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Perioperative prognostic factors in breast cancer
Černá, Monika ; Třeška, Vladislav (advisor) ; Gaťek, Jiří (referee) ; Šiller, Jiří (referee) ; Jandík, Pavel (referee)
Introduction: Breast cancer still remains the most common malignancy in women and its incidence is slowly increasing. A marked reduction of mortality has been achieved in the last 10 years thanks to modern diagnostic methods, mammary screening, and comprehensive and targeted cancer therapy. Modern diagnostic capabilities not only allow early diagnosis of a primary tumor lesion and precise determination of its biological nature before commencing treatment, but they also enable early diagnosis of local and regional recidives, including diagnosis of metastases in distant organs. In addition to clinical examination, conventional and complementary imaging examinations and tumor markers our objective was to determine the importance and use of growth factors in relation to the overall prognosis. The growth factors physiologically act already during the ontogenetic period when they control cell growth, proliferation, differentiation and apoptotic processes. It is known that they take part in the tumor growth processes which are characterized by autonomous behavior, increased proliferative activity, distinct differentiation activity and reduced apoptosis. Growth factors work as autoregulation factors in the neoplastic process as well as through their paracrine effects mediated by more or less specific receptors....
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Anemia in IBD children. Evaluation of soluble transferrin receptor and soluble transferrin receptor - ferritin index in diagnosis and differentiating iron deficiency anemia from anemia of chronic diseases
Šuláková, Astrid ; Pozler, Oldřich (advisor) ; Frühauf, Pavel (referee) ; Pospíšilová, Dagmar (referee)
Introduction: Prevalence of anemia in inflammatory bowel disease (IBD) is high and there is an important impact of anemia on the quality of life, morbidity and mortality in these patients. Iron deficiency anemia (IDA), anemia of chronic disease (ACD) and combination of both of these conditions represent the most frequent causes. It can be difficult to distinguish IDA in condition of inflammation. In fact, the common diagnostic tests (iron, ferritin and transferin saturation) are significantly influenced by inflammation and normal ferritin concentration does not exclude iron deficiency. Soluble transferin receptor (sTfR) and calculated sTfR/F index (sTfR/log ferritin) have a high diagnostic power in diagnosis of IDA in case of chronic inflammation. Aims: 1. To determine the prevalence of anemia and the prevalence of the types of anemia (IDA, ACD, ACD/ID) and 2. To compare common laboratory tests with sTfR and calculated sTfR/F index in diagnosis of iron deficiency in children at IBD onset. Methods: We examined 56 patients with newly diagnosed IBD. In all patients were examined red blood count, serum iron, total iron binding capacity, transferrin saturation, ferritin, sTfR and calculated sTfR/F index. C-reactive protein >5 mg/l was determined as a marker of inflammation. Anemia was defined by...
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Genetic Regulation of Limb Development
Šnajdr, Pavel ; Grim, Miloš (advisor) ; Peterka, Miroslav (referee) ; Slípka, Jaroslav (referee)
Lx in SHR.Lx rat manifests in homozygotes as hindlimb preaxial polydactyly. We showed that a 2,964-bp deletion in Plzf (Promyelocytic leukemia zinc finger) intron 2 is the only candidate for Lx. The deletion removes the most deeply conserved CNE with putative regulatory influence on Plzf expression. Using in situ hybridization we found reduced expression pattern of Plzf in Lx/Lx limb and anterior expansion of expression domains of Plzf targets Hoxd10-13 genes and Bmp2, in the absence of ectopic Shh expression. Rat hd manifests in homozygotes as reduction or loss of digits II and III on both hind and forelimb and impairment of spermatogenesis leading to male infertility. We showed that hd mutation is caused by an insertion of an endogenous retrovirus into intron 10 of the Cntrob gene resulting in the translation of a truncated protein. In situ hybridization showed that expression of cartilage condensation marker Sox9, and Bmp receptor Bmpr1b is absent from the distal parts of the digit condensations II and III. Studying spermatogenesis we showed that centrobin (protein of Cntrob) localizes to the centrosome, manchette, and the marginal ring of the spermatid acroplaxome. Mutant spermatids show a disruption of head-tail coupling apparatus leading to spermatid decapitation . We demonstrated distinct...
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Analysis of candidate transmembrane adaptor proteins
Šulcová, Jitka ; Černý, Jan (referee) ; Drbal, Karel (advisor)
Transmembrane adaptor proteins (TRAPs) function as a scaffolding anchor for numerous signaling molecules and facilitate formation of large signaling complexes near the plasma membrane. They regulate spatio-temporal organization of signaling events in order to transduce fast and effective signal from surface receptors into the cell nucleus. The importance of described TRAPs in the development and proper functioning of immune cells in relation to their localization within lipid rafts is still under debate. The simple reason is the lack of a profound phenotype in knock-out mice. The described phenotypes observed in animals deficient in ITAM-containing adaptors of immunoreceptors as well as lipid raft adaptor Lat all lead to the block in the T-cell development and impaired TCR signaling. The subject of my diploma thesis is to perform bioinformatic search and filter candidate TRAP genes according to predicted and published data. Selected TRAP candidates were subjected to functional characterization. I checked for their localization to the plasma membrane and correlate their ectopic overexpression with the expression of CD69 surface Tcell activation marker. From 14 candidate TRAPs, only a single Pdzk1ip1 protein is probably localized to the plasma membrane but its expression does not influence CD69...
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The Influence of Extracellular Matrix Components to Cells Cultured In Vitro
Peterová, Eva ; Mrkvicová, Alena (advisor) ; Dršata, Jaroslav (referee) ; Vítek, Libor (referee)
Myofibroblast expansion is a critical event in the pathogenesis of liver fibrosis. The activation of hepatic stellate cells (HSC) to myofibroblast (MFB) results in the enhanced production of extracellular matrix (ECM). We have studied the effect of fibroblast growth factor 1 (FGF-1) on liver MFB. In the second part we investigated effect of transforming growth factor β1 (TGF-β1) and FGF-1 on cell line HSC-T6. Cells were cultured on plastic dishes and in 3D collagen gel mimicking fibrotic tissue. MFB were isolated by repeated passaging of nonparenchymal liver cell fraction. The transfer of MFB from plastic dishes to collagen gel resulted in the change in their shape and phenotype. The expression of cytokine TGF-β1 and of MFB markers, α-smooth muscle actin (α-SMA) and cellular fibronectin (EDA-FN) on protein level was significantly decreased in collagen gel. The experiments with SB 431542, the inhibitor of TGF-β receptor type I, showed that EDA-FN and α-SMA are differently regulated. EDA-FN expression is dependent on TGF-β1, while the expression of α-SMA is primarily determined by the environment and modified by TGF-β1. EDA-FN is more sensitive to the U0126, the inhibitor of protein kinases MEK 1 and 2. Collagen gel does not change the expression of metalloproteinase MMP-2 but activates the proenzyme....
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TRAIL-induced Apoptosis in Populations of Colon Cancer Cell Lines under Various Cultivation Conditions
Nevařil, Leonard ; Anděra, Ladislav (advisor) ; Neužil, Jiří (referee)
Tumor Necrosis Factor-Related Apoptosis Inducing Ligand (TRAIL) is a cytokine of TNF family, which participates in the non-exclusive regulation of survival and proliferation of mainly hematopoietic cells. Shortly after its discovery it also brought significant attention as specific and potent inducer of apoptosis of cancer cells of various origins, and since then it has been investigated as a potential novel anti-tumor therapeutics. Recently, cancer stem cells (CSCs) were suggested to be a distinct subset of tumor cells that could be responsible at least in some tumors for their sustainment, recurrence and drug resistance. These cells in the "hierarchic" model of tumorigenesis thus represent an important and attractive target for efficient tumor therapy. In this study we use several colorectal adenocarcinoma cell lines as an experimental model for the analysis of CSC-prone cultivation conditions on TRAIL-induced apoptosis of these cells. For enrichment of eventual cancer stem cells we cultivated cell lines in a serum-free medium, originally developed for cultivation of neural stem cells, and assessed the expression of putative CSC markers CD133 and ABCG2 by flow cytometry (FACS). Simultaneously, we tested the expression of TRAIL receptors and susceptibility to TRAIL-induced apoptosis in these cells. We...
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Epidermal growth factor receptor as a predictor of tumor response to preoperative chemoradiation in locally advanced gastric carcinoma
Sirák, Igor ; Petera, Jiří (advisor) ; Šlampa, Pavel (referee) ; Soumarová, Renata (referee)
The purpose of my doctoral thesis was a retrospective evaluation whether the intensity of epidermal growth factor receptor (EGFR) expression in tumor biopsy predicts tumor response to preoperative chemoradiotherapy in patients with locally advanced gastric carcinoma. Thirty-six patients with gastric adenocarcinoma in clinical T2-4 stage and/or with nodal metastases were studied. Preoperative treatment consisted of 30-45 Gy of gastric irradiation with continuous 5-fluorouracil and weekly cisplatin. Surgical resection was performed 4-6 weeks later. EGFR expression in pretreatment tumor biopsies was assessed by immunohistochemistry. Level of EGFR expression was determined from the intensity and extent of staining. Tumor response after chemoradiotherapy was defined as a reduction of at least one T-stage level and/or finding of intense tumor regression in histopathologic examination. Seventeen patients responded to preoperative chemoradiation - 8 patients (22%) had pathologic complete response, 9 patients (25%) were downstaged. Positive EGFR expression was found in 8 tumors (22%), and represented a significant predictive marker of poor tumor response in multivariate logistic regression analysis (p = 0.015). Response to chemoradiotherapy was found in 57% (16/28) of EGFR negative patients and in 13% (1/8)...
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Th1/Th2 cytokine gene polymorphisms in patients with idiopathic pulmonary fibrosis
Vašáková, Martina ; Stříž, Ilja (advisor) ; Posová, Helena (referee) ; Šedivá, Anna (referee)
Objectives: Idiopathic pulmonary fibrosis (IPF) is a serious disease characterized with progressive scarring of the lungs in which the genetic background is supposed. The aim of our study was to investigate Th1/Th2 cytokine gene polymorphisms to evaluate their possible influence on IPF development. Then we have correlated selected polymorphisms of IL-1, IL-4 and IL-12 groups ( the selection was based on our previous results) with clinical parameters and high resolution computed tomography (HRCT) as a markers of disease stage and progression. Methods: We investigated 30 patients with IPF and 103 healthy volunteers for the cytokines polymorphisms of the IL-1 alpha, IL-1 beta, IL-1R, IL-1RA, IL-2, IL-4, IL-6, IL-10, IL-12, TNF alpha, IFN gamma, TGF beta, IL-1 beta, IL-2, IL-4 and IL-4RA genes. The PCR-SSP method was used for measurement. Then the correlations of vital capacity(VC) and diffusing capacity for carbon monoxide(DLCO), bronchoalveolar lavage (BAL) fluid cell counts and high resolution computed tomography (HRCT) alveolar and interstitial scores with different genotypes of groups of IL-1, IL-4, and IL-12 cytokines and their receptor antagonists. The HRCT results were evaluated by an experienced viewer using the interstitial and alveolar score scales, which were based on the IPF HRCT description system...
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