Ivanka Dimova | Medical University of Sofia (original) (raw)

Papers by Ivanka Dimova

Rearrangements of 1p36 resulting in deletion are observed in 1 in 5,000 live births. Molecular ch... more Rearrangements of 1p36 resulting in deletion are observed in 1 in 5,000 live births. Molecular characterisation of deletions, along with phenotypic correlations, have yielded regions in which to search for genes related to specific features of the syndrome.We report a child with sub-telomeric interstitial 1p36 deletion, spanning 3,683,364-8,822,150 bp (1p36.33-1p36.23) region. The capability of aCGH to provide high-resolution mapping of variation in copy number has been demonstrated. Determining the smallest region of overlap, we narrowed the common region between cases with hirsutism on chromosome 1 band 1p36.23 between 7,500,000 and 8,500,000 bp. Since our patient has overlapped symptom of hirsutism with the patients of proximal 1p36 deletion syndrome, we therefore searched the database to identify potential candidate genes for this feature. We suggest a new candidate-gene for hirsutism – PARK7, which is related to the function of androgens and hyperandrogenaemia. The suggestion i...

Tumori Journal, 2011

Aims and backgroundAngiogenesis is a key process in the early stages of tumor development. In thi... more Aims and backgroundAngiogenesis is a key process in the early stages of tumor development. In this study we aimed to evaluate the expression of a panel of angiogenesis-related genes in a group of Bulgarian patients with early-stage non-small cell lung cancer (NSCLC).Methods and study designWe analyzed the expression of 84 genes associated with the angiogenic process in 12 NSCLCs of two histological subtypes: 7 adenocarcinomas and 5 squamous cell carcinomas. Eight peripheral nontumorous tissues were used as controls. We performed real-time PCR on pathway-specific gene arrays (SABiosciences).ResultsOur pilot study identified upregulated genes in early-stage NSCLC including growth factors (TGFA and EFNA3), the adhesion molecule THBS2, cytokines and chemokines (MDK, CXCL9, CXCL10), and the serine protease PLAU. Several genes showed downregulation including one growth factor (FIGF), the receptors for growth factors TEK and S1PR1 as well as adhesion molecules (COL4A3 and CDH5), the cytoki...

Taiwanese Journal of Obstetrics and Gynecology, 2020

Objective: To study two major molecular alterations in spontaneous abortions (SA) with unexplaine... more Objective: To study two major molecular alterations in spontaneous abortions (SA) with unexplained etiology e fetal genomic anomalies and the endometrial expression of main angiogenic factors VEGFA/ VEGFR2 and chemokines SDF-1/CXCR4. Materials and methods: Whole genome copy number analysis by arrayCGH or Next Generation Sequencing (NGS) was applied for detection of fetal genomic imbalances. The abortive decidua of SA without fetal aneuploidies was further investigated for expression levels of the abovementioned factors using real time PCR analysis. A total of 30 abortive materials were collected from spontaneous abortions after exclusion of known predisposing factors. Results: In 21 of 30 spontaneous abortions (70%), genomic anomalies were discovered by whole genome copy number analysis. Numerical anomalies were detected in 90% of aberrant cases, and in 10%structural aberrations were revealed. An increased expression for essential factors of angiogenesis was identified in spontaneous abortions' tissues-3.44 times for VEGFA and 10.29 times for VEGFR2. We found an average of 14 times increase in the expression levels of SDF-1 and 3.21 times for its receptor CXCR4. Conclusion: We could suggest the occurrence of increased angiogenesis in SA without fetal aneuploidies, compared to the control tissues, which could lead to increased oxidative stress and fetal loss.

Despite of the large number of molecular studies in breast cancer, the data are still insufficien... more Despite of the large number of molecular studies in breast cancer, the data are still insufficient for understanding its molecular pathogenesis. The dramatic development of genetics in recent years has made it possible to gain insight into the molecular mechanisms of tumorigenesis. The aims of the study was to determine the type, frequency and fine mapping of unbalanced genomic alterations in ductal carcinoma of the breast. For this study we have used tumor samples of invasive ductal breast cancer to be analysed by comparative genomic hybridization on DNA microarrays. Two approaches were applied in the analysis of significant unbalanced genomic changes: a) identification of clones which presented unbalanced changes (log2 T: H> +0.25 for gain and <-0.25 for losses) in more than 70% of the tumors; b) establishing clones which harbor amplifications (log2 T: H> +0.5) or homozygous deletions (log2 T: H <- 0.5) in more than 50% of tumors. Our results showed that the most commo...

Journal of Cellular and Molecular Medicine, 2019

Angiogenesis is essential for normal embryonic development, and plays a key role in pathological ... more Angiogenesis is essential for normal embryonic development, and plays a key role in pathological conditions related to tumour growth and ischaemic cardiovascular diseases. This is a complex process involving essential signalling pathways such as VEGF, basic fibroblast growth factor (bFGF) and Notch in vasculature. Previously published results suggested that myeloid progenitor cells play important role in angiogenesis. 1 We have largely expanded our knowledge about the role of bone marrow-derived cells (BMDC) in stimulating angiogenesis after their discovery in 1997 2 and now their capability to promote vessel formation

Balkan Journal of Medical Genetics, 2009

Copy Number Changes in 1q21.3 and 1q23.3 have Different Clinical Relevance in Ovarian TumorsMany ... more Copy Number Changes in 1q21.3 and 1q23.3 have Different Clinical Relevance in Ovarian TumorsMany studies have reported aberrations such as amplifications, deletions and translocations of 1q21-q23 in ovarian tumors. These findings increase the scientific interest in analyzing this region using specific gene probes. We investigated the frequency of copy number changes of two specific bacterial artificial chromosomes (BAC) clones in 1q21.3 and 1q23.3 by fluorescent in situ hybridization (FISH) on tissue microarrays consisting of 540 ovarian tumors of different malignancies, histology, stage and grade. Such changes in 1q21.3 were established in 9.64% of malignant (2.41% amplification), in 8.33% of low malignant potential (LMP) and in 13.13% of benign ovarian tumors. Copy number changes of 1q23.3 were found in 17.78% of malignant (1.48% amplification), in 16.67% of LMP and in 12.64% of benign ovarian tumors. We found a significantly higher gain of 1q23.3 in non epithelial (50%) compared ...

Physiologic and Pathologic Angiogenesis - Signaling Mechanisms and Targeted Therapy, Apr 5, 2017

Intussusceptive angiogenesis (IA) known also as splitting angiogenesis is a recently described me... more Intussusceptive angiogenesis (IA) known also as splitting angiogenesis is a recently described mechanism of vascular growth alternative to sprouting. It plays an essential role in the vascular remodeling and adaptation of vessels during normal and pathological angiogenesis. It is an "escape" mechanism during and after irradiation and anti-VEGF therapy, both inducing angiogenic switch from sprouting to IA by formation of multiple transluminal tissue pillars. Our recently published data revealed the significant induction of IA after inhibition of Notch signaling associated with an increased capillary density by more than 50%. The induced IA was accompanied by detachment of pericytes from basement membrane, increased vessel permeability and recruitment of mononuclear cells toward the pillars; the process was dramatically enhanced after injection of bone marrowderived mononuclear cells. The extravasation of mononuclear cells with eventual bone marrow origin was associated with upregulation of chemotaxis factors SDF-1 and CXCR4. In addition, SDF-1 expression was upregulated in the endothelium of liver sinusoids in Notch1 knockout mouse, together with vascular remodeling by intussusception. In this chapter, we discuss this important mechanism of angiogenesis, as well as the role of Notch signaling, SDF-1 signaling and mononuclear cells in the complex process of angiogenesis.

Journal of B.U.ON. : official journal of the Balkan Union of Oncology

A vast amount of data shows that angiogenesis has a pivotal role in tumor growth, progression, in... more A vast amount of data shows that angiogenesis has a pivotal role in tumor growth, progression, invasiveness and metastasis. This is a complex process involving essential signaling pathways such as vascular endothelial growth factor (VEGF) and Notch in vasculature, as well as additional players such as bone marrow-derived endothelial progenitor cells. Primary tumor cells, stromal cells and cancer stem cells strongly influence vessel growth in tumors. Better understanding of the role of the different pathways and the crosstalk between different cells during tumor angiogenesis are crucial factors for developing more effective anticancer therapies. Targeting angiogenic factors from the VEGF family has become an effective strategy to inhibit tumor growth and so far the most successful results are seen in metastatic colorectal cancer (CRC), renal cell carcinoma (RCC) and non-small cell lung cancer (NSCLL). Despite the initial enthusiasm, the angiogenesis inhibitors showed only moderate su...

Balkan Journal of Medical Genetics, 2000

Congenital malformations present at delivery of an infant are due to genetic or non genetic facto... more Congenital malformations present at delivery of an infant are due to genetic or non genetic factors and occur in 15-20% of stillborn children. Most can be diagnosed prenatally by ultrasound examination, but some can only be diagnosed after birth. Seven to 10% of infants with abnormal phenotype have numerical or structural chromosomal abnormalities that require identification for accurate diagnosis and genetic counseling. Molecular-cytogenetic and array-based techniques have enabled screening at higher resolution for congenital anomalies that result from genomic imbalances. We have examined four children with congenital anomalies, with or without mental retardation, of unclear etiology. In one child, we detected a deletion (about 28 Mb) of the region 18q21.1-18q23, in mosaic form. This abnormality was missed in a routine cyto genetic examination. We detected different polymorphic copy number variations (CNVs) in the other children. We conclude that array-based comparative genomic hybridization (CGH) is a powerful diagnostic tool for the detection of low level mosaicism.

Aims and background. The literature data show that the most frequently affected chromosomes in ov... more Aims and background. The literature data show that the most frequently affected chromosomes in ovarian carcinogenesis are 1, 8 and 17. In the present study we aimed to define more precisely at a high resolution the genomic imbalances of these chromosomes in ovarian cancer and to determine genomic markers separating tumors of different histological types and stages. Methods. Array comparative genomic hybridization (CGH) with a resolution of ≈0.8 Mb was applied in 28 primary ovarian tumors. We identified regions of highly frequent gains or losses (affecting more than 40% of ovarian cancers) and determined sites showing alterations of elevated amplitude (amplifications or homozygous deletions). Doing this we also identified at least two adjacent changed clones. Results. We determined anomalies strongly associated with the disease such as deletions at 8p21-23, 17p12-13, 1p35-36 or amplifications at 1q23, 17q12, 17q23.2, 8q13.2, 8q24. We defined more precisely the gains in 17q12-q24, finding as strong candidates for ovarian tumorigenesis the genes LASP1 (17q12), TGF11 (17q21.32), MUL (17q23.2), TBX2 (17q23.2), AXIN2 (17q24.3) and GRB2 (17q25.1). Of particular note was gain of 8q13.2, which occurred at a high frequency in ovarian cancer, especially in serous and late-stage tumors. We found that gains of 1q32-1q43, 8p11-p12, 8q11.23, 8q13.2, and 8q24.21-8q24.22 and losses of 1p36.21, 8p23.1-8p21.1 and 8q21.2 were associated with serous histology, whereas losses of 1q23 and 1q32-43 and gains of 17q11.2-12 and 17q25 were associated with mucinous histology. Gains of 1q23, 8q24, 17q23.2, 17q24.2 and losses of 1p35-36, 8p, 17p, and 17q were specific for late-stage ovarian cancers. Conclusions. Our study has identified potential genomic markers of interest on chromosomes 1, 8 and 17 in ovarian cancer. Tumors showed a wide variety in the patterns of alteration, suggesting that alternative mechanisms of genomic instability may play a role in this tumor type.

Latest Findings in Intellectual and Developmental Disabilities Research, 2012

... J. Med. Genet. 42: 132-137, 2005. [39] Lindquist, SG, Kirchhoff, M., Lundsteen, C., Pedersen,... more ... J. Med. Genet. 42: 132-137, 2005. [39] Lindquist, SG, Kirchhoff, M., Lundsteen, C., Pedersen, W., Erichsen, G., Kristensen, K., Lillquist, K., Smedegaard, HH, Skov, L., Tommerup, N., Brondum-Nielsen, K. Further delineation of the 22q13 deletion syndrome. Clin. Dysmorph. ...

Journal of Cardiovascular Medicine, 2014

To evaluate the expression of atherosclerosis-associated genes in patients with hypertension and ... more To evaluate the expression of atherosclerosis-associated genes in patients with hypertension and type 2 diabetes mellitus. Twenty-seven patients (14 men, 13 women), mean age 43.26 ± 11.69 years, were included in the study, which was divided into three groups: group 1 - patients with newly diagnosed hypertension and normal glucose tolerance (n = 9), group 2 - normotensive individuals with newly diagnosed type 2 diabetes (n = 9), and control group - normotensive individuals with normal glucose tolerance (n = 9). Gene expression analysis was performed with Human Atherosclerosis RT2 Profiler PCR Array. In patients with hypertension, we found eight genes with increased expression - FABP3, FAS, FN1, IL1R2, LPL, SERPINE1, TGFB1, and VCAM1. Decreased expression was observed for two genes - SELPLG and SERPINEB2. In patients with type 2 diabetes we found seven up-regulated genes - APOE, BAX, MMP1, NFKB1, PDGFB, SPP1, and TGFB2, whereas no specifically down-regulated genes were observed. Three genes - KLF2, PDGFRB, and PPARD were found to be expressed only in groups 1 and 2. Hypertension is associated with increased expression of FABP3, FAS, FN1, IL1R2, LPL, SERPINE1, TGFB1, and VCAM1 and decreased expression of SELPLG and SERPINEB2. The up-regulation of FAS, FN1, SERPINE1, TGFB1, and VCAM1 might be associated with an increased cardiovascular risk. Type 2 diabetes is associated with increased expression of APOE, BAX, MMP1, NFKB1, PDGFB, SPP1, and TGFB2. KLF2 and PPARD might be part of protective mechanisms that limit target organ damage in both disease conditions. Expression of PDGFRB might play an important role in the pathogenesis of both hypertension and type 2 diabetes.

Biotechnology & Biotechnological Equipment, 2014

Lung cancer is a serious health problem, since it is one of the leading causes for death worldwid... more Lung cancer is a serious health problem, since it is one of the leading causes for death worldwide. MolecularÀcytogenetic studies could provide reliable data about genetic alterations which could be related to disease pathogenesis and be used for better prognosis and treatment strategies. We performed whole genome oligonucleotide microarray-based comparative genomic hybridization in 10 samples of non-small cell lung cancer. Trisomies were discovered for chromosomes 1, 13, 18 and 20. Chromosome arms 5p, 7p, 11q, 20q and X q were affected by genetic gains, and 1p, 5q, 10q and 15q, by genetic losses. Microstructural (<5 Mbp) genomic aberrations were revealed: gains in regions 7p (containing the epidermal growth factor receptor gene) and 12p (containing KRAS) and losses in 3p26 and 4q34. Based on high amplitude of alterations and small overlapping regions, new potential oncogenes may be suggested: NBPF4 (1p13.3); ETV1, AGR3 and TSPAN13 (7p21.3-7p21.1); SOX5 and FGFR1OP2 (12p12.1-12p11.22); GPC6 (13q32.1). Significant genetic losses were assumed to contain potential tumour-suppressor genes: DPYD (1p21.3); CLDN22, CLDN24, ING2, CASP3, SORBS2 (4q34.2-q35.1); DEFB (8p23.1). Our results complement the picture of genomic characterization of non-small cell lung cancer.

Turkish Journal of Hematology, 2011

Objective: Treatment of acute lymphoblastic leukemia (ALL) in adults focuses on the initial asses... more Objective: Treatment of acute lymphoblastic leukemia (ALL) in adults focuses on the initial assessment of the prognostic relevant cytogenetic features as well as a response-guided therapy based on molecular data. We examined the importance of molecular-cytogenetic abnormalities for complete remission (CR) rates and the overall survival (OS) in adult ALLs. Materials and Methods: Conventional cytogenetics and fluorescence in situ hybridization were performed on bone marrow cells from 33 newly-diagnosed ALL adults. Two karyotype categories [standard-risk group-normal karyotype, hyperdiplody and other structural aberrations, and high-risk group-t(11q23)/MLL, t(9;22)/bcr-abl, t(1;19), t(8;14), C-MYC and complex karyotype] and the biologically and clinically relevant ALL ploidy subgroups were prospectively defined. Results: Chromosomal abnormalities were found in 52% of the cases with a high rate of poor-risk translocations -t(9;22), t(8q24), t(11q23), . The total CR rate was 67% and the median time for achievement 2.33 months. Male sex, an age below 35 years and the absence of high risk translocations might have contributed to the high CR rates. Female patients, hyperdiplody, low white blood cells (WBC), and random cytogenetic aberrations had the longest OS. OS, 3-and 5-years survival periods were significantly shorter for poor-risk than standard risk group (p=.015, p=.001 and p=.005, respectively). Conclusion: This study emphasizes the lack of influence of cytogenetic aberrations on the CR and the time to achieve CR. However, our observations show that these aberrations are an independent prognostic factor in adult ALL -they allow predicting therapy resistance and the OS time after intense treatment. (Turk J Hematol 2011; 28: 176-85)

European Journal of Cancer, 1996

Tumor Biology, 2004

Colorectal cancer is one of the most common neoplastic diseases and one of the leading causes of ... more Colorectal cancer is one of the most common neoplastic diseases and one of the leading causes of cancer-related deaths. Elevated beta-catenin levels in colorectal cancer result in the binding of beta-catenin to LEF-1 and increased transcriptional activation of the CCND1 gene. Overexpression of cyclin D1 is observed in one third of colorectal tumors. CCND1 amplification is the main cause of protein overexpression in numerous human carcinomas. In colorectal cancer, however, no CCND1 amplification has been reported so far. The aim of this study was to determine the frequency of CCND1 amplifications and gains in a large number of colorectal carcinomas, arranged in a tissue microarray, in order to assess their role in colorectal cancer development. The copy number changes, detected by fluorescence in situ hybridization, were predominantly gains (7.6%) and only rarely amplifications (2.5%). In colorectal cancer, the CCND1 copy number increase was neither associated with the tumor phenotype (stage and grade) nor with the tumor localization (colon, rectum or sigmoid colon). In conclusion, even in a small number of colorectal tumors, CCND1 gene amplification is a possible mechanism for the increase in cyclin D1 oncoprotein.

Methods in Molecular Biology, 2014

Angiogenesis, the development of new blood vessels from preexisting ones, is driven by coordinate... more Angiogenesis, the development of new blood vessels from preexisting ones, is driven by coordinated signaling pathways governed by specific molecules, hemodynamic forces, and endothelial and periendothelial cells. The processes involve adhesion, migration, and survival machinery within the target endothelial and periendothelial cells. Factors that interfere with any of these processes may therefore influence angiogenesis either positively (pro-angiogenesis) or negatively (antiangiogenesis). The avian area vasculosa (AV) and the avian chorioallantoic membrane (CAM) are two useful tools for studying both angiogenesis and antiangiogenesis since they are amenable to both intravascular and topical administration of target, agents, are relatively rapid assays, and can be adapted very easily to study angiogenesis-dependent processes, such as tumor growth. Both models provide a physiological setting that permits investigation of pro-angiogenic and antiangiogenic agent interactions in vivo.

The literature data show that the most frequently affected chromosomes in ovarian carcinogenesis ... more The literature data show that the most frequently affected chromosomes in ovarian carcinogenesis are 1, 8 and 17. In the present study we aimed to define more precisely at a high resolution the genomic imbalances of these chromosomes in ovarian cancer and to determine genomic markers separating tumors of different histological types and stages.

Journal of Human Genetics, 2009

The development of molecular psychiatry in the last few decades identified a number of candidate ... more The development of molecular psychiatry in the last few decades identified a number of candidate genes that could be associated with schizophrenia. A great number of studies often result with controversial and non-conclusive outputs. However, it was determined that each of the implicated candidates would independently have a minor effect on the susceptibility to that disease. Herein we report results from our replication study for association using 255 Bulgarian patients with schizophrenia and schizoaffective disorder and 556 Bulgarian healthy controls. We have selected from the literatures 202 single nucleotide polymorphisms (SNPs) in 59 candidate genes, which previously were implicated in disease susceptibility, and we have genotyped them. Of the 183 SNPs successfully genotyped, only 1 SNP, rs6277 (C957T) in the DRD2 gene (P¼0.0010, odds ratio¼1.76), was considered to be significantly associated with schizophrenia after the replication study using independent sample sets. Our findings support one of the most widely considered hypotheses for schizophrenia etiology, the dopaminergic hypothesis.

Acta Oncologica, 2004

Literature data on the occurrence of CCND1 alterations in ovarian tumors are insufficient. The ob... more Literature data on the occurrence of CCND1 alterations in ovarian tumors are insufficient. The objective of this study was to assess the incidence of CCND1 copy number changes in a large number of ovarian tumors and its relation to the tumor phenotype: degree of malignancy, histological type, tumor stage, and grade. Fluorescence in situ hybridization (FISH) for analysis of CCND1 copy number changes was applied on a collection of 1 006 ovarian tumors--468 malignant, 48 with low malignant potency, and 490 benign tumors--arranged in tissue microarray. CCND1 amplification was found in 8.46% of the malignant cases and in 8.11% of those with low malignant potency. It was not found in benign ovarian tumors. CCND1 amplification was associated with the mucinous type of ovarian cancer (p&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.0001). CCND1 genetic gain was revealed in 9.06% of the malignant tumors, in 2.70% of the tumors with low malignant potency, and in 4.87% of the benign ovarian tumors. CCND1 gains and amplifications were not associated with the tumor grade and stage. Our results suggest that CCND1 gains are early events in ovarian tumorogenesis.