Browsing by Subject "Medulloblastoma"
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Item Effect of Extrinsic Motivation on Academic Fluency Outcomes in Survivors of Pediatric Medulloblastoma(2013-01-17) Spurgin, Alice Ann; Stavinoha, Peter L.Medulloblastoma is the most commonly diagnosed malignant pediatric brain tumor. While deficits in processing speed, memory, attention, and IQ are well documented in childhood medulloblastoma survivors, impairments in academic functioning have not been adequately studied in this population, despite the fact that most survivors require long-term special education services and are significantly less likely than their healthy peers to finish high school. The present study is the first to identify fluent academic performance as a significant weakness relative to academic skill development in childhood medulloblastoma survivors-thereby isolating fluency as a major contributing factor to survivors' academic difficulties. The present study is also the first to investigate the effects of enhanced extrinsic motivation on fluent academic performance in pediatric medulloblastoma survivors. As such, this study represents a new direction for research in this population, moving beyond basic documentation of deficits toward intervention-focused research. A previous study indicated that extrinsic motivation enables survivors of childhood medulloblastoma to improve their performance to the normal range on tasks related to processing speed and attention (Riva, Pantaleoni, Milani, & Belani, 1989). However, prior to the present study, there had been no further investigations of this isolated finding. Present results suggest that a performance-based incentive used to enhance extrinsic motivation predicted statistically significant improvement, but not normalization of function, in performance on measures of academic fluency relative to baseline. No demographic, medical, or neuropsychological variables predicted response to incentive. Findings suggest that academic performance of survivors can significantly improve under highly motivating conditions. Recognition of this potential for improvement in light of persisting limitations in fluency, suggesting deficits that cannot be fully overcome, may inform academic supports. Additionally, the findings of this study may provide a rationale for investigations of the effect of varying levels of motivation in other pediatric medical populations and with respect to other areas of neurocognitive functioning. The findings of this study also represent a significant and novel contribution to the debate regarding level of effort and the effect of motivational states on neuropsychological performance.Item Intelligence and Academic Achievement in Ten-Year Survivors of Childhood Medulloblastoma(2005-05-11) McDonald, Noelle Kristen; Silver, Cheryl H.Advances in the treatment of childhood medulloblastoma have markedly increased survival rates in recent decades. Although survival rates have improved, research has demonstrated that significant cognitive consequences are common in patients who have survived medulloblastoma. Few studies exist that examine the extent of long-term cognitive impairment as far as 10 years after treatment. The present pilot study examined the intellectual and academic achievement in a sample of 16 ten-year survivors of childhood medulloblastoma treated with surgery and craniospinal radiation. In addition, the relationships between the medical variables of age at treatment and dose of craniospinal radiation and cognitive and academic functioning were explored. The sample demonstrated significant cognitive impairment on measures of intellectual functioning and three measures of academic achievement. The academic domains that were most severely impaired were writing skills and practical math problem solving. The majority of participants demonstrated impairment in at least one domain of academic achievement, but the extent of achievement problems was underestimated when applying the traditional discrepancy model, in which an achievement score must be at least 15 points below the intelligence score to represent a learning disability. Age at treatment and dose of craniospinal radiation were not associated with performance on measures of intelligence and academic achievement in the present study; however, the small sample size may have limited the ability to detect significant results among these variables. The results of the present study demonstrate significant impairment in intellectual functioning and academic achievement in ten-year survivors of childhood medulloblastoma.Item Role of Primary Cilium-Mediated Signaling in Development, Disease and Cancer(2018-07-27) Somatilaka, Bandarigoda N.; Amatruda, James F.; Mukhopadhyay, Saikat; Kim, James; Wu, Jiang I.The primary cilium serves as an antenna in most vertebrate cells. Dysfunction of the primary cilium is associated with a variety of diseases, called "ciliopathies". Mechanisms underlying ciliogenesis have been well studied. However, deciphering the role of cilia in cellular signaling pathways is critical in understanding the basis behind the varied ciliopathic phenotypes, and remains a frontier mostly unexplored. Primary cilia are required for vertebrate Shh signaling. The final output of the Shh pathway is the formation of Gli transcriptional activators or repressors, both of which occur in a cilia-dependent manner. However, the role of cilia-generated signaling during development, particularly that of the poorly understood negative regulation and basal suppression of sonic hedgehog (Shh) signaling and its relationship to hyperproliferative conditions such as cystic kidney disease and carcinogenesis is not well understood. Here, I studied the role of primary cilium-generated signaling in the context of development and disease. Particularly, I focused on the role of poorly understood negative regulation of Shh signaling and ciliary trafficking in the context of cellular signaling pathways. My studies provide key insights into the role of: (a) novel mechanisms for trafficking adenylyl cyclases to cilia in Shh signaling during neural tube development; (b) primary cilium-generated signaling in cystic kidney disease; (c) and role of basal suppression of Shh pathway and cilia in Shh-subtype medulloblastoma initiation, progression and prognosis. In addition, I contributed to other projects on the role of negative regulation of Shh signaling in limb and skeletal development, and regulation of ciliary trafficking of membrane proteins. Overall, my projects highlight the importance of cilium-generated signaling, particularly that of negative regulation of Shh signaling in embryonic development, cystic kidney disease, and Shh-subtype medulloblastoma.Item Targeting Cilia Initiation & Maintenance in SHH-Medulloblastoma(2024-01-30) Popokh, BenjaminMedulloblastoma (MB) is the most common malignant pediatric brain tumor. Of the four molecular subtypes, Sonic Hedgehog Medulloblastoma (SHH-MB) involves aberrant growth signaling between SHH mitogen and its receptors on primary cilium in cerebellar granule cells. We hypothesized that in mouse models genetically engineered to induce SHH-MB, additional genetic modifications dysregulating primary cilium would inhibit the cancer phenotype, either decreasing severity or preventing it altogether. We established breeding cages with conditional knockouts of Gpr161 (GPR161 normally represses SHH signaling, knockout promotes SHH-MB), knockouts of Ptch1 (a SHH receptor with more aggressive tumors upon haploinsufficiency), and Pcm1 knockouts (centriolar satellite protein critical for primary cilia stability). Our methods included: PCR and gel electrophoresis to assess genotype, BrdU injections, cerebellum dissection, cryo-sectioning, antibody staining, and immunofluorescence imaging using confocal microscopy. We immunostained cerebellar tissues from various genotypes with cell cycle (CyclinD1), primary cilia (ARL13B), mitotic (pHH3), and proliferative markers (BrdU). We found that mice with Gpr161 or Ptch1 deletion develop SHH-MB and "persistent" external granular layers with increased cilia density versus controls. There is also a large presence of BrdU (-) and CyclinD1 (-) cells with cilia, begging the question of where in the cell cycle these cells belong. Heterozygous deletion of Pcm1 (+/ko) does not appear to diminish cancer phenotype, as a Ptch1 +/ko; Pcm1 +/ko mouse demonstrated SHH-MB and increased cilia density. A full knockout of Pcm1, however, does seem to rescue the cancer phenotype, as a Gpr161 f/f; Pcm1 ko/ko; Nestin-Cre mouse did not have any tumor, and it had low cilia density. We demonstrate that in mice with SHH-MB-predisposing genetic mutations, additional mutation of proteins regulating stability of primary cilia might prevent cancer phenotype. These results could open an avenue for investigating therapeutic inhibition or downregulation of cerebellar primary cilia in human patients with genetic predisposition for SHH-MB.