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Refinement of tissue diagnostics in the transplant program
Balko, Jan ; Zámečník, Josef (advisor) ; Škarda, Jozef (referee) ; Němejcová, Kristýna (referee)
Refinement of tissue diagnostics in the transplant program Abstract The thesis describes tissue diagnostics of organ transplants of the donor as well as recipient. In case of donated organs (grafts), it aims to improve the provisional scoring system of graft rejection after uterine transplantation. Using histopathological methods including immunohistochemistry, it compares lymphocytic population classified in the scoring system with histopathological findings within the resected uteri of women who underwent hysterectomy for benign reasons. The aim was to validate the necessity of the category of so called borderline changes, whose morphology was proven to overlap with physiological finding within healthy uterine cervix. Therefore, there is no need for immunosuppressive therapy in such cases. In case of recipients, the thesis investigates the role of pulmonary megakaryocytes in explanted lungs after transplantation. The idea was to elucidate pathogenesis of the diseases leading to the need of transplantation itself. Pulmonary megakaryocytes within explanted lungs of various recipients were mapped using histopathological methods and immunohistochemistry. The strikingly increased number of such cells was detected among vascular disorders, especially idiopathic pulmonary hypertension. This finding could...
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Patient-derived xenograft models of human lymphomas for experimental immunotherapy
Jakša, Radek ; Klener, Pavel (advisor) ; Škarda, Jozef (referee) ; Kalinová, Markéta (referee)
Non-Hodgkin lymphomas (NHL) represent the most common hematologic malignancies. Patient-derived xenografts (PDX) are used for various aspects of translational research including preclinical in vivo validation of experimental treatment approaches. While it was repeatedly demonstrated that PDX keep majority of somatic mutations with the primary lymphoma samples, from which they were derived, the composition of PDX tumor microenvironment (TME) has not been extensively studied. We derived 15 PDX models from patients with various subtypes of aggressive lymphomas. We implemented complex genetic and immunohistochemical analysis of the established PDX models head-to-head with the patient's primary lymphoma cells, from which the PDXs were derived. We clearly confirmed that the established PDX cells shared majority of somatic mutations with the patient's primary cells, from which they were derived. Thus, from the genetic perspective the PDX models represent relevant tools for the study of lymphoma biology. Immunohistochemistry analysis of selected antigens revealed some differences between the PDXs and patients' primary cells. Importantly, the analysis demonstrated complete loss of non-malignant cellular components of the tumor microenvironment frequently observed in lymphoma infiltrated lymph nodes,...
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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...
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Role of PARs and other biomarkers in the diagnosis of lung and neurodegenerative diseases
Brůžová, Magdalena ; Matěj, Radoslav (advisor) ; Němejcová, Kristýna (referee) ; Škarda, Jozef (referee)
1 SUMMARY In recent years, biomarker research has been the subject of many studies that address the etiopathogenetic processes of various diseases. Finding a biomarker that reflects the pathological processes of the disease with high sensitivity and specificity and was easily available and stable, would greatly facilitate the diagnosis of those diseases that are not easy to distinguish by conventional screening methods. Interstitial lung diseases (ILDs) include a heterogeneous group of disorders mostly of inflammatory nature. The resulting damage of the lung parenchyma can lead to its remodeling and fibrotization. The fibroproliferative process in different types of ILDs can result in similar clinical manifestations and findings on radiological images and biopsy specimens, which makes differential diagnosis difficult. Therefore, research in this area focuses on the presence of biomarkers in bronchoalveolar lavage fluid (BALF) to determine biomarker levels specific to individual ILDs. BALF analysis is used for differential diagnosis of patients with ILDs, but it can also be used to monitor the course of the disease, or response to the treatment. In our first study, we compared the levels of biomarkers in BALF in patients with sarcoidosis and hypersensitivity pneumonia (HP). From the results of the study, it...
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The comparison of morphology, expression, epigenetic changes and mutations of HNF1B in solid tumors and non-neoplastic lesions.
Bártů, Michaela ; Dundr, Pavel (advisor) ; Mandys, Václav (referee) ; Škarda, Jozef (referee)
Introduction HNF1B is a tissue-specific transcription factor, which plays a crucial role in the embryological development of a number of organs, especially kidneys, gastrointestinal system, pancreas and billiary system. While the significance of HNF1B in the development of urinary tract malformations has already been well described, its role in the pathogenesis of solid tumors has not yet been elucidated. Based on the current data it seems that depending on the type of individual tumor HNF1B can either act as an oncogene or a tumor suppressor. However, the precise mechanism of how it exerts its influence is still unclear. Aims: The thesis focuses on expanding the knowledge of the significance of HNF1B changes in selected solid tumors and non-neoplastic lesions. The individual goals include: 1) determining the role which HNF1B plays in the pathogenesis of these lesions, 2) evaluating the significance of HNF1B for differential diagnosis, 3) analysis of the prognostic and predictive meaning of HNF1B, 4) mutation analysis of the HNF1B gene in all the tumor and non-tumor tissues with the aim to identify novel pathogenic mutations, 5) methylation analysis of the HNF1B promoter. Material and methods: Immunohistochemical examination with the antibody against HNF1B was performed on 516 samples of tumor and...
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Colorectal cancer - from patogenesis to screening. Colorectal carcinogenesis in ulcerative colitis with primary sclerosing cholangitis and the issue of the screening of the colorectal cancer.
Wohl, Pavel ; Špičák, Julius (advisor) ; Škarda, Jozef (referee) ; Gregor, Martin (referee)
Colorectal carcinoma (CRC) ranks high in mortality and morbidity in most developed countries. Following theses focus on specific aspects of colorectal carcinoma pathogenesis including the issue of screening. The goal of the first study was assessment of expression of epithelial markers of colorectal carcinogenesis p53, COX-2, bcl-2. The study included patients with active ulcerative colitis (UCA), ulcerative colitis in remission (UCR), primary sclerosing cholangitis with ulcerative colitis (PSC-UC) (PSC), patients after liver transplantation for PSC (OLT) and a control group (N). We found significantly increased expression of tumour suppressor gene p53 in non-dysplastic mucosae in PSC-UC compared with UCA, UCR, OLT, and N, which may indicate higher neoplastic potential of PSC. Statistically significant correlation was found between PSC incidence and p53 expression. Surprisingly, OLT showed no p53 expression in non-dysplastic mucosa compared with PSC-UC. This indicates that PSC may contribute to increased expression of p53 and p53-induced colorectal carcinogenesis. Furthermore, a correlation between expression of p53 and COX-2 together with the increased expression of bcl-2 in UCA compared to N can support the role of inflammation in colorectal carcinogenesis. The goal of the second study was...
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