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H Kiaris

Publications and source records attributed to H Kiaris.

36 records · Page 2Linked to original sources
PubMed1996

Transcriptional activation of H-ras, K-ras and N-ras proto-oncogenes in human bladder tumors.

In this study we demonstrate the involvement of ras oncogenes in bladder cancer at the level of RNA overexpression. We examined 26 bladder specimens, consisting of paired tumor and adjacent normal tissue and found that H-ras transcripts were overexpressed in 39% of the specimens while K-ras and N-ras in 58% of total specimens. Each tumor specimen had a unique pattern of overexpression for the three ras genes. A competitive-RT-PCR was employed for H-ras and a beta-actin control gene was co-amplified with K-ras or N-ras genes. These results indicate that the involvement of ras oncogenes in bladder cancer could be relative to overexpression of these genes.

Genes, ras↗
PubMed1996

Instability at the H-ras minisatellite in human atherosclerotic plaques.

The development of atherosclerotic plaques is characterised by the accumulation of lipids and the proliferation of smooth muscle cells. At the subcellular level, the abnormal expression of cytokines and growth factors, as well as the presence of transforming oncogenes, has been recognised and associated with the disease. The aim of the present study was to investigate whether instability at a minisatellite region located downstream of the H-ras proto-oncogene possessing enhancer activity, is a detectable phenomenon in atherosclerotic plaques. Thirty specimens were analysed by polymerase chain reaction (PCR) in order to reveal alterations of the repetition number and by restriction fragment length polymorphism (RFLP) with BstNI restriction endonuclease for the detection of point mutations within the 28 bp core repetitive element. No point mutations were found among the 30 cases tested; however, alterations of the repetition number of the core were detected in 5 (17%) cases. Our results suggest that instability at the H-ras minisatellite may be associated with development of the disease.

Aged↗
PubMed1996

Loss of heterozygosity and microsatellite instability in human atherosclerotic plaques.

Several lines of evidence suggest that mutation events may be involved in the development of atherosclerosis. The aim of the present investigation was to perform an allelotype analysis in 30 atherosclerotic lesions in order to reveal any deletions involved in the development of the disease. Eighteen chromosomal arms were tested by one microsatellite marker located on each arm and allelic imbalance in at least one marker was observed in 7 (23%) cases. Furthermore, the analysis revealed the presence of microsatellite instability (MI) in 10 (33%) cases, suggesting that an increase in the mutation rate may be involved in the formation of the plaque. These results highlight the mutation concept for the atherogenesis and suggest that LOH and MI may be involved in the development of the disease.

Arteriosclerosis↗
PubMed1996

Quantitation of the allelic imbalance provides evidence on tumour heterogeneity: a hypothesis.

The observation of loss of heterozygosity (LOH) in tumours represents a useful clue to the presence of tumour suppressor genes (TSGs). However, analysis of this phenomenon is often complicated by tumour heterogeneity and the presence of DNA from adjacent normal tissues. The present study suggests a quantitative approach for measurement of LOH which may help to distinguish between these possibilities and to provide clues for the heterogeneous process of tumour progression. We applied this methodology to a laryngeal tumour with LOH at markers D9S171, D9S157, D8S87 and THRA1 and found that LOH at D9S171 is the commonest aberration among the tumour cells, while LOH at the THRA1 marker is present in only a small subset of the tumour cells. It is likely that LOH at D9S171 occurs early uin tumour development while LOH at the rest of the markers tested occurred later resulting in the generation of heterogeneous cell populations.

Alleles↗
PubMed1996

Microsatellite instability in human atherosclerotic plaques.

The aetiopathology of atherosclerosis remains obscure. Although histologically the accumulation of lipids and the proliferation of the smooth muscle cells represents the main feature of the disease, little is known as regards the molecular alterations associated with the atherosclerotic lesions. In the present study we investigated whether an elevated mutational rate is detectable in human atheromatous plaques. Thirty specimens were assessed for microsatellite instability (MI) by 7 microsatellite markers and MI, in at least one marker, was apparent in 6 (20%) cases. Our data suggest that decreased fidelity in DNA replication and repair may be associated with the development of the disease.

Aged↗
PubMed1996

Mutations and expression of the ras family genes in leukemias.

The levels of expression and the incidence of codon 12 point mutations of the ras family genes were studied in 18 cases of leukemia, seven with acute myeloblastic leukemia (AML), three with acute lymphoblastic leukemia (ALL), four cases with chronic myelogenic leukemia (CML) and four cases with chronic lymphocytic leukemia (CLL). Elevated expression of the ras genes was found for 39%, 61% and 67% of the specimens for the H-ras, K-ras and N-ras, respectively. A trend was found between the overexpression of the N-ras gene and the acute leukemias: all 10 acute leukemias exhibited overexpression of the N-ras gene, while only two of the CML cases, both in blastic crisis, showed elevated levels of the N-ras gene. Codon 12 point mutations at the N-ras gene were found in two of seven cases (28%) with AML and one of four cases (25%) with CML. The only K-ras codon 12 point mutation was found in a patient with CLL. No mutations were found in the codon 12 of H-ras. Our data suggest that apart from the point mutations, overexpression of the ras family genes is important in the development of the disease.

Codon↗
PubMed1995

Loss of heterozygosity at 9p and 17q in human laryngeal tumors.

Recent investigations revealed that the 9p arm and 17q arm of human chromosomes harbour tumour suppressor genes (TSGs) with an important role in multistage carcinogenesis. At the 9p arm is located the p16 (MTS1) TSG and probably others with an effect on various human tumours such as acute lymphoblastic leukaemia, bladder cancer, gliomas, malignant mesotheliomas, melanomas and non-small cell lung carcinomas. In addition, the 17q arm harbours BRCA1 TSG which is responsible for approximately 80% of the familial breast/ovarian cancer cases. In order to investigate the implication of these performed a loss of heterozygosity (LOH) analysis with 10 polymorphic microsatellite markers (three at the 17q arm surrounding the BRCA1 region and seven at the 9p arm). Fourteen of the 17 (82%) tumours exhibited deletions at 9p. The highest incidence of LOH (6/13, 46%) was found for the marker D9S157 at 9p22. One sample exhibited deletion of all the informative markers tested indicating deletion of the complete 9p arm. No homozygous deletions were found. LOH at the 17q arm near the BRCA1 locus was found in 6 (35%) among 17 specimens. The results of this study indicate that allelic deletions at 9p are frequent in the development of laryngeal tumours. The highest incidence of LOH was found for the marker D9S157 which is near, but distinct from the location of p16 (MTS1) tumour suppressor gene, indicating the presence of multiple tumour suppressor genes within this chromosomal region. In addition, BRCA1 TSG is implicated in the development of laryngeal tumours.

Carcinoma, Squamous Cell↗
PubMed1995

Instability at the H-ras minisatellite is associated with the spontaneous abortion of the embryo.

Recently we have shown that microsatellite instability (MI) is a detectable phenomenon in aborted embryonic tissues. In the present study we investigated if instability is also detectable in a minisatellite located at the 3'-end of the H-ras proto-oncogene, affecting either the repetition number of the 28-bp core generating larger or smaller alleles or its sequence creating a detectable restriction fragment length polymorphism (RFLP). Among 30 aborted embryonic tissues, alterations at the repetition number of the core were found in 3 (10%) while point mutations were detected in 7 (23%) cases. These results indicate that structural alterations of the H-ras minisatellite may be associated with the rejection of the embryo.

Abortion, Spontaneous↗
PubMed1995

Microsatellite instability in squamous cell carcinoma of the head and neck.

Genomic instability or microsatellite instability (MI) in simple repeated sequences was initially recognised in colonic carcinomas and subsequently in other tumours. MI has been associated with mutations in genes concerned with replication and DNA repair. We investigated 34 microsatellite markers in squamous cell carcinoma of the head and neck (SCCHN). Fifty-six tumours, were studied, of which 25 were investigated with ten or more microsatellite markers. In this study we consider two or more microsatellite alterations in a tumour to be diagnostic of MI. We demonstrated that 7/25 (28%) of the tumours had MI at two or more loci and three of these tumours exhibited evidence of 20 or more loci with MI. No correlations were found between MI and previous treatment, site, histological differentiation, positive nodes at pathology, a history of alcohol intake or survival. MI has been demonstrated in T1N0 stage tumours, indicating that these changes may occur early in the disease process. A negative correlation was found between MI and a history of smoking (P = 0.02). Two or more markers of MI were found in three of four non-smokers compared with one of 13 in the smoking group of patients, which suggests a novel mechanism of carcinogenesis in non-smokers.

Carcinoma, Squamous Cell↗
PubMed1995

Mutations, expression and genomic instability of the H-ras proto-oncogene in squamous cell carcinomas of the head and neck.

Mutation and overexpression are the main activating mechanisms for the ras family of genes in human cancer and the variable tandem repeat (VTR) located at the 3' end of H-ras has been associated with this risk. In the present study, we have analysed the relative levels of expression of H-ras mRNA in 26 samples of squamous cell carcinomas of the head and neck (SCCHN) by competitive reverse transcription-polymerase chain reaction (competitive RT-PCR) and also investigated whether there is an association between ras expression and alterations in the 3'-VTR region. In addition, we have studied the incidence of point mutations in codon 12 of H-ras, codons 12 and 13 of K-ras and codon 61 of N-ras in 120 SCCHN samples. Our results indicate that only two samples carry mutations, both of which are located in codon 12 of K-ras, but that overexpression of the H-ras proto-oncogene is a frequent event in SCCHN [54% (14/26)] and is associated with a favourable prognosis: 3 of 14 patients with H-ras overexpression have died, whereas 9 of 12 patients with low levels of H-ras expression have died. We have also undertaken an analysis of these results together with our previous investigations on microsatellite instability and loss of heterozygosity in SCCHN, but no associations were found. We therefore conclude that ras mutations are an infrequent event in the progression of the SCCHN in the Western world, whereas overexpression of the H-ras proto-oncogene is a common event.

Base Sequence↗
PubMed1995

Allelotype of squamous cell carcinoma of the head and neck: fractional allele loss correlates with survival.

Allelic imbalance or loss of heterozygosity (LOH) studies have been used extensively to identify regions on chromosomes that may contain putative tumour-suppressor genes. We have undertaken an extensive allelotype of 80 specimens of squamous cell carcinoma of the head and neck (SCCHN) using 145 polymorphic microsatellite markers on 39 chromosome arms. Allelic imbalances were found most frequently on chromosome arms 3p, 9p, 17p and 18q with over 45% LOH and imbalances on 1p, 1q, 2p, 5q, 6p, 6q, 8p, 8q, 9q, 11q, 13q, 17q and 19q were found in more than 20% of SCCHN. These LOH data were analysed against a range of clinicopathological parameters which included previously untreated and previously treated tumours; correlations were found between LOH on 9q and nodes at pathology (P = 0.02) and between histopathological grade and LOH on 12q (P = 0.02) and 13q (P = 0.01). In the group of previously untreated tumours, a correlation was found between site of tumour and LOH on 3p (P = 0.019), and 8p (P = 0.029), while TNM staging correlated with LOH on 3p (P = 0.019) and 17p (P = 0.016). Fractional allele loss (FAL) was calculated for 52 tumours with LOH data on nine or more chromosomal arms and found to have a median value of 0.22 (range 0.0-0.80). Correlations were found between FAL > median value and nodes at pathology (P = 0.01) and tumour grade (P = 0.06), demonstrating that advanced tumours with lymph node metastasis often had LOH at multiple sites. FAL > median value was found to correlate with a poor survival (P < 0.03) and, furthermore, FAL > median value correlated with poor survival in the previously untreated patients (P < 0.019). These results indicate that assessment of the accumulation of genetic damage, as provided by allelotype data, provides a useful molecular indicator of the tumour behaviour and clinical outcome.

Alleles↗
PubMedDate not supplied

Antagonists of growth hormone-releasing hormone inhibit the growth of U-87MG human glioblastoma in nude mice.

Antagonists of growth hormone-releasing hormone(GH-RH)inhibit the growth of various cancers by mechanisms that involve the suppression of the insulin-like growth factor (IGF)-I and/or IGF-II. In view of the importance of the IGF system in glioma tumorigenesis, the effects of GH-RH antagonists MZ-5-156 and JV-1-36 were investigated in nude mice bearing subcutaneous and orthotopic xenografts of U-87MG human glioblastomas. After 4 weeks of therapy with MZ-5-156 or JV-1 -36 at the dose of 20 microg/day per animal, the final volume of subcutaneous U-87MG tumors was significantly (P < .01) decreased by 84% and 76%, respectively, as compared with controls. Treatment with GH-RH antagonists also reduced tumor weight and the levels of mRNA for IGF receptor type I (IGFR-I). A reduction in the mRNA levels for IGF-II was found in tumors of mice treated with MZ-5-156. Treatment with MZ-5-156 or JV-1 -36 also extended the survival of nude mice implanted orthotopically with U-87MG glioblastomas by 81% (P < .005) and 18%, respectively, as compared with the controls. Exposure in vitro to GH-RH antagonists MZ-5-156 or JV-1 -36 at 1 microM concentration for 24 hours decreased the tumorigenicity of U-87MG cells in nude mice by 10% to 30% and extended the latency period for the development of subcutaneous palpable tumors by 31% to 56%, as compared with the controls. Exposure of U-87MG cells to GH-RH antagonists in vitro also resulted in a time-dependent increase in the mRNA levels of IGFR-II or a decrease in the mRNA levels of IGFR-I. mRNA for GH-RH was detected in U-87MG cells and xenografts implying that GH-RH may play a role in the pathogenesis of this tumor. Our results suggest that GH-RH antagonists MZ-5-156 and JV-1-36 inhibit the growth of U-87MG human glioblastoma by mechanisms that involve the suppression of IGF system. Antagonistic analogs of GH-RH merit further development for the treatment of malignant glioblastoma.

Animals↗
PubMedDate not supplied

Detection of Epstein-Barr virus genome in squamous cell carcinomas of the larynx.

Epstein-Barr virus (EBV) is a B-lymphotropic virus with a tumorigenic potential. EBV infection has been recognized as the main cause of nasopharyngeal carcinoma and Burkitt's lymphoma. The aim of our study was to determine the incidence of EBV in squamous cell carcinomas of the larynx. We employed for our analysis a sensitive polymerase chain reaction (PCR) assay, followed by restriction fragment length polymorphism (RFLP) for further confirmation of the specificity of the PCR-amplification reaction. Our analysis revealed that 9 of 27 (33%) specimens harbored the EBV genome in the tumor tissue while only 4 (15%) specimens from adjacent normal tissue exhibited evidence of EBV infection. Three were EBV positive for both normal and tumor tissue. No association has been found with disease stage, histological differentiation and nodes at pathology. The relatively high incidence of EBV in the tumor tissue (33%) of patients with laryngeal cancer, as compared to the low (15%) incidence of the virus genome detected in the adjacent normal tissue of the patients, indicates a probable role of EBV in the development of the disease.

Base Sequence↗
PubMedDate not supplied

Ras oncogene activation in benign and malignant colorectal tumours.

Activation of ras family genes has been implicated in colorectal tumourigenesis. K-ras is the most frequently altered gene in colorectal neoplasias. The major activating mechanism involves point mutations, although recent data have shown a more complex role, through qualitative alterations. The incidence of codon 12 mutations in K-ras and N-ras genes in patients with primary colorectal adenocarcinomas was examined. We employed a non radioactive PCR-RFLP assay for the detection of mutant samples. We found a significant K-ras activation at codon 12 (38%), while the incidence of N-ras codon 12 activation was limited to 1.5%. These results are in agreement with previous reports. Association has been investigated with clinical and histopathological parameters. Point mutations appear to be more frequent in carcinomas with elements indicating a development from adenoma, in ages below 50 years, in females who had the tumor located at the rest of the large bowel in comparison with rectosigmoid and in higher grade of differentiation.

Adenocarcinoma↗