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C Simon

Publications and source records attributed to C Simon.

At least 109 records · Page 6Linked to original sources
PubMed1997

Breast cytology and biomarkers obtained by random fine needle aspiration: use in risk assessment and early chemoprevention trials.

In a prospective pilot study, we performed breast fine needle aspirations (FNAs) on 224 high-risk and 30 low-risk women and analyzed these aspirates for cytologic changes and biomarker abnormalities of aneuploidy and overexpressed estrogen receptor (ER), epidermal growth factor receptor (EGFR), p53 and HER-2/neu. High-risk women had a first-degree relative with breast cancer (74%), prior biopsy indicating premalignant breast disease (25%), a history of breast cancer (13%), or some multiple of these risk factors (12%). Median ages of the high- and low-risk groups were 44 and 42, respectively. Seventy percent of high-risk and 17% of low-risk women had cytologic evidence of hyperplasia with or without atypia (P < .0001). Aneuploidy and overexpression of EGFR and p53 occurred in 27, 37, and 29% of high-risk subjects but only 0, 3, and 3% of low-risk subjects (P < .0023). Overexpression of ER and HER-2/neu occurred in 7 and 20% of high-risk women but in none of the low-risk subjects. Biomarker abnormalities were more frequent with increasing cytologic abnormality. Restricting the analysis to those 3 biomarkers most frequently overexpressed in the high-risk group (ploidy, EGFR, p53), 13% of high-risk women with normal cytology, 19% of high-risk women with epithelial hyperplasia, and 49% of high-risk women with hyperplasia with atypia had abnormalities of 2 or more of these 3 biomarkers (P = .00004). At a median follow-up of 32 months, four women have been diagnosed with invasive cancer and two with ductal carcinoma in situ (DCIS). Later detection of these neoplastic conditions was associated (P < or = .016) by univariate analysis with prior FNA evidence of hyperplasia with atypia; overexpression of p53 and EGFR; the modified Gail risk of breast cancer development at 10 years; and multiple biomarker abnormalities. By multivariate analysis, later detection of cancer was primarily predicted by the number of biomarker abnormalities in the 3-test battery (P = .0005) and secondarily by the Gail risk at 10 years (P = .0049). In turn, hyperplasia with atypia was associated with multiple biomarker abnormalities, particularly p53 and EGFR overexpression. Thus, hyperplasia with atypia and cytologic markers in breast FNAs have promise as risk predictors and as surrogate endpoint biomarkers for breast cancer chemoprevention trials.

Adult↗
PubMed1996

Effect of PD 098059, a specific inhibitor of mitogen-activated protein kinase kinase, on urokinase expression and in vitro invasion.

The elevated expression of the urokinase-type plasminogen activator gene, which is necessary for the invasive phenotype of several types of cancers, is controlled by growth factors such as epidermal growth factor, transforming growth factor a, and fibroblast growth factor which bind to and activate protein tyrosine kinase transmembrane receptors. Since these activated receptors communicate with the nucleus via a signaling pathway in which c-Raf-1, mitogen-activated protein kinase kinase 1 (MEK1), and the extracellular signal-regulated kinases are sequentially activated, we determined the effect of a specific MEK1 inhibitor (PD 098059) on urokinase expression in two squamous cell carcinoma cell lines (UM-SCC-1 and MDA-TU-138) characterized as avid secretors of the plasminogen activator. PD 098059 treatment of either cell line reduced the amount of secreted urokinase in a dose-dependent manner. In contrast, a compound (daidzein) chemically unrelated to PD 098059 had little effect on urokinase secretion. The effect of PD 098059 on urokinase secretion in UM-SCC-1 cells was reversible and correlated with decreased extracellular signal-regulated kinase 1 activity. PD 098059 caused a dose-dependent reduction in the in vitro invasiveness of UM-SCC-1 cells whereas it had little effect on proliferation rates. Transient transfection assays with a chloramphenicol acetyl transferase reporter driven by the urokinase promoter indicated that diminished secretion of the protease was largely a consequence of reduced promoter activity. These findings suggest that interfering with MEK1 may provide a novel means of controlling the invasiveness of tumors in which this signaling cascade is activated by autocrine and/or paracrine growth factors.

Carcinoma, Squamous Cell↗
PubMed1996

The effect of topology on estimates of among-site rate variation.

Among-site rate variation, as quantified by the gamma-distribution shape parameter, a or alpha, and the ratio of transition rate to transversion rate (Ts/Tv) influence phylogenetic inference. We examine the effect of topology on estimates of these two parameters in 12S rRNA sequences from nine species of mice belonging to the genera Onychomys and Peromyscus by generating 100 random topologies and estimating these parameters using parsimony and maximum-likelihood methods for each of the random topologies. The parsimony-based estimate of Ts/Tv from the well-corroborated topology falls within the distribution of estimates based on random topologies, whereas the maximum-likelihood estimate of Ts/Tv based on the well-corroborated topology lies well outside the distribution of estimates derived from random topologies. The Ts/Tv ratio derived via maximum-likelihood estimation is three times the parsimony-based estimate, suggesting that parsimony-based estimates are severe underestimates even when the correct topology is used. Both parsimony- and likelihood-based estimates of the gamma-distribution shape parameter (alpha) are sensitive to topology because the best estimates based on the well-corroborated topology are well outside the distributions of estimates derived from random topologies for both methods. We show that the reason for topology dependence is the presence of long internal branches in the underlying topology.

Animals↗
PubMed1996

[Hydrosonography of the pancreas. Initial results of a pilot study].

PURPOSE: To evaluate a new ultrasonographic imaging technique of the pancreas (hydrosonography), based on a combination of chemical intestinal paralysis and water distension of the stomach and duodenum, regarding its significance for tumor detection, staging and assessment of tumor resectability. MATERIAL AND METHODS: In an open prospective study 51 patients with suspected pancreatic neoplasm were examined between July 1995 and October 1995. The technique of hydrosonography included intravenous injection of 40 mg N-butyl-scopolaminiumbromid (Buscopan) and maximum gastric and duodenal wall distension by oral administration of an average of 11 warm tap water (0.5-1.51). A detailed evaluation form was used to assess (1) overall imaging quality; (2) accuracy of identification of the pancreas in its various anatomic regions and of peripancreatic vessel structures relevant for resectability, such as splenic, superior mesenteric, and portal veins, celiac trunk, and superior mesenteric, splenic and hepatic arteries; and (3) tumor size, sonographic structure and level of organ and vessel infiltration. As gold standards for positive tumor detection and description, surgery and microscopic diagnosis were used, and for negative tumor detection, event-free survival of 6 months. RESULTS: All examinations were diagnostic. Identification of the pancreas was complete in all 51 patients with an excellent overall imaging quality in 53%. In 86% of cases the various examined organ and vessel structures were depicted with either good or average imaging quality. In 48 of the 51 patients diagnosis positive for tumor or other organ pathology was made. A total of 16 pancreatic carcinomas and 5 benign tumors were diagnosed. Twenty-seven patients had pathology not related to a pancreatic neoplasm. For tumor detection, sensitivity was 82% and specificity 100%. For correct assessment of tumor resectability, sensitivity was 86% and specificity 100%. CONCLUSION: The new technique of hydrosonography combines the value of routine non-invasive abdominal ultrasound with increased sensitivity and specificity for tumor detection and assessment of resectability by improved imaging accuracy.

Adult↗
PubMed1996

[Hydrospiral CT of the pancreas in thin section technique].

PURPOSE: To evaluate a new technique for imaging the pancreas (spiral hydro-CT) based on a combination of pharmacological intestinal paralysis and water distension of the stomach and duodenum with specific reference to tumor detection rate, differentiation of malignant versus benign tumors, differential diagnosis and assessment of tumor resectability. MATERIAL AND METHODS: In an open prospective study, 151 patients with a suspected pancreatic neoplasm based on clinical, laboratory or other imaging data were examined between May 94 and October 95. Our newly developed Hydro-CT methodology included intravenous injection of 40 mg N-butylscopolaminium bromide (Buscopan) for intestinal paralysis, gastric and duodenal wall distension by oral administration of an average of 1.51 warm tap water, 30 degrees RAO patient positioning, an individualized contrast injection technique as determined beforehand by time-to-peak measurement in the portal vein and thin-slice spiral CT (3 mm increment, 6 mm table feed and 3 mm secondary reconstruction). A detailed evaluation form was used to assess (1) tumor detection rate, (2) differentiation of malignant versus benign disease, (3) differential diagnosis, and (4) accuracy of assessment of resectability by identification of infiltration into adjacent organs and vessel structures relevant for resectability such as splenic, superior mesenteric, portal vein and celiac trunk, superior mesenteric, splenic and hepatic arteries. As the gold standard for positive tumor detection surgery and microscopic diagnosis were used, and for negative tumor detection an event-free survival of 6 months. RESULTS: Almost all examinations were well tolerated. In only 4% was on-site administration of a gastric tube required because of vomiting. In 2% of the patients a slight allergic reaction to the contrast medium was seen. The prevalence of a pancreatic neoplasm was 38%. In tumor detection Hydro-CT reached an overall accuracy of 97.4% with a sensitivity of 100% and a specificity of 95.9%. In the differentiation of benign versus malignant disease Hydro-CT reached an overall accuracy of 89.7% with a sensitivity of 92.5% and a specificity of 83.3%. The prevalence of a pancreatic carcinoma was 24%; 4% other malignant tumors were found (distal common bile duct carcinoma, cystadenocarcinoma). Fifty-eight patients underwent surgical exploration. In those assessment of resectability reached an overall accuracy of 95% with a sensitivity of 90.5% and specificity of 100%. CONCLUSION: The new technique of Hydro-CT based on thin slice and spiral methodology, including pharmacological intestinal paralysis and water distension, results in a high tumor detection rate and increases sensitivity and specificity of tumor differential diagnosis and of assessment of resectability.

Adult↗
PubMed1996

Enzymatic conversion of adenosine to inosine and to N1-methylinosine in transfer RNAs: a review.

Inosine (6-deaminated adenosine) is a characteristic modified nucleoside that is found at the first anticodon position (position 34) of several tRNAs of eukaryotic and eubacterial origins, while N1-methylinosine is found exclusively at position 37 (3' adjacent to the anticodon) of eukaryotic tRNA(Ala) and at position 57 (in the middle of the psi loop) of several tRNAs from halophilic and thermophilic archaebacteria. Inosine has also been recently found in double-stranded RNA, mRNA and viral RNAs. As for all other modified nucleosides in RNAs, formation of inosine and inosine derivative in these RNA is catalysed by specific enzymes acting after transcription of the RNA genes. Using recombinant tRNAs and T7-runoff transcripts of several tRNA genes as substrates, we have studied the mechanism and specificity of tRNA-inosine-forming enzymes. The results show that inosine-34 and inosine-37 in tRNAs are both synthesised by a hydrolytic deamination-type reaction, catalysed by distinct tRNA:adenosine deaminases. Recognition of tRNA substrates by the deaminases does not strictly depend on a particular "identity' nucleotide. However, the efficiency of adenosine to inosine conversion depends on the nucleotides composition of the anticodon loop and the proximal stem as well as on 3D-architecture of the tRNA. In eukaryotic tRNA(Ala), N1-methylinosine-37 is formed from inosine-37 by a specific SAM-dependent methylase, while in the case of N1-methylinosine-57 in archaeal tRNAs, methylation of adenosine-57 into N1-methyladenosine-57 occurs before the deamination process. The T psi-branch of fragmented tRNA is the minimalist substrate for the N1-methylinosine-57 forming enzymes. Inosine-34 and N1-methylinosine-37 in human tRNA(Ala) are targets for specific autoantibodies which are present in the serum of patients with inflammatory muscle disease of the PL-12 polymyositis type. Here we discuss the mechanism, specificity and general properties of the recently discovered RNA:adenosine deaminases/editases acting on double-stranded RNA, intron-containing mRNA and viral RNA in relation to those of the deaminases acting on tRNAs.

Adenosine↗
PubMed1996

Conserved sequence motifs, alignment, and secondary structure for the third domain of animal 12S rRNA.

Secondary structure models are an important step for aligning sequences, understanding probabilities of nucleotide substitutions, and evaluating the reliability of phylogenetic reconstructions. A set of conserved sequence motifs is derived from comparative sequence analysis of 184 invertebrate and vertebrate taxa (including many taxa from the same genera, families, and orders) with reference to a secondary structure model for domain III of animal mitochondrial small subunit (12S) ribosomal RNA. A template is presented to assist with secondary structure drawing. Our model is similar to previous models but is more specific to mitochondrial DNA, fitting both invertebrate and vertebrate groups, including taxa with markedly different nucleotide compositions. The second half of the domain III sequence can be difficult to align precisely, even when secondary structure information is considered. This is especially true for comparisons of anciently diverged taxa, but well-conserved motifs assist in determining biologically meaningful alignments. Patterns of conservation and variability in both paired and unpaired regions make differential phylogenetic weighting in terms of "stems" and "loops" unsatisfactory. We emphasize looking carefully at the sequence data before and during analyses, and advocate the use of conserved motifs and other secondary structure information for assessing sequencing fidelity.

Animals↗
PubMed1996

Large differences in substitutional pattern and evolutionary rate of 12S ribosomal RNA genes.

We demonstrate using Drosophila, periodical cicadas, and hominid primates, that the molecular clock based on animal mitochondrial small-subunit (12S) rRNA genes ticks at significantly different relative rates depending on which taxa and which region of the gene are examined. Drosophila, which are commonly used as model taxa, are evolving in a highly peculiar manner with the majority of sites in the 3' half of the 12S gene apparently invariant. The analogous 3' half of the mitochondrial large-subunit rRNA gene (16S) appears to be similarly constrained. It is surprising that these regions that are already highly constrained in all animals should be even more constrained in Drosophila, especially when the Drosophila mitochondrial genome as a whole does not display a similar rate slowdown. This extreme 12S rate slowdown is not apparent in periodical cicadas or hominid primates and appears to be related to strong structural and functional constraints rather than a depressed mutation rate. Finally, the slow average rate of evolution in the third domain of Drosophila does not imply that the few variable sites lack multiple hits.

Animals↗
PubMed1995

Among-site rate variation and phylogenetic analysis of 12S rRNA in sigmodontine rodents.

We analyze sequences from two mitochondrial genes, cytochrome b (cyt b) and 12S rRNA (12S), for a group of sigmodontine rodents among which phylogenetic relationships are well understood based on concordance of morphological, chromosomal, allozyme, and other DNA data sets. Because these two genes are physically linked on the nonrecombining mitochondrial genome, they necessarily share the same history. Phylogenetic analysis of the cyt b gene recovers the well-corroborated relationships, generally with strong support. None of the methods that we employed, including variously weighted parsimony, neighbor joining on both single-rate and gamma-corrected distances, and maximum likelihood, were able to recover these relationships for the 12S gene. Parsimony analyses of the 12S data resulted in a relatively strongly supported placement of Peromyscus eremicus that conflicts with that suggested by cyt b and all other data. There is extreme among-site rate variation in the 12S sequences and moderate levels in the cyt b sequences. This highly skewed distribution of rates in the 12S gene makes phylogenetic analyses of these sequences particularly susceptible to the misleading effects of nonindependence and other nonrandom noise, suggesting that phylogenetic analyses of data sets that contain a great deal of among-site rate variation be interpreted with caution.

Animals↗