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Wnt/beta-catenin and mTOR signaling in regulation of T-cell phenotype and cytotoxic activity for adoptive cellular immunotherapy of cancer
Stakheev, Dmitry ; Smrž, Daniel (advisor) ; Černý, Jan (referee) ; Říhová, Blanka (referee)
1. Abstract (EN) The adoptive cellular immunotherapy (ACI) based on ex vivo produced T cells is a modern treatment modality of cancer. However, the ex vivo production of T cells with high therapeutic efficacy is far to be well established. Wnt/β-catenin and mTOR signaling have been shown to affect both cancer cells and immune cells. Therefore, the modulation of these pathways seems to be perspective for the production of T cells with superior therapeutic efficacy. The aim of our project was to investigate, how interventions into Wnt/β-catenin and mTOR signaling during the ex vivo production of tumor-associated antigen-specific T cells could improve the production of T cells with a desired and controlled phenotype that would best fit for use in ACI of cancer. In the first part of our study, we investigated the role of Wnt/β-catenin inhibition by XAV939 on cancer cell elimination by lymphocytes from patients with localized biochemically recurrent prostate cancer (BRPCa). We found that preconditioning BRPCa lymphocytes with 5 µM XAV939 accelerated the elimination of LNCaP and PC3 cells during the coculturing. However, during subsequent re-coculturing with fresh LNCaP cells, BRPCa lymphocytes were no longer able to eliminate cancer cells unless coculturing and re-coculturing were performed in the presence of...
Wnt/beta-catenin and mTOR signaling in regulation of T-cell phenotype and cytotoxic activity for adoptive cellular immunotherapy of cancer.
Stakheev, Dmitry ; Smrž, Daniel (advisor) ; Černý, Jan (referee) ; Říhová, Blanka (referee)
1. Abstract (EN) The adoptive cellular immunotherapy (ACI) based on ex vivo produced T cells is a modern treatment modality of cancer. However, the ex vivo production of T cells with high therapeutic efficacy is far to be well established. Wnt/β-catenin and mTOR signaling have been shown to affect both cancer cells and immune cells. Therefore, the modulation of these pathways seems to be perspective for the production of T cells with superior therapeutic efficacy. The aim of our project was to investigate, how interventions into Wnt/β-catenin and mTOR signaling during the ex vivo production of tumor-associated antigen-specific T cells could improve the production of T cells with a desired and controlled phenotype that would best fit for use in ACI of cancer. In the first part of our study, we investigated the role of Wnt/β-catenin inhibition by XAV939 on cancer cell elimination by lymphocytes from patients with localized biochemically recurrent prostate cancer (BRPCa). We found that preconditioning BRPCa lymphocytes with 5 µM XAV939 accelerated the elimination of LNCaP and PC3 cells during the coculturing. However, during subsequent re-coculturing with fresh LNCaP cells, BRPCa lymphocytes were no longer able to eliminate cancer cells unless coculturing and re-coculturing were performed in the presence of...
Identification of prognostic biomarkers for immunotherapy of ovarian carcinoma
Quaiserová, Lenka ; Palich Fučíková, Jitka (advisor) ; Říhová, Blanka (referee) ; Reiniš, Milan (referee)
Ovarian cancer belongs to the gynecological malignancies with the worst prognosis, mainly due to the late diagnosis of this disease and limited therapeutic options for patients. Despite the undeniable progress in surgical and chemotherapy treatment, the mortality of this disease is still rather high. For this reason, several preclinical and clinical studies have been involved in identification of new treatment strategies (including immunotherapy) and characterization of new prognostic and predictive biomarkers to help determine the development of the clinical condition of patients or their response to treatment. The aim of this thesis was to better understand the role of the immune system in the tumor microenvironment (TME) of high-grade serous ovarian cancer (HGSC) and its possible prognostic role in the treatment of patients. Our results show that the presence of activated DC-LAMP+ dendritic cells in the TME is associated with the induction of anti-tumor T helper type 1 response (Th1) and cytotoxic response. Surprisingly, the resulting effector activity of the cytotoxic T lymphocytes (CTLs) is not inhibited by the presence of programmed death-ligand 1 (PD-L1), programmed cell death (PD- 1), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and lymphocyte-activation gene 3 (LAG-3), as...
Immunogenic cell death and it's relevance for biology and therapy of malignant diseases
Truxová, Iva ; Špíšek, Radek (advisor) ; Říhová, Blanka (referee) ; Kalina, Tomáš (referee)
Immunostimulatory potential of tumor cells depends on various factors, including primarily tumor antigen repertoire and the capacity to emit molecules associated with cellular stress or injury, so called DAMPs, during immunogenic forms of cell death. These molecules mainly act on dendritic cells (DCs), thus activating the antitumor immune response. Several immunogenic cell death (ICD) inducers have been described in the past years. The contribution of my PhD thesis into this topic was the characterization of the apoptotic pathways activated by high hydrostatic pressure (HHP). HHP induces rapid tumor cell death accompanied by DAMP release (mainly calreticulin (CRT), HSP70, HSP90, HMGB1 and ATP) that is characterized by the overproduction of reactive oxygen species (ROS) causing the establishment of integrated stress response. ROS-PERK-eIF2α-caspase-2-caspase-8 signaling pathway plays an essential role in CRT translocation to the tumor cell surface upon HHP treatment, thus influencing the immunogenic potential of these cells. Moreover, the importance of ICD concept was also confirmed in vivo. The results point out that the presence of CRT on the surface of malignant blasts from AML patients correlates with the activation of specific antitumor immune response and improved clinical outcome. Another...
Polymeric-drug Conjugates in Treatment of Head and Neck Squamous Cell Carcinoma
Betka, Jaroslav ; Říhová, Blanka (advisor) ; Prausová, Jana (referee) ; Reiniš, Milan (referee)
Malignant diseases are after cardiovascular diseases the second most common cause of death in the developed countries. The number of patients newly diagnosed with cancer is constantly rising, on average by 2.5% yearly. This trend also applies to squamous cell carcinoma of the head and neck, which is the sixth most common oncological disease. Its occurrence is most influenced by two external risk factors: smoking and abuse of alcohol; latest research indicates that for the emergence of neoplasia is crucial not only the amount of and duration of the use of a harmful substance but also the time of day when a harmful substance is used as well as psychological dependence on the substance. But recently, we are witnessing growth of the frequency of occurrence of the squamous cell carcinoma of the pharynx with non-smokers and younger age groups in connection with presence of the HPV infection in tumor. The forms of so far most commonly used anticancer therapy (surgery, radiotherapy, chemotherapy) have, despite progressions over the last decades, lead to significant improvement only with some types of cancer but in the case of squamous cell carcinoma of the head and neck is the total probability of five-year survival still low, approximately 40%. Therefore we are turning our attention to the new forms of...
Glycobiology of the head and neck cancer
Valach, Jaroslav ; Smetana, Karel (advisor) ; Dřízhal, Ivo (referee) ; Říhová, Blanka (referee)
iii Abstract Glycobiology represents a very progressive subject of cell biology. Protein-saccharide interactions play not only supporting and cell organization role, but they also represent medium for information storage and its decoding. Galectins, group of animal lectins (saccharide-binding proteins), which have selective affinity to ß-galactosides, are multifactorial molecules. They participate in cell-cell and cell-matrix interaction, transmembrane signaling, apoptosis, pre- mRNA splicing and are also present in various types of carcinomas. High expression of galectin-1 has been detected in cancer stroma originated from squamous cell epithelium. In the previous study we established that the fibroblasts - myofibroblasts transition, apart from the known TGF- beta, is also induced by galectin-1. We compared relationship between galectin-1 expression, presence of myofibroblasts and gene expression in tissue samples from patients with head and neck squamous cell carcinoma. Cancer stroma with myofibroblasts was rich in galectin-1 expression in comparison with stroma without myofibroblasts. Moreover, we used microarray analysis (ILLUMINA) to compare the whole genome transcriptome from samples with and without presence of galectin-1. High expression of galectin-1 in tissue samples corresponded with expression...
Recombinant vaccines against solid and hematological cancer: development and monitoring of vaccines-induced immunity
Babiarová, Katarína ; Němečková, Šárka (advisor) ; Říhová, Blanka (referee) ; Mikyšková, Romana (referee)
K. Babiarová Ph.D. Thesis ABSTRACT Cancer immunotherapy is concerned generally with the activation of cancer immunity specific for tumor antigens (TA) produced by cancer cells. My PhD thesis focused on the development of different types of cancer vaccines expressing various TA and predominantly on the determination of the efficacy of these vaccines. For studying TA-specific cancer cellular immunity in mice immunized with these vaccines, I used mainly the ELISPOT-IFNγ assay. First, DNA, recombinant vaccinia virus (rVACV) and peptide vaccines against WT1 positive tumors were prepared. They consist of a fragment of WT1 protein with motifs predicted to bind to Db murine MHC class I. The administration of peptide vaccines by tattoo delivery in combination with unmethylated CpG motifs and anti-TGFβ monoclonal antibody was the most effective. Next, I was interested in the immunotherapy of chronic myeloid leukemia (CML). Hruskova et al. prepared the mouse polyomavirus-like particles (MPyV-VLP) carrying the junction region of BCR-ABL fusion protein (1). In our laboratory, there were constructed the other types of CML vaccines with the expression of the junction region of BCR-ABL fusion protein, such as DNA or rVACV, too. Prepared vaccines failed to induce effective cancer immune response. It seems that BCR-ABL...
Immuno-biological Aspects of Head and Neck Squamous Cell Carcinoma
Bouček, Jan ; Říhová, Blanka (advisor) ; Fučíková, Terezie (referee) ; Šlapák, Ivo (referee)
The process of tumorigenesis is conditioned by change or the series of changes at a gene level. The development of cancer is largely pre-ordained by this change, but very important role is played by other factors. In case of solid tumors it is mainly a tumor microenvironment, where the tumor cells are in contact with stromal cells, especially fibroblasts, and immune cells. Tumor microenvironment can also critically modify the nature and intensity of anti- tumor immune response. Squamous cell carcinomas of the head and neck are the sixth most common cancer, which affect each year more than half a million patients worldwide. Despite advances and improvements in all treatment modalities, achieved therapeutic results even in Western countries are not satisfactory and remain at approximately the same values for several decades. At prezent, the 5 years survival rate, regardless of the location and stage of disease, is approximately only 40%. In the prezented work the immunological and biological aspects of squamous cell carcinoma of the head and neck are discussed. It summarizes the recent findings on the molecular basis of the behavior of tumor cells and the influence and significance of regulation of the immune system for the clinical course of disease and the modern therapeutic approaches.

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11 Říhová, Barbora
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