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Implementation of Immunohistochemical and Molecular-Genetic Methods in Differential Diagnosis of Urogenital and Gynecologic Tract Lesions
Ondič, Ondrej ; Hes, Ondřej (advisor) ; Mandys, Václav (referee) ; Vernerová, Zdeňka (referee)
This thesis focuses on gynecopathology. It consists of a collection of seven papers published in pathology journals with impact factor. Introduction section contains selection of examples showing scientific application of molecular genetic methods. Further on the aims of individual research projects are described. The first project comprises histomophologic study of skin endometriosis addressing "mullerian" differentiation. A case report of a rare tumor namely borderline papillary serous tumor of the fimbriated end of the fallopian tube follows with molecular genetic analysis of KRAS, BRAF and p53 gene mutation status. Prospective longitudinal study on high grade squamous dysplasia (HSIL) of the cervix in HPV vaccinated women, so called DAV (dysplasia after vaccination), aims to elucidate pathogenesis of this phenomenon. Two other studies focus on incidence of fumarate hydratase deficient leiomyomas of the uterus and hereditary leiomyomatosis and renal cell carcinoma syndrome (HLRCC). The aim of those studies is to improve our diagnostic capability and increase detection rate of the patients with HLRCC syndrome. Finally a new subtype of HSIL namely bizarre cell dysplasia is described in two separate studies. Conclusion remarks contemplate the role of molecular genetics in surgical pathology.
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Epigenetic and Cytotoxic Effects of Histone Deacetylase Inhibitors in Combination with Cytostatics on Neuroblasma
Abdel Rahman, Mohamed Ashraf Khalil ; Eckschlager, Tomáš (advisor) ; Mandys, Václav (referee) ; Krsková, Lenka (referee)
The enhanced expression of histone deacetylases (HDACs) in a variety of malignancies drew attention to investigate a new category of anti-cancer drugs that are based on the inhibition of those enzymes. Valproic acid (VPA) is a well-known antiepileptic drug that exhibits antitumor activities through inhibition of HDACs class I and IIa. Cancer stem cells (CSCs) have been recognized to drive the tumor growth and progression hence; attention has been given to target this small subpopulation of CSCs rather than the whole bulk tumor cells. CD133 is considered to be a CSC marker in several tumors and its transcription is strongly influenced by epigenetic changes that will be altered upon administration of histone deacetylase inhibitors (HDACi) in cancer treatment. Therefore, we evaluated the epigenetic and cytotoxic effects of treatment with 1 mM VPA in combination with other chemotherapeutics and its influence on the expression of CD133 in human neuroblastoma (NB) cell lines. Our results revealed that addition of VPA to DNA-damaging chemotherapeutics induced a synergistic anti-tumor effect that was associated with caspase-3 dependent induction of apoptosis in UKF-NB-4 cells. This synergism was related to the increase of the acetylation status of histones H3 and H4 and was only produced either by...
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Atrial Fibrillation - Morphological and Electrophysiological Changes of the Atrial Myocardium
Matějková, Adéla ; Šteiner, Ivo (advisor) ; Mandys, Václav (referee) ; Pařízek, Petr (referee)
Atrial fibrillation - morphological and electrophysiological changes of the atrial myocardium Atrial fibrillation (AF), the most common sustained cardiac arrhythmia, was considered as pure functional disorder for long time. In recent years, there were identified atrial locations, which are involved in the initiation and maintenance of this arrhythmia. These structural changes, so called remodelation, start at electric level and later they affect contractility and morphology. We attempted to find a possible relation between morphological (scarring, isolated atrial amyloidosis (IAA), left atrial (LA) enlargement) and electrophysiological (ECG features) changes in patients with AF. We examined grossly and histologically 70 hearts of necropsy patients - 44 with a history of AF (subclassified into two subgroups: PERM - patients with permanent or persistent AF - 20, and PAROX - patients with paroxysmal and newly diagnosed AF - 24), and 26 control cases without any history of AF. Premortem ECGs were evaluated. The patients with AF had significantly heavier hearts, larger LAs, more advanced fibrosis in atrial myocardium and more severe amyloidosis in both atria. The hearts of the PERM subgroup were the most affected. Severity of amyloidosis was significantly higher in the left vs. right atria. Distribution...
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Analysis of Growth-inhibitory Mechanism of Flubendazole in Malignant Melanoma Cells
Čáňová, Kristýna ; Rudolf, Emil (advisor) ; Slaninová, Iva (referee) ; Mandys, Václav (referee)
Analysis of growth-inhibitory mechanisms of flubendazole in malignant melanoma cells Malignant skin melanoma is at its advanced stage highly aggressive and chemoresistant to almost all currently available therapies. Moderns efforts are thus aimed to identify new targets in melanoma cells or to take advantage of novel indications of already approved drugs - a process called drug repurposing. This work was focused on evaluation of cell growth inhibitory properties of one such drug - flubendazole (FLU) - a widely used anthelmintic compound belonging to benzimidazole family. This drug specifically interacts with β-tubulin, which results in disruption of microtubule structure and function in the exposed cells. Several members of the benzimidazole family (including FLU) have already shown the growth inhibitory potential in tumor cells derived from breast, colon, blood and nervous system malignancies. Still, the specific activity of FLU in malignant melanoma has not been tested to the date. Cytotoxicity of FLU was tested in three malignant melanoma cell lines representing diverse melanoma molecular types (A-375, BOWES and RPMI-7951) during up to 72 hours using WST-1 and x-CELLigence assays. Based on achieved IC50 from individual cell lines, the 1 µM FLU concentration was selected for further testing. While...
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Tumors of Urogenital Tract, Molecular Genetic Characteristics and Impact on Biological Behavior
Pivovarčíková, Kristýna ; Hes, Ondřej (advisor) ; Mandys, Václav (referee) ; Vernerová, Zdeňka (referee)
The Ph.D. thesis is a collection of seven commented articles on the topic of molecular-genetic of urogenital tumors. The spectrum of urogenital lesions is very wide, there is lots of new insights in field of urogenital pathology. Therefore, presented Ph.D. thesis is focused only on small part of urogenital neoplasms - renal cell carcinomas characterized by papillary growing pattern. The introduction presents different entities with papillary morphology, there are specified basic morphological, immunohistochemical and molecular-genetic characteristic of these lesions, their differential diagnosis is commented. In the results, there are presented recently published studies dealing with newly described entities of renal neoplasias, heterogenity of molecular genetic studies in individual tumorous groups is established, prognostic significance is commented, typical pitfalls are introduced. In the conclusions, the limitations of the use molecular-genetic methods are discussed and clinical outcome and significance is evaluated.
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Dipeptidyl peptidase-IV and Fibroblast activation protein in gliomagenesis.
Trylčová, Jana ; Šedo, Aleksi (advisor) ; Mandys, Václav (referee) ; Mareš, Vladislav (referee)
"Dipeptidyl peptidase-IV Activity and/or Structure Homologues"(DASH) represent a newly defined group of multifunctional molecules, typically bearing dipeptidyl peptidase-IV- like hydrolytic activity. Dipeptidyl peptidase-IV (DPP-IV) cleaves out X-Pro dipeptides from the N-terminus of peptides. Other molecules carrying similar enzyme activity, such as Fibroblast activation protein (FAP), DPP-II, DPP8 and DPP9 or even DPP-IV structure-like but hydrolytically inactive molecules (DPP6 and DPP10) also belong to this group. Recent knowledge suggest a substantial role of DASH in cancer pathogenesis. The aim of this study is a preparation of a biological model and its use for understanding the mechanisms of interaction(s) between transformed glial cells and stroma in the processes of origin and development of tumors derived from neuroectoderm. Stable transfected human glioblastoma cell lines with inducible gene expression of DPP-IV, Fibroblast activation protein and their enzymatically inactive mutated forms, were prepared within the project. Prepared cell lines are used as a tool for studying not only the "autocrine" importance of DPP-IV and FAP for the expressing cells in in-vitro, but also for their potential "paracrine" effect(s) within the tumor microenvironment after homotopic implantation into the...
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Dipeptidyl peptidase IV in orthotopic models of glioma
Hilšer, Marek ; Šedo, Aleksi (advisor) ; Mandys, Václav (referee) ; Šefc, Luděk (referee)
Malignant gliomas belong to a highly aggressive class of tumours. Average patient survival time generally does not exceed 15 months. Despite intensive research, no therapeutic strategies capable of significantly extending the lives of those affected by the disease have been established to date. One potentially viable area of research into possible therapeutic targets in cancer therapy focuses on cell surface proteases. This group of proteins includes dipeptidyl peptidase IV (DPP-IV). Changes to DPP-IV expression have been established in the case of various cancer types including malignant gliomas. Understanding the role of DPP-IV in the biological processes of this malignant disease may thus contribute to the development of new therapeutic modalities. This thesis is therefore dedicated to establishing an orthotopic xenograft model as well as a genetically engineered model (GEM) of the glioma. The effects of DPP-IV on the growth of an experimental glioma were subsequently examined, as was the ratio of catalytic and non- catalytic mechanisms in this process. The GEM model was used for monitoring enzymatic activity and DPP-IV distribution. Non-invasive fluorescence imaging was employed in order to monitor the intraexperimental dynamics of experimental gliomas. The results indicated that DPP-IV...
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Clinicaly-pathological and moleculary-genetical characteristics of tumors of urogenital tract
Branžovský, Jindřich ; Hes, Ondřej (advisor) ; Daniš, Dušan (referee) ; Mandys, Václav (referee)
Tumors of urogenital tract are a highly heterogenous group of lesions. In last 30 years, there were several classifications, which couldn't fully describe all neoplasias, especially those arising in kidneys, because many newly discovered tumorous entities still emerge. The most active institution concentrating on tumors of urogenital tract is International Society of Urological Pathology (ISUP). As well as is diagnostics complicated, therapy of these tumors is also complicated in the same way. In some exchanging patterns main terapeutical procedures consist of surgical intervention, chemotherapy and radiotherapy. Biological targeted therapy is a treatment, that is very popular in these days. There has been discovered only slice from the whole problematics of tumoral genetics, so that meens lots of work to be done. This kind of resaech, as well as precise categorisation, is possible only at those places, that are capable of collecting realy large sum of tumors and pseudotumors, including leasions rare or new and yet not fully described. Powered by TCPDF (www.tcpdf.org)
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The role of selected molecules in biologic behaviour of human breast cancer
Gojiš, Ondřej ; Mandys, Václav (advisor) ; Kolář, Zdeněk (referee) ; Kinkor, Zdeněk (referee)
The role of selected molecules in biologic behaviour of human breast cancer Abstract Ondřej Gojiš In human breast cancer the rate of immunohistochemical discordance between primary tumour and secondary deposits were reported to range from 28% - 42% for ER and was 17% for PgR. Depending on the study and techniques utilized, discordance rates of Her2 ranged between 0% - 37%. It has been showed that PAX2 competes with SRC-3 for binding and regulation of HER-2 transcription. Human breast cancers that were PAX2 positive and SRC-3 negative had the lowest recurrence rate, and the relationship between PAX2 and SRC-3, with regard to levels that determine relapses, were found to be inversely dependent. This suggests a transcriptional link between the two subtypes of breast cancer, namely ER positive and HER2 positive tumors. Immunohistochemical profiles were performed for 30 metastatic deposits using antigens for SRC3, Pax2, ER, PgR, Her2, CK5/6, Ki67 and EGFR. SRC-3 was positive in 66.6% of cases and Pax2 in 73.3%. No correlation was observed between the patient's age, cancer grade, histotype, lymphatic node status, and protein expression. Using all seven antigens, the primary tumor's protein expression differed from that of the brain deposits in 13 cases out of 14 (93%). Constant expression of SRC3 and Pax2 was...
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