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Oncolytic viruses in cancer immunotherapy
Zupko, Jakub ; Bartůňková, Jiřina (advisor) ; Janovec, Václav (referee)
Oncolytic virotherapy is a field dedicated to exploiting viruses in the battle against cancer, where their specific cytolytic effects are sorely needed. This work focuses on the mechanisms and limitations of oncolytic virotherapy, on the recent advances in the field and on the potential oncolytic viruses hold for the future.
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Modification of murine tumor cell lines with CRISPR/Cas9 system and their characterization
Lhotáková, Karolína ; Poláková, Ingrid (advisor) ; Brábek, Jan (referee)
MHCI molecules are constitutively expressed in all nucleated cells and play a key role in antigen presentation to CD8+ T lymphocytes. One of the tumor immune evasion strategies is MHCI expression downregulation. This leads to an impaired recognition of tumor antigens by CD8+ T lymphocytes that are unable to start the immune response. Since the MHCI expression downregulation occurs in up to 90 % of some tumors it is neccesary to have a clinical relevant tumor model without a MHCI surface expression that would be used for testing of immunotherapeutic approaches. This thesis describes a production of new model cell lines of TC-1 tumor cells with irreversibly downregulated MHCI. That was achieved by an inactivation of B2m, which is a part of MHCI, by gene editing using CRISR/Cas9. The B2m inactivation was confirmed by flow cytometry, western blot and sanger sequencing of single alleles. The inactivation slowed down the cell growth for both in vitro and in vivo. The cell metastatic activity was not affected. The tumors established by cells without the B2m expression are not sensitive to DNA vaccine against HPV16 E7 oncoprotein by a pBSC/PADRE.E7GGG vaccine. The main effector function against these tumors possess the NK1.1+ cells. In a therapeutic vaccination experiment it was repeatedly achieved of...
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Helminths as causative agents of vertebrate cancers
Schreiber, Manfred ; Horák, Petr (advisor) ; Kolářová, Iva (referee)
Opisthorchis viverrini, Clonorchis sinensis, and Schistosoma haematobium have been classified as the group 1 of carcinogens by the International Agency for Research on Cancer. Infections with opisthorchid flukes may lead to the development of cholangiocarcinoma of the liver, and those with schistosomes to the squamous carcinoma of the bladder. The link between helminth infections and carcinomas has been confirmed, and the exact mechanisms of carcinoma induction are at present intensively studied. There are some other representatives of helminths that are probably associated with cancers, but their direct effect on the process of carcinogenesis has not been confirmed yet. The formation of tumors can also occur via malignant transformation of totipotent parasite cells that become invasive and metastasize to different parts of the host body. However, some types of helminths may exhibit an opposite effect and show an anti-tumor activity. This review primarily focuses on the helminths associated with the development of cancer and the currently described mechanisms of carcinogenesis caused by such infections.
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Correlation of Immunohistochemistry and Molecular Biologic Methods in The Diagnosis of Tumors
Michal, Michael ; Skálová, Alena (advisor) ; Rychlý, Boris (referee) ; Zambo, Iva (referee)
This thesis is a collection of commentaries on altogether 13 first-authored and 20 co- authored publications where morphology, immunohistochemistry (IHC) and molecular genetic methods were used to provide novel clues for arriving at an accurate diagnosis of tumors, as well as to propose novel approaches and refinement of classification of certain tumors. The presented manuscripts are the result of the postgraduate studies of MUDr. Michael Michal at the Charles University in Prague, Faculty of Medicine in Pilsen in the period between 2015-2018. The author focused the main part of his research, particularly his first-authored manuscripts, on soft tissue tumors but also largely participated in research activities focusing on other body systems. Over the course of his studies, four main areas of interests within the topic of soft tissue pathology emerged. The first is oriented on soft tissue tumors of presumed (but unconfirmed) fibroblastic lineage. First two publications regard two related low-grade sarcomas called Myxoinflammatory fibroblastic sarcoma (MIFS) and Pleomorphic hyalinizing angiectatic tumor (PHAT). In the first manuscript, a high-grade variant of the former is described. The latter publication is focused on the morphological and IHC similarities between both MIFS and PHAT. The third and...
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The role of biotransformation enzymes in the resistance of cancer cells against standard cytostatics
Giannitsi, Anna ; Hofman, Jakub (advisor) ; Čečková, Martina (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Anna Giannitsi Supervisor: RNDr. Jakub Hofman, Ph.D Title of diploma thesis: The role of biotransformation enzymes in the resistance of cancer cells against standard cytostatics Drug resistance is currently one of the major problems of chemotherapy. Tumor cells are able to defend themselves against the effect of cytostatic drugs due to various mechanisms which leads to a failure of anticancer therapy. The effort to describe new mechanisms of resistance and to develop new therapeutic methods, which would limit this therapeutic obstacle, is logically the subject of many studies. The activity of drug metabolizing enzymes and the subsequent decrease of intercellular concentration of anticancer drugs belongs to one of the possible mechanisms of pharmacokinetic resistance. Enzymes of I. and II. phase of biotransformation participate in this phenomenon. Cytochromes P450, main enzymes of the I. phase, play a major role in the metabolism of many cytostatic agents producing either pharmacologically active or inactive metabolites. Increased expression in tumors and the involvement of individual isoforms into the overall metabolism of cytostatic, which is deactivated by their activity, seems to be one of the...
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Anti-tumor activity of mesenchymal stem cells
Džuganová, Barbora ; Krulová, Magdaléna (advisor) ; Indrová, Marie (referee)
Mesenchymal stem cells (MSCs) are multipotent cells with the ability to migrate to inflammation sites and to tumor sites. They are able to regenerate the damaged tissues and also easy to isolate and cultivate. Furthermore, they can inhibit tumor cells and modulate the immune response. They are non-toxic in the organism and genetic modification of them can enhance their antitumor effect. MSCs can also serve as a vehicle for delivery of the therapeutic agent to the tumor. These properties make them special for anti-tumor therapy. Under some conditions, MSCs can also stimulate the tumor growth. This work discusses conditions in which MSCs inhibit the growth of cancer cells, as it is not yet clear on which precise mechanisms this inhibition is based.
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Studium nádorové imunoterapie založené na instalaci ligandů fagocytárních receptorů na nádorové buňky a objasnění probíhajících procesorů
CAISOVÁ, Veronika
Immunotherapy became a very promising approach for cancer therapy. Tumor cells are eliminated using the body's own immune system with minimal negative effect on healthy tissue. This thesis is focused on immunotherapy based on activation of innate immunity, specifically on intratumoral application of ligands stimulating phagocytosis and Toll-like receptor ligands. This therapeutic approach was tested in several types of tumor mouse models, such as melanoma B16-F10, pancreatic adenocarcinoma, and pheochromocytoma. The composition of the therapeutic mixture as well as the application schedule were optimized in our studies. Subsequently the underlying mechanisms involved in tumor elimination during this therapy were investigated.
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Tumours in historical and social context in the modern period
Hrudka, Jan ; Komárek, Stanislav (advisor) ; Tinková, Daniela (referee) ; Stingl, Josef (referee)
Univerzita Karlova v Praze Přírodovědecká fakulta Studijní program: Filosofie a dějiny přírodních věd MUDr. Jan Hrudka Nádory v dějinném a kulturním kontextu v novověku Tumours in historical and social context in the modern period Disertační práce Školitel / Supervisor: Prof. RNDr. Stanislav Komárek, Dr. Praha, 2017 SUMMARY: The PhD thesis called Tumours in historical and social context in the modern period is an attempt to describe a change of medical thinking in modern period; science and medicine turns from antique humoral pathology, explaining all diseases as an imbalance of the four body humours, to pathological anatomy and experimental physiology. In the point of view of pathological anatomy, the viscera of diseased person are no more "screen" or "mirror" of the disease, but it becomes directly the "stage" or "theatre" of the acting disease. This shift in the thought may be labelled as movement from humoralism to localism or ontologism; the disease isn't just abnormal amount of some natural juice any more, but becomes new original entity. This change undergoes the understanding of tumours and cancerous disease as well. Instead of antique understanding tumours as precipitates of black bile, the cell theory occurs in the 19th century. This theory explains tumours as a mass of cells undergoing excessive...
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