The purpose of this research is to validate various forms of mathematical modeling of glioblastoma multiforme (GBM) expressed as differential equations, numerically. The first work was involved in the numerical solution of the reaction-convection model, efficacy of which is expressed in terms of survival time. It was calculated using simple numerical scheme for the standard-of-care treatment in clinics which includes surgery followed by the radiation and chemotherapy. Survival time using all treatment options increased significantly to 57 weeks compared to that of surgery close to 14 weeks. It was also observed that survival time increased significantly to 90 weeks if tumor is totally resected. In reaction-diffusion model using simple numerical scheme, tumor cell density patterns due to variation in patient specific tumor parameters such as net proliferation rate and diffusion coefficient were computed. Significant differences were observed in the patterns while using dominant diffusion and proliferation rate separately. Numerical solution of the tumor growth model under the anti-angiogenic therapy revealed some impacts in optimum tumor growth control however it was not significant. / Includes bibliography. / Thesis (M.S.)--Florida Atlantic University, 2016. / FAU Electronic Theses and Dissertations Collection

Pharmacological ascorbate, intravenous administration of high-dose vitamin C aimed at peak plasma concentrations ~ 20 mM, has recently re-emerged, after a controversial history, as a potential anti-cancer agent in combination with standard-of-care radiation and chemotherapy-based regimens. The anti-cancer effects of ascorbate are hypothesized to involve the auto-oxidation or metal-catalyzed oxidation of ascorbate to generate H2O2, and preclinical in vitro and in vivo studies in a variety of disease sites demonstrate the efficacy of adjuvant ascorbate. Furthermore, phase I clinical trials in pancreatic and ovarian cancer have demonstrated safety and tolerability in combination with chemotherapy and preliminary results suggest therapeutic efficacy. Both preclinical in vitro and in vivo studies as well as phase I clinical trials suggest a cell-intrinsic mechanism of selective toxicity of cancer cells as compared to normal cells; however, the mechanism(s) for cancer cell-selective toxicity remain unknown. The current study aims to investigate the preclinical therapeutic efficacy of pharmacological ascorbate in combination with standard cancer therapies in three novel disease sites: non-small cell lung cancer (NSCLC), glioblastoma multiforme (GBM), and some histological subtypes of sarcoma. In vitro experiments demonstrate cancer cell-selective susceptibility to pharmacological ascorbate as compared to normal cells of identical cell lineages. Furthermore, in vivo murine xenograft models of NSCLC, GBM, and fibrosarcoma demonstrate therapeutic efficacy of pharmacological ascorbate in combination with chemotherapy and/or radiation as compared to chemotherapy and/or radiation alone without any additional therapeutic toxicity. Additionally, a phase I clinical trial in GBM subjects demonstrates the safety and tolerability of ascorbate in combination with radiation and temozolomide therapy. Although not powered for efficacy, preliminary results suggest that ascorbate may be efficacious in these subjects (median survival 18.2 months vs. 14.6 months in historical controls), and, importantly, that ascorbate therapy may be independent of MGMT promoter methylation status (median survival 23.0 months vs. 12.7 months in historical controls with absent MGMT promoter methylation). Preliminary results from a phase II clinical trial of ascorbate in combination with carboplatin/paclitaxel chemotherapy in advanced stage NSCLC subjects also demonstrate promising preliminary results related to efficacy (objective response rate (ORR) 29% and disease control rate (DCR) 93% vs. historical control ORR 15-19% and DCR 40%). In addition to demonstrating the potential efficacy of pharmacological ascorbate in combination with standard anti-cancer therapies, this work demonstrates that the selective toxicity of ascorbate may be mediated by perturbations in cancer cell oxidative metabolism. Increased mitochondrial-derived O2- and H2O2 disrupts cellular iron metabolism, resulting in increased iron uptake via Transferrin Receptor and a larger intracellular labile iron pool. The larger pool of labile iron in cancer cells underlies the selective sensitivity of cancer cells to ascorbate toxicity through pro-oxidant chemistry with ascorbate-produced H2O2. This mechanism is further supported by the finding of increased levels of O2- and labile iron in patient lobectomy-derived NSCLC tissue as compared to adjacent normal fresh frozen tissue. Together, these studies demonstrate the feasibility, selective toxicity, tolerability, and potential efficacy of pharmacological ascorbate in NSCLC, GBM, and sarcoma therapy and propose that further investigations of tumor and systemic iron metabolism are required to determine if these alterations can be exploited to enhance therapeutic efficacy or serve as therapeutic biomarkers.

Das Glioblastoma multiforme gehört zu den ZNS-Tumoren neuroepithelialen Ursprungs. Es zeichnet sich durch ein multiformes Zellbild, einen geringen Differenzierungsgrad und eine schnelle Krankheitsprogression aus. Trotz mikrochirurgischer Entfernung und anschließender Radiochemotherapie entwickeln die Patienten im Durchschnitt nach 7 Monaten einen Rezidivtumor und haben eine mittlere Überlebenszeit von 14,6 Monaten. Die Rezidivneigung stellt somit ein großes Problem in der Behandlung von Glioblastompatienten dar. In früheren Arbeiten konnte nachgewiesen werden, dass die Rezidivtumore eine andere Zellzusammensetzung und auch ein aggressiveres Wachstumsverhalten als deren Primärformen aufweisen. Ziel dieser Arbeit war es, zu prüfen ob mittels 2D-Gelelektrophorese und anschließender MALDI-TOF-Massenspektrometrie Unterschiede im Proteinexpressionsmuster zwischen Gewebeproben vom Primärtumor eines Glioblastoms WHO Grad IV und dem korrespondierendem Rezidivtumor eines Patienten detektierbar sind. Hierbei wurden 43 Proteine als differentiell exprimiert erkannt, von denen mit Hilfe der MALDI-TOF-Massenspektrometrie sechs genauer charakterisiert wurden. Vier der sechs Proteine waren im Rezidivtumor erhöht: EnoylCoA-Hydratase, ATP-Synthase Untereinheit d, Tropomyosin alpha-3-Kette Isoform 2 und Cathepsin D. Die anderen zwei waren im Rezidivtumor niedriger ausgeprägt: Nukleosid-Diphosphatkinase A und L-3-Phosphoserin-Phosphatase. Eine weitere Untersuchung mittels Western-Blot-Analyse bestätigte, dass Cathepsin D (als eines der sechs charakterisierten Proteine) tatsächlich auch in den Rezidivtumoren dreier weiterer Patienten stärker exprimiert war als in den korrespondierenden primären Glioblastomen.

Glioblastoma multiforme (GBM) ist der nach WHO am gefährlichsten eingestufte Hirntumor astrozytären Ursprungs. Patienten versterben ohne Behandlung etwa drei bis sechs Monaten nach Diagnose, die derzeitig modernste Behandlung mit Chemo-Radiotherapie verlängert das mediane Überleben auf 12-15 Monate. Trotz intensiver Forschung gibt es zurzeit keine realistische Heilungschance. Bislang erfolgt der Großteil der Forschung an Zellkulturen oder mit Hilfe von Tiermodellen, bei denen ein Tumor künstlich erzeugt wird. Dabei ergeben sich Probleme für die Übertragung der Ergebnisse auf den Menschen. Zellkulturen werden z.B. als sogenannte Monolayer-Kulturen gehalten, was bedeutet, dass ihnen der natürliche Gewebeverband und die für Signalling-Wege wichtige extrazelluläre Matrix fehlen. Außerdem werden solche Langzeitkulturen häufig subkultiviert und mutieren dadurch in Richtung einer klonalen Linie, was zwar Ergebnisse leichter reproduzierbar macht, aber nicht die Situation im Patienten widerspiegelt. Tierversuche implizieren zwar den Gewebeverband im Körper, jedoch müssen die dafür verwendeten Nager immunsupprimiert sein, so dass sie den induzierten Tumor nicht abstoßen. Dies erzeugt wiederum ein künstliches Umfeld. In diesem Projekt wird untersucht, ob sich humane GBM-Gewebe als sogenannte Slice-Kultur halten lassen und als Testsysteme zur Untersuchung der Wirkung von Chemotherapeutika sowie Bestrahlung geeignet sind. Bei dieser Kultivierungsmethode wird das Gewebe in Scheiben (Slices) geschnitten, wobei alle Zellen im Verband sowie die 3D-Struktur erhalten bleiben. Wegen des humanen Ursprungs entfällt das Problem des Speziesunterschiedes. Das Gewebe wird direkt aus dem Operationssaal ins Labor transferiert und weiterverarbeitet. Wir konnten bislang zeigen, dass Slice-Kulturen von humanem GBM über mindestens zwei Wochen in Kultur vital bleiben und ihre ursprüngliche charakteristische Morphologie beibehalten. Etablierte Behandlungsmethoden wie die Gabe von Temozolomid oder Röntgenbestrahlung zeigen auch in kultivierten Slices bekannte Effekte wie Induktion von DNA-Doppelstrangbrüchen, Reduktion von Proliferation und Aktivierung des Apoptose-Enzyms Caspase 3. Eine neue Therapieoption besteht seit einigen Jahren in der Bestrahlung mit Kohlenstoffionen (12C), die an der GSI Helmholtzzentrum für Schwerionenforschung in Darmstadt entwickelt und getestet wurde. Derzeit wird diese Therapie sehr erfolgreich an soliden Tumoren im Kopf- und Halsbereich angewendet und soll nun auf weitere Tumorarten ausgedehnt werden. Eine Kooperation mit der dortigen Biophysik-Gruppe wurde initiiert, um humane GBM-Slices mit 12C zu bestrahlen. Bislang wurde das entsprechende Setup etabliert und erste Experimente durchgeführt. Die ersten Ergebnisse wurden kürzlich publiziert. Weiterhin soll nun geprüft werden, ob das Ansprechen der GBM Slice-Kulturen mit dem Überleben der Patienten korreliert bzw. ob resistente Kulturen aus Patienten stammten, die schlecht auf die Therapie reagierten. Außerdem sollen überlebende Zellen in den Slices nach Behandlung auf ihre molekularen Eigenschaften geprüft werden, um Hinweise auf die Mechanismen der Tumorresistenz zu erhalten. Langfristig könnten diese Slice-Kulturen genutzt werden, um neuartige Wirkstoffe in der Vorklinik zu prüfen oder eine optimierte, personalisierte Therapie für Patienten zu ermitteln.

No description available.

Glioblastoma multiform (GBM) is an aggressive primary brain tumour. Despite treatment advances in recent years, outcomes remain poor. Disease progression tends to occur adjacent to the original tumour or surgical resection bed, usually within the radiotherapy planning field. This local recurrence and progression is believed to be the result of invasive disease in the surrounding tissue at the time of diagnosis and treatment, which is not currently detectable by conventional non-invasive methods. A number of novel therapies are currently under development which target specific aspects of the tumour behaviour, to try and improve outcomes from this devastating disease. Imaging biomarkers are under development, therefore, in order to provide a non-invasive assessment of tumour extent and behaviour, to provide bespoke image-guided therapies, and detect recurrence or treatment failure at the earliest opportunity. These are also of value in the context of novel therapeutics, which may have a very specific affect on an aspect of tumour behaviour that is not readily apparent on standard clinical imaging. Key to the progression of GBM is the invasion into surrounding white matter. This is followed by a period of tumour growth and subsequent angiogenesis in which microvasculature is produce that is distinct from the highly regulated blood-brain barrier. This thesis covers the development of suite of advanced magnetic resonance imaging (MRI) techniques aimed at characterising those very traits of GBM responsible for the aggressiveness and treatment resistance. Repeatability studies are undertaken to determine the performance of the biomarkers in healthy tissues, and also in a range of gliomas. Dynamic Contrast Enhanced (DCE-) and dynamic susceptibility-enhanced (DSC-)MRI are used to provide estimates of perfusion and permeability in the tumour. In order to address the reasons behind preferential invasion of the corpus callosum, they are used in conjunction with ASL to non-invasively map perfusion territories and watershed regions in the brain through perfusion timing parameters. Diffusion Tensor Imaging (DTI) and quantitative magnetisation transfer (qMT) are used to provide complementary information about white matter integrity, in order to identify changes occurring with glioma invasion as early as possible and direct image-guided treatments at presentation. Their complementary nature is assessed by comparing the two parameters simultaneously in white matter. Additionally, one of the qMT parameters which may be related to tissue pH is shown to be sensitive and specific for the detection of high-grade tumour tissue. Finally, a novel multiparametric imaging biomarker is introduced. Tumour surface mapping assesses the boundary between the solid tumour and surrounding tissue in order to identify areas of potential aggressiveness and invasion. Multiple imaging parameters can be combined to improve specificity and sensitivity. Using the diffusion-weighted imaging parameter, mean diffusivity (MD - also referred to as the apparent diffusion coefficient (ADC)), it is shown to be predictive of clinical outcome in a retrospective and prospective study, while a multiparametric example is given indicating the utility as a predicative biomarker for regions of progression and recurrence, and as potential spatial discriminator for image-guided therapies.

No description available.

Glioblastoma multiforme (GBM) is a destructive brain cancer that results in death 12 to 15 months after diagnosis. The purpose of this retrospective study was to determine if variations in tumor size at diagnosis, treatment options, and survival rate occur in GBM patients living in urban and rural areas of the United States. Using the behavior model of health services as the theoretical framework, this study used secondary data sets of GBM cases reported from 1988 to 2011 from the Surveillance, Epidemiology, and End Results program. Tumor size was measured in millimeters; treatment was evaluated by ascertaining the number of GBM patients who had surgical resection of their tumors, radiation, and chemotherapy; and survival rate was evaluated using Cox Regression analysis. With a sample size of 33,202 cases, data were examined using descriptive and multivariable analyses with SPSS. Results showed statistically significant differences in tumor size at diagnosis in rural patients compared to urban patients (p = 0.0085; p = 0.018), more urban patients were treated with radiation compared to rural patients (p < 0.001), and rural patients had poorer survival rates than urban patients (p < 0.001). Finally, when controlling for region, race, age, gender, education, and income, longer survival time was associated with urban status, female cases, and higher family income (p < 0.0001), and greater age was associated with reduced survival time (p < 0.0001). Study results could promote positive social change by identifying predictive variables associated with health outcomes of GBM patients. It may also educate providers on the risk of rurality of patients diagnosed with GBM, and inform lawmakers responsible for the creation of healthcare policy and the equitable allocation of healthcare resources.

No description available.

O desenvolvimento de nanocarreadores a base de albumina são considerados biocompatíveis e biodegradáveis, e tem sido extensivamente estudada com objetivo de novas alternativas de tratamento para inúmeras doenças. A característica mais relevante reside no fato de que estes sistemas proteicos serem capazes de atravessar a barreira Hematoencefálica (BHE) e atingir as células-alvo, a partir de sinalizações por canais específicos na barreira cerebral. Por serem proteínas com ligações covalentes, pode-se afirmar que o processo de clivagem proteolítica tende a ser realizado pelas enzimas pertencente à família das proteases. Dada à importância desses sistemas de entrega de fármacos (DDS) e sua eficaz permeação através da BHE, propôs-se um desenvolvimento científico multidisciplinar combinando-se protocolos, técnicas e ensaios experimentais das áreas de tecnologia farmacêutica, nanotecnologia e química para realização da incorporação do fotoativo ou outros compostos, como a ftalocianina de cloro alumínio (AlClPc ou Pc) livre e/ou pré encapsuladas e as nanopartículas magnéticas, nestes sistemas de DDS conhecidos como nanopartícula de albumina (NpA). Dentre as técnicas usadas nestes estudos destaca-se tanto o método de cross-linking térmico (via Térmica) quanto o químico (via Química), sendo que no segundo, foram utilizados 2 reagentes distintos, o glutaraldeído e o gliceraldeído, os quais foram analisados e comparados neste projeto de pesquisa. Análises de Microscopia Eletrônica de Varredura (MEV), Microscopia de Força Atômica (MFA), medidas de estabilidade por ZetaSizer demonstraram claramente que as nanopartículas preparadas pelos diferentes reagentes possuíam formato esféricos, diâmetro médio em torno de 200 nm e eram homogêneas, entretanto, apenas os nanocarreadores preparados com GU apresentaram elevada repulsão eletrostática (prevenindo a agregação das mesmas). Após caracterização, os estudos foram baseados na utilização da AlClPc como fotoativo aplicado a terapia fotodinâmica (TFD) para o tratamento in vitro das doenças que acometem o sistema nervoso central (SNC). / The development of albumin-based nanocarriers, which are nontoxic and biocompatible and biodegradable, have been extensively studied for seeking new alternatives of the treatment for numerous diseases. The most relevant characteristic is that these protein-based systems could across the blood-brain barrier (BBB) and selectively achieve the target cells within of the brain. These nanocarriers are proteins-based and have covalent bonds, and consequently it can be digested by a class of enzymes belonging to the protease family, which rapidly degrade the protein-based nanoparticles through of the proteolytic cleavage process. Given the importance of these drug delivery systems (DDS) and their effective permeation through BBB, it was proposed a multidisciplinary scientific development combining protocols, techniques and experimental tests of the areas of pharmaceutical technology, nanotechnology and chemistry to carry out the incorporation of the photoactive or another compound, as aluminum chlorine phthalocyanine (AlClPc or Pc), free and/or pre-encapsulated or magnetic nanoparticles in these albumin-based DDS systems known as albumin nanoparticles (NpA). Among the techniques used in these studies we highlight by thermal cross-linking method (via Thermal) and chemistry (via Chemistry), in this second, it was used 2 reagents, glutaraldehyde and glyceraldehyde, that were analyzed and compared in this research project. From Scanning Electron Microscopy, Atomic Force Microcopy, Zeta potential measurements, we have clearly shown that the elaborated nanoparticles (NPs) have a smaller size with a spherical shape and are more homogeneous, however only the nanoparticles prepared with glutaraldehyde showed greater electronic repulsion (preventing their aggregation). After the characterization, the studies were based on the use of AlClPc as a photoactive applied in the photodynamic therapy (PDT) for the treatment of central nervous system (CNS) diseases.