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ABSTRACT: Human papillomavirus type 16 (HPV16) is an oncogenic virus that causes persistent infections in cervical epithelium. The chronic nature of HPV16 infections suggests that this virus actively evades the host immune response. Intraepithelial Langerhans cells (LC) are antigen-presenting cells that are critical in T-cell priming in response to viral infections of the skin. Here we show that HPV16 infection is directly associated with a reduction in the numbers of LC in infected epidermis. Adhesion between keratinocytes (KC) and LC, mediated by E-cadherin, is important in the retention of LC in the skin. Cell surface E-cadherin is reduced on HPV16-infected basal KC, and this is directly associated with the reduction in numbers of LC in infected epidermis. Expression of a single viral early protein, HPV16 E6, in KC reduces levels of cell surface E-cadherin thereby interfering with E-cadherin-mediated adhesion. Through this pathway, E6 expression in HPV16-infected KC may limit presentation of viral antigens by LC to the immune system, thus preventing the initiation of a cell-mediated immune response and promoting survival of the virus.
Journal of Virology 09/2003; 77(15):8378-85. · 5.40 Impact Factor
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The New Zealand medical journal 03/2003; 116(1169):U332.
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ABSTRACT: The purpose of this study was to determine the prognostic significance of occult lymph node metastases in colon cancer detected by cytokeratin 20 reverse transcription polymerase chain reaction.
Two hundred patients undergoing elective colonic resections were enrolled in the study. Lymph nodes from resected specimens were dissected fresh and assessed by both reverse transcription polymerase chain reaction and histopathology. Follow-up was undertaken for up to five years, and the major end point of death was recorded. Univariate survival analysis was performed by the log-rank method and the change-in-estimate method was used to construct multivariate analysis models for the effect of cytokeratin 20 reverse transcription polymerase chain reaction lymph node status on overall survival.
A total of 2,317 lymph nodes from 200 patients were assessed by both histopathology and cytokeratin 20 reverse transcription polymerase chain reaction. Forty-eight of 141 (34 percent) histologically lymph node-negative patients had evidence of occult metastases by cytokeratin 20 reverse transcription polymerase chain reaction. An interim analysis was performed at a median of 42 (range, 23-75) months. Cytokeratin 20 reverse transcription polymerase chain reaction lymph node status was a highly significant predictor of overall survival (P < 0.0001) on univariate analysis. In addition, the number of reverse transcription polymerase chain reaction-positive lymph nodes was a significant predictor of survival in the histologically lymph node-negative group (P < 0.0001) on univariate analysis. On multivariate analysis cytokeratin 20 reverse transcription polymerase chain reaction lymph node status had independent prognostic significance for overall survival (P = 0.021; hazard ratio = 2.7) and the number of cytokeratin 20 reverse transcription polymerase chain reaction-positive lymph nodes was a significant predictor of overall survival in the histologically lymph node-negative group (P = 0.005; hazard ratio = 1.1-11.1).
Cytokeratin 20 reverse transcription polymerase chain reaction has potential as a clinically useful marker for staging colorectal cancer. Further follow-up is required, but if the current trends continue, a study of the effect of adjuvant therapy in patients with occult metastases detected by cytokeratin 20 reverse transcription polymerase chain reaction is indicated.
Diseases of the Colon & Rectum 02/2003; 46(2):221-31. · 3.13 Impact Factor
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Medical and Pediatric Oncology 08/2002; 39(1):52-4.
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ABSTRACT: The mouse achaete-scute homolog-2 gene (Ascl2 or Mash2) encodes a transcription factor playing a role in the development of the trophoblast. The Ascl2 is an imprinted gene with maternal expression and assigned to an imprinting gene cluster region (ICR) at a distal region of mouse chromosome 7. We previously isolated a phage clone carrying the human homolog, ASCL2, and mapped it to human chromosome 11p15.5, a human ICR. In the present study, we demonstrate the expression patterns of the human ASCL2 in the fetus at a stage between first and second trimesters and in the placental tissues. In addition, it has been shown that the human ASCL2 gene escapes genomic imprinting.
Journal of Assisted Reproduction and Genetics 06/2002; 19(5):240-4. · 1.84 Impact Factor
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Australian family physician 05/2002; 31(4):359-60. · 0.73 Impact Factor
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ABSTRACT: PURPOSE: The aim of this study was to compare the lymphatic drainage of colon cancer with the anatomic distribution of histologic and submicroscopic lymph node metastases. METHODS: Patients attending for colectomy were eligible to enter the study. At the commencement of surgery, 40 MBq of 99mTc colloidal antimony sulfide in 2 ml of Patent Blue dye was injected subserosally around the tumor. Resection was completed in a standard fashion. After resection, specimens were imaged with a gamma camera to determine the site of sentinel lymph nodes, and then dissected, recording the position of the lymph nodes on an anatomic diagram. Recovered lymph nodes were bisected, one-half for routine histology and one-half for assessment by keratin 20 (K20) reverse transcription polymerase chain reaction. The kappa measure of agreement was used to assess concordance between sentinel nodes and histologic and submicroscopic metastases. RESULTS: Four hundred fifty-six lymph nodes were dissected from 26 tumors and evaluated using lymphoscintigraphy and lymph node mapping. Sentinel nodes were evident in 23 tumors (88 percent). The sensitivity of sentinel nodes involvement as a predictor of metastatic disease was 55 percent (95 percent confidence interval, 23–83), with a false negative (nondiagnostic) rate of 45 percent. Sentinel nodes involved the apical group in four tumors, and represented anatomic skip lesions in four tumors. CONCLUSIONS: Direct lymphatic drainage to the apical group does occur in colon cancer; however, sentinel node mapping of colon cancer by this technique is of little clinical value because of the poor concordance between lymph node metastases and sentinel nodes.
Diseases of the Colon & Rectum 02/2001; 44(3):410-417. · 3.13 Impact Factor
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Kiyonori Miura,
Osamu Miyoshi, Kankatsu Yun,
Johji Inazawa,
Toshinobu Miyamoto,
H. Hayashi,
H. Masuzaki,
Shuichiro Yoshimura,
Norio Niikawa,
Y. Jinno,
Tadayuki Ishimaru
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ABSTRACT: Using a repetitive sequence of tandemly arrayed pentanucleotides in the human H19 3′-flanking region, we isolated a phage clone (λ PEN11) which localized to chromosome 11p15.5. The λ PEN11 phage encodes
a 2.3-kb cDNA consisting of seven exons at least. The gene was mainly expressed in brain and pancreas (and less abundantly
in testis), and demonstrated differential allele usage, with maternal expression being predominant in placenta, which indicates
the gene is an atypical imprinted gene. While the pentamer repeat might contribute to this effect, it is also possible that
the differential allele usage might reflect the local chromosomal structure known as the imprinting domain.
Journal of Human Genetics 12/1998; 44(1):1-9. · 2.57 Impact Factor
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ABSTRACT: The mouse achaete-scute homolog-2 gene (Ascl2 or Mash2) encodes a transcription factor playing a role in the development of the trophoblast. The Ascl2 gene is paternally imprinted in the mouse, but whether this applies to its human homolog is unknown. In the present study,
we found a SacII polymorphism in the possible 3′ untranslated region (UTR) of the gene. It would be very useful to determine definitively
whether the gene is imprinted, as well as to analyze the allelic methylation status of the gene.
Journal of Human Genetics 01/1998; 43(1):69-70. · 2.57 Impact Factor
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ABSTRACT: We have examined the imprinting of the Wilms' tumour suppressor gene (WT1) in human tissues. We confirm that WT1 is biallelically expressed in the kidney, however, in five of nine preterm placentae WT1 was expressed largely or exclusively from the maternal allele. Monoallelic expression of WT1 was also found in two fetal brains. These data demonstrate that WT1 can undergo tissue specific imprinting. Furthermore, because monoallelic expression of WT1 was not found in all placentae examined, WT1 imprinting may be genetically polymorphic within the human population.
Nature Genetics. 02/1994; 6(3):305-309.
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ABSTRACT: Wilms tumors with WT1 mutations [ WT1(-)] have a stromal-predominant histology with varying extents of rhabdomyogenesis. These tumors also frequently have mutations in the beta-catenin gene ( CTNNB1). We have investigated the molecular events that may explain the origins of rhabdomyogenesis in WT1(-) tumors. Of 35 Wilms tumors, we identified 12 with WT1 mutations, of which 9 carried CTNNB1 mutations. We compared WT1 wild-type tumors [ WT1(+)] with WT1(-) tumors for histological features, localization of beta-catenin, Bcl-2 expression, and apoptosis using an in-situ end-labeling technique. WT1(+) tumors showed triphasic and blastemal- and epithelial predominant-histology. Expression of WT1, beta-catenin, and Bcl-2 recapitulated those of normal kidney epithelial development. Localization of beta-catenin was observed in the cytoplasm and cytoplasmic membrane of early glomerular epithelial structures. Bcl-2 is also expressed in condensing blastema and early glomerular epithelial structures which had little apoptosis. WT1(-) tumors, regardless of whether CTNNB1 mutations were detected or not, showed a stromal-rich phenotype with abundant expression of beta-catenin in the nucleus of the rhabdomyoblasts. Bcl-2 was expressed in rhabdomyoblasts, but not in blastemal cells undergoing apoptosis, suggesting that WT1 regulates Bcl-2 positively in the epithelial pathway, but negatively in the myogenic pathway. These data indicate that mutations in WT1 might alter the Wnt signaling pathway and Bcl-2 related-apoptosis. In WT1(-) tumors, the nuclear accumulation of beta-catenin and Bcl-2 expression are associated with rhabdomyogenesis, and dysregulation of Bcl-2 may be a mechanism by which the histogenesis (loss of blastemal component, muscle differentiation) may be explained.
Pediatric and Developmental Pathology 7(2):125-37. · 0.99 Impact Factor
