Browsing by Subject "Neurofibromatosis 1"
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Item ADHD and Medical Correlates of Bullying of Pediatric Neurofibromatosis Patients(2016-08-25) Patel, Sarita; Holland, Alice A.; Faith, Melissa A.; Silver, Cheryl H.Neurofibromatosis Type 1 (NF1) is an autosomal dominant disorder that involves nervous system tumor growth, and it is one of the most frequently occurring genetic disorders. NF1 is a multisystem disease with a complex phenotype. Given the range in severity of presentation in NF1, research has shown that disease severity could impact children's social-emotional functioning. Physical deformities such as tumor growth often are associated with NF1, and as a result, children and adolescents with NF1 may be at greater risk for being victims of bullying by peers. Children with NF1 also tend to have higher rates of Attention-Deficit/Hyperactivity Disorder (ADHD) as compared to children without NF1 (Barton & North, 2004; Martin et al., 2012). Common issues experienced by children with ADHD, such as social immaturity and behavioral dysregulation, may put them at higher risk for both bullying and peer victimization (Wiener & Mak, 2009; Unnever & Cornell, 2003). Overall, the current study found that parentreported ADHD symptoms predicted parent-reported but not self-reported bullying. Furthermore, the current study found that parent-reported ADHD symptoms were more predictive of being bullied than provider-rated severity of physical deformity. Since the present study was the first to examine whether physical appearance and ADHD symptoms may be associated with bullying in children with NF1, the novel information gained from the study may be used to direct future research, educate parents and teachers, and inform the development of interventions specific to the NF1 population.Item Mechanistic and Therapeutic Insights for Epigenetic Regulation in Cancer Development(2014-10-03) Patel, Amish Jayantibhai; Galindo, Rene; Martinez, Elisabeth; Brekken, Rolf A.; Le, Lu Q.Malignant Peripheral Nerve Sheath Tumors (MPNSTs) are highly aggressive sarcomas that develop sporadically or in patients with Neurofibromatosis type 1 (NF1). Effective treatment options are lacking, and MPNSTs are typically fatal. To gain insights into MPNST pathogenesis, we utilized a novel MPNST mouse model that allowed us to study the evolution of these tumors at the transcriptome level. Strikingly, we found that progression to MPNST and loss of MPNST relevant tumor suppressors is associated with increased levels of chromatin regulator/BET bromodomain protein BRD4, and paradoxically, sensitivity and resistance to BET bromodomain inhibition with small molecule inhibitor JQ1. Indeed, genetic and pharmacological inhibition of BRD4 profoundly suppresses both growth and tumorigenesis of MPNSTs. Mechanistically, we uncovered that BET bromodomain inhibition leads to engagement of the ER stress/UPR pathway, and apoptosis through induction of pro-apoptotic effector molecule BIM and suppression of anti-apoptotic BCL-2 in MPNSTs. Moreover, we find that suppressed transcription of Cyclin D1 oncogene upon BRD4 inhibition correlates with reduced proliferation of MPNSTs. All together, this dual restraint on proliferation (via Cyclin D1 downregulation) and survival (via BIM induction) may indicate how BRD4 inhibition is exquisitely effective against MPNSTs and may represent a paradigm shift in therapy for MPNST patients. Moreover, these findings indicate an epigenetic mechanism underlying the balance of anti-/pro-apoptotic molecules, which suggests that BET bromodomain inhibition can shift this balance in favor of cancer cell death. Collectively, these studies provide new insights for developing strategies to overcome resistance to BET bromodomain inhibitor therapy for subverting cancer cell survival.Item [Southwestern News](1999-12-10) Stieglitz, HeatherItem Tumor Segmentation of Whole-Body Magnetic Resonance Imaging in Neurofibromatosis Type 1 Patients: Tumor Burden Correlates(2017-01-17) Heffler, Michael A.; Chhabra, Avneesh; Le, Lu Q.; Xi, YinPURPOSE: To use software segmentation of whole body MRI (WBMRI) to quantitate total body tumor volume (tumor burden) in patients with Neurofibromatosis type 1 (NF1) and examine associations between demographic factors and tumor burdens. METHODS: Patients with NF1 underwent WBMRI, and the images were reviewed by a board-certified radiologist for tumors. Each tumor was classified as superficial or internal, and discrete or plexiform. Tumors were then segmented by a trained assistant using a semi-automated software-based tool (SliceOMatic, TomoVision, Québec, Canada). Segmentation times were recorded. Segmentation yielded the total quantity and tumor burden of superficial, internal, and plexiform tumors. Correlations between the segmentation data and patient demographic factors were examined. RESULTS: 15 patients were included (42.3 +/- 13.6 years, 10 female, 5 male). Segmentation time ranged from 20 to 60 minutes, and yielded 2328 tumors (1582 superficial, 746 internal, and 23 plexiform). One tumor (0.04%) was malignant, all others were benign. The number of tumors per patient ranged from 14 to 397. Tumor burden ranged from 6.95 cm3 to 571 cm3. Individual tumor volume ranged from 0.0120 cm3 to 298 cm3. Significant correlation was found between total volume of superficial tumors and height (ρ = 0.5966, p < 0.02). Male patients had larger overall tumor burdens (p < 0.05) and larger superficial tumor burdens (p < 0.03). Patients with a negative family history of NF1 tended to have more tumors (p < 0.05). CONCLUSION: Segmentation of WBMRI in patients with NF1 is possible and can elucidate meaningful relationships between disease phenotype and demographic factors.