|
|
Immunohistochemical and molecular-genetic markers in predicting the progression of esophageal neoplasia in correlation with pathophysiology
Kollár, Marek ; Martínek, Jan (advisor) ; Suchánek, Štěpán (referee) ; Mandys, Václav (referee)
Introduction: Esophageal cancer ranks eighth among the most common malignancies worldwide. The two most common types are adenocarcinoma and spinocellular carcinoma. Correct histopathological diagnosis, cancer staging and identification of predictive risk factors of progression are important in terms of further disease course and management. While patients with mucosal carcinoma without risk factors are treated endoscopically, those with submucosal invasion or mucosal carcinoma with risk factors are referred for surgical therapy according to current recommendations. Histopathology is still considered the gold standard in diagnosis, often used in conjunction with immunohistochemistry, e.g., to document a TP53 gene mutation, which plays an important role in the pathogenesis and progression of esophageal dysplasia. New diagnostic methods, such as confocal laser endomicroscopy (CLE), also play an important role. Other crucial factors include patient follow-up, early and reliable detection of persistent or recurrent lesions. Aims, methods and patients: In the thesis, 4 separate, partly connected projects are assessed together, with a partial overlap of patients. The aims of the individual projects were as follows: 1) To identify predictive factors of esophageal cancer progression, risk of metastasis and...
|
|
|
Morphological, immunohistochemical, and molecular analysis of leiomyocellular tumors of the female reproductive system
Gregová, Mária ; Dundr, Pavel (advisor) ; Mandys, Václav (referee) ; Škarda, Jozef (referee)
Introduction Leiomyoma with bizarre nuclei (LBN) and cellular leiomyoma (CL) are rare variants of uterine smooth muscle tumors. In diagnostic practice, LBN can be mistaken for leiomyosarcoma (LMS), while CL may mimic low grade endometrial stromal sarcoma (LG ESS). Careful evaluation of morphological features is necessary when making the diagnosis; in some borderline cases, immunohistochemical and molecular examinations may help. Literature data on molecular genetic alterations in LBN and CL is limited, but some of these tumors appear to share certain aberrations with classical leiomyomas (UL) and LMS. Aims The aim of the work is to expand the knowledge about smooth muscle tumors of the uterus, especially LBN and CL, and perform a complex morphological, immunohistochemical (IHC), and molecular evaluation of their features. The individual goals include: 1) confirmation of the hypothesized benign behaviour of LBN, 2) morphological analysis of LBN, 3) more detailed clarification of LBN tumorigenesis with a focus on the FH gene, 4) clarification of CL tumorigenesis, 5) the use of IHC FH antibody as a screening method to identify FH gene mutations, 6) the use of morphological evaluation and results of IHC examination to facilitate differential diagnostic balance between benign and malignant smooth muscle...
|
|
|
The role of proteinases-activatable receptor - 2 (PAR-2) in pathogenesis of human disease
Matěj, Radoslav ; Mandys, Václav (advisor) ; Fakan, František (referee) ; Ehrmann, Jiří (referee) ; Rudolf, Emil (referee)
It was presented that one of the pancreatic enzymes, trypsin, modulates many biological processes by acting on specific proteinase-activated receptor 2 (PAR-2). PAR-2 belongs to a family of G protein coupled receptors activated by tethered ligand sequences within the N-terminal, which is made accessible after the site-specific cleavage of the protein. Trypsin activates PAR-2 by the mediation of a unique process inhering in the recognition of the receptor by enzyme, subsequent c1eavage at the specific site ofNH2-terminal and presentation of a new NH2 terminal, which behaves as a tethered ligand. This ligand interacts with the extracellular doma in of receptor molecule. Thus, P AR-2 is a receptor, whose I igand is a physical part of the receptor molecule. This receptor was previously described on norma I as well as ma lignant immunocompetent cells, on endothelial and muscle cells of major as well as minor vessels. Its presence was also immunohistochemically demonstrated on intestinal epithelial cells, epithcl ial cells of exocrine organs, keratinocytes, fibroblasts and other cell types in stomach, small intestine, colon, liver and kidney. PAR-2 is expressed on various cells with a wide spectrum of cellular responses after activation. ln the firs t part of th is work we focused on the role of PAR-2 dUl·ing the...
|
|
|
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...
|
|
|
Morphological and Immunohistochemical Analysis of Melanocytic Lesions
Důra, Miroslav ; Dundr, Pavel (advisor) ; Mandys, Václav (referee) ; Pock, Lumír (referee)
This doctoral thesis deals with morphological and immunohistochemical analysis of melanocytic lesions. Melanoma is the most dangerous malignant skin tumor with its potential occurrence outside the skin. Its early diagnosis is the basic aspect of a favorable disease prognosis. Distant metastases development occurring several years after the initial diagnosis is a typical feature of melanoma. Histopathological differential diagnostics of melanocytic lesions is extremely difficult because of the diversity of melanocytic lesions. Contemporary research is focused on the identification of new surrogate markers based on immunohistochemistry or molecular genetics, which would be enable to estimate the behavior of a certain lesion and clarify the gray zone of melanocytic lesions of uncertain biological behavior. The doctoral thesis is focused on the immunohistochemical analysis of GLUT-1 protein expression in 400 cases of benign and malignant melanocytic lesions. Significant expression of this marker was identified in the group of melanomas, it was not identified in melanocytic nevi. Expression of GLUT-1 corresponded to the worse prognosis of the disease. The doctoral thesis also deals with the issue of TILs. The analysis of TILs (tumor infiltrating lymphocytes) in 213 melanomas compared the prognostic...
|
|
|
Management of Morphological Diagnstics of Genetically Defined Tumours of the Tract
Vaňková, Bohuslava ; Daum, Ondřej (advisor) ; Mandys, Václav (referee) ; Šíma, Radek (referee)
MUDr. Bohuslava Vaňková Abstract The dissertation called "Management of morphological diagnostics of molecularly- genetically defined tumors of the digestive tract" is an annotated file of a total of eight published works (four original works published in an English literature in an impact-factor journal, one letter to an editor in English language also having an impact factor, and three works in Czech language published in domestic reviewed journals: two of these are reviews of the literature, one is an original work). Currently, molecular genetics is significantly entering the classifications of different tumor units and in some units it is undoubtedly becoming an integral part of the diagnostic algorithm; as a result molecular genetic traits of individual tumors are hardly to be ignored. In contemporary pathology, at the same time you may find the classifications based exclusively on morphological traits, but also the classifications mostly using molecularly-genetic traits (e.g. the classification of the central nervous system or hematological malignancies), as well as the classifications combining the both traits (part of renal neoplasia). For practical medicine it is however always necessary to find an intersection of the both approaches to ensure the correct and complete diagnosis for a patient. Most...
|
|
|
Expression of adaptor protein PAG/Cbp in non-neoplastic and neoplastic lymphoid tissue
Švec, Alexandr ; Mandys, Václav (advisor) ; Plank, Lukáš (referee) ; Kodet, Roman (referee) ; Stöckbauer, Petr (referee)
New notions about cell development, cell cycle, differentiation and cell signalling are now being used for refinement of classification of malignant lymphomas (ML) and for development of new drugs specifically targeting deregulated proteins some of which play a role in immune signalling. The first step in most of the signalling pathways is transduction of the signal through the plasma membrane mediated by a plasma cell receptor. Certain proximal signalling molecules such as a family of Src-kinases (SFK) are segregated in particular plasma membrane compartments called lipid rafts or glycosphingolipid-enriched microdomains (GEM). I studied expression of PAG in non-neoplastic and neoplastic lymphoid tissue in order to determine its expression pattem and to investigate its utility in routine diagnostic haematopathology.
|
|
|
Expression of CD44 molecules in urothelial bladder cancer
Kuncová, Jitka ; Mandys, Václav (advisor) ; Smetana, Karel (referee) ; Hes, Ondřej (referee) ; Záťura, František (referee)
The main aim of presented work was to contribute to clarify the significance of changes in expression of adhesion molecules and CD44 in the malignant behavior of urothelial carcinomas of the urinary bladder. The individual stages to meet this goal were: 2.1 Detailed determination of expression of CD44s and CD44v6 protein in urothelial carcinomas of the urinary bladder in relation to the degree of tumor differentiation. 2.2 Determine the relationship of CD44 protein expression changes depending on the characteristics histomorphologic urothelial carcinoma of the urinary bladder, and other indicators of biological behavior of tumor (proliferative activity, p53 expression). 2.3 Evaluation of expression of CD44s and CD44v6 protein in two phenotypically distinct cell lines, urothelial carcinomas (HT1197 and 5637) and determine relationships CD44 expression on morphological and growth characteristics of tumor cells of these lines.
|
|
|
Receptors involved in regulations of inflammatory reactions in renal diseases
Eis, Václav ; Mandys, Václav (advisor) ; Hes, Ondřej (referee) ; Zemanová, Zdeňka (referee)
Eis, V., Luckow, B., Vielhauer, V., Sireke, J., Linde, Y., Segerer, S., Perez de Lema, G., Cohen, C. D., Kretzler, M., Mack, M., Horuk, R., Murphy, P. M., Gao, J.-L., Hudkins, K. L., Alpers, C. E., Gröne, H.-J., Schlöndorff, D., Anders, H.-J.: Chemokine receptor CCR1 but not CCR5 mediates leukocyte recruitment and subsequent renal fibrosis after unilateral ureteral obstruction. J Am Soc Nephrol, 15, 2004; 2: 337-347. We examined the role of chemokine receptor CCR1 and CCR5 in renal inflammatory infiltrate and subsequent interstitial fibrosis. Unilateral ureteral obstruction model in mice deficient for CCR1 or CCR5 was used for experiments. Analysis of UUO kidneys from CCR1-deficient mice or BX471 treated mice revealed a reduction of interstitial macrophages and lymphocytes compared with wild type controls. In contrast, renal leukocytes and fibrosis were unaffected in CCR5-deficient mice with UUO. Interstitial fibroblasts, renal TGF-β1 mRNA expression, interstitial volume and collagen I depositions were significantly reduced in CCR1-deficient mice. Lack of CCR5 does not affect renal fibrosis after UUO. Thus, CCR1 but not CCR5 is required for leukocyte recruitment and fibrosis after UUO in mice. Anders, H.-J., Belemezova, E., Eis, V., Segerer, S., Vielhauer, V., Perez de Lema, G., Kretzler, M., Cohen, C. D.,...
|
|
|
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)
|
guest ::
RSS feed.