Biomedical subjects

E Oláh

Publications and source records attributed to E Oláh.

At least 19 recordsLinked to original sources

PubMed2006

Diagnostic significance of HLA-DQ typing in patients with previous coeliac disease diagnosis based on histology alone.

BACKGROUND: Coeliac disease is strongly associated with human leukocyte antigen (HLA)-DQ2 or DQ8 genotypes. The diagnosis is based on demonstrating crypt-hyperplastic villous atrophy, endomysial or transglutaminase antibodies and correlation of disease activity with gluten intake. AIM: To evaluate the clinical utility of HLA-DQ typing, when coeliac disease diagnosis had previously been established solely by histology. METHODS: HLA-DQ alleles, endomysial and transglutaminase antibodies were investigated and histology slides reviewed in 70 patients diagnosed 2-25 years earlier by small-intestinal biopsy but without measuring endomysial or transglutaminase antibodies. Patients without DQ2 or DQ8 or without unequivocal villous atrophy were followed-up on free diet by using serology and biopsies. RESULTS: All 40 endomysial/transglutaminase antibodies positive patients carried DQ2 or DQ8, and 39 of them had severe villous atrophy. Only 56% of patients without endomysial or transglutaminase antibodies positivity had DQ2 or DQ8 (P < 0.001). Seropositivity and relapse developed in 4 of 11 DQ2 positive but in none of 15 DQ2 and DQ8 negative patients on long-term gluten exposure. CONCLUSIONS: Coeliac disease diagnosis based solely on histology is not always reliable. HLA-DQ typing is important in identifying DQ2 and DQ8 negative subjects who need revision of their diagnosis, but it does not have additive diagnostic value if endomysial positivity is already known.

Adolescent↗

PubMed2003

Frequent methylation of p16INK4A and p14ARF genes implicated in the evolution of chronic myeloid leukaemia from its chronic to accelerated phase.

The frequency and mechanism of p16(INK4A) and p14(ARF) gene alterations were studied in cell samples from 30 patients with Philadelphia (Ph) chromosome-positive chronic myeloid leukaemia (CML), both at diagnosis and at the onset of the accelerated phase (AP) of the disease. No alterations in the p16(INK4A) or p14(ARF) genes were found in any of the chronic phase (CP) samples. DNA sequencing analyses detected p16(INK4A) or p14(ARF) mutations in 17 AP samples. All mutations were heterozygous without loss of the other allele. Aberrant methylation of the p16(INK4A) or p14(ARF) promoters was found in 14 of 30 AP samples. The most common situation was the simultaneous methylation of both promoters. Our data indicate that p16(INK4A) and p14(ARF) are primary targets for inactivation by promoter methylation in the acceleration of CML. Transcriptional silencing of the p16(INK4A) and p14(ARF) genes may be important in the conversion of CML from the CP to the AP.

Chromosome Disorders↗

PubMed2001

[Genetics of renal tumors].

The quintessence of malignant transformation is the genetic alteration of the tumor progenitor cell, i.e. somatic mutation. The genetic change appearing at chromosome and/or gene level results in the disturbance of the balance of cell proliferation and differentiation. In solid tumors, including renal tumors, the basic genetic mechanism proved to be the loss of function of a specific gene pair caused by loss of the particular chromosome or chromosomal region (monosomy, deletion) or by mutation of the gene. In the well studied Wilms' tumor-aniridia-syndrome the distal part of 11p13 region is deleted. The responsible gene is the WT-1 tumor suppressor gene, a Zn finger type transcription factor. In the majority of cases the mutation of this gene leads to the tumor formation without cytogenetically detectable deletion. For manifestation of the tumor the functional damage of both alleles is needed. In other histological types of renal tumors a great variation of chromosome losses and gains, as well as translocations can be identified. In Wilms tumor of embryonic origin, tumor suppressor genes located on the short arms of chromosomes 16 and 17 play a role in the pathogenesis. Besides, the significance of abnormal genomic imprinting of IGF2 and H19 genes located on 11p15 has also been confirmed. If a part of the embryonic cells do not regress, they may develop to papillary carcinoma together with the appearance of trisomies of chromosomes 7 and 17 and loss of Y. In the transformation process from papillary adenoma to carcinoma, duplication of several chromosomal regions is involved (3q+, +8, +12, +16, +20). The origin of renal carcinoma developing from normal nephron cells is associated with a deletion of 3p and 5q+, while during the progression of the disease further variable chromosome losses appear (6q-, 8p-, 14q-, -9). Tumor-specific cytogenetic and molecular genetic changes confirm the morphological classification of epithelial renal tumors pointing at the relation of the various entities or their independence. Based on cytogenetic alterations, a sequential predictive model of renal tumors can be developed. Individual types, together with joining and sequential appearance of aberrations are in line with the multistep mechanism of carcinogenesis. At the same time, the specific cytogenetic and molecular genetic changes confirm the diagnosis, provide further information about the histological type and progression of the disease. In hereditary cases, the members of the family at risk can be identified by recognizing the possibly associating clinical symptoms and/or by detecting the constitutional mutation of the gene using molecular genetic methods. Consequently, the genetic study of renal tumors plays important role not only in diagnosis and choosing adequate therapy but also in prevention of the disease.

Adenoma↗

PubMed2001

Molecular genetic abnormalities in the pathogenesis of human lung cancer.

In the past few years our knowledge of the molecular pathogenesis of lung cancer has significantly increased. There are several molecular mechanisms involved in the multistage carcinogenesis through which respiratory epithelial cells become preneoplastic and then invasive cancer. In this review we summarize some of these changes including, genomic alterations such as loss of heterozygosity and microsatellite alterations, autocrine-paracrine loops, alterations in oncogenes and tumor suppressor genes, tumor angiogenesis, aberrant promoter methylation and inherited predisposition to lung cancer. Translation of these findings to the clinic is also discussed.

Apoptosis↗

PubMed2001

Effect of myelopoietic and pleiotropic cytokines on colony formation by blast cells of children with acute lymphoblastic leukemia.

The aim of this study was to see whether pleiotropic or myeloid hematopoietic growth factors, which do not stimulate normal lymphoid cells, can induce proliferation of blast cells of the acute lymphoid leukemia (ALL) of childhood. Bone marrow cells of 13 children with untreated ALL (nine common ALL, two myeloid antigen positive ALL and two early T-cell ALL) formed colonies of leukemic blast cells in primary methylcellulose cultures. Spontaneous growth was observed in three of 13 cases, whereas phytohemagglutinin-stimulated leukocyte conditioned medium (PHA-LCM), a conventional source of various natural human cytokines, induced colony formation in ten of 13 cases. A similar rate of responsiveness was seen with recombinant human granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF) and stem cell factor (SCF); a combination of these three cytokines induced colony formation in all cases studied. The effect of these growth factors on colony formation seemed to be dose-dependent in some cases. Of the stimuli studied, GM-CSF induced the smallest number of colonies, whereas the effects of G-CSF, SCF and PHA-LCM were similar in this respect. Combination of cytokines proved to be even more efficient in inducing clonal proliferation of leukemic lymphoblasts. In double combinations, G-CSF and GM-CSF as well as G-CSF and SCF were able to potentiate each other's effects. Triple combination of these cytokines mediated the most potent growth stimulus. Our results demonstrate that myeloid and pleiotropic cytokines are able to stimulate clonal proliferation of pediatric leukemic lymphoblasts. This may present a potential hazard to children with ALL while on adjuvant therapy with hematopoietic growth factors. In vitro colony assays performed prior to or in parallel with the administration of hematopoietic growth factors to ALL patients may help to forecast their possible effects on leukemic cells in vivo.

Adolescent↗

PubMed2001

Allelic imbalance and microsatellite instability in BRCA1 associated breast and ovarian tumors.

We have investigated the involvement of microsatellite instability (MSI) and allelic imbalance (AI) at chromosome 13q and 17 in 41 breast and 41 ovarian carcinomas and their association with BRCA1 and BRCA2 gene mutations. MSI was detected in 20% of ovarian and 7% of breast tumors. AI at the BRCA1 locus was detected in 59% and 32% of ovarian and breast tumors, respectively. At the BRCA2 locus, AI rates were 49% and 44% for ovarian and breast tumors, respectively. Germline BRCA1 mutations, identified in 5 (12%) ovarian tumors and in one (2%) breast tumor were not associated with MSI. In only 2/5 BRCA1 positive tumors loss of the wild-type allele was observed. We conclude that BRCA1 mutation status is not associated with MSI and that MSI found in a fraction of ovarian tumors may reflect possible mutations in one of the DNA mismatch repair genes.

Aged↗

PubMed2000

A sporadic breast tumor with a somatically acquired complex genomic rearrangement in BRCA1.

Germ-line mutations in BRCA1 cause a substantial proportion of inherited breast cancer, and most result in inactivated BRCA1 proteins upon translation. Tumours developing in BRCA1 mutation carriers generally show loss of the wild-type allele. However, acquired inactivating mutations in BRCA1 in non-inherited breast tumours showing loss of heterozygosity at the gene locus have not been detected so far. Here we provide evidence that such mutations can be detected in a small proportion of breast tumours. Prompted by recent reports of Alu-mediated large genomic rearrangements in BRCA1, we have investigated whether such rearrangements might occur in sporadic breast cancer as well and have been missed thus far by traditional PCR-based mutation screening technology. To this end, we performed Southern blot analysis of 81 apparently sporadic breast tumours using probes covering exons 6-24 and 3 restriction enzymes. We identified 1 case with an acquired rearrangement (1.2%), indicating that BRCA1 inactivation through changes in the primary genomic sequence of the gene is uncommon in breast cancer. Genes Chromosomes Cancer 27:295-302, 2000.

Aged↗

PubMed2000

Alterations of P53 and RB genes and the evolution of the accelerated phase of chronic myeloid leukemia.

Using the single-strand conformation polymorphism and heteroduplex analyses, the P53 and RB genes were analyzed in cell samples from twenty-eight patients with chronic myeloid leukemia (CML) both at diagnosis and at the onset of accelerated phase (AP) of the disease. No alterations of the P53 or RB genes were found in any of the chronic phase (CP) samples. Structural abnormalities of the P53 gene were observed in ten of twenty-eight AP samples within exons 4, 5, 7 and 9. Of the ten cases of AP disease with altered P53 genes, five patients also suffered from the deletion of the other allele. Alterations of the RB gene could be detected in six AP samples, and aberrant band patterns were found in the analysis of exons 2, 3, 4, 6, 7, 13, 14, 17, 21 and 26. Among the six AP samples with structural abnormalities of the RB gene, two showed the loss of the other allele. It is of note that alterations of both P53 and RB genes were observed in two AP samples. Our data strongly suggest that abnormalities of the P53 and RB genes and acceleration of CML are linked events in some cases of AP.

Adult↗

PubMed1999

Deletion of the sep1(+) forkhead transcription factor homologue is not lethal but causes hyphal growth in Schizosaccharomyces pombe.

sep1(+), the Schizosaccharomyces pombe homologue of the forkhead/HNF-3 transcription factors, plays a role in the cell separation at the end of mitosis. Its inactivation by interruption of the coding region is not lethal but renders the sister cells unable to separate and causes hyphal growth. The persistence of unsplit septa indirectly interferes with the establishment of new cell polarity by preventing cell growth at cell tips. Temporal changes in the transcription of sep1(+) correlate with the cell cycle progression showing maximal expression at the peak of cell plate index in synchronized cultures. The constitutive overexpression of sep1(+) has no discernible effect on the morphology and physiology of the cells.

Cell Polarity↗

PubMed1999

[Hereditary neoplastic diseases (genetic predisposition and cancer syndromes)].

After one decade of molecular genetic studies, little doubt remains that cancer is a genetic disease. While mutations in somatic cells may cause cancer, they don't carry forward to the next generation. In fact, most cancers arise in this way. In some individuals mutations in cancer related genes may be present at the constitutional level, inherited from one of the parents. An individual who carries a mutant allele of an inherited cancer gene has a variable risk of cancer that is influenced by other genetic and non-genetic factors (such as other cellular genes, dietary, lifestyle, and environmental factors). Collectively, the syndromes affect about 1% of cancer patients. During the past decade about 25 different cancer susceptibility genes have been reported to be linked to the known hereditary cancer syndromes. Over the period of the last three to five years, studies of the specific mutations responsible for these syndromes and the cellular signaling pathways disrupted by the mutant proteins have begun to provide unprecedented insights into the molecular origin and pathogenesis of inherited and sporadic forms of cancer. This article reviews the cancer susceptibility genes and cancer syndromes, particularly those associated with common malignancies (breast, prostate and colorectal carcinomas). Results of the mutation analysis in BRCA1 and BRCA2 genes of Hungarian breast/ovarian cancer families will be briefly discussed. These data indicate a strong founder effect for some mutations of BRCA1 gene in Hungary. As a results of recent publicity of discoveries of molecular genetics--particularly those related to common malignancies--due to publicity in the scientific and the lay press awareness and demand for predictive DNA tests have dramatically increased worldwide over the past 3 years. The author, as a member of the Breast Cancer Linkage Consortium, shares the consensus view that genetic testing and genetic counseling for cancer risk together with surveillance and management should for the present be offered only through specialist clinical genetic departments as part of a research evaluation.

DNA, Neoplasm↗

PubMed1999

Biclonal chromosomal aberrations in a child with myelodysplastic syndrome.

Hematological malignancies and premalignant diseases are generally of monoclonal origin. The prognostic and therapeutic significance of finding two genetically independent clones remains to be determined. We followed a case of childhood myelodysplastic syndrome showing biclonal chromosomal abnormalities (+8, -7) by conventional cytogenetic examination and double target fluorescence in situ hybridization (FISH). A 7-year-old girl presented with Plaut-Vincent angina and leukopenia. The cytogenetic aberration of +8 was the first sign to suggest MDS. Serial bone marrow controls, prompted by a progressive clinical course detected myelodysplastic changes and a new clonal aberration (-7). The presence of -7 and +8 in two independent clones was verified by double-target FISH. While at diagnosis and during cytokine treatment more cells showed +8, after successful all-trans retinoic acid (ATRA) therapy, the clone with -7 predominated. Following allogeneic bone marrow transplantation the patient displayed donor-derived hematopoesis. Our data stress the significance of cytogenetic and FISH examinations in detecting specific genetic abnormalities and progressive clonal changes as an indicator and guideline for therapy. Different cell clones characterized by different genetic changes might be associated with different biologic features reflected in their response to treatment.

Angina Pectoris↗

PubMed1998

Fluorescence in situ hybridization reveals trisomy 2q by insertion into 9p in hepatoblastoma.

Cytogenetics and fluorescence in situ hybridization (FISH) of a hepatoblastoma are presented. The results of standard chromosome analysis were as follows: 47,XY,+2,add(4)(q35),-9,+20[10]. FISH with the use of whole-chromosome paints revealed partial trisomy of the long arm of chromosome 2 by insertion into chromosome 9. Comparison of the G-banded metaphases with metaphase FISH led to a reinterpretation of the karyotype as: 47,XY,add(4)(q35),der(9)ins(9;2)(p22;q?21q?25),+20. This case supports previous observations that the critical region of trisomy 2 lies between 2q21 and 2qter and shows how partial trisomy 2q may evade detection in G-banded metaphases.

Child, Preschool↗

PubMed1998

Changes in oncogene expression implicated in evolution of chronic granulocytic leukemia from its chronic phase to acceleration.

Expression of nine oncogenes was investigated in cell samples from fifteen patients with Philadelphia chromosome (Ph)-positive chronic granulocytic leukemia (CGL) both at diagnosis and at the onset of accelerated phase (AP) of the disease. The bcr-abl fusion gene, the H-ras gene and the c-myb gene were universally expressed. In comparison with the chronic phase (CP) of the disease, an increase in the levels of bcr-abl-, c-myb- and H-ras-related transcripts was found in three, two and three AP samples, respectively. Elevation of the bcr-abl-related message was associated with duplication of the Ph chromosome and amplification of the bcr-abl fusion gene in one AP sample. No CP samples were positive for c-myc or c-sis expression. On the contrary, c-myc and c-sis were expressed in three and four AP samples, respectively. The presence of c-myc-related transcript was associated with trisomy 8 with or without amplification of the c-myc oncogene in leukemia cells of two patients with CGL in AP. No changes of oncogene expression were found in four AP samples. However, we observed deletions of chromosome 13 and 17 or i(17q) in three of them, suggesting that tumor suppressor gene alterations may also be responsible for the development of AP of CGL. Our data indicate that heterogeneous alterations in oncogenes and tumor suppressor genes accompany the evolution of CGL-CP to the AP of the disease.

Acute-Phase Reaction↗

PubMed1997

[2q21-qter trisomy in hepatoblastoma].

Cytogenetic findings and fluorescens in situ hybridization results of a hepatoblastoma of a boy of two and half years of age are presented. Cytogenetic analysis and fluorescens in situ hybridization technique were performed using tumor tissue obtained by biopsy. The direct culture was harvested after 16 hour colcemid treatment. The results of G-banding were as follows: 47,XY,add(4) (q26),-9,+20. There were considerable variation in the degree of condensation and hence in the number of visible G-bands both between metaphases and between homologous chromosomes in the same metaphases. Fluorescens in situ hybridisation were carried out by whole chromosome painting probes: 2,3,4, and 20. The karyotype of the malignant cells was adjusted accordingly: 47,XY,der(4)(q35),dir ins(9;2)(p22;q?21q?25),+20. The results confirm the most common primary chromosome abnormalities in hepatoblastoma are the following: trisomy 2, trisomy 20 and 4q structural rearrangement. Fluorescens in situ hybridization confirms the importance of trisomy 2q21-qter in hepatoblastoma. Authors recommend the use of fluorescens in situ hybridization to correct any tumor karyotype with difficult or ambiguous chromosome morphology.

Biopsy↗

PubMed1997

Diagnostic and prognostic significance of chromosome abnormalities in childhood acute lymphoblastic leukemia.

Current intensive chemotherapies cure about 70% of the children with ALL. On the other hand a significant number of the children are not cured despite intensive treatment. At the same time some highly curable patients are treated too intensively and suffer from unnecessary side effects of the chemo- and radiotherapy applied. In order to further improve the therapeutic results in this disease, we have to distinguish between the cases with a better and a worse prognosis. The initial karyotype (both numerical and structural chromosome abnormalities) proved to be one of the most reliable prognostic parameters, leading to the suggestion of developing genotype-specific therapies. Although the prognosis in patients with pseudodiploid karyotype is usually unfavorable, a significantly better prognosis can be observed in those with more than 50 chromosomes. Because the latter patients can achieve remission on a metabolite-based therapy, the toxic effects of more aggressive chemotherapy with anthracyclines and genotoxic agents can be avoided; thus, the reliable and accurate identification of patients with > 50 chromosomes is of particular importance. For this purpose three methods: chromosome analysis, DNA flow cytometry, and fluorescence in situ hybridization can be used. In 1993 it was decided to develop a comprehensive nationwide project in order to perform the initial genetic analysis of all ALL children diagnosed in the hematological/oncological centers of Hungary. Here the data obtained on 187 ALL patients diagnosed in the period from 1993 to 1995 are presented. In about 75% of patients (in 140 of 187) chromosome analysis was performed, in 78 cases (55.7%) successfully. The proportion of patients with abnormal karyotype was 36 of 78 (46.1%), and hyperdiploidy with more than 50 chromosomes was detected in 13 of 78 (16.6%) children. The lower ratio of hyperdiploid cases in our patients as compared to the data in the literature may be due to technical difficulties and the small number of patients studied, but it may reflect real geographic characteristics. Using flow cytometry, seven of 31 patients investigated (22.5%) proved to be hyperdiploid with a DNA index above 1.16. A higher ratio of hyperdiploid patients in this study calls attention to the significance of simultaneous application of the two methods. Taken together, 16 of 80 (20.0%) successfully studied patients proved to be hyperdiploid (> 50 chromosomes and/or DNA index above 1.16). The pattern of chromosome involvement in our study determined by chromosome analysis and/or FISH technique proved also to be different from the data of large international series. In addition to trisomies of chromosomes 4, 6, 10, 14, 17, 18, 21, and X, which are known to be the most frequently involved chromosomes, trisomies of chromosomes 3, 8, 11, and 13 were also observed with a high frequency. Comparison of survival curves of various cytogenetic subgroups showed a significant difference between diploid-pseudodiploid and diploid-hyperdiploid A (with 47-50 chromosomes) subgroups. No favorable prognosis of hyperdiploid patients (> 50 chromosomes) could be proved. Because of the small number of patients studied, prognostic differences of cytogenetic subgroups need further confirmation. The clinical and genetic differences observed, however, call attention to the necessity for further genetic studies of ALL patients in Hungary, because these differences may reflect real geographic characteristics and may be related to different environmental mutagen/carcinogen effects of the given geographic area. It is essential to determine whether or not these differences really exist and if they do to reveal the causes leading to these differences. In our view this is one of the routes by which the therapeutic results in childhood ALL can be further improved simultaneously with the avoidance of early and late toxicity of chemotherapy.

Child↗

PubMed1997

Loss of heterozygosity at 7q31 in breast cancer: results from an International Collaborative Study Group. The Breast Cancer Somatic Genetics Consortium.

Loss of heterozygosity (LOH) at 7q31 has been claimed to occur in over 80% of all breast cancers and to be of prognostic significance. This would make this genetic alteration the most common event observed in breast cancer to date. Others, however, have been unable to confirm this high incidence. In this multicenter study, we have complied LOH scorings for three polymorphic markers for 7q31-q32 in 683 breast tumors. Although some significant differences between centers existed, no center reported more than 40% LOH, and the average rate was 19%. Disease-free and overall survival of the patients whose tumors carried LOH at 7q31 did not differ significantly from those patients whose tumors showed retention of heterozygosity at 7q31. In a double-blind scoring of a subset of the raw data, an average discordant rate of LOH scoring of 12% was observed. While startling in itself, this was unable to explain the variation among centers, nor the difference with the initially reported high rate of LOH. We conclude that LOH at 7q31 is not important as a genetic alteration in breast cancer as originally suggested, nor a strong determinant of disease outcome.

Breast Neoplasms↗

PubMed1997

Idiopathic scoliosis--new surgical methods or search for the reasons.

Idiopathic scoliosis (IS) is a deformity of the spine whose aetiology is unknown despite of extensive clinical and basic research work. The significance of this disease lies in the consequences of a spine deformity (deformation of the chest, compromise of the cardio-pulmonar function, compression of the neurological elements, severe somatic and psychological sufferings). According to statistical data, one third of the idiopathic scoliotic cases progress and need surgical intervention. Cotrel and Dubousset introduced the three dimensional correction surgical method for the treatment of spine deformities in 1983 (CD method). The authors report on the application of the CD method for the treatment of IS from 1991 to date. After the operation of 36 patients they give an account of good results and report on the modifications of the surgical technique on the basis of their experiences. Aware of the late consequences of the surgical treatment of IS the authors started with the investigation of the aetiology of the disease in order to introduce a causal treatment. As for the aetiological background of IS, data on the role of heritable factors were relevant only. They gave a hint to start with studies aimed at the investigation of genetic determinants of the syndrome. I aberration of chromosome #10 [karyotype: inv(10)(p11q26)]. In one of the cases there was a multiple familial occurrence of the syndrome coupled with the same anomaly of the karyotype. The probands' father and grandfather all had the same pattern of scoliotic deformity and the same aberrant karyotype of chromosome #10 was found both in the proband and his father. Preparation of genomial DNA from peripheral blood of the patients was started. Fragment length polymorphism (RFLP) examination with PCR technique using oligonucleotide primers specific for chromosome #10 and for regulatory genes of left-right body assymetry is underway.

Chromosome Aberrations↗

PubMed1996

Special features of childhood and juvenile thyroid carcinomas.

A retrospective analysis was conducted on 36 patients who underwent surgery for childhood or juvenile thyroid cancers and who were regularly followed up during the course of 30 years. The biological properties and late prognosis of these patients were assessed, and the clinical and morphological characteristics of the tumors were examined. The distribution of the DNA content in the tumor cells was compared with that in adult tumor cells, and the results of cytogenetic tests performed on mothers operated on for thyroid tumors and their children are also discussed.

Adenocarcinoma, Follicular↗