidence and etiology of premature removal of the tissue expander before planned exchange to a permanent breast implant. The purpose of this study was to review our 10-year experience with tissue expander breast reconstruction and identify factors relating to the premature removal of the tissue expander. This study is a retrospective review of 770 consecutive patients who underwent breast reconstruction with tissue expanders over the past 10 years. Breast reconstruction was immediate in 90 percent of patients. Patients were expanded weekly, and adjuvant chemotherapy was begun during the expansion process when required. Factors potentially affecting premature expander removal (chemotherapy, diabetes, obesity, radiation therapy, and smoking) were evaluated. Fourteen patients (1.8 percent) with a mean age of 47 years (range, 38 to 62 years) required premature removal of their tissue expander. Expanders were removed a mean of 3.2 months (0.1 to 8 months) after insertion. Causes for premature removal of the tissue expander included infection (7 patients), exposure (2), skin necrosis (2), patient dissatisfaction (2), and persistent breast cancer (1). Positive wound cultures were obtained in four of the seven infected patients (57 percent), requiring expander removal for infection. Tissue expanders were removed in 11 patients for complications directly related to the expander. Among these, six (55 percent) were receiving adjuvant chemotherapy, and one was a smoker. Diabetes, obesity, other concomitant medical illnesses, and prior mantle irradiation were not associated with expander removal. Premature removal of the tissue expander was required in only 1.8 percent of the patients in this series. Infection was the most common complication necessitating an unplanned surgical procedure to remove the expander. This study demonstrates that the use of tissue expanders in breast reconstruction is reliable, with the vast majority of patients completing the expansion process.

Adult↗
PubMed1999

Proximodistal axis formation in the Drosophila leg: subdivision into proximal and distal domains by Homothorax and Distal-less.

The developing legs of Drosophila are subdivided into proximal and distal domains by the activity of the homeodomain proteins Homothorax (Hth) and Distal-less (Dll). The expression domains of Dll and Hth are initially reciprocal. Wingless and Dpp define both domains by activating Dll and by repressing Hth in the distal region of the disc. Wg and Dpp do not act through Dll to repress Hth. Hth functions to reduce the sensitivity of proximal cells to Wg and Dpp. This serves to limit the effective range of these signals in regulating later-acting genes such as Dac. We present evidence that proximal and distal cells tend to sort-out from one another. Cells forced to express Hth are unable to mix with distal cells. Likewise, cells forced to express Dll are unable to mix with proximal cells. Clones of cells unable to express Dll in the distal region sort-out from the disc. Clones of cells unable to express Hth lose the specialized population of cells at the interface between proximal and distal territories and cause fusion between body wall and leg segments. These observations suggest that sorting-out behavior of Hth- and Dll-expressing cells contributes to subdivision of the leg into proximal and distal domains.

Animals↗
PubMed1999

Lineage-tracing cells born in different domains along the PD axis of the developing Drosophila leg.

Patterning of the developing limbs by the secreted signaling proteins Wingless, Hedgehog and Dpp takes place while the imaginal discs are growing rapidly. Cells born in regions of high ligand concentration may be displaced through growth to regions of lower ligand concentration. We have used a novel lineage-tagging method to address the reversibility of cell fate specification by morphogen gradients. We find that responses to Hedgehog and Dpp in the wing disc are readily reversible. In the leg, we find that cells readily adopt more distal fates, but do not normally shift from distal to proximal fate. However, they can do so if given a growth advantage. These results indicate that cell fate specification by morphogen gradients remains largely reversible while the imaginal discs grow. In other systems, where growth and patterning are uncoupled, nonreversible specification events or 'ratchet' effects may be of functional significance.

Animals↗
PubMed1998

Identification of chromosomal bands replicating early in the S phase of normal human fibroblasts.

Normal human fibroblasts (NHF1) were released from confluence arrest (G0) and replated in medium containing bromodeoxyuridine (BrdU) and aphidicolin. Despite severe reduction in the rate of DNA synthesis by aphidicolin, cells reentering the cell cycle incorporated BrdU at regions of the human genome that replicated very early in S phase. After removal of aphidicolin and BrdU from the tissue culture medium, cells were collected in mitosis. Q-banding with 4', 6-diamidino-2-phenylindole/actinomycin D was used to identify metaphase chromosomes. A monoclonal anti-BrdU antibody and a fluorescein isothiocyanate (FITC)-conjugated goat anti-mouse antibody were used to identify the BrdU-labeled sites. The criterion for scoring DNA replication sites was the detection of FITC fluorescence at homologous regions of both sister chromatids. Early replicating regions mapped within R-bands, but not all R-bands incorporated BrdU. Chromosomal bands 1p36.1, 8q24.1, 12q13, 15q15, 15q22, and 22q13 were labeled in 53% or more of the copies of these chromosomes in the data set, suggesting that these sites replicated very early in S phase. Chromosomal band 15q22 was the most frequently labeled site (64%), which indicates that it contains some of the earliest replicating sequences in normal human fibroblasts.

Aphidicolin↗
PubMed1998

Notchless encodes a novel WD40-repeat-containing protein that modulates Notch signaling activity.

Signaling by Notch family receptors is involved in many cell-fate decisions during development. Several modifiers of Notch activity have been identified, suggesting that regulation of Notch signaling is complex. In a genetic screen for modifiers of Notch activity, we identified a gene encoding a novel WD40-repeat protein. The gene is called Notchless, because loss-of-function mutant alleles dominantly suppress the wing notching caused by certain Notch alleles. Reducing Notchless activity increases Notch activity. Overexpression of Notchless in Xenopus or Drosophila appears to have a dominant-negative effect in that it also increases Notch activity. Biochemical studies show that Notchless binds to the cytoplasmic domain of Notch, suggesting that it serves as a direct regulator of Notch signaling activity.

Amino Acid Sequence↗
PubMed1998

Beadex encodes an LMO protein that regulates Apterous LIM-homeodomain activity in Drosophila wing development: a model for LMO oncogene function.

Formation of the dorsal-ventral axis of the Drosophila wing depends on activity of the LIM-homeodomain protein Apterous (Ap). Here we report that Ap activity levels are modulated by dLMO, the protein encoded by the Beadex (Bx) gene. Overexpression of dLMO in Bx mutants interferes with Apterous function. Conversely, Bx loss-of-function mutants fail to down-regulate Apterous activity at late stages of wing development. Biochemical analysis shows that dLMO protein competes for binding of Apterous to its cofactor Chip. These data suggest that Apterous activity depends on formation of a functional complex with Chip and that the relative levels of dLMO, Apterous, and Chip determine the level of Apterous activity. The dominant interference mechanism of dLMO action may serve as a model for the mechanism by which LMO oncogenes cause cancer when misexpressed in T cells.

Animals↗
PubMed1998

Boundary formation in Drosophila wing: Notch activity attenuated by the POU protein Nubbin.

Cell interactions mediated by Notch-family receptors have been implicated in the specification of tissue boundaries in vertebrate and insect development. Although Notch ligands are often widely expressed, tightly localized activation of Notch is critical for the formation of sharp boundaries. Evidence is presented here that the POU domain protein Nubbin contributes to the formation of a sharp dorsoventral boundary in the Drosophila wing. Nubbin represses Notch-dependent target genes and sets a threshold for Notch activity that defines the spatial domain of boundary-specific gene expression.

Animals↗
PubMed1998

13C NMR study of the effects of leptin treatment on kinetics of hepatic intermediary metabolism.

The recent discovery of leptin receptors in peripheral tissue raises questions about which of leptin's biological actions arise from direct effects of the hormone on extraneural tissues and what intracellular mechanisms are responsible for leptin's effects on carbohydrate and lipid metabolism. The present study is focused on the action of leptin on hepatic metabolism. Nondestructive 13C NMR methodology was used to follow the kinetics of intermediary metabolism by monitoring flux of 13C-labeled substrate through several multistep pathways. In perfused liver from either ob/ob or lean mice, we found that acute treatment with leptin in vitro modulates pathways controlling carbohydrate flux into 13C-labeled glycogen, thereby rapidly enhancing synthesis by an insulin-independent mechanism. Acute treatment of ob/ob liver also caused a rapid stimulation of long-chain fatty acid synthesis from 13C-labeled acetyl-CoA by the de novo synthesis route. Chronic leptin treatment in vivo induced homeostatic changes that resulted in a tripling of the rate of glycogen synthesis via the gluconeogenic pathway from [2-13C]pyruvate in ob/ob mouse liver perfused in the absence of the hormone. Consistent with the 13C NMR results, leptin treatment of the ob/ob mouse in vivo resulted in significantly increased hepatic glycogen synthase activity. Chronic treatment with leptin in vivo exerted the opposite effect of acute treatment in vitro and markedly decreased hepatic de novo synthesis of fatty acids in ob/ob mouse liver. In agreement with the 13C NMR findings, activities of hepatic acetyl-CoA carboxylase and fatty acid synthase were significantly reduced by chronic treatment of the ob/ob mouse with leptin. Our data represent a demonstration of direct effects of leptin in the regulation of metabolism in the intact functioning liver.

Animals↗
PubMed1998

Tumorigenicity of sodium ascorbate in male rats.

Sodium ascorbate, like other sodium salts such as saccharin, glutamate, and bicarbonate, produces urinary alterations when fed at high doses to rats, which results in mild superficial urothelial cytotoxicity and regeneration but not tumors in a standard 2-year bioassay. Sodium saccharin was shown to produce a low incidence of bladder tumors in rats if administered in a two-generation bioassay. In the present study, we evaluated sodium ascorbate in a two-generation bioassay that involved feeding to the male and female parental F344 rats for 4 weeks before mating, feeding the dams during gestation and lactation, and then feeding the weaned (at 28 days of age) male F1 generation rats for the remainder of their lifetime (up to 128 weeks of the experiment). Dietary levels of 1.0, 5.0, and 7.0% sodium ascorbate were tested. At 5.0 and 7.0% sodium ascorbate, there was an increase in urinary bladder urothelial papillary and nodular hyperplasia and the induction of a few papillomas and carcinomas. There was a dose-responsive increase in renal pelvic calcification and hyperplasia and inhibition of the aging nephropathy of rats even at the level of 1% sodium ascorbate. Because the short-term urothelial effects of sodium ascorbate in rats are inhibited by treatments producing urinary acidification to pH < 6.0, we coadministered high doses of long-term NH4Cl to groups of rats with 5.0 or 7.0% sodium ascorbate to evaluate the long-term effects. The combination of 7.0% sodium ascorbate plus 2.78% NH4Cl in the diet was toxic, and the group was terminated early during the course of the experiment. The group fed 5.0% sodium ascorbate plus 2.04% NH4Cl showed complete inhibition of the urothelial effects of sodium ascorbate and significant inhibition of its renal effects. We also demonstrated the presence of a calcium phosphate-containing urinary precipitate in rats fed sodium ascorbate at all doses, in a dose-responsive manner. The formation of the precipitate was inhibited by coadministration with NH4Cl. The proliferative effects of sodium ascorbate on the male rat urinary tract in this study are similar to those seen with sodium saccharin when administered in a two-generation bioassay. Mechanistic information suggests that this is a high-dose, rat-specific phenomenon.

Ammonium Chloride↗
PubMed1998

Long-term feeding of sodium saccharin to nonhuman primates: implications for urinary tract cancer.

BACKGROUND: It was observed in the early 1970s that saccharin produced bladder cancer in rats. However, it has been unclear whether sodium saccharin when consumed by humans poses a substantial carcinogenic hazard. Numerous epidemiologic studies have not shown any evidence of increased urothelial proliferation associated with ingestion of sodium saccharin. PURPOSE: Our purpose was to determine the effects of long-term feeding of sodium saccharin to three species of nonhuman primates. METHODS: Twenty monkeys of three species (six African green, seven rhesus, six cynomolgus, and one hybrid [of rhesus male and cynomolgus female parentage]) were treated with sodium saccharin (25 mg in the diet/kg body weight daily for 5 days a week) beginning within 24 hours after birth and continuing for up to 24 years. Sixteen monkeys (seven rhesus and nine cynomolgus) served as controls. During their last 2 years of life, urine was collected from selected treated and control animals and evaluated for various urinary chemistries and for the presence of calculi, microcrystalluria, and precipitate. Urinary bladders were examined by light microscopy and by scanning electron microscopy. RESULTS: Sodium saccharin treatment had no effect on the urine or urothelium in any of these monkeys. There was no evidence of increased urothelial cell proliferation, and there was no evidence of formation of solid material in the urine. CONCLUSION: Although the dose of sodium saccharin administered to these monkeys was only five to 10 times the allowable daily intake for humans, the results provide additional evidence that sodium saccharin is without a carcinogenic effect on the primate urinary tract.

Animals↗
PubMed1998

Frequent p53 mutations and occasional loss of chromosome 4 in invasive bladder carcinoma induced by N-butyl-N-(4-hydroxybutyl)nitrosamine in B6D2F1 mice.

B6D2F1 mice (45/group) were treated with N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) or uracil as follows: Group 1 received 0.05% BBN in drinking water for the entire experiment, Group 2 received 5 mg of BBN by gastric gavage in 0.1 mL of 20% ethanol twice per week for 10 wk, Group 3 received a 2.5% uracil-containing diet for the entire experiment, and Group 4 was controls (received 0.1 ml of 20% ethanol by gavage twice per week for 10 wk). The surviving mice in Group 1 were killed after week 26 and those in the other groups after week 30. By week 15, three of 11 Group 1 and one of 15 Group 2 mice had bladder carcinoma. By 26 and 30 wk, respectively, invasive carcinomas were observed in 33 of 34 and six of 21 mice in Groups 1 and 2 and renal pelvic carcinomas in 11 of 34 and three of 21 mice in Groups 1 and 2. Four of 19 uracil-treated mice had bladder nodular hyperplasia. By polymerase chain reaction-single-strand conformation polymorphism and sequence analyses, 16 of 20 and two of five bladder carcinomas from Groups 1 and 2, respectively, showed mutations in the p53 gene. Ha-ras mutation was present in one case. Loss of heterozygosity analysis with simple-sequence length polymorphism markers for chromosome 4 showed that 10 of 21, two of 15, and nine of 13 mice in Groups 1-3, respectively, had heterozygous or homozygous deletions. B6D2F1 mice are therefore susceptible to the urothelial carcinogenic effects of BBN and develop frequent p53 mutations and chromosome 4 deletions. Chromosome 4 deletions were also seen with uracil.

Animals↗