Biomedical subjects

Paul C Park

Publications and source records attributed to Paul C Park.

5 recordsLinked to original sources

PubMed2003

Evidence of multifocality of telomere erosion in high-grade prostatic intraepithelial neoplasia (HPIN) and concurrent carcinoma.

Mechanisms underlying prostate cancer (CaP) initiation and progression are poorly understood. A chromosomal instability mechanism leading to the generation of numerical and structural chromosomal changes has been implicated in the preneoplastic and neoplastic stages of CaP. Telomere dysfunction is one potential mechanism associated with the onset of such instability. To determine whether there was alteration in telomere length and chromosome number, 15 paraffin-embedded prostatectomy specimens were investigated using quantitative peptide nucleic acid (PNA) FISH analysis of representative foci of carcinoma, putative precancerous lesions (high-grade prostatic intraepithelial neoplasia, HPIN) and nondysplastic prostate epithelium. A significant decrease in telomere length was shown in both HPIN and CaP in comparison with normal epithelium. In addition, elevated rates of aneusomy suggested that increased levels of chromosomal aberrations were associated with decreased telomere length. Moreover, multiple foci of HPIN were shown to have a heterogeneous overall reduction of telomere length. This reduction was more evident in the histologic regions of the prostate containing CaP. Such observations lend support to the hypothesis that telomere erosion may be a consistent feature of CaP oncogenesis and may also be associated with the generation of chromosomal instability that characterizes this malignancy.

Adenocarcinoma↗

PubMed2003

Transcriptional profiling of medulloblastoma in children.

OBJECT: Although medulloblastoma is the most common malignant brain tumor found in children, little is known about its molecular pathogenesis. The authors have attempted to compare patterns of gene expression in medulloblastoma samples with those in the healthy cerebellum. METHODS: The authors used complementary (c)DNA microarray analysis to compare the expression of genes in samples of medulloblastoma and normal cerebellum. The expression levels of a subset of genes were then verified by immunohistochemical analysis. Six genes were identified that were expressed at a much higher level in at least five of six medulloblastomas: ezrin, cyclin D2, high mobility group protein 2, MAPRE1, histone deacetylase 2, and ornithine decarboxylase 1. A number of potentially important genes whose expression was much lower in medulloblastomas than in control cerebellum were also identified: tenascin R, TRK-B, FGF receptor, and death receptor 3. The expression levels of a subset of the identified genes were confirmed by immunohistochemical analysis, which was performed on fetal cerebellum and medulloblastoma samples. CONCLUSIONS: The authors demonstrate that cDNA microarray analysis is an effective method of increasing understanding of the molecular biology of medulloblastomas found in children. A comparison between gene expression patterns in medulloblastoma and those observed in healthy cerebellum may provide clues as to the origin of these tumors and may lead to the identification of new genes or pathways to be targeted for future therapies.

Brain Neoplasms↗

PubMed2002

Intranuclear relocation of the Plc beta3 sequence in cerebellar purkinje neurons: temporal association with de novo expression during development.

Interphase nuclei exhibit a cell type-specific topology of chromatin domains. This topology has been proposed to be established at a specific developmental stage and to be associated, in turn, with cell type-specific gene expression. Using murine, cerebellar Purkinje neurons, we have shown previously that the number and the extent of clustering as well as the spatial, intranuclear distribution of centromeric domains change as a function of postnatal development. Specifically, the redistribution of centromeric domains was determined to be associated temporally with major changes in gene expression. Given that centromeric sequences are not transcribed, we tested the hypothesis that the de novo expression of a specific sequence is similarly associated with a change in its spatial, intranuclear position. In Purkinje neurons, Plc beta3 is expressed de novo between postnatal day 2 and 7. In contrast, the level of expression of Rora remains constant throughout development, following its initial expression at embryonic day 15. Plc beta3 and Rora were labeled by fluorescence in situ hybridization within intact nuclei and their intranuclear, spatial positions quantified by confocal microscopy. When analyzed as the distance from the nuclear centroid, the mean fraction of radial distance of Plc beta3 signals changed from 57.3%+/-2.35 (+/-SEM) (n=50) at P3 to 37.9%+/-2.35 (n=50) at P5. In contrast, the mean fraction of the radial distance of Rora signals did not change during postnatal development, remaining at a mean of 60.1%+/-2.01 (n=208) from the nuclear centroid. While the results do not support a causal relationship between the spatial relocation of Plc beta3 and its de novo expression, their temporal association, as described herein, may be taken to support the hypothesis that its intranuclear, spatial positioning may represent one level of transcriptional control.

Animals↗

PubMed2002

Resolution of genotypic heterogeneity in prostate tumors using polymerase chain reaction and comparative genomic hybridization on microdissected carcinoma and prostatic intraepithelial neoplasia foci.

Prostate cancer (CaP) is a multifocal heterogenous disease. A major challenge in CaP research is to identify genetic biomarkers that herald aggressive transformation. To investigate the effect of tumor heterogeneity on the analysis of genomic aberration, we compared the results of comparative genomic hybridization (CGH) analysis of DNA extracted from tumor bulk against that of DNA amplified by degenerate oligonucleotide primed polymerase chain reaction (DOP-PCR) from homogeneous cell population obtained by laser capture microdissection of discrete tumor foci. Sampling by microdissection, aberrations were observed in three of three foci of carcinoma involved with prostatic capsule, and in two of three prostatic intraepithelial neoplasia (PIN) foci examined. Carcinoma foci consistently exhibited more extensive aberrations than the PIN samples obtained from the same tumor. Within these samples, the different tumor foci exhibited gain of 8q, whereas PIN showed no consistent aberration. Using bulk extracted DNA, CGH detected aberrations in only 3 of 21 samples investigated, despite the known trisomy 8 status, as revealed by fluorescence in situ hybridization. The results of this study demonstrate that CGH analysis using bulk dissected fresh tissue is insufficiently sensitive to fully detect the chromosomal numerical aberrations in CaP. Given the considerable intratumor genomic heterogeneity, CGH with microdissection and DOP-PCR amplification provides a more complete repertoire of aberrations as well as a better phenotype-genotype correlation in prostate tumors.

Carcinoma↗

PubMed2002

Microarray CGH.

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Computational Biology↗