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Disruption of transcription regulatory networks in childhood Acute lymphoblastic leukemia
Sadílek, Vojen ; Fišer, Karel (advisor) ; Frič, Jan (referee)
Transcription factor aberrations are the initiating lesion in a majority of pediatric Acute Lymphoblastic Leukemia (ALL) cases, often acquired in utero. These mutations play a crucial role in determining the disease phenotype and prognosis. This work advocates for a broad evaluation of the transcriptomic landscape from the viewpoint of transcription factors and their targets. We adapted SCENIC (Aibar et al., 2017), a tool for single-cell gene regulatory network inference, for an extensive dataset of 633 bulk RNA sequencing samples of pediatric ALL. This allows us to evaluate the gene expression profile as a result of transcription factor activity. Furthermore, we aimed to deepen our understanding of valuable preexisting data by incorporating information from several "-omics" databases. We utilized resources of single cell RNA sequencing data, protein-protein interactions and putative cis-regulatory elements in our analysis. Our approach covers the transcriptomic landscape without an overt bias for differentially expressed or highly variable genes. We demonstrate that most B-ALL subtypes have specific patterns of transcription factor activity and, for subtypes initiated by transcription factor mutations, we examine the influence of such aberrations on their activity. With MEF2D as an example, we...
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Inhibitory NK cell receptors and possibilities of manipulation of cytotoxic properties.
Švubová, Veronika ; Frič, Jan (advisor) ; Krulová, Magdaléna (referee)
Acute myeloid leukemia makes up for 18 % of all leukemias among pediatric and young adult patients. The complete remission rate (80-90 %) and the overall survival (70 %) of the patients is relatively high, nevertheless, the relapse rate is still almost at 50 % and the prognosis remains extremely bad. The relapse treatment is rather challenging because the persisting leukemic clones might in fact start to be refractory to chemotherapy. Lately, NK cells are being perceived as an attractive therapeutical tool for treatment of the relapses. NK cells are a subpopulation of innate lymphoid cells, possessing the ability to eliminate dysfunctional cells through cytotoxic activities and further perpetuate the immune response. One of the advantages of NK cells is their functional independency of specific antigens. In the light of growing evidence about the role of leukemic stem cells in context of acute myeloid leukemia, NK cells seem to offer a new perspective in therapeutical efforts to eliminate them via several cytotoxic mechanisms. Yet despite optimistic preliminary results, treating this disease has proved to be rather challenging and the NK cell-based immunotherapy is still facing several limitations. Transforming growth factor β is partially responsible for maintenance of leukemic stem cell...
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The Role of TRPV1 in Macrophage Activation and Polarisation
Fikarová, Natálie ; Krulová, Magdaléna (advisor) ; Frič, Jan (referee)
The ability to sense painful stimuli is essential to protect the body. Up to date, the underlying molecular mechanisms are still not completely understood; therefore, the treatment of chronic inflammatory pain remains challenging. The TRPV1 channel is one of the known nociceptors mediating the sensation of burning stimuli. Its agonist is capsaicin, the pungent compound of chilli peppers. This channel has been extensively studied in neurones; however, its function in immune cells is not well understood. Especially in macrophages, data regarding the role of TRPV1 in macrophage polarisation are often contradictory. Thus, further research in this area is desired to clarify the function of TRPV1 in immune cells. This diploma thesis aims to investigate the role of TRPV1 in macrophage polarisation during the inflammatory response. In this work, macrophages were stimulated with capsaicin prior to, after or concurrently with the application of LPS to determine the effect of TRPV1 activation on the inflammatory response. The involvement of MAP kinases in signalling after TRPV1 activation by capsaicin was addressed confirming that ERK 1/2 is part of the signalling cascade. Furthermore, this work proposes that activation of TRPV1 in the context of the LPS-induced inflammatory response could lead to the switch...
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Immune Monitoring and Adoptive Immunotherapy FollowingAllogeneic Hematopoietic Stem Cell Transplantation
Hejretová, Lenka ; Lysák, Daniel (advisor) ; Frič, Jan (referee) ; Raida, Luděk (referee)
Immune monitoring and adoptive immunotherapy following allogeneic hematopoietic stem cell transplantation - ABSTRACT Allogeneic hematopoietic stem cell transplantation (aloHSCT) is a specialized therapeutic method that is potentially curative for a number of hematological and non-hematological diseases. Despite continuous advances in transplant medicine, the prognosis of patients is still limited by a number of post-transplant complications, dominated by relapse and graft-versus- host disease (GvHD). These complications affect the survival of patients, but also reduce their quality of life. So, we are looking for new treatment modalities that would improve their prognosis. One of the promising procedures in the treatment of GVHD is the administration of cells with immunomodulatory potential (immunotherapy). In a number of European centers, including ours, mesenchymal stem cells (MSCs) are administered to patients after alloHSCT in the steroid-refractory GvHD (SR-GvHD) indication. Invariant NKT lymphocytes are a new cell population with a promising potential to suppress GvHD and at the same time they potentiate the graft-versus-leukemia (GvL) effect. The introduction of these cell populations into clinical practice must be preceded by a number of preclinical studies and continuous optimization of...
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The dynamics of T regulatory lymphocytes generation during pregnancy
Kopřivová, Helena ; Krulová, Magdaléna (advisor) ; Frič, Jan (referee)
Regulatory T cells (Tregs) are CD 4+ T lymphocytes with regulatory and reparative properties. Tregs are functionally and differentially controlled by Foxp3 transcription factor, and they are considered a key factor inducing feto-maternal tolerance. Disruption of this unique type of time-limited immune tolerance leads to pregnancy complications including miscarriages, intrauterine growth retardation of the fetus, and premature delivery. Tregs' production and functional properties are influenced by the cytokine environment, especially by TGF-β1, IL-2, and retinoic acid. These pleiotropic factors are involved in the differentiation of tolerogenic populations of decidual cells. In the present work, a detailed immunophenotyping of Tregs was performed, and a determination of serum concentrations of TGF-β1 during physiological pregnancy was realized. The examined subpopulations of Tregs have shown different signs or markers of their functional and maturity properties. In some subpopulations, apparent changes in Treg counts were observed during pregnancy. Moreover, typical development was observed for TGF-β1 serum levels. The main goal of the current work was an examination of differences in Treg subpopulation counts in women with premature deliveries compared to females with full term births....
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Cultural history of selected segments of Everyday Life. Cult of Absinth: Absinth in culture
Frič, Jan ; Půtová, Barbora (advisor) ; Soukup, Václav (referee)
In the introduction the reader is introduced to the brief facts related to the history of absinthe, to what absinthe really is and what it means for many people today. The author mentions several myths with which he argues and notes that it is very likely they have contributed to current popularity of the absinthe. In the History section the readers are given the opportunity to find out where absinthe comes from and how the geographical distribution of this beverage proceeded, as well as its subsequent fall, which ended with a Europe-wide ban. At the end of this passage the latest development regarding the absinthe is mentioned. The description of its redistribution due to termination of the ban in almost all countries it was first established in can be found here as well. Next section is dedicated to the actual form of absinthe. The author states which essentials should be present in production of the absinthe and how new absinthes are born today from vintage bottles that remember the pre-ban era. The consumer has the opportunity to taste the exact replicas of the drinks produced in the 19th century. The following passage is about the real and perceived effects of absinthe, as well as familiarization with the most discussed substance contained in absinthe, thujone. Absinthe ritual is described in...
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