Biomedical subjects
K Neshat
Publications and source records attributed to K Neshat.
Cervicofacial subcutaneous emphysema after lower root canal therapy.
Subcutaneous emphysema can occur when high-speed, air-cooled, rotary cutting instruments are used near open wounds and introduce air into subcutaneous or facial spaces of the face and neck. The case reported here describes an episode of cervicofacial subcutaneous emphysema after lower tooth root canal therapy.
Allelic loss of 9p21 and mutation of the CDKN2/p16 gene develop as early lesions during neoplastic progression in Barrett's esophagus.
High frequency allelic loss of chromosome 9p21 has been reported in a number of human cancers, including those of the esophagus. The CDKN2 gene on chromosome 9p21 that encodes the p16 inhibitor of cyclinD/Cdk4 complexes is a target of allelic loss and inactivation in a variety of human cancers and cell lines. However, the roles of 9p21 allelic losses and CDKN2 mutations in human neoplastic progression in vivo remain controversial. We determined the prevalence of allelic loss at 9p21 and mutations in CDKN2 in esophageal adenocarcinomas and investigated the order in which they occurred relative to the development of aneuploidy and cancer during neoplastic progression. Aneuploid cell populations from 32 patients with Barrett's esophagus who had premalignant epithelium, cancer, or both, were purified by DNA content flow cytometric cell sorting and evaluated by polymerase chain reaction. Twenty-four of 32 informative patients (75%) had allelic loss at 9p21 in aneuploid cell populations. Premalignant epithelium was available for seven of the patients who had 9p21 allelic losses in cancer; allelic loss of 9p21 was detected before cancer in all seven (100%). Allelic loss of 9p21 preceded the development of aneuploidy in 13 of 15 patients (87%) who had aneuploid cell populations detected in premalignant epithelium, and the two events were detected simultaneously in the remaining two patients. Five of 22 aneuploid populations (23%) with 9p21 loss had somatic mutations in the remaining CDKN2 allele. The same mutations and 9p21 allelic losses were also found in the corresponding diploid cells from premalignant epithelium in all three cases that were evaluable. However, there was no evidence for mutation or homozygous deletion of p16 in the other 17 patients with 9p21 allelic loss. Our results indicate that 9p21 allelic losses and CDKN2 mutations develop as early lesions in diploid cells before aneuploidy and cancer during neoplastic progression in Barrett's esophagus.
Barrett's esophagus: ordering the events that lead to cancer.
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Inactivation of p53 and the development of tetraploidy in the elastase-SV40 T antigen transgenic mouse pancreas.
Human pancreatic cancer develops in association with an acquired genomic instability, but the events that lead to instability are difficult to investigate because they occur sporadically and unpredictably. The elastase-SV40 T antigen transgenic mouse model of pancreatic adenocarcinoma reproducibly proceeds through a diploid --> tetraploid --> multiple aneuploid sequence of genetic abnormalities. We investigated the relationship between inactivation of p53 and development of tetraploidy in this model. Because T antigen inactivates p53 by forming a stable complex with it, we used multiparameter flow cytometry to assess p53 expression in pancreatic samples of transgenic and control mice between 8 and 24 days of age. On day 18, a cell cycle-specific inactivation of p53 developed between diploid G, and S phase and was associated with the appearance of a cycling tetraploid cell population that had p53 protein overexpression in both G1- and S-phase cells. Cytogenetic analysis of pancreatic samples confirmed the development of a tetraploid cell population. Inactivation of p53 in diploid cells of the transgenic pancreas is followed by the development of a tetraploid cell population. We have shown previously that this tetraploid intermediate is predisposed to progression to aneuploidy because it has abnormal mitotic poles. Therefore, our results suggest that inactivation of p53 by T antigen leads to formation of a tetraploid cell intermediate that is predisposed to chromosome segregation abnormalities and the development of multiple aneuploid cell populations.
17p allelic losses in diploid cells of patients with Barrett's esophagus who develop aneuploidy.
Inactivation of the p53 gene, located on chromosome 17p, leads to genetic instability and aneuploidy in vitro. Aneuploid cell populations from Barrett's adenocarcinomas have a high prevalence of 17p allelic losses, and there is substantial evidence that the target of these losses is the p53 gene. If 17p allelic losses lead to aneuploidy in Barrett's esophagus, then they should be present in diploid cells from patients who develop aneuploidy. We detected 17p allelic losses in diploid cells from 10 of 11 patients (91%) with Barrett's esophagus who developed aneuploid cell populations. Our data strongly suggest that 17p allelic losses precede the development of aneuploidy during neoplastic progression in Barrett's esophagus in vivo and, therefore, support in vitro evidence for the role of p53 in genetic instability.
p53 mutations in Barrett's adenocarcinoma and high-grade dysplasia.
BACKGROUND/AIMS: Allelic losses of chromosome 17p and overexpression of p53 protein have been reported in Barrett's adenocarcinomas. This study aimed to determine the stage in which p53 mutations arise in neoplastic progression in Barrett's esophagus and their relationship to the clonal evolution of cancer. METHODS: Fourteen patients with high-grade dysplasia, adenocarcinoma, or both arising in Barrett's esophagus were evaluated. Flow cytometric cell sorting was used to obtain purified populations of neoplastic cells for analysis of p53 mutations. DNA was extracted, and exons 5 through 9 of the p53 gene were amplified by polymerase chain reaction. Amplified DNA was sequenced and analyzed by automated sequencing. RESULTS: Nine of the 14 patients had p53 mutations. Six of the 9 patients had regions of high-grade dysplasia that could be evaluated; all 6 had p53 mutations in high-grade dysplasia. In 3 patients, the same p53 mutations were found in both high-grade dysplasia and adenocarcinoma. All 14 patients had aneuploidy. In 4 patients, diploid cell populations could also be evaluated for p53 mutations; 3 of the 4 patients had p53 mutations in diploid cell populations. In 2 patients, the same p53 mutation was found in multiple aneuploid cell populations within a cancer. CONCLUSIONS: p53 mutations occur frequently in Barrett's adenocarcinomas. They develop in diploid cell populations. The same p53 mutations are then found in aneuploid cell populations in high-grade dysplasia, in cancer, and in multiple aneuploid cell populations in cancer.
Barrett's esophagus: a model of human neoplastic progression.
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Barrett's esophagus: the biology of neoplastic progression.
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Evaluation of p53 protein expression in Barrett's esophagus by two-parameter flow cytometry.
Barrett's esophagus is a condition in which the normal stratified squamous epithelium is replaced by metaplastic columnar epithelium that predisposes to the development of esophageal adenocarcinoma. Neoplastic progression in Barrett's esophagus occurs by a multistep process associated with genomic instability and the development of aneuploid cell populations. p53 protein overexpression and allelic deletions on chromosome 17p have been shown to be present in some Barrett's adenocarcinomas, but the stage in neoplastic progression at which p53 protein overexpression develops has not been investigated. To determine the stages in neoplastic progression at which p53 protein overexpression could be detected, biopsy specimens from patients with Barrett's esophagus at all stages of histological progression from Barrett's metaplasia negative for dysplasia to esophageal adenocarcinoma were investigated using a multiparameter flow-cytometric assay. p53 protein overexpression was found in 1 of 21 patients (5%) with Barrett's metaplasia negative for dysplasia, 2 of 13 patients (15%) with Barrett's metaplasia with abnormalities in the indefinite/low-grade dysplasia range, 5 of 11 patients (45%) with high-grade dysplasia, and 8 of 15 patients (53%) with Barrett's adenocarcinoma (P less than 0.01). p53 protein overexpression was found in 9% of patients with Barrett's esophagus who had neither high-grade dysplasia nor adenocarcinoma. Whether or not patients whose biopsy specimens show p53 protein overexpression are at increased risk for progression to adenocarcinoma can be determined by prospective endoscopic surveillance.