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Immune response and tumor microenvironment in the treatment with polymer cytotoxic drugs
Malátová, Iva ; Šírová, Milada (advisor) ; Stollinová Šromová, Lucie (referee)
Chemotherapy is still one of the most widely used anticancer therapies. It is mostly about inhibiting the proliferation of rapidly dividing cells, so it is not selective for tumor cells. As a result, many undesirable side effects are associated with chemotherapy. The disadvantageous properties of chemotherapeutics can be largely eliminated by using conjugates of polymers with low molecular weight drugs. An example of such a conjugate is a doxorubicin-linked HPMA polymer. In addition to the properties obtained by polymer binding, such as achieving solubility in aqueous solutions, reducing systemic toxicity, increasing the maximum tolerated dose, or passive targeting by the EPR effect, the fact that doxorubicin induces immunogenic cell death is used in therapy with this drug. It has already been shown that after complete cure of the experimental mice with polymeric conjugates of HPMA with doxorubicin, some mice develop long-term resistance to re-inoculation with a lethal dose of tumor cells. Resistance is specific to the particular line of tumor cells from which the mouse was cured, and CD8+ cytotoxic T cells and IFNγ play an important role. In this work, we monitored changes in the proportion of immune populations and their activation markers after treatment with HPMA-based polymers with doxorubicin...
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Fibroblast activation protein and local immunosuppression in glioblastoma
Ternerová, Nikola ; Stollinová Šromová, Lucie (advisor) ; Drbal, Karel (referee)
Glioblastomas (GBMs) are one of the most common malignant tumors in the central nervous system. The tumor microenvironment of GBMs contains malignant and non-malignant stromal cells, whose interactions contribute to several GBMs characteristics, including aberrant angiogenesis, high proliferation rate, and systemic and local immunosuppression. Fibroblast activation protein α (FAP) is a membrane serine protease that is sparsely expressed in healthy tissues but is upregulated in solid tumors, including GBMs. FAP can be expressed by both malignant and non- malignant stromal cells in the tumor microenvironment, and its expression in stromal cells has frequently been linked to impaired anti-tumor immune response. The role of FAP and FAP expressing stromal cells in the infiltration of immune subpopulations into the GBM microenvironment is still unclear. This diploma thesis aimed to develop a flow cytometry protocol for the analysis of immune cell subpopulations present within the tumor microenvironment in wild-type and FAP knockout mouse syngeneic glioblastoma model. Four methods combining mechanical and enzymatic dissociation were evaluated for their ability to preserve cell viability and expression of studied surface molecules using mouse non-tumorous and GBM tissue. The most suitable method for mouse...
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Fibroblast activation protein and local immunosuppression in glioblastoma
Ternerová, Nikola ; Stollinová Šromová, Lucie (advisor) ; Drbal, Karel (referee)
Glioblastoma multiforme (GBM) is the most aggressive type of primary brain tumor. Current treatment includes surgical resection with following radio/chemotherapy, but prognosis of patients remains poor with median survival only about 15 months. GBM is characteristic for necrotic regions, abnormal vascularization and strong immunosuppression. Dynamic interactions of cancer cells, immune cells and other stromal cells in the tumor microenvironment can promote tumor growth and progression. Fibroblast activation protein α (FAP) is overexpressed by the cells in tumor tissue. FAP is important in angiogenesis, remodelation of extracellular matrix and immunomodulation in cancers. The role of FAP in the tumor microenvironment is the subject of recent research. The aim of the thesis was to prepare a syngeneic mouse model of glioblastoma with and without FAP expression, implement and optimalize the dissociation method for GBM tumor tissue and detect a variety of infiltrated immune cell populations in the GBM microenvironment by flow cytometry. Optimization of dissociation protocol for glioblastoma tissue was a crucial step for viable cell suspension required for cytometry study of immune cell populations. A combination of dissection by dissociator and enzymatic digestion with mild enzymes was found to be the...
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Humoral aspects of common diseases in musculoskeletal system
Stanžovská, Adéla ; Machač, Stanislav (advisor) ; Vránová, Hana (referee) ; Stollinová Šromová, Lucie (referee)
This research thesis speaks about humoral aspects of common musculoskeletal diseases. In the beginning, we present the most common diagnoses in physical therapy connected to body substances. For that reason, the thesis also gives a brief review of laboratory diagnostic methods that is often crucial for successful diagnosis of certain diseases and their aetiology. Also, the laboratory testing plays an important role in so called Red flags, signalising serious pathologies which should not be excluded forgotten in diagnostic thinking, especially in cases where the therapy is inefficient. Lastly, patient's psychological state significantly influences these parameters.
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Immunosuppression in the microenvironment of glioblastoma
Ternerová, Nikola ; Stollinová Šromová, Lucie (advisor) ; Javorková, Eliška (referee)
Glioblastomas (GBM) are the most malignant brain tumors, which are thought to originate from neoplastic transformation of glial cells. These tumors are characterized with highly infiltrative growth, neovascularization, and radio- and chemoresistance. In spite of current therapy including surgical resection of the tumor and chemo/radio therapy, patient's prognosis is still poor and median survival is about 15 months. Certain non-tumor cells present in the GBM microenvironment participate in tumor progression using mechanisms contributing to the local and systemic immunosuppression. Critical roles in the immune escape of GBM have the regulatory T-cells (Tregs), the tumor-associated macrophages (TAMs) and the myeloid-derived suppressor cells (MDSCs). Immunosuppressive mechanisms in GBM are conducted through direct cell-mediated contacts and soluble mediators secreted by tumor-associated cells into the local tumor microenvironment and circulating blood. Both these processes may inhibit immune response mounted against cancer cells. Certain cancer associated cells and secreted mediators are distributed by peripheral blood and potentiate systemic immunosuppression in the GBM host organism. Gaining knowledge about these mechanisms may reveal to possible targets for GBM immunotherapy. For instance,...
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