Drug delivery methods for the treatment of brain tumor cells have been both inefficient and potentially dangerous for cancer patients. Drug delivery must be done in a controlled manner so that the effective amount of medication is delivered to the patient and ensure over-dosage does not cause adverse side reactions in the patient. The focus of this investigation is to design a drug delivery system that would allow for site-specific administration of the drug, protection of the drug from the surrounding environment, and controlled sustained release of the drug. We have proposed a model that incorporates a niosome, which is a non-ionic surfactant vesicle, within a biodegradable polymer hydrogel. The drug is encapsulated in the niosome, and the niosome is embedded within a three-dimensional hydrogel network. It is therefore critical that the release rate of the drug from the niosome be studied. This investigation provides information about the release rate and behavior of the drug within the niosome as it is placed in a semi-permeable membrane. The niosome and dye solution in the cellulose membrane are placed in contact with water or PBS. Intensity measurements are taken using fluorescence spectrometry, and the readings are converted to concentration and moles values. The release rates of the dye from of the niosome and across the membrane are studied as the concentration data is collected over time. The results indicate that most of the niosomes will release their dye within ten hours. The water will create instability in the niosomes, while the PBS solution will maintain the stability of the niosomes. The concentration that diffuses across the cellulose membrane will steadily increase and can be predicted well by a simple diffusion model. We hope to use the information provided in this study to continue to design a drug delivery method that will stabilize the niosomes and allow for the maximum control over the release rate of the drug.

Comprehensive statistical models for non-normally distributed cancerous tumor sizes are of prime importance in epidemiological studies, whereas a long term forecasting models can facilitate in reducing complications and uncertainties of medical progress. The statistical forecasting models are critical for a better understanding of the disease and supply appropriate treatments. In addition such a model can be used for the allocations of budgets, planning, control and evaluations of ongoing efforts of prevention and early detection of the diseases. In the present study, we investigate the effects of age, demography, and race on primary brain tumor sizes using quantile regression methods to obtain a better understanding of the malignant brain tumor sizes. The study reveals that the effects of risk factors together with the probability distributions of the malignant brain tumor sizes, and plays significant role in understanding the rate of change of tumor sizes. The data that our analysis and modeling is based on was obtained from Surveillance Epidemiology and End Results (SEER) program of the United States. We also analyze the discretely observed brain cancer mortality rates using functional data analysis models, a novel approach in modeling time series data, to obtain more accurate and relevant forecast of the mortality rates for the US. We relate the cancer registries, race, age, and gender to age-adjusted brain cancer mortality rates and compare the variations of these rates during the period of the study that data was collected. Finally, in the present study we have developed effective statistical model for heterogenous and high dimensional data that forecast the hazard rates with high degree of accuracy, that will be very helpful to address subject health problems at present and in the future.

<p>Despite decades worth of research, glioblastoma remains one of the most lethal cancers. The identification of <italic>IDH1</italic> as a major cancer gene in glioblastoma provides an exceptional opportunity for improving our understanding, diagnostics, and treatment of this disease. In addition to mutations in <italic>IDH1</italic>, recent studies from our laboratory have characterized the genetic landscape of gliomas and have shown the cooperation between IDH1 mutations and other oncogenic alterations such at TP53 mutations. Normally, IDH1 functions in the oxidative decarboxylation of isocitrate to &alpha;&ndash;ketoglutarate, however the mutant form confers neomorphic enzymatic activity by producing 2&ndash;hydroxyglutarate, an oncometabolite responsible for aberrant methylation in IDH1&ndash;mutated tumors, among other mutant <italic>IDH1</italic>&ndash;mediated phenotypes. To determine the role of mutant IDH1 <italic>in vivo</italic>, we generated a conditional knock&ndash;in mouse model. This genetically faithful system is both biologically and clinically relevant and will promote the understanding of mutant IDH1&ndash;mediated tumorigenesis while offering a route for therapeutic targeting.</p><p>We observed that broad expression of mutant IDH1 throughout the brain leads to hydrocephalus in 80% of animals. In assessing the earliest effects of mutant IDH1 on the brain, we determined mutant IDH1 confers a decrease in the proliferative cells of the subventricular zone of the lateral ventricle, the area which houses the neural stem cells in embryonic and adult animals. Additionally, a perturbation to the normal neural stem cell niche was observed in these animals. Combined, this data suggests that mutant IDH1 may be affecting the signaling pathways involved in differentiation in this population of cells. <italic>In vivo</italic> and <italic>in vitro</italic> studies will further elucidate mutant IDH1's effects on the differentiation patterns of neural stem cells expressing mutant IDH1.</p><p>To express mutant IDH1 in a more restricted manner and harness spatiotemporal control, we crossed mutant animals to a Nestin&ndash;CreER<super>T2</super> strain of mouse that permits expression of floxed alleles upon treatment with tamoxifen. Animals were sacrificed at the onset of symptoms or at 1&ndash;year of age. We observed the development of both low&ndash; and high&ndash;grade gliomas in approximately 15&ndash;percent of E18.5 tamoxifen&ndash;treated animals. All tumors were found in a TP53&ndash;deleted background with mutant IDH1 being detected in only those tumors with the mutant allele. Lastly, to decrease the latency and increase the penetrance of tumor formation, an orthotopic intracranial injection model was generated to allow for visualization of tumor formation and development, as well as investigation of therapeutic modalities. The models generated and the knowledge gained from these studies will offer an understanding of the biological effects of the most common mutations found in the astrocytic subset of gliomas, bringing us strides closer to determining mechanisms and therapeutic targets for <italic>IDH1</italic>&ndash;mutated cancers.</p> / Dissertation

Behavioral studies have documented impaired working memory in childhood brain tumor survivors; however, neural mechanisms have yet to be identified using fMRI. The current study investigated BOLD response differences between twenty survivors (Mean age=23.1(4.14), 55% female) and twenty age- and gender-matched controls from the start to the end of a twenty minute 3-back task. There were no differences in task performance between groups or over time. Effects of practice were present in left prefrontal regions, with both groups showing decreases in activation as the task progressed. There were qualitative and quantitative differences in the brain regions that survivors recruited relative to controls in bilateral prefrontal (including the dorsolateral prefrontal cortex) and parietal cortices. Findings suggest that areas under top-down control of the dorsolateral prefrontal cortex become less activated with practice, and that survivors may require more top-down processing and attentional control to perform at similar levels to healthy controls.

<p>During development, the precise regulation of the processes of proliferation, migration, and differentiation is required to establish proper organ structure and function and to prevent the deregulation that can lead to disease, such as cancer. Improved understanding of the signals that regulate these processes is therefore necessary to both gain insight into the mechanisms by which organ development proceeds and to identify strategies for treating the consequences of deregulation of these processes. In the cerebellum, some of the factors that regulate these processes have been identified but remain incompletely understood. Our studies have focused on the signals that regulate the migration of cerebellar granule neuron progenitors (GNPs) and the contribution of the SDF-1/CXCR4 signaling axis to postnatal cerebellar development. Using conditional knockout mice to delete CXCR4 specifically in GNPs, we show that loss of CXCR4 results in premature migration of a subset of GNPs throughout postnatal development that are capable of proliferation and survival outside of their normal mitogenic niche. Loss of CXCR4 also causes a reduction in the activity of the Sonic hedgehog (SHH) pathway (the primary mitogen for GNPs) but does not affect GNP proliferation, differentiation, or capacity for tumor formation. Our data suggest that while other factors likely contribute, SDF-1/CXCR4 signaling is necessary for proper migration of GNPs throughout cerebellar development. </p><p>In addition to understanding the signals that regulate normal development, the identification of vulnerabilities of established tumors is also necessary to improve cancer treatment. One strategy to improve treatment involves targeting the cells that are critical for maintaining tumor growth, known as tumor-propagating cells (TPCs). In the context of the cerebellar tumor medulloblastoma (MB), we have previously identified a population of TPCs in tumors from patched mutant mice that express the cell surface carbohydrate antigen CD15/SSEA-1. Here, we employed multiple approaches in an effort to target these cells, including a biochemical approach to identify molecules that carry the CD15 carbohydrate epitope as well as an immunotoxin approach to specifically target CD15-expressing cells. Unfortunately, these strategies were ultimately unsuccessful, but an alternative approach that recognized a vulnerability of CD15+ cells was identified. We show that CD15+ cells express elevated levels of genes associated with the G2/M phases of the cell cycle, progress more rapidly through the cell cycle than CD15- cells, and contain an increased proportion of cells in G2/M. Exposure of tumor cells to inhibitors of Aurora and Polo-like kinases, key regulators of G2/M, induces cell cycle arrest, apoptosis and enhanced sensitivity to conventional chemotherapy, and treatment of tumor-bearing mice with these agents significantly inhibits tumor progression. Importantly, cells from human patient-derived MB xenografts are also sensitive to Aurora and Polo-like kinase inhibitors. Our findings suggest that targeting G2/M regulators may represent a novel approach for the treatment of human MB.</p> / Dissertation

Bakgrund: Varje år drabbas ungefär 1100 personer i Sverige av en hjärntumör. Symtomen som uppstod innan diagnosbesked upplevdes som mindre allvarliga, men under behandlingen blev symtomen svårare. Hjärntumören påverkade hela patientens livsvärld. Det var sjuksköterskans ansvar att stötta patienten och att hjälpa patienten att uppnå livskvalitet. Hoppet var ett existentiellt grundvillkor som hjälpte människor att skapa mening med livet. Syfte: Syftet med studien var att beskriva kvinnors upplevelser av hur livet förändrades av en hjärntumör. Metod: Studien var en kvalitativ innehållsanalys med induktiv ansats. Materialet var baserat på fem bloggar skrivna på internet. Resultat: Resultatet presenterades i fem teman; En förändrad kropp tvingade livet att ta en paus, Familjen blev viktigare, Sjukvården blev en känsloladdad del av vardagen, Hjärntumören blev en efterhängsen fiende och Existentiella tankar hanterades med olika strategier. Slutsats: Att drabbas av en hjärntumör medförde många förändringar i livet. Livsvärlden förändrades för kvinnorna och innebar inte bara en kamp mot sjukdomen utan även en kamp mot alla känslor. / Background: Every year about 1100 people get diagnosed having with brain tumour.  The symptoms that occurred in the beginning of disease aren’t quite as bad as those occurring later. The brain tumour affect the entire life-world of the patient. It was the nurse’s responsibility to support and improve the life quality of the patient. To help the patient maintain her hope was crucial to create a meaningful life. Aim: The purpose of the study was to describe how women’s everyday life was changed by a brain tumour. Method: The study was a qualitative content analysis with an inductive approach. Data was based on five internet based blogs. Results: The results are presented in five themes; A body in change puts life on hold, The family became even more important, Nursing care was an emotional daily event, The brain tumour appeared as an intrusive enemy and Thoughts about existentialism were dealt with in different ways. Conclusion: To suffer from a brain tumour affected the patients’ lives in many ways. The life-world of the women changed and did not only result in a struggle against the disease, but as well as an emotional one.

Research suggests that the cerebellum is involved in cognition, but its exact role is unclear. The efficiency theory posits that the cerebellum supports processing speed. Other researchers argue that the cerebellum is functionally heterogeneous, and damage to lobes of the cerebellum causes selective loss of cognitive functions. This study sought to determine whether selective impairment in motor, verbal fluency, or processing speed occurred depending on the lobe of the cerebellum that was lesioned. Lesion mapping was used to measure lesion size and volumetric methods were used to measure atrophy in 25 adult survivors of cerebellar tumors. Participants had too a high degree of heterogeneous cerebellar lesions and accompanying atrophy to explore specialization. However, total cerebellar atrophy negatively impacted written and oral processing speed to a greater degree than total cerebellar lesion size. Younger ages at diagnosis and radiation therapy were associated with greater cerebellar atrophy.

Verbal memory (VM) has been shown to be impacted in brain tumor (BT) survivors, but the nature of VM problems and underlying neuropathology are poorly understood and a long-term outlook is lacking. Our study examined hippocampus volume (HV) and VM in adult survivors of pediatric BT (n=32) and controls (n=48). Results indicate that disruption to a maturing brain in childhood is detectable 17 years (mean) after diagnosis, as HV is significantly lower in survivors compared to controls. Analysis of the VM scores shows that survivors have significantly lower overall immediate recall compared to controls, but learning slope, retention, and recognition are not different across the groups. Survivors’ memory profile indicates that auditory attention and retrieval difficulties could be contributing to their lower immediate recall. For survivors, HV is significantly correlated with delayed free recall but not with other VM indices. Implications of these findings are discussed.

Malignant brain tumors, especially malignant gliomas, have a poor prognosis, a fact which has remained unchanged over the last decades despite the employment of multimodal therapeutic approaches. Malignant gliomas are among the most vascularized tumors known and the amount of vascularization has been correlated to their prognosis. Since tumor growth is dependent on concomitant vascularization, recent experimental studies have focused on the use of anti-angiogenic molecules as a novel strategy in brain tumor therapy. Angiogenesis inhibitors target at proliferating endothelial cells and suppress the formation of a sufficient vascular bed. Inhibitors such as TNP-470, suramin and angiostatin have shown their therapeutic potential in experimental studies. In a clinical setting, they could be applied for the treatment of multiple tumors or postsurgically as an adjuvant therapy to prevent recurrence. This article discusses presently available anti-angiogenic agents, emphasizing on substances already in clinical trials. / Maligne Hirntumoren, insbesondere die malignen Gliome, haben trotz multimodaler Therapieansätze eine unverändert schlechte Prognose. Diese Aggressivität korreliert mit der Tatsache, daß maligne Gliome zu den gefäßreichsten Tumoren zählen, die wir kennen. Die Quantifizierung der Gefäßdichte in diesen Tumoren erlaubte die Korrelation zur Überlebenszeit der Patienten. Da das Tumorwachstum von einer begleitenden Neovaskularisierung abhängt, wurden erste experimentelle Therapieansätze durchgeführt, um das Tumorwachstum durch Inhibierung der Neovaskularisierung zu verhindern. Inhibitoren der Angiogenese, z.B. TNP-470, Suramin und Angiostatin hemmen die Proliferation von Endothelzellen und die Ausbildung eines funktionsfähigen Gefäßbettes. Erste experimentelle Ansätze haben ihre tumorstatische Wirksamkeit in vivo bewiesen. Zur klinischen Behandlung wären diese Substanzen in Verbindung mit bestehenden Therapien einsetzbar, insbesondere für die Behandlung multipler Tumoren und zur postoperativen Therapie. Diese Übersichtsarbeit beschreibt die neuesten anti-angiogenen Therapiekonzepte besonders mit Hinblick auf Substanzen, die in ersten klinischen Studien eingesetzt werden. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

Prior research suggests aggressive cancer treatments contribute to cognitive impairments in children diagnosed with pediatric brain tumors. The literature also suggests that younger age at diagnosis (AAD) and treatment may result in disrupted cognitive trajectories due to limited brain plasticity. In line with this research, we hypothesized an interaction between radiation therapy (RT) and young AAD of brain tumors, where young AAD and RT results in lower standard scores on the WRAT-R Reading Comprehension Subtest. Analyses included archival data; the sample consists of 134 children diagnosed with pediatric brain tumors with multiple assessments resulting in 487 cases for analysis. Participants were diagnosed with mixed tumor types and locations. A two level multilevel model was used to analyze reading trajectories while taking into account AAD, time since diagnosis, socioeconomic status (SES), and RT. Results detected a positive interaction between AAD and RT (γ =2.08, p=.02). For participants with RT, younger AAD was associated with lower reading scores, whereas AAD had no effect for participants without RT. Results also detected a negative interaction between radiation and time (γ =-2.29, p=.00) indicating that children treated with RT have reading scores that decrease over time. These data suggested that children diagnosed with pediatric brain tumors treated with RT are at higher risk of reading impairment as reflected in their reading scores.