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Dive into the research topics where Laura Vízkeleti is active.

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Featured researches published by Laura Vízkeleti.


International Journal of Cancer | 2007

EGFR gene copy number alterations in primary cutaneous malignant melanomas are associated with poor prognosis

Zsuzsa Rákosy; Laura Vízkeleti; Szilvia Ecsedi; Zoltán Vokó; Ágnes Bégány; Márk Barok; Zsuzsa Krekk; Mónika Gallai; Zoltán Szentirmay; Róza Ádány; Margit Balázs

Copy number alterations of the epidermal growth factor receptor (EGFR) gene have been extensively analyzed in different cancers, but no data are available for primary malignant melanoma. The aim of the present study was to simultaneously investigate the EGFR gene and chromosome 7 copy number alterations in 81 cutaneous malignant melanomas by interphase FISH and correlate the data with clinicopathological parameters of patients. EGFR mRNA levels were detected by Affymetrix GeneChip Human Genome U133 Plus 2.0 expression arrays for 16 lesions. Both increased gene dosage and chromosome 7 alterations were found in 70% of tumors. Extra EGFR copies were detected in an additional 10% of samples. Polysomy 7 was associated with EGFR gene amplification. Significant correlation was found between EGFR alterations and histological subtypes, tumor thickness, ulceration and metastases formation. Amplification was significantly higher in lesions that developed metastases within 2 years after surgical excision of the primary tumor. Gene copy alterations were associated with elevated mRNA expression in 77% of lesions when compared to tumors with disomic EGFR status, the correlation was not directly proportional to gene copy number. Associations between protein expression and mRNA levels were even less prominent. In conclusion, our study indicates that amplification of the EGFR gene and polysomy 7 are frequent alterations in primary melanomas and are associated with bad prognosis. Further studies are required to clarify whether melanoma patients with EGFR alterations can benefit from anti‐EGFR therapy.


Modern Pathology | 2009

Characterization of candidate gene copy number alterations in the 11q13 region along with BRAF and NRAS mutations in human melanoma

Viktória Lázár; Szilvia Ecsedi; Attila G Szöll odblac; si; Réka Tóth; Laura Vízkeleti; Zsuzsa Rákosy; Ágnes Bégány; Róza Ádány; Margit Balázs

Amplification of the 11q13 chromosomal region is a common event in primary melanomas. Several candidate genes are localized at this sequence; however, their role in melanoma has not been clearly defined. The aim of this study was to develop an accurate method for determining the amplification pattern of six candidate genes that map to this amplicon core and to elucidate the possible relationship between BRAF, NRAS mutations and CCND1 copy number alterations, all of which are key components of the MAP kinase pathway. Characterization of gene copy numbers was performed by quantitative PCR and, as an alternative method, fluorescence in situ hybridization was used to define the CCND1 amplification pattern at the single cell level. Samples with amplified CCND1 (32%) were further analyzed for copy number alterations for the TAOS1, FGF3, FGF19, FGF4 and EMS1 genes. Coamplification of the CCND1 and TAOS1 was present in 15% of tumors and was more frequent in ulcerated lesions (P=0.017). Furthermore, 56% of primary melanomas had either BRAF or NRAS mutations, but these two mutations were not present in any of the lesions analyzed. Of these cases, 34% also had CCND1 amplification. There was a significant relationship between NRAS activating mutations and UV exposure (P=0.005). We did not find correlations between CCND1 gene amplification status and any of the patients’ clinicopathological parameters. However, CCND1 amplification simultaneously with either BRAF or NRAS activation mutations was observed mainly in primary tumors with ulcerated surfaces (P=0.028). We assume that coamplification of these candidate genes in the 11q13 region or CCND1 gene alterations along with either BRAF or NRAS mutations might be more important for prognosis than the presence of these alterations alone.


Tumor Biology | 2012

The role of CCND1 alterations during the progression of cutaneous malignant melanoma

Laura Vízkeleti; Szilvia Ecsedi; Zsuzsa Rákosy; Adrienn Orosz; Viktória Lázár; Gabriella Emri; Viktória Koroknai; Tímea Kiss; Róza Ádány; Margit Balázs

It is well demonstrated that CCND1 amplification is a frequent event in the acral subtype of cutaneous malignant melanoma; however, its role in the other subtypes of the disease is still controversial. The objectives of this study were to evaluate genetic and expression alterations of CCND1 with a focus on primary cutaneous melanomas, to define BRAF and NRAS mutation status, and correlate the data with clinical–pathological parameters. CCND1 amplification was associated with ulceration and the localization of the metastasis. After correction for the mutation state of BRAF and NRAS genes, CCND1 amplification in samples without such mutations was associated with ulceration and sun exposure. The cyclin D1 (CCND1) mRNA level decreased in lesions with multiple metastases and was correlated with both the mRNA levels and mutation state of BRAF and NRAS genes. Primary melanomas with BRAFV600 or NRASQ61 mutations exhibited lower CCND1 mRNA level. CCND1 protein expression was associated with Breslow thickness, metastasis formation, and shorter survival time. These observations suggest that CCND1 alterations are linked to melanoma progression and are modified by BRAF and NRAS mutations. Our data show that CCND1 amplification could have a prognostic relevance in cutaneous melanoma and highlight that altered CCND1 gene expression may influence the metastatic progression, survival, and the localization of metastases.


Cancer Genetics and Cytogenetics | 2008

Characterization of 9p21 copy number alterations in human melanoma by fluorescence in situ hybridization

Zsuzsa Rákosy; Laura Vízkeleti; Szilvia Ecsedi; Ágnes Bégány; Gabriella Emri; Róza Ádány; Margit Balázs

Alteration of the CDKN2A (alias p16) tumor suppressor gene, located on 9p21, occurs frequently in familial and sporadic melanomas. Beside CDKN2A, other genes (e.g., CDKN2B, and ARF/p14(ARF), long considered distinct from CDKN2A) on this locus are often deleted or mutated in a large number of tumors including glioma, bladder cancer, and lung cancer. The aim of this study was to evaluate the deletion pattern of the 9p21 locus on a cell-by-cell basis in a large number of melanoma samples using fluorescence in situ hybridization (FISH). In an analysis of 81 primary lesions targeting the 9p21 region and chromosome 9 centromere, high frequency of 9p21 loss (84%) was found. Deletion of 9p21 was present in both early- and late-stage melanomas with similar frequencies. Extra 9p21 copies were rarely seen; they were always associated with polysomy 9 and were observed only in advanced stage melanomas (6 tumors). This FISH study strengthens the hypothesis that the loss of 9p21 occurs frequently in primary melanoma, that the deletion is present in early and late stages of the disease with similar frequency, and that it affects a large extent of the locus.


Melanoma Research | 2012

Marked genetic differences between braf and nras mutated primary melanomas as revealed by array comparative genomic hybridization

Viktória Lázár; Szilvia Ecsedi; Laura Vízkeleti; Zsuzsa Rákosy; Gábor Boross; Balázs Szappanos; Ágnes Bégány; Gabriella Emri; Róza Ádány; Margit Balázs

Somatic mutations of BRAF and NRAS oncogenes are thought to be among the first steps in melanoma initiation, but these mutations alone are insufficient to cause tumor progression. Our group studied the distinct genomic imbalances of primary melanomas harboring different BRAF or NRAS genotypes. We also aimed to highlight regions of change commonly seen together in different melanoma subgroups. Array comparative genomic hybridization was performed to assess copy number changes in 47 primary melanomas. BRAF and NRAS were screened for mutations by melting curve analysis. Reverse transcription PCR and fluorescence in-situ hybridization were performed to confirm the array comparative genomic hybridization results. Pairwise comparisons revealed distinct genomic profiles between melanomas harboring different mutations. Primary melanomas with the BRAF mutation exhibited more frequent losses on 10q23–q26 and gains on chromosome 7 and 1q23–q25 compared with melanomas with the NRAS mutation. Loss on the 11q23–q25 sequence was found mainly in conjunction with the NRAS mutation. Primary melanomas without the BRAF or the NRAS mutation showed frequent alterations in chromosomes 17 and 4. Correlation analysis revealed chromosomal alterations that coexist more often in these tumor subgroups. To find classifiers for BRAF mutation, random forest analysis was used. Fifteen candidates emerged with 87% prediction accuracy. Signaling interactions between the EGF/MAPK–JAK pathways were observed to be extensively altered in melanomas with the BRAF mutation. We found marked differences in the genetic pattern of the BRAF and NRAS mutated melanoma subgroups that might suggest that these mutations contribute to malignant melanoma in conjunction with distinct cooperating oncogenic events.


International Journal of Oncology | 2011

Combined GM-CSF treatment and M-CSF inhibition of tumor-associated macrophages induces dendritic cell-like signaling in vitro.

Yusuke Kitoh; Masanao Saio; Naoe Gotoh; Naoki Umemura; Kenichi Nonaka; Juncheng Bai; Laura Vízkeleti; Dániel Töröcsik; Margit Balázs; Róza Ádány; Tsuyoshi Takami

Macrophages demonstrate plasticity, and tumor-associated macrophages (TAM) can function as immunosuppressive cells in the tumor microenvironment. Therefore, in this study, we aimed to reprogram TAM in vitro with cytokine signal alteration. Granulocyte macrophage colony stimulating factor (GM-CSF) treatment alone did not lead to changes in the expression of M1 (including IL-1β, TNFα and CXCL-10) or M2 (including CD36, CD206 and CCL17) molecules by TAM in vitro, although they adopted a round morphology and were less adhesive to the culture dish. When macrophage colony stimulating factor (M-CSF) signals were suppressed by siRNA against the M-CSF receptor (M-CSFR) in conjunction with GM-CSF treatment, the signal transduction pathway of TAM was altered, and the expression of STAT1, STAT5 and STAT6, which are usually expressed by dendritic cells, was increased. However, the same treatment did not alter the TAM expression pattern of M1/M2 marker molecules. With respect to the NF-κB pathway, GM-CSF and M-CSFR siRNA combination treatment significantly induced the expression of p65, which is usually not expressed by TAM, while p50 and p105 expression by TAM was not affected by the treatment. These findings indicate that our model could not redirect TAM to a monocyte-derived dendritic cell-like phenotype based on the analysis of M1/M2 marker expression, but it was able to modify cell signaling pathways toward a dendritic cell-like pattern. Therefore, the present data suggest that TAM demonstrate plasticity toward dendritic cell-like signal transduction patterns, and that the alteration of the tumor microenvironment has the potential to reverse the immunosuppressive properties of TAM.


Otolaryngology-Head and Neck Surgery | 2008

Chromosomal imbalances are associated with increased proliferation and might contribute to bone destruction in cholesteatoma

Szilvia Ecsedi; Zsuzsa Rákosy; Laura Vízkeleti; Attila Juhász; István Sziklai; Róza Ádány; Margit Balázs

Objectives Our aim was to evaluate the copy number alterations of chromosomes 3, 7, 8, and 17 in middle ear cholesteatomas and define the association between the rate of cell proliferation and chromosome number changes. Methods Tissues were obtained from 16 patients. Fluorescence in situ hybridization was performed on tumor imprint preparations. Cell proliferation was characterized with Ki-67 monoclonal antibody on cholesteatoma samples and on postauricular skins as control. Results Different degrees of aneusomy were found for all chromosomes except for chromosome 3. Chromosome copy number alterations were associated with elevated proliferative rate and related also with the aggressiveness of the lesions. Conclusions Based on our results, we assume that aneusomy of chromosomes 7, 8, and 17 might play an important role during invasion of the adjacent bony structures of cholesteatoma, as well as associate with increased cell proliferation activity, which might lead to the aggressive behavior of the tissue.


Archive | 2011

Genomics of Human Malignant Melanoma

Margit Balázs; Szilvia Ecsedi; Laura Vízkeleti; Ágnes Bégány

Malignant melanoma is considered the most aggressive form of skin cancer. The incidence rate of the disease has steadily risen over the past few decades throughout the world. If melanoma is diagnosed early, it can be cured by surgical resection, but as soon as the first distant metastasis appears, the disease becomes one of the most aggressive types of metastatic, chemoresistant lesions. Cutaneous melanocytes originate from highly motile neural crest progenitors that migrate to the skin during embryonic development. They are pigment-producing skin cells that reside between keratinocytes in the basal layer of the epidermis, producing melanin in response to a variety of external stimuli, such as ultraviolet (UV) radiation. Although UV radiation is the main exogenous etiological risk factor for the development of the disease, other presently unknown factors are also involved. As estimated by the World Health Organization worldwide number of newly diagnosed skin cancer cases is between 2 and 3 million each year, of which 132,000 are melanoma. Additionally, in most western countries, the incidence of melanoma doubles roughly every decade. Malignant melanoma progresses through a series of well-defined clinical and histopathological stages, advancing in a stepwise manner from either a common acquired or a dysplastic nevus through the primary radial growth phase (RGP) and the vertical growth phase (VGP) to distant metastasis [Welch et al., 1997]. Different subtypes of the disease represent diverse entities, as there are marked differences in their biological behaviours. While the most common superficial spreading subtype (SSM) is characterised by a prolonged RGP, nodular melanoma (NM) begins to grow vertically from its onset. Clinical staging of primary cutaneous melanoma is based on measurements of tumour thickness (in millimetres), the presence or absence of ulceration, penetration through cutaneous layers, mitotic rate and evidence of lymph node, cutaneous or distant metastasis [Chin et al., 2006]. The vertical progression of lesions is representative of the degree of tumour progression and is measured by the Breslow thickness, which was first used in the early 1970s and measures the thickness of the tumour from the top of the epidermal granular layer (or from the ulcer base if the tumour is ulcerated) to the innermost depth of invasion. Ulceration of the tumour surface of melanoma covering the epidermis is one of the most sensitive parameters of metastatic potential. The currently used diagnostic and prognostic approaches to recognise


PLOS ONE | 2014

The strong in vivo anti-tumor effect of the UIC2 monoclonal antibody is the combined result of Pgp inhibition and antibody dependent cell-mediated cytotoxicity

Gábor Szalóki; Zoárd Tibor Krasznai; Ágnes Tóth; Laura Vízkeleti; Attila Gábor Szöllősi; György Trencsényi; Imre Lajtos; István Juhász; Zoltán Krasznai; Teréz Márián; Margit Balázs; Gábor Szabó; Katalin Goda

P-glycoprotein (Pgp) extrudes a large variety of chemotherapeutic drugs from the cells, causing multidrug resistance (MDR). The UIC2 monoclonal antibody recognizes human Pgp and inhibits its drug transport activity. However, this inhibition is partial, since UIC2 binds only to 10–40% of cell surface Pgps, while the rest becomes accessible to this antibody only in the presence of certain substrates or modulators (e.g. cyclosporine A (CsA)). The combined addition of UIC2 and 10 times lower concentrations of CsA than what is necessary for Pgp inhibition when the modulator is applied alone, decreased the EC50 of doxorubicin (DOX) in KB-V1 (Pgp+) cells in vitro almost to the level of KB-3-1 (Pgp-) cells. At the same time, UIC2 alone did not affect the EC50 value of DOX significantly. In xenotransplanted severe combined immunodeficient (SCID) mice co-treated with DOX, UIC2 and CsA, the average weight of Pgp+ tumors was only ∼10% of the untreated control and in 52% of these animals we could not detect tumors at all, while DOX treatment alone did not decrease the weight of Pgp+ tumors. These data were confirmed by visualizing the tumors in vivo by positron emission tomography (PET) based on their increased 18FDG accumulation. Unexpectedly, UIC2+DOX treatment also decreased the size of tumors compared to the DOX only treated animals, as opposed to the results of our in vitro cytotoxicity assays, suggesting that immunological factors are also involved in the antitumor effect of in vivo UIC2 treatment. Since UIC2 binding itself did not affect the viability of Pgp expressing cells, but it triggered in vitro cell killing by peripheral blood mononuclear cells (PBMCs), it is concluded that the impressive in vivo anti-tumor effect of the DOX-UIC2-CsA treatment is the combined result of Pgp inhibition and antibody dependent cell-mediated cytotoxicity (ADCC).


Melanoma Research | 2017

Altered integrin expression patterns shown by microarray in human cutaneous melanoma

Laura Vízkeleti; Tímea Kiss; Viktória Koroknai; Szilvia Ecsedi; Orsolya Papp; István Szász; Róza Ádány; Margit Balázs

A large variety of molecular pathways in melanoma progression suggests that no individual molecular alteration is crucial in itself. Our aim was to define the molecular alterations underlying metastasis formation. Gene expression profiling was performed using microarray and qRT-PCR to define alterations between matched primary and metastatic melanoma cell lines. These data were integrated with publicly available unmatched tissue data. The invasiveness of cell lines was determined by Matrigel invasion assays and invasive clones from primary melanoma-derived cell lines were also selected. Two metastatic cell line models were created: the regional lymph node WM983A–WM983AINV–WM983B and the distant lung WM793B–WM793BINV–1205Lu metastatic models. The majority of metastasis genes were downregulated and enriched in adhesion and ITGA6-B4 pathways. Upregulation of immune pathways was characteristic of distant metastases, whereas increased Rap1 signaling was specific for regional (sub)cutaneous metastases. qRT-PCR analysis of selected integrins (A2, A3, A4, A9, B5, B8, A6, B1, and B3) highlighted the possible importance of ITGA3/4 and B8 in the metastatic process, distinguishing regional and distant metastases. We identified functionally relevant gene clusters that influenced metastasis formation. Our data provide further evidence that integrin expression patterns may be important in distant metastasis formation.

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Viktória Lázár

Hungarian Academy of Sciences

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Réka Tóth

University of Debrecen

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Tímea Kiss

University of Debrecen

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