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Pilocytic astrocytoma (PA) is the most common brain tumor in children. This tumor is usually benign and has a good prognosis. Total resection is the treatment of choice and will cure the majority of patients. However, often only partial resection is possible due to the location of the tumor. In that case, spontaneous regression, regrowth, or progression to a more aggressive form have been observed. The dependency between the residual tumor size and spontaneous regression is not understood yet. Therefore, the prognosis is largely unpredictable and there is controversy regarding the management of patients for whom complete resection cannot be achieved. Strategies span from pure observation (wait and see) to combinations of surgery, adjuvant chemotherapy, and radiotherapy. Here, we introduce a mathematical model to investigate the growth and progression behavior of PA. In particular, we propose a Markov chain model incorporating cell proliferation and death as well as mutations. Our model analysis shows that the tumor behavior after partial resection is essentially determined by a risk coefficient γ, which can be deduced from epidemiological data about PA. Our results quantitatively predict the regression probability of a partially resected benign PA given the residual tumor size and lead to the hypothesis that this dependency is linear, implying that removing any amount of tumor mass will improve prognosis. This finding stands in contrast to diffuse malignant glioma where an extent of resection threshold has been experimentally shown, below which no benefit for survival is expected. These results have important implications for future therapeutic studies in PA that should include residual tumor volume as a prognostic factor.

The thesis deals with the natural substances in context with the cancer disease. The natural substances have a positive effect on the human organism and they are able to influence the viability and the growth of the cancer cells. The main mechanical device is to influence the mechanisms needed to start the apoptosis of the cancer cells and stopping further proliferation. The cancer cell lines utilization in the cancer disease is discussed in the thesis too. The thesis states common methods of determining the natural substances cytotoxicity. For the experimental part of the thesis it was chosen the MTT test method and the xCELLigence system for monitoring in real time. The mechanical device of the tested substance capsaicin in application on the prostate cell lines, tumorous PC3 and nontumorous PNT1A influence will be observed within the experimental part of the thesis.

MCur / Department of Advanced Nursing Science / See the attached abstract below

Indiana University-Purdue University Indianapolis (IUPUI) / Resveratrol has been shown to inhibit cell growth and induce apoptosis, as well as augment chemotherapeutics and irradiation in multiple cancer types. However, it is unknown if resveratrol is beneficial for treating drug-resistant cancer cells. To study the effects of resveratrol in triple negative breast cancer cells that are resistant to the common cancer drug, paclitaxel, a novel paclitaxel-resistant cell line was generated from the MDA-MB-231 breast cancer cell line. The resulting cell line, MDA-MB-231/PacR, exhibited a 12-fold increased resistance to paclitaxel but remained sensitive to resveratrol treatment. Resveratrol treatment reduced cell proliferation and colony formation and increased senescence and apoptosis in both the parental MDA-MB-231 and MDA-MB-231/PacR cell lines. Importantly, resveratrol treatment augments the effects of paclitaxel in both cell lines. The expression of the drug efflux transporter gene, MDR1, and the main metabolizing enzyme of paclitaxel gene, CYP2C8, was increased in the resistant cells. Moreover, pharmacological inhibition of the protein products of these genes, P-glycoprotein and CYP2C8, decreased paclitaxel resistance in the resistant but not in the parental cells, which suggests that the increase of these proteins are important contributors to the resistance of these cells. In conclusion, these studies imply that resveratrol, both alone and in combination with paclitaxel, may be useful in the treatment of paclitaxel-sensitive and paclitaxel-resistant triple negative breast cancers.

Indiana University-Purdue University Indianapolis (IUPUI). / The abysmal five year pancreatic cancer survival rate of less than 6% highlights the need for new treatments for this deadly malignancy. Cytotoxic drugs normally target rapidly dividing cancer cells but unfortunately often target stem cells resulting in toxicity. This warrants the development of compounds that selectively target tumor cells. An inhibitor of the mitotic kinase, MPS1, which has been shown to be more selective towards cancer cells than non-tumorigenic cells, shows promise but its effects on stem cells has not been investigated. MPS1 is an essential component of the Spindle Assembly Checkpoint and is proposed to be up-regulated in cancer cells to maintain chromosomal segregation errors within survivable limits. Inhibition of MPS1 kinase causes cancer cell death accompanied by massive aneuploidy. Our studies demonstrate that human adipose stem cells (ASCs) and can tolerate higher levels of a small molecule MPS1 inhibitor than pancreatic cancer cells. In contrast to PANC-1 cancer cells, ASCs and telomerase-immortalized pancreatic ductal epithelial cells did not exhibit elevated chromosome mis-segregation after treatment with the MPS1 inhibitor for 72hrs. In contrast, PANC-1 pancreatic cancer cells exhibited a large increase in chromosomal mis-segregation under similar conditions. Furthermore, growth of ASCs was minimally affected post treatment whereas PANC-1 cells were severely growth impaired suggesting a favorable therapeutic index. Our studies, demonstrate that MPS1 inhibition is selective towards pancreatic cancer cells and that stem cells are less affected in vitro. These data suggest MPS1 inhibition should be further investigated as a new treatment approach in pancreatic cancer.

Microtubule targeting agents (MTAs) are chemotherapeutics commonly used in the treatment of breast, ovarian, lung, and lymphoma cancers. There are two main classes of MTAs based upon their effects on microtubule stability. The two classes are the destabilizing agents, which include the drug vincristine, and the stabilizing agents, which include paclitaxel and epothilone B. These drugs are highly effective antineoplastics, but their use is often accompanied by several side effects, one of which is peripheral neuropathy. Peripheral neuropathy can be characterized by burning pain, tingling, loss of proprioception, or numbness in the hands and feet. In some patients, the MTA-induced peripheral neuropathy is debilitating and dose-limiting; however, there are no effective prevention strategies or treatment options for peripheral neuropathy as the mechanisms mediating this side effect are unknown. The goal of this work was to investigate MTA-induced effects on neuronal activity and morphology in order to elucidate the underlying mechanisms involved in the development of MTA-induced peripheral neuropathy. As an indicator of sensory neuronal activity, the basal and stimulated release of the putative nociceptive peptide, calcitonin gene-related peptide (CGRP), was measured from sensory neurons in culture after exposure to the MTAs paclitaxel, epothilone B, and vincristine. Neurite length and branching were also measured in sensory neuronal cultures after treatment with these MTAs. The results described in this thesis demonstrate that MTAs alter the stimulated release of CGRP from sensory neurons in differential ways depending on the MTA agent employed, the CGRP evoking-stimulus used, the concentration of the MTA agent, the duration of exposure to the MTA agent, and the presence of NGF. It was also observed that MTA agents decrease neurite length and branching, independent of the concentration of NGF in the culture media. Thus, this thesis describes MTA-induced alterations of sensory neuronal sensitivity and neurite morphology and begins to elucidate the underlying mechanisms involved in MTA-induced alterations of sensory neurons. These findings will undoubtedly be used to help elucidate the mechanisms underlying MTA-induced peripheral neuropathy.

Karolinska University Hospital's problem regarding the CAR-T cells' journey has been impacting thetreatment of patients and therefore a solution was in dire need to be presented. Visual mappingmethods have been used to review and map the journey with the aim of identifying factors that seemto be impacted. Previous research concerns user journey mapping, mapping methods andcollaboration theories. To carry out the mapping of the cells' journey, semi-structured interviews werecarried out with selected experts within the research area. These experts consisted of the unit managerat the apheresis clinic at Karolinska, a medically responsible researcher at the apheresis clinic atKarolinska and a senior patient operation manager at Bristol Myers Squibb. Their expertise andexperiences were the basis for the visual mapping, and this provided deep insights into the researcharea where the problem has been identified. Lastly, the data was mapped to create a visual map oftheir current management approach regarding CAR-T cell therapy where their experiences around theproblems could be identified. As a result, a solution to the identified factors that expose the cells tothe risks is presented with several visual maps and a proposed solution for a redesign withinKarolinska.

I denna avhandling studeras elektromagnetisk vågutbredning i graderade materialkompositer med extraordinära egenskaper. Två sådana materialkompositsystem studeras särskilt, med hjälp av både analytiska och beräkningstekniska elektromagnetiska metoder. Det första systemet används för utvecklingen av en lovande icke-invasiv metod för cancerbehandling, som bygger på att tumören med insatta guldnanopartiklar värms upp med hjälp av mikrovågsstrålning. En vågledarstruktur föreslås bestående av ett tunt dielektriskt skikt med en kontinuerlig graderad materialövergång till dess omgivande material till vardera sidan av skiktet. Det tunna lagret består av cancervävnad med insatta guldnanopartiklar som drivs in i elektroforetisk svängning med hjälp av elektromagnetisk strålning. Analytiska lösningar för det givna vågledarproblemet erhålls, vilket möjliggör beräkning av absorptionskoefficienterna endast inom det tunna skiktet, vilket är viktigt för bedömning av genomförbarheten av den tänkta medicinska tillämpningen. De dispersiva dielektriska modellerna som beskriver de elektromagnetiska egenskaperna hos de relevanta biologiska vävnaderna föreslås och diskuteras. Numeriska simuleringar gjorda i COMSOL Multiphysics är i utmärkt överensstämmelse med och validerar de analytiska resultaten. Det andra systemet involverar vågutbredning från ett högerhänt material till ett vänsterhänt metamaterial i fri rymd. De två materialen är impedansmatchade, vilket säkerställer ingen reflektion, och det graderade gränssnittet mellan dem beskrivs av en kontinuerlig funktion. Metamaterialkompositer med rumsligt varierande materialparametrar har fått ett ökande teoretiskt och experimentellt intresse de senaste två decennierna. De är användbara för ett antal tillämpningar, såsom transformationsoptik. I denna uppsats diskuteras egenskaperna hos vänsterhänta material. Fältlösningarna till det impedansmatchade graderade gränssnittet härleds, och en numerisk modell utvecklas i COMSOL. Resultaten bekräftar de extraordinära egenskaperna hos vänsterhänta material. / In this thesis, electromagnetic wave propagation in graded material composites with extraordinary properties are studied. Two such material composite systems are studied in particular, using both analytical and computational electromagnetic methods. The first system is used for the development of a promising non-invasive method of cancer treatment based on heating the tumors with inserted gold nanoparticles by means of microwave radiation. A waveguide structure is proposed consisting of a thin dielectric layer with a continuous graded material transition to its surrounding materials to either side of the layer. The thin layer consists of cancer tissue with inserted gold nanoparticles that are driven into electrophoretic oscillation by means of electromagnetic radiation. Analytical solutions for the given waveguide problem are obtained, allowing the calculation of the absorption coefficients within the thin layer only, which is important for assessment of the feasibility of the envisioned medical application. The dispersive dielectric models describing the electromagnetic properties of the relevant biological tissues are proposed and discussed. Numerical simulations done in COMSOL Multiphysics are in excellent agreement with and validate the analytical results. The second system involves wave propagation from a right-handed material to a left-handed metamaterial in an open boundary system. The two materials are impedance-matched, thus ensuring no reflection, and the graded interface between them is described by a continuous function. Metamaterial composites with spatially varying material parameters have been given an increasing theoretical and experimental interest the last two decades. They are useful for a number of applications, such as transformation optics. In this thesis, the properties of left-handed media are discussed. The field solutions to the impedance-matched graded interface are derived, and a numerical model is developed in COMSOL. The results confirm the extraordinary properties of left-handed media. / <p>QC 20221129</p>

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